1,2,4-triazole derivatives containing thiazole / oxazole groups, processes for their preparation and use

Abstract

The application discloses a thiazole / oxazole group-containing 1,2,4-triazole derivative, a preparation method and application thereof, and relates to the technical field of medicinal chemistry.The thiazole / oxazole group-containing 1,2,4-triazole derivative has excellent broad-spectrum antifungal effect and the advantage of a simple synthesis method, and has important reference significance for developing a novel high-efficiency antiplant pathogenic fungus agent.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to a 1,2,4-triazole derivative containing a thiazole / oxazole group, its preparation method, and its application. Background Technology

[0002] The long-term and frequent use of traditional triazole fungicides has led to resistance in many varieties, causing them to lose their original efficacy. Furthermore, increasingly stringent pesticide management policies may result in the banning of some triazole products. Since the introduction of silfluzazole in 2002, only chlorfluazuron and prothioconazole have been successfully commercialized. Therefore, the development of new, highly effective triazole fungicides is urgently needed.

[0003] Thiazole and oxazole fragments, as special functional groups for constructing bioactive small molecules, exhibit broad-spectrum and excellent biological activities, including antifungal, antibacterial, antiviral, insecticidal, and anticancer properties. Furthermore, the application of thiazolium and oxazole fragments as active groups in the development of agricultural fungicides has numerous successful precedents, such as thiabendazole (a microtubule polymerization inhibitor), thifluzamide (a succinate dehydrogenase inhibitor), ethiazole (a β-tubulin inhibitor), and bensulfuron-methyl (potentially acting as a cell wall synthesis inhibitor). However, the application of thiazolium and oxazole fragments is rarely seen in existing CYP51 inhibitors. Introducing this pharmacophore may promote the development of novel, highly effective triazole antifungal molecules. Summary of the Invention

[0004] Based on the above research background, this invention aims to develop novel and highly efficient CYP51 inhibitors. By introducing thiazole fragments as hydrophobic components into the core skeleton of traditional triazole fungicides through a skeleton transition strategy, while retaining the active fragments of 1,2,4-triazole groups and hydroxyl groups, a series of 1,2,4-triazole derivatives containing thiazole / oxazole groups were innovatively designed and synthesized, and their inhibitory activity against various plant pathogenic fungi and oomycetes was evaluated.

[0005] The present invention relates to 1,2,4-triazole derivatives containing thiazole / oxazole groups, the general structural formula of which is shown below:

[0006]

[0007] Among them, R 1 It is one of H, alkyl, aryl, or heteroaryl; R 2 It is one of H, alkyl, aryl, or heteroaryl; in addition, R 1 R 2 It can form saturated or unsaturated rings.

[0008] R 3It is one of substituted or unsubstituted alkyl, substituted or unsubstituted aryl; the substituents used for substitution include one or more of halogen substitution, heteroatom (O, S, N, etc.) substitution, alkyl substitution, and alkoxy substitution.

[0009] Y represents either a sulfur atom or an oxygen atom.

[0010] Furthermore, the alkyl group is a straight-chain or branched alkyl group with 1-10 carbon atoms.

[0011] This invention further provides a method for preparing the above-mentioned 1,2,4-triazole derivatives containing thiazole / oxazole groups, comprising the following steps:

[0012] Step 1: Using R 1 and R 2 Group-substituted thiazoles or oxazoles and R 3 Starting with a group-substituted aldehyde, the reaction proceeds in an organic solvent in the presence of a base to give compound A. The reaction route for this step is shown below:

[0013]

[0014] Step 2: Compound A and the oxidizing agent are added to an organic solvent to undergo an oxidation reaction, yielding compound B. The reaction route for this step is shown below:

[0015]

[0016] Step 3: Compound B, the epoxidizing agent, and the base are dissolved in an organic solvent to carry out an epoxidation reaction, yielding compound C. The reaction route for this step is shown below:

[0017]

[0018] Step 4: Mix compound C, 1,2,4-triazole, base and organic solvent to react and obtain the target product.

[0019] Among them, R 1 It is one of alkyl, aryl, or heteroaryl; R 2 It is one of alkyl, aryl, or heteroaryl; R 3 It is one of alkyl, aryl, or heteroaryl; Y is one of sulfur or oxygen atoms.

[0020] Furthermore, the R 1 and R 2 The substituted thiazole or oxazole is one of 4,5-dimethylthiazole, 4,5-dimethyloxazole, 4-methylthiazole, 4-methyloxazole, 5-methylthiazole, 5-methyloxazole, benzothiazole, and benzoxazole.

[0021] Furthermore, the R3 The aldehydes with substituted groups are alkyl aldehydes, aryl aldehydes, or heteroaryl aldehydes.

[0022] Furthermore, in step 1, the reaction is carried out under a protective atmosphere, at a temperature of -78°C to 0°C, and for a time of 2-4 hours.

[0023] Furthermore, in step 1, the R 1 and R 2 Thiazoles or oxazoles with substituent groups and R 3 The molar ratio of substituted aldehydes is 1:1.1.

[0024] Furthermore, in step 1, the alkali is one of n-butyllithium, tert-butyllithium, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, or potassium carbonate.

[0025] Further, in step 2, the oxidant is one of manganese dioxide, perchlorate, permanganate, dichromate, sodium peroxide, oxygen, sodium dichromate, potassium dichromate, or potassium permanganate. The molar ratio of compound A to the oxidant is 1:10.

[0026] Furthermore, in step 2, the oxidation reaction is carried out at a temperature of 20-50℃ for 2-4 hours.

[0027] Further, in step 3, the base is one of triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, lithium bis(trimethylsilylamine), potassium bis(trimethylsilylamine), or sodium hydride. The epoxidizing agent is trimethylsulfur iodide or trimethyl sulfoxide iodide. The molar ratio of compound B, the epoxidizing agent, and the base is 1:1.2:1.5.

[0028] Furthermore, in step 3, the epoxidation reaction is carried out at a temperature of 0-40℃ for 1-24 hours.

[0029] Further, in step 4, the base is one of triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, lithium bis(trimethylsilylamine), potassium bis(trimethylsilylamine), or sodium hydride. The molar equivalent ratio of compound C, 1,2,4-triazole, and the base is 1:2:2.

[0030] Furthermore, in step 4, the reaction temperature is 0-80℃ and the reaction time is 3h-12h.

[0031] As a further preferred option, after the reactions in steps 1, 3, and 4 are completed, the process also includes extraction, drying, filtration, vacuum distillation, and column chromatography separation.

[0032] More preferably, the extraction specifically involves: after the reaction is completed, extraction is performed sequentially using saturated ammonium chloride solution, saturated sodium bicarbonate solution, saturated saline solution, and ethyl acetate; the column chromatography separation specifically involves: 200-300 mesh silica gel powder for column chromatography, and the eluent is a mixture of petroleum ether and ethyl acetate in a volume ratio of 1:1; the drying reagent used is anhydrous sodium sulfate.

[0033] The reaction process of this invention can be determined using thin-layer chromatography plates to determine the reaction endpoint.

[0034] This invention relates to the application of 1,2,4-triazole derivatives containing thiazole / oxazole groups in the preparation of antifungal drug formulations.

[0035] The fungi include apple rot fungus ( ) Bad waltz ), Sclerotium sclerotium ( Sclerotinia skeletons ), gray mold ( Botrytis cinerea Rhizoctonia solani ( ) Rhizoctonia solani Alternaria ( Alternaria alternata ), wheat scab ( Fusarium graminearum ), Curvularia crescentis ( Curvularia lunata ), Phytophthora capsici ( Phytophthora capsica One or more of them.

[0036] This invention also provides an antifungal pharmaceutical formulation, the active pharmaceutical ingredient of which includes the 1,2,4-triazole derivative containing a thiazole / oxazole group. The fungus includes *Phyllostachys edulis* (the causal agent of apple rot). Bad waltz ), Sclerotium sclerotium ( Sclerotinia scleotiorum ), gray mold ( Botrytis cinerea Rhizoctonia solani ( ) Rhizoctonia solani Alternaria ( Alternaria alternata ), wheat scab ( Fusarium graminearum ), Curvularia crescentis ( Curvularia lunata ), Phytophthora capsici ( Phytophthora capsica One or more of them.

