Aromatic acrylamide-triazole compounds, methods for preparing the same, and uses thereof

Abstract

This invention discloses aromatic acrylamide-triazole compounds, their preparation methods, and applications, belonging to the field of medicinal chemistry. The general structural formula of this class of compounds is shown below, R... 1 It consists of hydrogen atoms and halogen atoms; R 2 The compounds are alkenyl, alkynyl, pyridyl, aryl-alkenyl, and substituted aryl-alkenyl groups. In vitro activity studies have demonstrated that these compounds exhibit significant antifungal activity, with good activity against drug-resistant bacteria, and can be used as CYP51 inhibitors in the preparation of antifungal drugs.

Description

Technical Field

[0001] This invention discloses a novel aromatic acrylamide-triazole compound, its preparation method, and its use in the preparation of antifungal drugs, belonging to the field of medicinal chemistry. Background Technology

[0002] In recent decades, with the increase in the number of people undergoing cancer chemotherapy, organ transplantation, and those with weakened immune systems, the incidence and mortality rates of invasive fungal infections have shown a significant upward trend, resulting in 1.5 to 2 million deaths annually. The overuse of antibiotics, the widespread use of antifungal drugs, and the extensive implementation of interventional catheterization procedures have led to increasingly serious fungal resistance, even multidrug resistance (Fisher, MC; Hawkins, NJ; Sanglard, D.; Gurr, SJScience 2018, 360, 739). Given the limited types of antifungal drugs and the emergence of resistance in all types, the development of highly effective, broad-spectrum antifungal drugs that are effective against drug-resistant bacteria is urgently needed and has significant social and practical value.

[0003] Fungi and mammals both belong to eukaryotes. The formation of fungal cell membranes requires ergosterol, while the formation of mammalian cell membranes requires cholesterol. This is the most significant difference between the two (Watt, K.; Manzoni, P.; Cohen-Wolkowiez, M.; Rizzollo, S.; Boano, E.; Jacqz-Aigrain, E.; Benjamin Jr, DK. Current Drug Metabolism 2013, 14, 193.). Studies have shown that ergosterol plays an important role in maintaining the fluidity and integrity of fungal cell membranes, regulating cell morphology, and influencing the fungal invasion process. Since fungi can only synthesize ergosterol themselves, inhibiting the activity of lanosterol 14α-demethylase (CYP51), a key enzyme required for ergosterol synthesis, is an effective way to inhibit fungal growth (Shrestha, SK; Garzan, A.; Garneau-Tsodikova, S., Eur J Med Chem 2017, 133, 309-318.). CYP51 inhibitors based on azole structures are currently the most widely used and largest-market-share antifungal drugs. Based on the cocrystal model of existing drugs and CYP51, synthesizing new types of CYP51 inhibitors while retaining the imidazole or triazole ring structure is a major approach to finding highly active antifungal molecules and an effective way to solve drug resistance problems.(Fuentefria, AM; Pippi, B.; Dalla Lana, DF; Donato, KK; de Andrade, SFLetters In Applied Microbiology 2018, 66, 2; Li, Z.; Liu, N.; Tu, J.; Ji, C.; Han, G.; Sheng, C. ACS Infectious Diseases2019,5,1376;Fuentefria,AM;Pippi,B.;Dalla Lana,DF;Donato,KK;de Andrade,SFLetters In Applied Microbiology 2018,66,2;Thamban Chandrika,N.;Shrestha,SK;Ngo,HX;Tsodikov,OV;Howard,KC;Garneau-Tsodikova,S.Journal ofMedicinal Chemistry 2018, 61, 158; Benhamou, RI; Bibi, M.; Berman, J.; Fridman, M. Localizing Antifungal Drugs to the Correct Organelle can Markedly Enhancetheir Efficacy. Angewandte Chemie International Edition 2018, 57, 6230.).

[0004] Quinoline structures are widely found in pharmacologically active natural product molecules and marketed drug molecules, and can enhance activity and improve pharmacokinetics through molecular structure modification (Boger, DL; Tse, WCBioorganic & Medicinal Chemistry, 2001, 9, 2511-2518; Wang, M., Gao, M., Miller, KD, Sledge, GW, Hutchins, GD, and Zheng, QHEur J Med Chem, 2009, 44, 2300-2306). Meanwhile, thiazole orange compounds containing quinoline structures have attracted considerable attention from pharmacologists due to their various pharmacological activities, including antitumor, immunomodulatory, and anti-inflammatory effects.

[0005] Therefore, it is worthwhile to study the synthesis of a new class of compounds using splicing techniques based on triazole ring and quinoline structures for the development of antifungal drugs. Summary of the Invention

[0006] In order to obtain new structural molecules with high activity, strong selectivity and effectiveness against drug-resistant bacteria, this invention has obtained a class of aromatic acrylic acid-triazole compounds through drug molecule splicing technology. These substances have significant antifungal activity and CYP51 inhibitory activity. At present, there are no reports on the synthesis and antifungal activity of such compounds.

[0007] Therefore, the purpose of this invention is to provide a new compound with good antifungal activity—an aromatic acrylate-triazole compound.

[0008] Another object of the present invention is to provide a method for synthesizing aromatic acrylic acid-triazole compounds.

[0009] Another object of the present invention is to provide the use of aromatic acrylic acid-triazole compounds and their salt forms in the preparation of antifungal drugs.

[0010] The objective of this invention is achieved through the following technical solution:

[0011] The aromatic acrylic acid-triazole compounds have the structure shown in general formula (1):

[0012]

[0013] Among them, R 1 It consists of hydrogen atoms, mono-substituted or di-substituted halogen atoms;

[0014] R 2 It can be alkenyl, alkynyl, pyridyl, aromatic alkenyl, or aromatic alkenyl with substituents;

[0015] Preferred choice: R 1 It consists of hydrogen, chlorine, and fluorine atoms; chlorine and fluorine atoms are mono- or di-substituted on the benzene ring.