[0037] The beneficial effects of this invention are reflected in:

[0038] This invention provides a 1,2,4-triazole derivative containing a thiazole / oxazole group, which exhibits excellent broad-spectrum antifungal effects.

[0039] This invention has the advantage of a simple synthesis method, which is of great significance for overcoming the drug resistance of plant pathogenic fungi. Detailed Implementation

[0040] Various exemplary embodiments of the present invention will now be described in detail. This detailed description should not be considered as a limitation of the present invention, but rather as a more detailed description of certain aspects, features, and embodiments of the present invention.

[0041] It should be understood that the terminology used in this invention is merely for describing particular embodiments and is not intended to limit the invention. Furthermore, with respect to numerical ranges in this invention, it should be understood that each intermediate value between the upper and lower limits of the range is also specifically disclosed. Any stated value or intermediate value within a stated range, as well as each smaller range between any other stated value or intermediate value within said range, is also included in this invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0042] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. While only preferred methods and materials have been described herein, any methods and materials similar or equivalent to those described herein may be used in the implementation or testing of this invention. All references to this specification are incorporated by way of citation to disclose and describe methods and / or materials associated with those references. In the event of any conflict with any incorporated reference, the content of this specification shall prevail.

[0043] Various modifications and variations can be made to the specific embodiments described in this specification without departing from the scope or spirit of the invention, as will be apparent to those skilled in the art. Other embodiments derived from this specification will also be readily apparent to those skilled in the art. This specification and embodiments are merely exemplary.

[0044] The terms “include,” “including,” “have,” “contain,” etc., used in this article are all open-ended terms, meaning that they include but are not limited to.

[0045] The column chromatography conditions in this embodiment of the invention are: 200-300 mesh silica gel powder. The molar numbers indicated in this embodiment refer to the amount of the substance used in the reaction system.

[0046] Example 1: Preparation of compound D1

[0047] The synthetic route for compound D1 is shown below:

[0048]

[0049] The synthesis steps of compound D1 are as follows:

[0050] (1) Using anhydrous tetrahydrofuran as solvent, 10 mmol of 4,5-dimethylthiazole and 12 mmol of n-butyllithium were added and reacted at -40 °C for 1 hour under a nitrogen atmosphere. After the reaction was complete, 12 mmol of benzaldehyde was added, and the mixture was allowed to react for another hour. Subsequently, the solvent was evaporated, and the residue was dissolved in 20 mL of saturated NH4Cl solution. The mixture was then extracted with ethyl acetate (3 × 20 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was recrystallized from a mixture of ethyl acetate and petroleum ether to give precursor A.

[0051] (2) Add precursor A (1 mmol) to a 100 mL round-bottom flask, followed by MnO2 (10 mmol) and dichloromethane (10 mL). Stir the reaction mixture at 25 °C for 2 hours, monitoring with TLC. After completion, filter the reaction solution through diatomaceous earth. Then concentrate the collected filtrate under reduced pressure to obtain precursor B, which requires no further processing.

[0052] (3) Place NaH (1.5 mmol, 60% mineral oil) in a dry round-bottom flask. Add THF (2 mL) and DMSO (2 mL) to suspend the NaH, and cool the mixture in an ice bath. Add trimethylsulfonium iodide (1.2 mmol) and precursor B (1 mmol) sequentially to the suspension. Stir the resulting mixture at 0 °C for 30 minutes, then allow it to return to room temperature and stir overnight. After completion, evaporate the solvent and dissolve the residue in 20 mL of saturated NaCl solution. Extract the solution with ethyl acetate (3 × 20 mL). Dry the organic phase with anhydrous Na2SO4, filter, and concentrate under reduced pressure to obtain an oily crude epoxide (precursor C), which is immediately used in the next step.

[0053] (4) K₂CO₃ (1.5 mmol) and 1,2,4-triazole (1.5 mmol) were added sequentially to a DMF (5 mL) solution of crude epoxide (precursor C). The resulting mixture was stirred overnight at 65 °C. After completion, the reaction mixture was cooled, and the residue was dissolved in 20 mL of saturated NaCl solution. The solution was extracted with ethyl acetate (3 × 20 mL). The organic phase was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography using a mixture of n-hexane and ethyl acetate (1:1) to give the target compound D1.

[0054] Compound D1: 1-(4,5-dimethylthiazol-2-yl)-1-phenyl-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0055]

[0056] Compound D1 is a white solid with a yield of 78%; mp, 184-185 °C.

[0057] 1 H NMR (600 MHz, Chloroform-d) δ 8.00 (s, 1H), 7.85 (s, 1H), 7.65 (d,J = 7.2 Hz, 2H), 7.34 (d, J = 7.4 Hz, 2H), 7.27 (dd, J = 13.0, 5.9 Hz, 1H), 5.69 (s, 1H), 5.15 (d, J = 13.9 Hz, 1H), 4.63 (d, J = 14.0 Hz, 1H), 2.27 (s, 3H), 2.22 (s, 3H). 13 HRMS (ESI)calculated for C 15 H 16 N4NaOS [M+Na] + , 323.0937; found, 323.0947.

[0058] Example 2: Preparation of compound D2

[0059] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with o-methylbenzaldehyde.

[0060] The compound D2 was obtained as 1-(4,5-dimethylthiazol-2-yl)-1-(o-tolyl)-2-(1H-1,2,4-triazol-1-yl)ethanol, with the structural formula shown below:

[0061]

[0062] Compound D2 is a white solid with a yield of 81%; mp, 118-119 °C.

[0063] 1H NMR (600 MHz, Chloroform-d) δ 7.95 (d, J = 3.3 Hz, 1H), 7.76 (d, J= 3.3 Hz, 1H), 7.33 (dd, J = 7.9, 3.4 Hz, 1H), 7.19 (td, J = 7.6, 3.5 Hz, 1H), 7.12 (dt, J = 19.7, 5.6 Hz, 2H), 5.47 (s, 1H), 5.18 (dd, J = 13.9, 3.4Hz, 1H), 4.94 (dd, J = 13.9, 3.4 Hz, 1H), 2.41 (s, 3H), 2.26 (dd, J = 8.5,3.4 Hz, 6H). 13 C NMR (151 MHz, Chloroform-d) δ 168.9, 151.7, 147.3, 144.9,138.6, 136.8, 132.9, 128.5, 128.3, 126.6, 125.8, 78.8, 56.4, 21.8, 14.7,11.3. HRMS (ESI) calculated for C 16 H 19 N4OS [M+H] + , 315.1274; found, 315.1282.

[0064] Example 3: Preparation of compound D3

[0065] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with m-methylbenzaldehyde.

[0066] The compound D3 was obtained as 1-(4,5-dimethylthiazol-2-yl)-1-(m-tolyl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0067]

[0068] Compound D2 is a white solid with a yield of 77%; mp, 165-166 °C.

[0069] 1H NMR (600 MHz, Chloroform-d) δ 8.02 (s, 1H), 7.86 (s, 1H), 7.52 –7.37 (m, 2H), 7.25 – 7.18 (m, 1H), 7.09 (d, J = 7.4 Hz, 1H), 5.65 (s, 1H), 5.16 (d, J = 14.0 Hz, 1H), 4.62 (d, J = 13.7 Hz, 1H), 2.34 (s, 3H), 2.28 (s,3H), 2.23 (s, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 168.9, 151.9, 147.8,144.9, 140.9, 138.2, 128.9, 128.3, 127.6, 125.9, 122.5, 78.1, 58.0, 21.5,14.8, 11.2. HRMS (ESI) calculated for C 16 H 19 N4OS [M+H] + , 315.1274; found,315.1281.

[0070] Example 4: Preparation of compound D4

[0071] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with p-methylbenzaldehyde.

[0072] Compound D4 was obtained as 1-(4,5-dimethylthiazol-2-yl)-1-(p-tolyl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0073]

[0074] Compound D4 is a white solid with a yield of 85%; mp, 189-190 °C.

[0075] White solid, yield: 85%; mp: °C; 1H NMR (600 MHz, Chloroform-d) δ8.01 (s, 1H), 7.87 (s, 1H), 7.53 (d, J = 7.6 Hz, 2H), 7.14 (d, J = 7.6 Hz,2H), 5.59 (s, 1H), 5.14 (d, J = 13.8 Hz, 1H), 4.63 (d, J = 13.9 Hz, 1H), 2.31(s, 3H), 2.27 (s, 3H), 2.22 (s, 3H). 13 HRMS (ESI) calculated for C 16 H 19 N4OS [M+H] + , 315.1274; found,315.1288.

[0076] Example 5: Preparation of compound D5

[0077] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with o-methoxybenzaldehyde.

[0078] Compound D5 was obtained as 1-(4,5-dimethylthiazol-2-yl)-1-(2-methoxyphenyl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0079]

[0080] Compound D5 is a yellow solid with a yield of 886%; mp, 112-113 ℃.

[0081] 1 H NMR (600 MHz, Chloroform-d) δ 7.99 (s, 1H), 7.80 (s, 1H), 7.42(d, J = 5.9 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 6.92 (t, J = 9.9 Hz, 2H), 5.63(s, 1H), 5.18-5.10 (m, 2H), 3.87 (s, 3H), 2.31 (d, J = 15.7 Hz, 6H).13 C NMR(151 MHz, Chloroform-d) δ 167.5, 156.3, 151.0, 147.0, 144.5, 129.9, 128.8,128.2, 128.0, 121.3, 111.6, 78.0, 57.0, 55.5, 14.7, 11.2. HRMS (ESI)calculated for C 16 H 18 N4NaO2S [M+Na] + , 353.1043; found, 353.1047.

[0082] Example 6: Preparation of compound D6

[0083] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with m-methoxybenzaldehyde.

[0084] Compound D6 was obtained as 1-(4,5-dimethylthiazol-2-yl)-1-(3-methoxyphenyl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0085]

[0086] Compound D6 is a yellow solid with a yield of 79%; mp, 132-133 °C.

[0087] 1 H NMR (600 MHz, Chloroform-d) δ 8.01 (s, 1H), 7.86 (s, 1H), 7.23 (d,J = 19.1 Hz, 3H), 6.81 (d, J = 11.3 Hz, 1H), 5.64 (s, 1H), 5.14 (d, J = 14.0Hz, 1H), 4.62 (d, J = 13.7 Hz, 1H), 3.79 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 168.6, 159.7, 152.0, 147.8, 144.9, 142.56,129.5, 127.7, 117.7, 113.6, 111.3, 78.1, 58.0, 55.2, 14.8, 11.2. HRMS (ESI)calculated for C 16H 18 N4NaO2S [M+Na] + , 353.1043; found, 353.1047.

[0088] Example 7: Preparation of compound D7

[0089] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with p-methoxybenzaldehyde.

[0090] The compound D7 was obtained as 1-(4,5-dimethylthiazol-2-yl)-1-(4-methoxyphenyl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0091]

[0092] Compound D7 is a yellow solid with a yield of 82%; mp, 163-164 °C.

[0093] 1 H NMR (600 MHz, Chloroform-d) δ 7.99 (s, 1H), 7.84 (s, 1H), 7.54 (d,J = 8.7 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 5.66 (s, 1H), 5.11 (d, J = 13.9Hz, 1H), 4.62 (d, J = 13.9 Hz, 1H), 3.77 (s, 3H), 2.27 (s, 3H), 2.22 (s, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 169.2, 159.4, 151.9, 147.8, 144.7, 133.1,127.5, 126.8, 113.6, 77.9, 58.0, 55.3, 14.9, 11.3. HRMS (ESI) calculated forC 16 H 19 N4O2S [M+H] + , 331.1223; found, 331.1237.

[0094] Example 8: Preparation of compound D8

[0095] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with o-ethylbenzaldehyde.

[0096] Compound D8 was obtained as 1-(4,5-dimethylthiazol-2-yl)-1-(2-ethylphenyl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0097]

[0098] Compound D8 is a yellow solid with a yield of 60%; mp, 152-153 °C.

[0099] 1 H NMR (600 MHz, Chloroform-d) δ 7.96 (s, 1H), 7.79 (s, 1H), 7.30 (d,J = 8.0 Hz, 1H), 7.25 (d, J = 6.0 Hz, 2H), 7.14 – 7.08 (m, 1H), 5.45 (s, 1H), 5.20 (d, J = 13.9 Hz, 1H), 4.89 (d, J = 13.9 Hz, 1H), 2.87 (th, J = 14.5, 7.4Hz, 2H), 2.26 (d, J = 10.9 Hz, 6H), 1.14 (t, J = 7.4 Hz, 3H). 13 C NMR (151MHz, Chloroform-d) δ 169.6, 151.5, 147.3, 144.9, 143.3, 138.0, 131.2, 128.7,128.2, 126.6, 125.6, 79.3, 57.2, 26.7, 16.2, 14.7, 11.3. HRMS (ESI)calculated for C 17 H 21 N4OS [M+H] + , 329.1431; found, 329.1436.

[0100] Example 9: Preparation of compound D9

[0101] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with p-ethylbenzaldehyde.

[0102] Compound D9 was obtained as 1-(4,5-dimethylthiazol-2-yl)-1-(4-ethylphenyl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0103]

[0104] Compound D9 is a white solid with a yield of 68%; mp, 180-181 °C.

[0105] 1 H NMR (600 MHz, Chloroform-d) δ 8.01 (s, 1H), 7.85 (s, 1H), 7.55 (d, J = 7.9 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 5.63 (s, 1H), 5.15 (d, J =13.9 Hz, 1H), 4.63 (d, J = 13.9 Hz, 1H), 2.61 (q, J = 7.6 Hz, 2H), 2.27 (s,3H), 2.22 (s, 3H), 1.20 (t, J = 7.7 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ169.1, 151.9, 147.8, 144.9, 144.2, 138.3, 127.9, 127.6, 125.4, 78.1, 58.0,28.4, 15.3, 14.8, 11.2. HRMS (ESI) calculated for C 17 H 21 N4OS [M+H] + , 329.1431;found, 329.1442.

[0106] Example 10: Preparation of compound D10

[0107] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with o-fluorobenzaldehyde.

[0108] The compound D10 was obtained as 1-(4,5-dimethylthiazol-2-yl)-1-(2-fluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0109]

[0110] Compound D10 is a yellow solid with a yield of 75%; mp, 132-133 °C.

[0111] 1H NMR (600 MHz, Chloroform-d) δ 8.06 (s, 1H), 7.82 (s, 1H), 7.60 (s, 1H), 7.10 (s, 1H), 7.02 (d, J = 11.0 Hz, 1H), 5.54 (s, 1H), 5.19 (s, 2H),2.28 (s, 6H). 13 C NMR (151 MHz, Chloroform-d) δ 166.7, 159.4 (d, J = 246.1Hz), 151.7, 147.5, 144.7, 130.5 (d, J = 9.1 Hz), 128.4 (d, J = 4.5 Hz), 128.3, 124.5 (d, J = 3.0 Hz), 116.2 (d, J = 24.2 Hz), 76.5 (d, J = 3.0 Hz), 56.2, 56.1, 14.7, 11.2. 19 F NMR (376 MHz, Chloroform-d) δ -110.8. HRMS (ESI)calculated for C 15 H 16 FN4OS [M+H] + , 319.1023; found, 319.1039.

[0112] Example 11: Preparation of compound D11

[0113] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with m-fluorobenzaldehyde.