[0016] R 2 The substituents are vinyl, ethynyl, pyridyl, styryl, naphthylvinyl, pyridinevinyl, indolevinyl, morpholine styryl, quinoxalolinevinyl, and quinolinevinyl; the substituted quinolinevinyl: the substituents on its benzene ring are selected from methyl, methoxy, ester, fluorine, bromine, chlorine, iodine, or trifluoromethyl.

[0017] Preferred choice:

[0018] R 1 It consists of hydrogen atoms, 2,4-dichloro, and 2,4-difluorine.

[0019] R 2The substituents are vinyl, ethynyl, 2-pyridyl, 4-pyridyl, styryl, 1-naphthylvinyl, 2-pyridylvinyl, 3-pyridylvinyl, 4-pyridylvinyl, 3-indolylvinyl, 4-morpholinostyryl, 2-quinoxalolinevinyl, and 2-quinolinevinyl; the substituted 2-quinolinevinyl: the substituents on the benzene ring are selected from methyl, methoxy, phenyl, ester, fluorine, bromine, chlorine, iodine, or trifluoromethyl.

[0020] The aromatic acrylic acid-triazole compounds of the present invention are preferably the following compounds:

[0021] N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)acrylamide;

[0022] N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)propynamide

[0023] N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)cinnamamide

[0024] N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)nicotinamide

[0025] N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)isonicotinamide

[0026] N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(pyridin-2-yl)acrylamide

[0027] N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(pyridin-3-yl)acrylamide

[0028] N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(pyridin-4-yl)acrylamide

[0029] N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(naphthyl-1-yl)acrylamide

[0030] N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(4-morpholinylphenyl)acrylamide

[0031] N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(1H-indole-3-yl)acrylamide

[0032] N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(quinoxalo-2-yl)acrylamide

[0033] N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(quinoline-2-yl)acrylamide

[0034] N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(6-methoxyquinoline-2-yl)acrylamide

[0035] N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(6-methylquinoline-2-yl)acrylamide

[0036] N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(6-fluoroquinoline-2-yl)acrylamide

[0037] N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(6-(trifluoromethyl)quinoline-2-yl)acrylamide

[0038] 3-(6-Chloroquinoline-2-yl)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-acrylamide

[0039] Ethyl-2-(3-((2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)amino)-3-oxopropyl-1-en-1-yl)quinoline-6-carboxylic acid ester

[0040] N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(6-phenylquinoline-2-yl)acrylamide

[0041] N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(8-methoxyquinoline-2-yl)acrylamide

[0042] N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(6-bromoquinoline-2-yl)acrylamide

[0043] N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(6-iodoquinoline-2-yl)acrylamide

[0044] N-(2-(2,4-dichlorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(quinoline-2-yl)acrylamide

[0045] N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(quinoline-3-yl)acrylamide

[0046]

[0047]

[0048]

[0049] The method for preparing the aromatic acrylamide-triazole compound is as follows:

[0050]

[0051] R 1 R 2 As defined above.

[0052] The specific steps are as follows:

[0053] Compound A and an azole reagent were placed in a reaction flask containing a magnetic rotor. Toluene was added as a solvent and a solid base as an acid-binding agent. The mixture was heated and stirred. After the reaction was completed, the mixture was cooled, extracted, and then distilled under reduced pressure and subjected to column chromatography to obtain intermediate B. Intermediate B and trimethyl sulfoxide were placed in a reaction flask containing toluene. Sodium hydroxide solution was added and the mixture was heated. After the reaction was completed, the mixture was cooled, extracted, washed with the organic phase, and the solvent was removed under reduced pressure. Column chromatography was then used to obtain intermediate C. Intermediate C was dissolved in methanol, and sodium azide and ammonium chloride were added. The mixture was stirred and reacted... After the reaction was completed, the solvent was removed under reduced pressure, and column chromatography was used to obtain azide intermediate D. Intermediate D was dissolved in isopropanol solution, palladium / carbon was added, and the reaction was carried out at room temperature. After the reaction was completed, the solvent was removed under reduced pressure, and column chromatography was used to obtain key intermediate E. Intermediate E and organic carboxylic acid were dissolved in dry DMF, and coupling reagents 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added. The reaction was carried out at room temperature. After the reaction was completed, the solvent was removed under reduced pressure, and the product was extracted, the organic layer was washed, dried, filtered, and separated by column chromatography to obtain the pure target product.

[0054] Advantages of this invention: This invention designs and synthesizes a novel class of aromatic acrylamide-triazole compounds with strong CYP51 inhibitory activity using a pharmacodynamic group splicing method. Most of these compounds exhibit significant antifungal activity and good activity against drug-resistant bacteria. Their in vitro cell inhibitory activity is significantly superior to drugs such as fluconazole and miconazole. The compounds provided by this invention represent a new structural type of azole CYP51 inhibitor with further development value, providing a foundation for the development of new antifungal drugs and the solution of fungal resistance problems. The preparation process of the target compounds is simple and easy to operate, with an overall yield of over 25%, making it suitable for industrial production. Detailed Implementation

[0055] To better illustrate the present invention, the following embodiments are provided:

[0056]

[0057] Example 1: Preparation of N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)acrylamide

[0058] (1) Preparation of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethyl ketone

[0059] Weigh 5.0 g of 2-bromo-2',4'-difluoroacetophenone and 2.22 g of 1,2,4-triazole and place them in a 100 mL round-bottom flask containing 2.68 g of sodium bicarbonate and 25 mL of toluene. Stir the mixture under reflux until the starting material disappears. Add 20 mL of deionized water and extract the mixture separately. Wash the organic layer with saturated brine and dry it with sodium sulfate. Filter to remove the drying agent, remove the solvent under reduced pressure, and precipitate the product by column chromatography to obtain the target product (4.1 g, yield 86.4%). 1 H NMR (400MHz, CDCl3) δ8.54(s,1H),8.07(dd,J=15.0,8.1Hz,2H),7.13–7.03(m,1H),7.03–6.92(m,1H),5.66(s,2H).