[0114] The compound D11 was obtained as 1-(4,5-dimethylthiazol-2-yl)-1-(3-fluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0115]

[0116] Compound D11 is a white solid with a yield of 69%; mp, 171-172 °C.

[0117] 1H NMR (600 MHz, Chloroform-d) δ 8.02 (s, 1H), 7.88 (s, 1H), 7.44 (d,J = 13.8 Hz, 2H), 7.31 (s, 1H), 6.98 (s, 1H), 5.79 (s, 1H), 5.14 (d, J = 13.3Hz, 1H), 4.61 (d, J = 13.7 Hz, 1H), 2.28 (s, 3H), 2.23 (s, 3H). 13 C NMR (151MHz, Chloroform-d) δ 168.14, 162.8 (d, J = 246.1 Hz), 152.1, 148.1, 145.0,143.5 (d, J = 6.0 Hz), 130.0 (d, J = 7.6 Hz), 127.9, 121.1 (d, J = 3.0 Hz), 115.0 (d, J = 21.1 Hz), 112.9 (d, J = 22.7 Hz), 77.8 (d, J = 3,0 Hz), 57.8, 14.8, 11.2. 19 F NMR (376 MHz, Chloroform-d) δ -112.0. HRMS (ESI) calculated for C 15 H 16 FN4OS [M+H] + , 319.1023; found, 319.1036.

[0118] Example 12: Preparation of compound D12

[0119] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with p-fluorobenzaldehyde.

[0120] The compound D12 was obtained as 1-(4,5-dimethylthiazol-2-yl)-1-(4-fluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0121]

[0122] Compound D12 is a white solid with a yield of 69%; mp, 198-199 °C.

[0123] 1H NMR (600 MHz, Chloroform-d) δ 8.00 (d, J = 19.6 Hz, 1H), 7.87 (d,J = 19.8 Hz, 1H), 7.69 (s, 2H), 7.07 (s, 2H), 5.72 (d, J = 19.9 Hz, 1H), 5.13(d, J = 14.3 Hz, 1H), 4.61 – 4.54 (m, 1H), 2.24 (dd, J = 28.5, 16.0 Hz, 6H). 13 C NMR (151 MHz, Chloroform-d) δ 168.6, 162.5 (d, J = 247.4 Hz), 152.1,148.0, 144.9, 136,7, 127.8, 127.4 (d, J = 7.6 Hz), 115.3 (d, J = 21.1 Hz),77.9, 58.0, 14.8, 11.2. 19 F NMR (376 MHz, Chloroform-d) δ -114.2. HRMS (ESI)calculated for C 15 H 16 FN4OS [M+H] + , 319.1023; found, 319.1037.

[0124] Example 13: Preparation of compound D13

[0125] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with o-chlorobenzaldehyde.

[0126] The compound D13 was obtained as 1-(4,5-dimethylthiazol-2-yl)-1-(2-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0127]

[0128] Compound D13 is a yellow solid with a yield of 82%; mp, 137-138 °C.

[0129] 1H NMR (600 MHz, Chloroform-d) δ 7.92 (s, 1H), 7.78 (s, 1H), 7.59 (d,J = 7.8 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 7.27 – 7.17 (m, 2H), 5.54 (d, J =14.9 Hz, 1H), 5.29 (t, J = 7.1 Hz, 2H), 2.30 (d, J = 18.0 Hz, 6H). 13 C NMR(151 MHz, Chloroform-d) δ 166.8, 151.5, 147.4, 144.6, 138.0, 132.0, 131.3,130.1, 128.9, 128.5, 127.0, 77.2, 54.8, 14.7, 11.3. HRMS (ESI) calculated for C 15 H 16 ClN4OS [M+H] + , 335.0728; found, 335.0740.

[0130] Example 14: Preparation of compound D14

[0131] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with m-chlorobenzaldehyde.

[0132] The compound D14 was obtained as 1-(4,5-dimethylthiazol-2-yl)-1-(3-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0133]

[0134] Compound D14 is a white solid with a yield of 79%; mp, 178-179 °C.

[0135] 1 H NMR (600 MHz, Chloroform-d) δ 8.03 (s, 1H), 7.88 (s, 1H), 7.72 (s,1H), 7.57 (s, 1H), 7.27 (s, 2H), 5.80 (s, 1H), 5.14 (d, J = 13.5 Hz, 1H), 4.59 (d, J = 13.2 Hz, 1H), 2.28 (s, 3H), 2.23 (s, 3H). 13C NMR (151 MHz, Chloroform-d) δ 168.1, 152.1, 148.1, 144.9, 142.9, 134.5, 129.7, 128.4,127.9, 125.9, 123.7, 77.8, 57.8, 14.8, 11.2. HRMS (ESI) calculated forC 15 H 16 ClN4OS [M+H] + , 335.0728; found, 335.0731.

[0136] Example 15: Preparation of compound D15

[0137] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with p-chlorobenzaldehyde.

[0138] The compound D15 was obtained as 1-(4,5-dimethylthiazol-2-yl)-1-(4-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0139]

[0140] Compound D15 is a white solid with a yield of 83%; mp, 179-180 °C.

[0141] 1 H NMR (600 MHz, Chloroform-d) δ 8.02 (s, 1H), 7.88 (s, 1H), 7.62 (s,2H), 7.31 (d, J = 8.7 Hz, 2H), 5.75 (s, 1H), 5.13 (d, J = 13.1 Hz, 1H), 4.59(d, J = 13.3 Hz, 1H), 2.28 (s, 3H), 2.23 (s, 3H). 13 HRMS (ESI) calculated for C 15 H 16 ClN4OS [M+H]+ ,335.0728; found, 335.0737.

[0142] Example 16: Preparation of compound D16

[0143] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with o-bromobenzaldehyde.

[0144] The compound D16 was obtained as 1-(4,5-dimethylthiazol-2-yl)-1-(2-bromophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0145]

[0146] Compound D16 is a yellow solid with a yield of 65%; mp, 130-131 °C.

[0147] 1 H NMR (600 MHz, Chloroform-d) δ 7.89 (s, 1H), 7.72 (s, 1H), 7.55(dd, J = 18.0, 7.9 Hz, 2H), 7.20 (t, J = 7.6 Hz, 1H), 7.12 (t, J = 7.7 Hz, 1H), 5.67 – 5.58 (m, 2H), 5.26 (d, J = 14.4 Hz, 1H), 2.31 (s, 3H), 2.28 (s, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 167.1, 151.2, 147.4, 144.5, 139.4,134.8, 130.2, 129.3, 128.7, 127.4, 121.5, 77.5, 54.9, 14.7, 11.3. HRMS (ESI)calculated for C 15 H 16 ClN4OS [M+H] + , 379.0223; found, 379.0228.

[0148] Example 17: Preparation of compound D17

[0149] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with m-bromobenzaldehyde.

[0150] The compound D17 was obtained as 1-(4,5-dimethylthiazol-2-yl)-1-(3-bromophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0151]

[0152] Compound D17 is a white solid with a yield of 76%; mp, 173-174 °C.

[0153] 1 H NMR (600 MHz, Chloroform-d) δ 8.02 (s, 1H), 7.86 (d, J = 7.3 Hz, 2H), 7.60 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 8.0 Hz,1H), 5.86 (s, 1H), 5.13 (d, J = 13.9 Hz, 1H), 4.58 (d, J = 13.9 Hz, 1H), 2.28(s, 3H), 2.22 (s, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 168.1, 152.0, 148.1,144.9, 143.2, 131.3, 130.0, 128.7, 127.9, 124.2, 122.7, 77.7, 57.8, 14.8,11.2. HRMS (ESI) calculated for C 15 H 16 ClN4OS [M+H] + , 379.0223; found,379.0232.

[0154] Example 18: Preparation of compound D18

[0155] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with p-bromobenzaldehyde.

[0156] The compound D18 was obtained as 1-(4,5-dimethylthiazol-2-yl)-1-(4-bromophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0157]

[0158] Compound D18 is a yellow solid with a yield of 85%; mp, 186-187 °C.

[0159] 1 H NMR (600 MHz, Chloroform-d) δ 8.00 (s, 1H), 7.84 (s, 1H), 7.55 (d,J = 8.7 Hz, 2H), 7.45 (d, J = 7.1 Hz, 2H), 5.85 (s, 1H), 5.11 (d, J = 13.8Hz, 1H), 4.60 (d, J = 13.9 Hz, 1H), 2.27 (s, 3H), 2.22 (s, 3H). 13 C NMR (151MHz, Chloroform-d) δ 168.3, 152.0, 148.1, 144.9, 140.0, 131.6, 127.9, 127.3,122.4, 77.9, 57.8, 14.8, 11.2. 13 C NMR (151 MHz, Chloroform-d) δ 168.1, 152.0,148.1, 144.9, 143.2, 131.3, 130.0, 128.7, 127.9, 124.2, 122.7, 77.7, 57.8,14.8, 11.2. HRMS (ESI) calculated for C 15 H 16 ClN4OS [M+H] + , 379.0223; found,379.0225.

[0160] Example 19: Preparation of compound D19

[0161] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with o-trifluoromethylbenzaldehyde.

[0162] Compound D19 was obtained as 1-(4,5-dimethylthiazol-2-yl)-2-(1H-1,2,4-triazol-1-yl)-1-(2-(trifluoromethyl)phenyl)ethyl-1-ol, with the structural formula shown below:

[0163]

[0164] Compound D19 is a yellow solid with a yield of 60%; mp, 49-50 °C.

[0165] 1H NMR (600 MHz, Chloroform-d) δ 8.07 (s, 1H), 7.87 (s, 1H), 7.82 (d,J = 9.3 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.43 (dt, J = 25.3, 7.5 Hz, 2H), 5.77 (s, 1H), 5.15 (d, J = 14.0 Hz, 1H), 4.93 (d, J = 14.0 Hz, 1H), 2.31 (s, 3H), 2.25 (s, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 168.8, 152.0, 147.5,145.0, 139.7, 131.5, 129.3, 128.7 (q, J = 6.0 Hz), 128.6, 128.5, 128.3, 124.4(q, J = 273.3 Hz), 79.1, 56.9, 14.8, 11.2. 19 F NMR (376 MHz, Chloroform-d) δ -54.2. HRMS (ESI) calculated for C 16 H 16 F3N4OS [M+H] + , 369.0991; found,369.1014.

[0166] Example 20: Preparation of compound D20

[0167] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with m-trifluoromethylbenzaldehyde.

[0168] The compound D20 was obtained as 1-(4,5-dimethylthiazol-2-yl)-2-(1H-1,2,4-triazol-1-yl)-1-(3-(trifluoromethyl)phenyl)ethyl-1-ol, with the structural formula shown below:

[0169]

[0170] Compound D20 is a white solid with a yield of 76%; mp, 149-150 °C.

[0171] 1H NMR (600 MHz, Chloroform-d) δ 8.01 (s, 2H), 7.88 (d, J = 8.1 Hz,1H), 7.85 (s, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.45 (t, J = 7.9 Hz, 1H), 6.02(s, 1H), 5.16 (d, J = 13.9 Hz, 1H), 4.60 (d, J = 13.9 Hz, 1H), 2.28 (s, 3H), 2.22 (s, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 168.1, 151.9, 148.23, 144.8,142.1, 130.9 (q, J = 31.7 Hz), 129.0, 128.9, 128.0, 125.0 (q, J = 3.0 Hz), 124.0 (q, J = 273.3 Hz), 122.5 (q, J = 4.5 Hz), 77.9, 57.9, 14.7, 11.1. 19 FNMR (376 MHz, Chloroform-d) δ -62.5. HRMS (ESI) calculated for C 16 H 16 F3N4OS [M+H] + , 369.0991; found, 369.1000.

[0172] Example 21: Preparation of compound D21

[0173] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with m-trifluoromethylbenzaldehyde.

[0174] The compound D21 was obtained as 1-(4,5-dimethylthiazol-2-yl)-2-(1H-1,2,4-triazol-1-yl)-1-(2-(trifluoromethyl)phenyl)ethanol-1-ol, with the structural formula shown below:

[0175]

[0176] Compound D21 is a white solid with a yield of 79%; mp, 183-184 °C.

[0177] 1H NMR (600 MHz, Chloroform-d) δ 8.03 (s, 1H), 7.88 (s, 1H), 7.84 (d,J = 8.2 Hz, 2H), 7.60 (d, J = 8.2 Hz, 2H), 5.90 (s, 1H), 5.17 (d, J = 13.9Hz, 1H), 4.61 (d, J = 13.9 Hz, 1H), 2.28 (s, 3H), 2.23 (s, 3H). 13 C NMR (151MHz, Chloroform-d) δ 168.0, 152.1, 148.2, 144.9, 144.7, 130.4 (q, J = 33.2Hz), 128.0, 126.0, 125.4 (q, J = 4.5 Hz), 123.9 (q, J = 271,8 Hz), 78.0,57.7, 14.8, 11.6. 19 F NMR (376 MHz, Chloroform-d) δ -62.6. HRMS (ESI)calculated for C 16 H 16 F3N4OS [M+H] + , 369.0991; found, 369.1001.

[0178] Example 22: Preparation of compound D22

[0179] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with 2,4-dimethylbenzaldehyde.

[0180] The compound D22 was obtained as 1-(2,4-dimethylphenyl)-1-(4,5-dimethylthiazol-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0181]

[0182] Compound D22 is a white solid with a yield of 63%; mp, 128-129 °C; 1H NMR (600 MHz, Chloroform-d) δ 7.94 (s, 1H), 7.73 (s, 1H), 7.22 (d, J = 6.2 Hz, 1H), 6.94 (d, J = 19.8 Hz, 2H), 5.44 (s, 1H), 5.16 (d, J = 13.8 Hz, 1H), 4.92 (d, J =13.5 Hz, 1H), 2.35 (s, 3H), 2.25 (d, J = 9.0 Hz, 9H). 13 C NMR (151 MHz, Chloroform-d) δ 169.3, 151.4, 147.2, 144.8, 138.2, 136.5, 135.8, 133.6,126.6, 126.4, 78.4, 56.7, 21.6, 20.8, 14.7, 11.3. HRMS (ESI) calculated forC 17 H 21 N4OS [M+H] + , 329.1431; found, 329.1440.

[0183] Example 23: Preparation of compound D23

[0184] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with 2,4-dimethoxybenzaldehyde.

[0185] The compound D23 was obtained as 1-(2,4-dimethoxyphenyl)-1-(4,5-dimethylthiazol-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0186]

[0187] Compound D23 is a yellow solid with a yield of 65%; mp, 115-116 °C.

[0188] 1H NMR (600 MHz, Chloroform-d) δ 7.97 (s, 1H), 7.78 (s, 1H), 7.29 (d,J = 8.6 Hz, 1H), 6.47 – 6.35 (m, 2H), 5.49 (s, 1H), 5.13 (d, J = 14.1 Hz,1H), 5.06 (d, J = 14.0 Hz, 1H), 3.82 (s, 3H), 3.76 (s, 3H), 2.29 (d, J = 16.0Hz, 6H). 13 C NMR (151 MHz, Chloroform-d) δ 168.0, 161.1, 157.3, 151.0, 147.1,144.5, 127.9, 128.3, 121.2, 104.6, 99.5, 77.7, 57.1, 55.5, 55.3, 14.7, 11.2.HRMS (ESI) calculated for C 17 H 21 N4O3S [M+H] + , 361.1329; found, 361.1339.

[0189] Example 24: Preparation of compound D24

[0190] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with 2,4-difluorobenzaldehyde.

[0191] The compound D24 was obtained as 1-(2,4-difluorophenyl)-1-(4,5-dimethylthiazol-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0192]

[0193] Compound D24 is a yellow solid with a yield of 60%; mp, 133-134 °C.