[0060] (2) Preparation of 1-((2-(2,4-difluorophenyl)ethylene oxide-2-yl)methyl)-1H-1,2,4-triazole

[0061] 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)acetone (2.56 g) and trimethyl sulfoxide (2.95 g) were dissolved in 40 mL of toluene. An aqueous solution of sodium hydroxide (2.7 mL, 20% w / w) was added dropwise with stirring. The mixture was heated to 60 °C and stirred for 6 hours. The organic phase was washed separately with water and saturated brine, dried over sodium sulfate, filtered to remove the drying agent, and the solvent was removed under reduced pressure. Column chromatography yielded the target product (2.2 g, yield 80.9%). 1 H NMR (400MHz, CDCl3) δ8.07(s,1H),7.88(s,1H),7.19(td,J=8.4,6.5Hz,1H),6.83(tdd,J=10.6,8.3,2. 4Hz, 2H), 4.84 (d, J = 14.9Hz, 1H), 4.52 (d, J = 14.9Hz, 1H), 2.95 (d, J = 4.7Hz, 1H), 2.89 (d, J = 4.7Hz, 1H).

[0062] (3) Preparation of 1-amino-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propane-2-ol

[0063] Weigh 1.0 g of 1-(2-(2,4-difluorophenyl)ethyleneoxy-2-yl)methyl)-1H-1,2,4-triazole and place it in a round-bottom flask equipped with a magnetic stirrer. Add methanol (12 mL), sodium azide (0.82 g), and ammonium chloride (0.29 g) successively. Heat to 70 °C and stir until the reactants disappear. Remove methanol under reduced pressure. Add dichloromethane and water and separate the layers. Wash the aqueous layer twice with dichloromethane. Combine the organic phases and dry them with sodium sulfate. Remove the solvent under reduced pressure to obtain the azide product, which can be used directly in the next step.

[0064] The crude product was dissolved in isopropanol (15 mL), and 5% palladium / carbon (20 mg) was added. The mixture was reacted overnight at room temperature under hydrogen atmosphere. The palladium / carbon was removed by filtration with filter paper, the solvent was removed under reduced pressure, and the product was purified by column chromatography to obtain the target product E (0.75 g). 1 H NMR(400MHz, CDCl3)δ8.09(s,1H),7.84(s,1H),7.57(td,J=8.9,6.6Hz,1H),6.94–6.68 (m,2H),4.71–4.52(m,2H),3.21(dd,J=12.9,0.9Hz,1H),2.99(dd,J=12.9,1.2Hz,1H); 13 CNMR(101MHz, CDCl3)δ164.16,163.81,161.80,161.67,160.47,157.82,151.70,144.78,130.51,130.45,130.42,1 30.36,124.72,111.86,111.82,111.65,111.62,104.70,104.44,104.17,74.43,74.38,55.98,55.92,47.24,47.19.

[0065] (4) Accurately weigh amine intermediate E (85.0 mg, 0.325 mmol) and acrylic acid (49.8 mg, 0.25 mmol) into a dry 10 mL double-necked round-bottom reaction flask. Add anhydrous DMF (10 mL), and under nitrogen atmosphere, add 1-hydroxybenzotriazole (HOBt, 26.0 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 37.0 mg). Stir the reaction at room temperature under nitrogen protection until the carboxylic acid disappears. Remove DMF under reduced pressure. Add ethyl acetate (30 mL) and dilute sodium hydroxide solution (0.5 mol / L, 10 mL) to the reaction flask. Extract and separate the layers. Wash the ethyl acetate layer with purified water and saturated brine, respectively. Dry the organic phase with anhydrous magnesium sulfate. Filter to remove the drying agent and remove ethyl acetate by distillation under reduced pressure. Purify the residue by column chromatography to obtain the pure product with a yield of 67%. 1H NMR (400MHz, DMSO) δ8.27 (s, 1H), 8.18 (t, J = 5.9Hz, 1H), 7.70 (s, 1H), 7.30 (dd ,J=8.9,7.0Hz,1H),7.13(ddd,J=11.9,9.2,2.5Hz,1H),6.90(td,J=8.5,2.4H z,1H),6.25–6.12(m,2H),5.99(dd,J=17.1,2.1Hz,1H),5.52(dd,J=10.1,2.1 Hz, 1H), 4.58 (d, J = 14.3Hz, 1H), 4.46 (d, J = 14.3Hz, 1H), 3.61 (d, J = 5.8Hz, 2H); 13 CNMR(101MHz,CDCl3)δ168.05,164.41,164.30,162.87,161.94,161.83,1 60.14,160.02,157.69,157.57,151.61,144.89,130.65,130.59,130.55,1 30.50,129.58,128.38,123.93,123.80,112.15,112.12,111.95,111.92, 104.62,104.36,104.09,99.68,76.58,76.53,56.11,56.06,47.53,47.48.

[0066] Example 2

[0067] Preparation of N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)propynamide

[0068] Following the method of Example 1, the yield was 63%. 1 H NMR (400MHz, DMSO) δ8.44(t,J=6.0Hz,1H),8.30(s,1H),7.72(s,1H),7.33(dd,J=16.0,9.0Hz,1H),7.16(ddd,J=11.8,9.2,2.4Hz,1H),6.94(t d,J=8.6,2.5Hz,1H),5.99(s,1H),4.61(d,J=14.4Hz,1H),4.49(d,J=14.4Hz,1H),3.64(dd,J=14.5,6.2Hz,1H),3.53(dd,J=13.9,5.8Hz,1H); 13C NMR (101MHz, DMSO) δ169.62,163.13,160.69,160.57,160.39,157.81,157.70,153.32,150.62,150.52,144.94,130.17,130.10,130.07,1 30.01,124.48,124.44,124.35,124.31,110.79,110.59,104.16,103 .90,103.62,83.56,75.21,74.61,74.55,54.94,54.89,45.91,45.86.