[0194] 1 H NMR (600 MHz, Chloroform-d) δ 8.06 (s, 1H), 7.78 (s, 1H), 7.57 (d,J = 7.8 Hz, 1H), 6.78 (dd, J = 19.9, 8.5 Hz, 2H), 5.73 (s, 1H), 5.15 (t, J =10.3 Hz, 2H), 2.27 (s, 6H).13 C NMR (151 MHz, Chloroform-d) δ 166.7, 163.0 (d,J = 250.7 Hz), 159.5 (d, J = 250.7 Hz), 151.6, 147.7, 144.7, 129.6 (d, J =6.0 Hz), 128.3, 124.4 (d, J = 4.5 Hz), 111.5 (d, J = 3.0 Hz), 104.6 (d, J =25.7 Hz), 76.2 (d, J = 3.0 Hz), 56.1 (d, J = 7.6 Hz), 14.6, 11.2. 19 F NMR (376MHz, Chloroform-d) δ -106.6, -109.4. HRMS (ESI) calculated for C 15 H 14 F₂N₄NaOS[M+Na] + , 359.0749; found, 359.0754.

[0195] Example 25: Preparation of compound D25

[0196] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with 2,4-dichlorobenzaldehyde.

[0197] Compound D25 was obtained as 1-(2,4-dichlorophenyl)-1-(4,5-dimethylthiazol-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0198]

[0199] Compound D25 is a yellow solid with a yield of 79%; mp, 200-201 °C.

[0200] 1 H NMR (600 MHz, Chloroform-d) δ 7.97 (s, 1H), 7.82 (s, 1H), 7.57 (d,J = 8.4 Hz, 1H), 7.35 (s, 1H), 7.18 (d, J = 6.0 Hz, 1H), 5.48 (d, J = 14.3Hz, 1H), 5.34 (s, 1H), 5.27 (d, J = 14.1 Hz, 1H), 2.30 (d, J = 8.8 Hz, 6H).13 C NMR (151 MHz, Chloroform-d) δ 166.1, 151.8, 147.6, 144.6, 136.8, 135.4,132.7, 131.0, 130.0, 128.8, 127.3, 77.1, 54.6, 14.7, 11.7. HRMS (ESI)calculated for C 15 H 15 Cl2N4OS [M+H] + , 369.0338; found, 369.0348.

[0201] Example 26: Preparation of compound D26

[0202] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with 2,4-dibromobenzaldehyde.

[0203] Compound D26 was obtained as 1-(2,4-dibromophenyl)-1-(4,5-dimethylthiazol-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0204]

[0205] Compound D26 is a yellow solid with a yield of 76%; mp, 188-189 °C.

[0206] 1 H NMR (600 MHz, Chloroform-d) δ 7.96 (s, 1H), 7.82 (s, 1H), 7.72 (s,1H), 7.47 (d, J = 8.6 Hz, 1H), 7.36 (d, J = 8.5 Hz, 1H), 5.57 (d, J = 14.4Hz, 1H), 5.37 (s, 1H), 5.26 (d, J = 14.3 Hz, 1H), 2.31 (d, J = 10.4 Hz, 6H). 13C NMR (151 MHz, Chloroform-d) δ 166.1, 151.8, 147.6, 144.6, 138.6, 137.1,130.6, 130.5, 129.0, 123.4, 122.0, 77.7, 54.4, 14.7, 11.4. HRMS (ESI)calculated for C 15 H 15 Br2N4OS [M+H] + , 456.9328; found, 456.9343.

[0207] Example 27: Preparation of compound D27

[0208] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with 2,4-ditrifluoromethylbenzaldehyde.

[0209] Compound D27 was obtained as 1-(2,4-ditrifluoromethylphenyl)-1-(4,5-dimethylthiazol-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0210]

[0211] Compound D27 is a yellow solid with a yield of 63%; mp, 144-145 °C.

[0212] 1 H NMR (600 MHz, Chloroform-d) δ 8.07 (s, 2H), 7.88 (s, 2H), 7.71 (d,J = 8.2 Hz, 1H), 5.98 (s, 1H), 5.15 (d, J = 13.8 Hz, 1H), 4.90 (d, J = 13.8Hz, 1H), 2.32 (s, 3H), 2.25 (s, 3H). 13C NMR (151 MHz, Chloroform-d) δ 168.0,152.2, 147.9, 145.0, 143.8, 131.0 (q, J = 34.7 Hz), 130.4, 129.6 (q, J = 33.2Hz), 129.1, 128.2 (q, J = 4.5 Hz), 125.9 (q, J = 4.5 Hz), 123.6 (q, J = 273.3Hz), 123.1 (q, J = 273.3 Hz), 79.2, 56.6, 14.8, 11.2. 19 F NMR (376 MHz,Chloroform-d) δ -54.4, -63.1. HRMS (ESI) calculated for C 17 H 15 F6N4OS [M+H] + ,437.0865; found, 437.0875.

[0213] Example 28: Preparation of compound D28

[0214] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with 2,3-dichlorobenzaldehyde.

[0215] Compound D28 was obtained as 1-(2,3-dichlorophenyl)-1-(4,5-dimethylthiazol-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0216]

[0217] Compound D28 is a yellow solid with a yield of 66%; mp, 136-137 °C.

[0218] 1H NMR (600 MHz, Chloroform-d) δ 7.94 (s, 1H), 7.77 (s, 1H), 7.55 (d,J = 9.6 Hz, 1H), 7.43 (d, J = 8.1 Hz, 1H), 7.14 (t, J = 8.0 Hz, 1H), 5.55 (s,1H), 5.52 (d, J = 14.4 Hz, 1H), 5.29 (d, J = 14.4 Hz, 1H), 2.30 (d, J = 11.2Hz, 6H). 13 C NMR (151 MHz, Chloroform-d) δ 166.3, 151.6, 147.5, 144.6, 140.5,134.6, 131.0, 128.67, 127.3, 127.2, 125.6, 77.4, 54.5, 14.7, 11.3. HRMS (ESI)calculated for C 15 H 15 Cl2N4OS [M+H] + , 369.0338; found, 369.0345.

[0219] Example 29: Preparation of compound D29

[0220] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with 2,5-dichlorobenzaldehyde.

[0221] Compound D29 was obtained as 1-(2,5-dichlorophenyl)-1-(4,5-dimethylthiazol-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0222]

[0223] Compound D29 is a yellow solid with a yield of 64%; mp, 139-140 °C.

[0224] 1H NMR (600 MHz, Chloroform-d) δ 7.98 (s, 1H), 7.80 (s, 1H), 7.68 (s,1H), 7.25 (d, J = 7.9 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 5.54 (s, 1H), 5.49 (d, J = 14.3 Hz, 1H), 5.28 (d, J = 14.4 Hz, 1H), 2.30 (d, J = 8.1 Hz, 6H). 13 CNMR (151 MHz, Chloroform-d) δ 165.8, 151.7, 147.5, 144.6, 139.9, 133.3,132.3, 130.2, 130.1, 129.2, 128.8, 76.9, 54.5, 14.7, 11.3. HRMS (ESI)calculated for C 15 H 15 Cl2N4OS [M+H] + , 369.0338; found, 369.0351.

[0225] Example 30: Preparation of compound D30

[0226] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with 4-pyridinecarboxaldehyde.

[0227] The compound D30 was obtained as 1-(4,5-dimethylthiazol-2-yl)-1-(pyridin-4-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0228]

[0229] Compound D30 is a yellow solid with a yield of 68%; mp, 196-197 °C.

[0230] 1 H NMR (600 MHz, Chloroform-d) δ 8.58 (s, 2H), 8.03 (s, 1H), 7.89 (s,1H), 7.63 (d, J = 5.2 Hz, 2H), 5.97 (s, 1H), 5.14 (d, J = 13.4 Hz, 1H), 4.60 (d, J = 13.5 Hz, 1H), 2.26 (d, J = 32.0 Hz, 6H).13 C NMR (151 MHz, Chloroform-d) δ 167.2, 152.2, 150.0, 149.7, 148.4, 144.9, 128.2, 120.4, 77.5, 57.4,14.8, 11.2. HRMS (ESI) calculated for C 14 H 16 N5OS [M+H] + , 302.1070; found, 302.1085.

[0231] Example 31: Preparation of compound D31

[0232] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with 3-pyridinecarboxaldehyde.

[0233] The compound D31 was obtained as 1-(4,5-dimethylthiazol-2-yl)-1-(pyridin-3-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0234]

[0235] Compound D31 is a yellow solid with a yield of 72%; mp, 154-155 °C.

[0236] 1 H NMR (600 MHz, Chloroform-d) δ 8.91 (d, J = 2.4 Hz, 1H), 8.50 (m, J= 4.9, 1.6 Hz, 1H), 8.03 (s, 1H), 8.00 (m, J = 8.0, 2.0 Hz, 1H), 7.85 (s,1H), 7.25 (dd, J = 8.4, 4.5 Hz, 1H), 6.16 (s, 1H), 5.16 (d, J = 13.9 Hz, 1H), 4.65 (d, J = 13.9 Hz, 1H), 2.27 (s, 3H), 2.22 (s, 3H). 13 HRMS (ESI) calculated for C14 H 16 N5OS [M+H] + ,302.1070; found, 302.1081.

[0237] Example 32: Preparation of compound D32

[0238] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with 2-pyridinecarboxaldehyde.

[0239] The compound D32 was obtained as 1-(4,5-dimethylthiazol-2-yl)-1-(pyridin-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the structural formula shown below:

[0240]

[0241] Compound D32 is a yellow solid with a yield of 68%; mp, 118-120 °C.

[0242] 1 H NMR (600 MHz, Chloroform-d) δ 8.40 (s, 1H), 8.11 (s, 1H), 7.93 (d,J = 7.8 Hz, 1H), 7.73 (d, J = 5.8 Hz, 1H), 7.68 (s, 1H), 7.22 (d, J = 7.5 Hz,1H), 6.69 (s, 1H), 5.29 (d, J = 3.1 Hz, 1H), 5.13 (dd, J = 14.3, 3.1 Hz, 1H), 4.94 (dd, J = 14.4, 3.0 Hz, 1H), 2.30 (d, J = 26.0 Hz, 6H). 13 HRMS (ESI) calculated for C 14 H 16 N5OS [M+H] + , 302.1070; found, 302.1079.

[0243] Example 33: Preparation of compound D33

[0244] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with acetaldehyde.

[0245] The compound D33 was obtained as 2-(4,5-dimethylthiazol-2-yl)-1-(1H-1,2,4-triazol-1-yl)prop-2-ol, with the structural formula shown below:

[0246]

[0247] Compound D33 is a yellow solid with a yield of 89%; mp, 94-95 °C.

[0248] 1 H NMR (600 MHz, Chloroform-d) δ 7.96 (s, 1H), 7.88 (s, 1H), 4.96 (s,1H), 4.73 (d, J = 13.9 Hz, 1H), 4.44 (d, J = 13.8 Hz, 1H), 2.24 (s, 6H), 1.58(s, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 170.1, 151.8, 148.1, 144.5, 127.0,74.9, 58.2, 27.0, 14.7, 11.2. HRMS (ESI) calculated for C 10 H 15 N4OS [M+H] + ,239.0921; found, 239.0970.

[0249] Example 34: Preparation of compound D34

[0250] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with propionaldehyde.

[0251] The compound D34 was obtained as 2-(4,5-dimethylthiazol-2-yl)-1-(1H-1,2,4-triazol-1-yl)but-2-ol, with the following structural formula:

[0252]

[0253] Compound D34 is a yellow solid with a yield of 91%; mp, 103-104 °C.

[0254] 1H NMR (600 MHz, Chloroform-d) δ 7.93 (s, 1H), 7.87 (s, 1H), 4.84 (s,1H), 4.74 (d, J = 13.6 Hz, 1H), 4.44 (d, J = 13.6 Hz, 1H), 2.25 (s, 6H), 2.03– 1.77 (m, 2H), 0.91 (d, J = 6.9 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ169.1, 151.9, 148.1, 144.5, 127.0, 77.5, 57.5, 32.8, 14.7, 11.2, 7.4. HRMS(ESI) calculated for C 11 H 17 N4OS [M+H] + , 253.1118; found, 253.1123.

[0255] Example 35: Preparation of compound D35

[0256] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with n-butyraldehyde.

[0257] The compound D35 was obtained as 2-(4,5-dimethylthiazol-2-yl)-1-(1H-1,2,4-triazol-1-yl)pentane-2-ol, with the structural formula shown below:

[0258]

[0259] Compound D35 is a yellow solid with a yield of 89%; mp, 62-63 °C.

[0260] 1 H NMR (600 MHz, Chloroform-d) δ 7.92 (s, 1H), 7.85 (s, 1H), 4.90 (s,1H), 4.72 (d, J = 13.9 Hz, 1H), 4.43 (d, J = 13.5 Hz, 1H), 2.23 (s, 6H), 1.89(td, J = 12.7, 4.6 Hz, 1H), 1.80 – 1.70 (m, 1H), 1.54 – 1.42 (m, 1H), 1.21(q, J = 11.6, 9.6 Hz, 1H), 0.86 (t, J = 7.3 Hz, 3H).13 C NMR (151 MHz,Chloroform-d) δ 169.5, 151.8, 148.1, 144.5, 126.9, 77.3, 57.7, 42.0, 16.4,14.7, 14.1, 11.2. HRMS (ESI) calculated for C 12 H 19 N4OS [M+H] + , 267.1274;found, 267.1284.

[0261] Example 36: Preparation of compound D36

[0262] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with isobutyraldehyde.

[0263] The compound D36 was obtained as 2-(4,5-dimethylthiazol-2-yl)-3-methyl-1-(1H-1,2,4-triazol-1-yl)but-2-ol, with the structural formula shown below:

[0264]

[0265] Compound D36 is a white solid with a yield of 93%; mp, 133-134 °C.

[0266] 1 H NMR (600 MHz, Chloroform-d) δ 7.84 (d, J = 18.4 Hz, 2H), 4.87 (d,J = 4.1 Hz, 1H), 4.80 (d, J = 13.1 Hz, 1H), 4.57 – 4.37 (m, 1H), 2.21 (d, J =8.4 Hz, 6H), 1.25 (d, J = 97.5 Hz, 1H), 1.06 (d, J = 6.3 Hz, 3H), 0.93 (d, J= 6.3 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 169.3, 151.8, 147.8, 144.6,126.8, 79.5, 56.0, 36.7, 17.3, 16.6, 14.7, 11.2. HRMS (ESI) calculated forC 12 H 19N4OS [M+H] + , 267.1274; found, 267.1282.

[0267] Example 37: Preparation of compound D37

[0268] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with pentamaldehyde.

[0269] The compound D37 was obtained as 2-(4,5-dimethylthiazol-2-yl)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)but-2-ol, with the structural formula shown below:

[0270]

[0271] Compound D37 is a white solid with a yield of 86%; mp, 147-148 °C.

[0272] 1 H NMR (600 MHz, Chloroform-d) δ 7.85 (s, 1H), 7.78 (s, 1H), 5.05 (d, J = 11.0 Hz, 2H), 4.44 (d, J = 13.4 Hz, 1H), 2.20 (d, J = 16.9 Hz, 6H),1.10 (s, 9H). 13 C NMR (151 MHz, Chloroform-d) δ 168.9, 151.8, 147.4, 144.9,126.8, 81.2, 53.6, 38.0, 25.6, 14.8, 11.1. HRMS (ESI) calculated for C 13 H 21 N4OS[M+H] + , 281.1431; found, 281.1440.