[0069] Example 3

[0070] Preparation of N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)cinnamamide

[0071] Following the method of Example 1, the yield was 73%. 1 H NMR (400MHz, DMSO) δ8.33(s,1H),8.25(t,J=5.8Hz,1H),7.76(s,1H),7.54(d,J=6.6Hz,2H),7.46–7.30(m,5H),7.20(ddd,J=11.7,9.3,2.4Hz ,1H),6.95(td,J=8.5,2.2Hz,1H),6.67(d,J=15.8Hz,1H),6.34(s,1H),4.65(d,J=14.4Hz,1H),4.54(d,J=14.3Hz,1H),3.73(d,J=5.9Hz,2H); 13 C NMR (101MHz, DMSO) δ170.33,166.38,163.12,160.68,160.56,160.31,160.19,157.86,157.73,150.56,144.97,139.37,134.69,130.28, 130.19,130.12,129.58,128.92,127.58,124.79,124.66,121.46,110.86,110.66,104.21,103.93,103.67,74.98,74.93,55.19,46.27.

[0072] Example 4

[0073] Preparation of N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)pyridine amide

[0074] Following the method of Example 1, the yield was 71%. 1 H NMR(400MHz,DMSO)δ8.78–8.56(m,2H),8.33(s,1H),8.08–7.91(m,2H),7.76 (s,1H),7.68–7.54(m,1H),7.48–7.32(m,1H),7.18(ddd,J=11.8,9.2,2.4Hz, 1H),6.92(td,J=8.5,2.5Hz,1H),6.34(s,1H),4.69(d,J=14.4Hz,1H),4.57( d,J=14.3Hz,1H),3.93(dd,J=13.9,6.9Hz,1H),3.81(dd,J=13.8,5.7Hz,1H); 13 C NMR (101MHz, CDCl3) δ166.84,164.32,164.19,161.83,161.71,160.18,160.06,15 7.73,157.61,151.59,148.79,148.45,144.74,137.60,130.60,130.54,130.51,13 0.45, 126.83, 123.96, 123.93, 123.83, 123.79, 122.54, 111.98, 111.95, 111.77, 111.74, 104.57, 104.32, 104.30, 104.05, 76.61, 76.56, 56.08, 56.03, 47.48, 47.43.

[0075] Example 5

[0076] Preparation of N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)isonicotinamide

[0077] Following the method of Example 1, the yield was 72%. 1 H NMR (400MHz, DMSO) δ8.85–8.63(m,3H),8.34(s,1H),7.76(s,1H),7.65(d,J=6.0Hz,2H),7.40(dd,J=15.9,8.9Hz,1H),7.19(ddd,J=11.8,9. 3,2.4Hz,1H),6.93(td,J=8.5,2.3Hz,1H),6.15(s,1H),4.73(d,J=14.4Hz,1H),4.60(d,J=14.4Hz,1H),3.79(ddd,J=19.5,13.8,6.2Hz,2H);13 C NMR (101MHz, CDCl3) δ167.38,164.41,162.04,161.92,160.16,157.71,15 7.59,152.09,150.78,144.83,140.78,130.39,130.33,130.30,130.24,12 4.62,124.12,123.51,123.42,123.38,121.00,112.28,112.25,112.08,1 12.04,104.83,104.56,104.30,76.54,76.49,55.63,55.58,47.34,47.30.

[0078] Example 6

[0079] Preparation of (E)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(pyridin-2-yl)acrylamide

[0080] Following the method of Example 1, the yield was 61%. 1 H NMR (400MHz, DMSO) δ8.58(d,J=4.1Hz,1H),8.45(t,J=5.8Hz,1H),8.32(s,1H),7.82(td ,J=7.7,1.7Hz,1H),7.74(s,1H),7.55(d,J=7.8Hz,1H),7.38(ddd,J=14.9,12.6,5.1Hz, 3H),7.18(ddd,J=11.8,9.2,2.4Hz,1H),7.07(d,J=15.4Hz,1H),6.94(td,J=8.5,2.4Hz, 1H), 6.31 (s, 1H), 4.65 (d, J = 14.4Hz, 1H), 4.54 (d, J = 14.3Hz, 1H), 3.71 (d, J = 5.9Hz, 2H); 13 C NMR (101MHz, CDCl3) δ168.08,152.79,151.82,150.23,144.89,141.24,137.18,130.61,125.23,12 4.50,123.28,112.14,111.97,104.39,104.12,103.98,76.68,76.63,56.17,56.13,47.80,47.76.

[0081] Example 7

[0082] Preparation of (E)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(pyridin-3-yl)acrylamide

[0083] Following the method of Example 1, the yield was 65%. 1 H NMR (400MHz, DMSO) δ8.74 (s, 1H), 8.55 (d, J = 3.5Hz, 1H), 8.32 (s, 1H), 8.26 (t, J = 5.9 Hz,1H),7.96(d,J=8.0Hz,1H),7.75(s,1H),7.41(ddd,J=24.6,11.8,7.0Hz,3H),7.1 9(ddd,J=11.9,9.3,2.5Hz,1H),6.94(td,J=8.5,2.4Hz,1H),6.78(d,J=15.9Hz,1H) ,6.28(s,1H),4.64(d,J=14.4Hz,1H),4.53(d,J=14.4Hz,1H),3.72(d,J=5.9Hz,2H); 13 C NMR (101MHz, CDCl3) δ167.52,164.35,164.27,161.98,161.93,161.86,161.78 ,160.20,160.11,160.08,160.04,157.60,151.88,150.87,149.41,144.93,13 9.29, 134.81, 130.67, 130.61, 130.57, 130.51, 130.41, 123.98, 121.32, 112.21, 112.04, 104.69, 104.44, 104.17, 76.66, 76.61, 56.08, 56.03, 47.67, 47.63.

[0084] Example 8

[0085] Preparation of (E)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(pyridin-4-yl)acrylamide

[0086] Following the method of Example 1, the yield was 61%. 1H NMR (400MHz, DMSO) δ8.61(d,J=5.8Hz,2H),8.39–8.27(m,2H),7.76(s,1H),7.51(d,J=6.0Hz,2H),7.42–7.33(m,2H),7.20(dd d,J=11.8,9.2,2.5Hz,1H),6.98–6.86(m,2H),6.25(s,1H),4.65(d,J=14.4Hz,1H),4.54(d,J=14.3Hz,1H),3.78–3.67(m,2H); 13 C NMR (101MHz, DMSO) δ165.35,163.13,163.01,160.69,160.57,160.34,160.22,157.88,157.76,150.57,150.04,144.96,142.31,136.63,13 0.28,130.18,130.12,126.30,124.63,124.54,121.76,110.88,110.6 5,104.22,103.94,103.68,74.81,74.76,55.12,55.07,46.12,46.07.

[0087] Example 9

[0088] Preparation of N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(naphth-2-yl)acrylamide

[0089] Following the method of Example 1, the yield was 73%. 1 H NMR (400MHz, DMSO) δ8.46–8.29(m,2H),8.26–8.10(m,2H),7.98(d,J=7.9Hz,2H),7 .76(d,J=9.7Hz,2H),7.70–7.49(m,3H),7.42(dd,J=15.9,9.0Hz,1H),7.21(ddd,J= 11.8,9.2,2.5Hz,1H),6.96(td,J=8.5,2.4Hz,1H),6.75(d,J=15.6Hz,1H),6.34(s ,1H),4.69(d,J=14.4Hz,1H),4.58(d,J=14.3Hz,1H),3.77(qd,J=14.0,6.0Hz,2H).

[0090] Example 10

[0091] Preparation of (E)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(4-morpholinophenyl)acrylamide

[0092] Following the method of Example 1, the yield was 35%. 1 H NMR (400MHz, DMSO) δ8.33(s,1H),8.12(d,J=5.8Hz,1H),7.76(d,J=3.4Hz,1H),7.40(d,J=8.7Hz,3H),7.31(d,J=15.7Hz,1H),7.24–7.15( m,1H),6.95(d,J=8.8Hz,3H),6.44(t,J=7.8Hz,2H),4.63(d,J=14.4Hz,1H),4.52(d,J=14.3Hz,1H),3.77–3.64(m,6H),3.22–3.12(m,4H).

[0093] Example 11

[0094] Preparation of (E)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(1H-indole-3-yl)acrylamide

[0095] Following the method of Example 1, the yield was 45%. 1 H NMR (400MHz, DMSO) δ11.59(s,1H),8.51–8.28(m,2H),8.15(t,J=5.9Hz,1H),7.87(d,J=7.8Hz,1H),7.76(d,J=5.5Hz,1H),7.59(d,J=15.8Hz,1H),7. 50–7.32(m,2H),7.29–7.08(m,3H),6.95(t,J=8.6Hz,1H),6.62(d,J=15.8 Hz,1H),4.63(d,J=14.2Hz,1H),4.54(d,J=14.2Hz,1H),3.75–3.65(m,2H); 13C NMR (101MHz, CDCl3) δ170.28,164.40,162.72,161.80,160.94,160.18,160.06 ,159.49,157.74,157.61,150.96,144.78,137.32,136.87,130.84,130.75,12 9.25, 125.40, 124.16, 124.03, 123.57, 121.67, 120.44, 113.93, 113.50, 112.11, 111.94, 104.57, 104.31, 104.04, 76.63, 76.58, 56.59, 56.55, 48.11, 48.07.

[0096] Example 12

[0097] Preparation of N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(quinoxalo-2-yl)acrylamide

[0098] Following the method of Example 1, the yield was 62%. 1 H NMR (400MHz, DMSO) δ9.16 (s, 1H), 8.54 (t, J = 6.0Hz, 1H), 8.33 (s, 1H), 8.14–8. 00(m,2H),7.95–7.80(m,2H),7.76(s,1H),7.67(d,J=15.6Hz,1H),7.39(dd,J= 11.2,7.4Hz,2H),7.20(ddd,J=11.8,9.2,2.4Hz,1H),7.01–6.90(m,1H),6.23 (s,1H),4.67(d,J=14.4Hz,1H),4.57(d,J=14.4Hz,1H),3.77(d,J=6.0Hz,2H).

[0099] Example 13

[0100] Preparation of (E)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(quinoline-2-yl)acrylamide

[0101] Following the method of Example 1, the yield was 62%. 1H NMR (400MHz, DMSO) δ8.49(t,J=5.9Hz,1H),8.41(d,J=8.5Hz,1H),8.32(d,J=4.7Hz,1H),8.03–7.92(m,2H),7.87–7.70(m,3H),7.68–7.52(m,2H),7. 40(dd,J=15.9,8.9Hz,1H),7.30–7.12(m,2H),7.00–6.88(m,1H),6.26(s, 1H), 4.67 (d, J = 14.4Hz, 1H), 4.56 (d, J = 14.3Hz, 1H), 3.75 (d, J = 6.0Hz, 2H); 13 C NMR (101MHz, CDCl3) δ168.16,164.34,164.22,162.79,161.86,161.74,160.16,160.01,15 7.68,157.54,153.01,151.56,148.30,144.85,141.43,137.08,130.69,130.63,130.60,13 0.54, 130.31, 129.67, 128.29, 127.76, 127.40, 124.86, 123.95, 123.91, 123.81, 123.78, 121.64, 112.04, 111.84, 104.55, 104.28, 104.02, 76.60, 76.55, 56.22, 56.17, 47.84, 47.79.

[0102] Example 14

[0103] Preparation of (E)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(6-methoxyquinoline-2-yl)acrylamide

[0104] Following the method of Example 1, the yield was 67%. 1 H NMR (400MHz, CDCl3) δ8.34–8.05(m,3H),7.85(s,1H),7.72(d,J=15.3Hz,1H),7.66–7.50(m,2H),7.46(d,J=9.1Hz,1H),7.28(d,J= 11.4Hz,1H),7.10(s,1H),6.93–6.62(m,3H),6.10(s,1H),4.62(q,J=14.0Hz,2H),4.08–3.89(m,4H),3.83(dd,J=14.0,5.0Hz,1H); 13C NMR (101MHz, CDCl3) δ168.17,164.40,164.29,161.92,161.80,160.15,160.03,158.75,157.7 0,157.58,151.74,150.36,144.89,144.17,141.28,135.93,130.94,130.73,130.67,130.64,1 30.58,129.61,123.95,123.85,123.82,123.62,122.21,118.80,112.15,112.12,111.94,111.91,110.80,105.13,104.61,104.35,104.09,76.66,76.61,56.22,56.18,55.82,47.87,47.83.

[0105] Example 15

[0106] Preparation of (E)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(6-methylquinoline-2-yl)acrylamide

[0107] Following the method of Example 1, the yield was 71%. 1 H NMR (400MHz, CDCl3) δ8.12(d,J=6.1Hz,2H),8.04(d,J=8.8Hz,1H),7.85(s,1H) ,7.72(d,J=15.3Hz,1H),7.60(d,J=18.0Hz,3H),7.49(d,J=8.4Hz,1H),7.14(d ,J=15.3Hz,1H),6.89–6.74(m,2H),6.67(s,1H),6.13(s,1H),4.62(q,J=14.1H z,2H),3.96(dd,J=14.4,5.8Hz,1H),3.82(dd,J=14.4,5.5Hz,1H),2.55(s,3H); 13C NMR (101MHz, CDCl3) δ168.06,164.39,164.28,161.91,161.80,160.15,160.02,157.69,15 7.57,151.95,151.72,146.60,144.89,141.22,137.78,136.72,132.94,130.71,130.66,1 30.62,130.56,129.09,128.44,126.64,124.69,123.96,123.82,121.82,112.11,111.94,111.91,104.61,104.34,104.08,100.19,76.65,76.60,56.20,56.16,47.85,47.80,21.85.

[0108] Example 16

[0109] Preparation of (E)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(6-fluoroquinoline-2-yl)acrylamide

[0110] Following the method of Example 1, the yield was 66%. 1 H NMR (400MHz, CDCl3) δ8.28–8.01(m,3H),7.86(s,1H),7.71(d,J=15.1Hz,1H),7.66–7.49(m,3H),7.45(d,J=8.4Hz,1H),7.08(d,J =15.2Hz,1H),6.90–6.71(m,2H),6.55(s,1H),4.62(q,J=14.1Hz,2H),3.97(dd,J=14.3,5.9Hz,1H),3.83(dd,J=14.4,5.7Hz,1H); 13C NMR (101MHz, CDCl3) δ167.65,162.46,159.96,157.72,157.60,152.21,152.18,151.77,144.88, 144.69,140.30,137.33,137.27,131.77,131.68,131.12,130.68,130.62,130.59,130.53,129.1 2,129.06,129.02,125.70,123.89,123.85,123.75,123.72,122.57,121.45,121.20,112.19,111.98,111.11,110.89,104.68,104.41,104.15,76.65,76.60,56.14,56.10,47.82,47.78,30.79.

[0111] Example 17

[0112] Preparation of (E)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(6-(trifluoromethyl)quinoline-2-yl)acrylamide

[0113] Following the method of Example 1, the yield was 64%. 1 H NMR(400MHz,DMSO)δ8.62(d,J=8.6Hz,1H),8.58–8.48(m,2H),8.33(s,1H),8.17(d,J=8.9Hz,1H) ,8.02(dd,J=8.9,1.8Hz,1H),7.91(d,J=8.5Hz,1H),7.76(s,1H),7.60(d,J=15.6Hz,1H),7.40(d d,J=15.9,8.9Hz,1H),7.31(d,J=15.6Hz,1H),7.21(ddd,J=11.8,9.2,2.4Hz,1H),6.96(td,J=8. 5,2.4Hz,1H),6.25(s,1H),4.67(d,J=14.4Hz,1H),4.57(d,J=14.3Hz,1H),3.76(d,J=5.7Hz,2H); 13CNMR(101MHz,DMSO)δ165.47,163.10,163.00,160.67,160.55,160.32,160.22,157.89,157. 77,155.94,150.54,148.51,144.93,138.28,130.47,130.27,130.20,130.15,130.11,128.35 ,126.88,126.68,126.56,126.35,126.25,126.21,125.43,125.35,124.67,124.64,124.54,124.50,122.72,122.56,110.82,110.65,104.18,103.90,103.64,74.87,74.82,55.07,46.17.

[0114] Example 18

[0115] Preparation of (E)-3-(6-chloroquinoline-2-yl)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)acrylamide

[0116] Following the method of Example 1, the yield was 68%. 1 H NMR (400MHz, DMSO) δ8.51(t,J=5.9Hz,1H),8.39(d,J=8.6Hz,1H),8.33(s,1H) ,8.13(d,J=2.3Hz,1H),8.00(d,J=9.0Hz,1H),7.89–7.72(m,3H),7.56(d,J=1 5.6Hz,1H),7.40(d,J=7.0Hz,1H),7.31–7.12(m,2H),7.03–6.88(m,1H),6.26 (s,1H),4.67(d,J=14.4Hz,1H),4.57(d,J=14.3Hz,1H),3.76(d,J=5.9Hz,2H); 13C NMR(101MHz,DMSO)δ165.64,163.13,163.01,160.69,160.56,160.36,160.23,157.90,1 57.77,154.01,150.56,145.95,144.96,138.54,136.41,131.31,131.01,130.68,130.28 ,130.22,130.19,130.12,128.32,127.39,126.61,124.70,124.66,124.57,124.53,122.17,110.88,110.67,104.21,103.95,103.67,74.91,74.85,55.14,55.09,46.23,46.19.

[0117] Example 19

[0118] (E)-Ethyl 2-(3-((2-2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)amino)-3-oxopropyl-1-en-1-ylquinoline-6-carboxylic acid ester

[0119] Following the method of Example 1, the yield was 59%. 1 H NMR(400MHz, CDCl3)δ8.56(d,J=1.6Hz,1H),8.35–8.24(m,2H),8.14–8.02(m,2H),7.87(s,1H), 7.73(d,J=15.2Hz,1H),7.61(dd,J=15.7,9.1Hz,1H),7.54(d,J=8.5Hz,1H),7.08(d,J=15.2Hz, 1H),6.90–6.76(m,2H),6.36(t,J=6.0Hz,1H),6.03(s,1H),4.71–4.56(m,2H),4.47(td,J=14.2 ,7.1Hz,2H),3.99(dd,J=14.4,6.2Hz,1H),3.82(dd,J=14.7,5.8Hz,1H),1.45(t,J=7.1Hz,3H); 13C NMR (101MHz, CDCl3) δ167.63,166.17,161.96,161.89,160.16,160.04,157.71,157.59,154.98, 151.90,151.51,150.17,145.02,144.90,141.17,139.28,138.45,130.78,130.69,130.64,130. 60,130.54,130.01,129.87,129.16,127.48,125.81,123.90,123.86,123.76,123.72,122.56,112.24,112.04,104.70,104.43,104.17,76.69,76.64,61.69,56.06,55.92,47.79,47.74,14.57.

[0120] Example 20

[0121] Preparation of (E)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(6-phenylquinoline-2-yl)acrylamide

[0122] Following the method of Example 1, the yield was 61%. 1 H NMR (400MHz, DMSO) δ8.51(t,J=6.0Hz,1H),8.46(d,J=8.5Hz,1H),8.34(s,1H),8.29(d,J=1.8Hz,1H ),8.13(dd,J=8.9,2.0Hz,1H),8.06(d,J=8.8Hz,1H),7.85(d,J=7.3Hz,2H),7.81–7.73(m,2H),7.5 6(dd,J=21.1,11.7Hz,3H),7.41(dt,J=17.8,8.2Hz,2H),7.21(dd,J=7.4,4.7Hz,1H),6.96(td,J=8 .5,2.5Hz,1H),6.28(s,1H),4.67(d,J=14.4Hz,1H),4.57(d,J=14.3Hz,1H),3.76(d,J=6.0Hz,2H); 13C NMR (101MHz, DMSO) δ165.83,163.15,163.02,162.30,160.70,160.58,160.37,160.2 5,157.91,157.79,153.49,150.57,146.97,144.97,139.12,138.93,138.41,137.30, 130.23,129.54,129.28,129.12,128.01,127.92,127.06,126.86,125.20,124.70,124.57,121.65,110.87,110.69,104.22,103.96,103.68,74.95,74.90,55.16,46.24.

[0123] Example 21

[0124] Preparation of (E)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(8-methoxy-quinoline-2-yl)acrylamide

[0125] Following the method of Example 1, the yield was 66%. 1 H NMR (400MHz, DMSO) δ8.55(t,J=5.9Hz,1H),8.37–8.29(m,2H),7.84–7.69(m,2H),7.58(d,J=15.6Hz,1H),7.55–7.36(m,3H),7.27–7.12(m,3H) ),6.95(td,J=8.5,2.4Hz,1H),6.31(s,1H),5.75(s,1H),4.68(d,J=14.3Hz,1H),4.58(d,J=14.3Hz,1H),3.98(s,3H),3.77(d,J=5.9Hz,2H); 13C NMR (101MHz, DMSO) δ166.04,163.15,163.03,160.71,160.59,160.37,160.25,157.91,157. 79,155.21,152.00,150.56,144.98,139.50,139.26,136.73,130.30,130.24,130.21,130.1 5,128.67,127.44,126.43,124.75,124.72,124.62,124.59,121.49,119.29,110.89,110.66,108.89,104.20,103.94,103.67,79.15,75.01,74.96,55.69,55.21,55.16,46.35,46.31.

[0126] Example 22

[0127] Preparation of (E)-3-(6-bromoquinolin-2-yl)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)acrylamide

[0128] Following the method of Example 1, the yield was 53%. 1 H NMR (400MHz, CDCl3) δ8.14–8.05(m,2H),7.98(d,J=2.0Hz,1H),7.93(d,J=9.0Hz,1H),7.87(s,1H ),7.80(dd,J=9.0,2.1Hz,1H),7.71(d,J=15.2Hz,1H),7.66–7.55(m,1H),7.51(d,J=8.5Hz,1H),7 .05(d,J=15.3Hz,1H),6.82(qd,J=9.9,5.1Hz,2H),6.32(t,J=5.7Hz,1H),6.03(s,1H),4.66(d,J =14.2Hz,1H),4.58(d,J=14.2Hz,1H),3.99(dd,J=14.4,6.2Hz,1H),3.82(dd,J=15.1,6.0Hz,1H); 13CNMR (101MHz, CDCl3) δ167.74,157.74,157.62,157.58,157.57,153.36,151. 94,146.93,144.95,141.17,136.28,136.23,134.00,131.44,130.73,130.67 ,130.63,130.58,129.99,129.92,129.39,125.30,123.90,123.81,122.72,121.59,112.27,112.24,112.07,112.04,104.47,76.72,76.67,56.15,47.77.

[0129] Example 23

[0130] Preparation of ((E)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(6-iodoquinoline-2-yl)acrylamide

[0131] Following the method of Example 1, the yield was 41%. 1 H NMR (400MHz, CDCl3) δ8.21(d,J=1.6Hz,1H),8.10(s,1H),8.04(t,J=9.4Hz,1H),7.96(dd,J=8.9,1.8 Hz,1H),7.86(d,J=8.5Hz,1H),7.73(dd,J=22.9,12.1Hz,2H),7.61(dd,J=15.8,9.0Hz,1H),7.49(d, J=8.5Hz,1H),7.03(d,J=15.2Hz,1H),6.89–6.72(m,2H),6.27(t,J=5.7Hz,1H),6.03(s,1H),4.66(d ,J=14.2Hz,1H),4.57(d,J=14.1Hz,1H),3.99(dd,J=14.3,6.3Hz,1H),3.81(dd,J=14.5,5.9Hz,1H); 13C NMR (101MHz, CDCl3) δ167.50,153.29,151.70,150.13,147.12,144.68,141.05,138.92,136.47,136.40,135.65,131.17,130.51,130.46 ,130.41,130.33,130.30,129.68,124.97,122.32,112.04,112.00,111.83,111.79,104.48,104.21,93.02,76.47,76.42,55.84,47.56.

[0132] Example 24

[0133] Preparation of (E)-N-(2-(2,4-dichlorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(quinoline-2-yl)acrylamide

[0134] Following the method of Example 1, the yield was 57%. 1 H NMR (400MHz, DMSO) δ8.32(t,J=5.9Hz,1H),8.24(d,J=8.5Hz,1H),8.12(d,J=4.7Hz,1H),7.93–7.85(m,2H),7.82–7.61(m,3H),7.62–7.50(m,2H),7. 25(dd,J=15.9,8.9Hz,1H),7.18–7.12(m,2H),6.84–6.76(m,1H),6.21(s, 1H), 4.53 (d, J = 14.4Hz, 1H), 4.44 (d, J = 14.3Hz, 1H), 3.65 (d, J = 6.0Hz, 2H); 13 C NMR (101MHz, CDCl3) δ168.06,164.30,162.70,161.71,160.02,157.54,153.01,151.40,148.11,144.65,141.40,136. 98,130.42,130.43,130.28,129.42,128.12,127.52,124.23,123.41,123.71,112.02,104.43,,76.52,56.12,47.67.

[0135] Example 25

[0136] Preparation of (E)-N-(2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl)-3-(quinoline-3-yl)acrylamide

[0137] Following the method of Example 1, the yield was 65%. 1 H NMR (400MHz, DMSO) δ9.09 (s, 1H), 8.49 (s, 1H), 8.30 (dd, J = 13.3, 7.8Hz, 2H) ,8.13–7.92(m,2H),7.86–7.71(m,2H),7.62(dd,J=21.7,11.8Hz,2H),7.41 (dd,J=16.0,8.7Hz,1H),7.20(t,J=9.7Hz,1H),7.04–6.86(m,2H),6.31(s, 1H), 4.66 (d, J = 14.3Hz, 1H), 4.56 (d, J = 14.3Hz, 1H), 3.76 (d, J = 5.6Hz, 2H); 13 C NMR (101MHz, DMSO) δ165.90,163.14,163.01,160.69,160.57,160.34,160.21,157.88,157 .76,150.57,149.22,147.59,144.96,136.23,134.82,130.28,130.21,130.14,128.76,12 8.53, 127.90, 127.38, 127.30, 124.74, 124.70, 124.61, 124.57, 123.48, 110.91, 110.88, 110.70, 110.68, 104.23, 103.97, 103.95, 103.69, 74.91, 74.86, 55.19, 55.14, 46.22, 46.18.

[0138] Pharmacological experiments demonstrate the inhibitory effect of the amide-triazole compounds of this invention on the growth of fungal cells.

[0139] 1. Experimental Methods

[0140] The target compound was diluted two-fold with BHI broth and added to an equal volume of bacterial culture in the logarithmic growth phase in a 96-well plate. The concentration of the target compound was 1-64 μg / mL, the final cell concentration was 1 × 10⁶ CFU / mL, and the final volume of the solution in each well was 200 μL. The plate was incubated anaerobicly at 37°C for 24 h, and the OD value at 625 nm was measured using a microplate reader. A blank control, a fungal control, and a fluconazole positive control were also included.

[0141] MIC 80 (%) = (OD sample – OD blank) / (OD reference – OD blank) × 100

[0142] 2. Experimental Results

[0143] Table 1. Inhibitory effects of amide-triazole compounds on bacterial growth

[0144]

[0145] Note: 5314 is Candida albicans; CG4 is Candida glabrata; H99 is Cryptococcus neoformans.

[0146] The evaluation results of the bacterial cell inhibitory activity of the above compounds show that most of the compounds have certain antibacterial effects. Compounds 9, 12, 13, 14, 15, 16, 17, 18, 19, 20, and 23 have better inhibitory activity against Candida albicans, Candida glabrata, and Cryptococcus neoformans than marketed drugs such as fluconazole, miconazole, and itraconazole, and have significant inhibitory effects. Among them, compounds 9, 13, 16, 18, 20, and 23 have further development and research value.

Claims

1. An aromatic acrylamide-triazole compound, characterized in that, Selected from the following compounds:

Images