[0273] Example 38: Preparation of compound D38

[0274] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with isovaleraldehyde. The resulting compound D38 is 2-(4,5-dimethylthiazol-2-yl)-4-methyl-1-(1H-1,2,4-triazol-1-yl)pentan-2-ol, with the following structural formula:

[0275]

[0276] Compound D38 is a yellow solid with a yield of 82%; mp, 106-107 °C.

[0277] 1 H NMR (600 MHz, Chloroform-d) δ 7.88 (d, J = 10.2 Hz, 2H), 4.85 (s,1H), 4.69 (d, J = 13.3 Hz, 1H), 4.41 (d, J = 13.4 Hz, 1H), 2.24 (s, 6H), 1.90(dd, J = 13.8, 5.4 Hz, 1H), 1.79 – 1.68 (m, 2H), 0.95 (d, J = 6.0 Hz, 3H), 0.75 (d, J = 6.2 Hz, 3H). 13 HRMS(ESI) calculated for C 13 H 21 N4OS [M+H] + , 281.1431; found, 281.1436.

[0278] Example 39: Preparation of compound D39

[0279] The only difference from Example 1 is that benzaldehyde in step (1) is replaced with n-decanal. The resulting compound D39 is 2-(4,5-dimethylthiazol-2-yl)-1-(1H-1,2,4-triazol-1-yl)undecane-2-ol, with the following structural formula:

[0280]

[0281] Compound D39 is a yellow solid with a yield of 69%; mp, 42-43 °C.

[0282] 1H NMR (600 MHz, Chloroform-d) δ 7.90 (s, 1H), 7.82 (s, 1H), 4.94 (s,1H), 4.70 (d, J = 13.7 Hz, 1H), 4.42 (d, J = 13.8 Hz, 1H), 2.22 (s, 6H),1.93-1.86 (m, 1H), 1.78-1.70 (m, 1H), 1.19 (s, 14H), 0.83 (t, J = 7.2 Hz,3H). 13 C NMR (151 MHz, Chloroform-d) δ 169.5, 151.7, 148.0, 144.4, 126.8,77.3, 57.7, 39.8, 31.8, 29.6, 29.4, 29.3, 29.2, 22.9, 22.6, 14.7, 14.0, 11.2.HRMS (ESI) calculated for C 18 H 31 N4OS [M+H] + , 351.2213; found, 351.2222.

[0283] Example 40: Preparation of compound D40

[0284] The only difference from Example 13 is that 4,5-dimethylthiazole in step (1) is replaced with thiazole. The resulting compound D40 is 1-(2-chlorophenyl)-1-(thiazol-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the following structural formula:

[0285]

[0286] Compound D40 is a white solid with a yield of 72%; mp, 144-145 °C.

[0287] 1H NMR (600 MHz, Chloroform-d) δ 7.92 (s, 1H), 7.76 (d, J = 5.7 Hz,2H), 7.63 (d, J = 7.8 Hz, 1H), 7.38-7.33 (m, 2H), 7.27 (s, 1H), 7.23 (d, J =7.2 Hz, 1H), 5.85 (s, 1H), 5.58 (d, J = 14.4 Hz, 1H), 5.36 (d, J = 14.3 Hz, 1H). 13 HRMS (ESI) calculated for C 13 H 12 ClN4OS [M+H] + , 307.0415; found, 307.0430.

[0288] Example 41: Preparation of compound D41

[0289] The only difference from Example 13 is that 4,5-dimethylthiazole in step (1) is replaced with benzothiazole. The resulting compound D41 is 1-(benzo[d]thiazol-2-yl)-1-(2-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanol, with the following structural formula:

[0290]

[0291] Compound D41 is a white solid with a yield of 76%; mp, 145-146 °C.

[0292] 1H NMR (600 MHz, Chloroform-d) δ 8.04 (d, J = 8.2 Hz, 1H), 8.00 (s,1H), 7.83 (d, J = 11.8 Hz, 2H), 7.68 (d, J = 7.6 Hz, 1H), 7.50 (t, J = 7.9Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.27 – 7.23 (m,2H), 5.68 (s, 1H), 5.63 (d, J = 14.1 Hz, 1H), 5.47 (d, J = 13.6 Hz, 1H). 13 CNMR (126 MHz, Chloroform-d) δ 172.5, 152.2, 151.9, 144.8, 137.3, 135.8,132.0, 131.4, 130.5, 128.8, 127.3, 126.2, 125.7, 123.67, 121.9, 77.9, 54.6.HRMS (ESI) calculated for C 17 H 14 ClN4OS [M+H] + , 357.0571; found, 357.0583.

[0293] Example 42: Preparation of compound D42

[0294] The only difference from Example 13 is that 4,5-dimethylthiazole in step (1) is replaced with 4-methylthiazole. The resulting compound D41 is 1-(2-chlorophenyl)-1-(4-methylthiazole-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the following structural formula:

[0295]

[0296] Compound D42 is a white solid with a yield of 82%; mp, 132-133 °C.

[0297] 1H NMR (600 MHz, Chloroform-d) δ 7.93 (s, 1H), 7.81 (s, 1H), 7.61 (d,J = 7.7 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.26 (s, 1H), 7.22 (t, J = 7.7 Hz,1H), 6.90 (s, 1H), 5.58 (d, J = 13.0 Hz, 1H), 5.46 (s, 1H), 5.33 (d, J = 14.3Hz, 1H), 2.47 (s, 3H). 13 C NMR (126 MHz, Chloroform-d) δ 171.2, 152.1, 151.7,144.6, 137.8, 132.0, 131.4, 130.3, 128.9, 127.1, 115.6, 77.4, 54.9, 17.2.HRMS (ESI) calculated for C 14 H 14 ClN4OS [M+H] + , 321.0571; found, 321.0583.

[0298] Example 43: Preparation of compound D43

[0299] The only difference from Example 13 is that 4,5-dimethylthiazole in step (1) is replaced with 5-methylthiazole. The resulting compound D43 is 1-(2-chlorophenyl)-1-(5-methylthiazole-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the following structural formula:

[0300]

[0301] Compound D43 is a white solid with a yield of 81%; mp, 149-150 °C.

[0302] 1H NMR (600 MHz, Chloroform-d) δ 7.93 (s, 1H), 7.79 (s, 1H), 7.62 (d,J = 7.8 Hz, 1H), 7.39 (s, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 7.8 Hz,1H), 7.21 (t, J = 7.6 Hz, 1H), 5.64 (s, 1H), 5.55 (d, J = 14.3 Hz, 1H), 5.30 (d, J = 14.2 Hz, 1H), 2.43 (s, 3H). 13 HRMS (ESI) calculated for C 14 H 14 ClN4OS [M+H] + , 321.0571; found,321.0578.

[0303] Example 44: Preparation of compound D44

[0304] The only difference from Example 13 is that 4,5-dimethylthiazole in step (1) is replaced with benzoxazole. The resulting compound D44 is 1-(benzo[d]azol-2-yl)-1-(2-chlorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanol, with the following structural formula:

[0305]

[0306] Compound D44 is a white solid with a yield of 72%; mp, 162-163 °C.

[0307] 1 H NMR (600 MHz, Chloroform-d) δ 7.96 (s, 1H), 7.83 (s, 1H), 7.78 –7.63 (m, 2H), 7.47 (s, 1H), 7.35 (d, J = 17.7 Hz, 3H), 7.26 (s, 2H), 5.67 (s,1H), 5.43 (s, 2H). 13C NMR (126 MHz, Chloroform-d) δ 164.4, 151.6, 150.4,144.8, 140.3, 135.8, 131.1, 130.8, 130.5, 128.4, 127.3, 125.9, 124.8, 120.6,111.2, 74.2, 54.0. HRMS (ESI) calculated for C 17 H 14 ClN4O2 [M+H] + , 341.0800;found, 341.0805.

[0308] Example 45: Preparation of compound D45

[0309] The only difference from Example 13 is that 1,2,4-triazole in step (4) is replaced with imidazole. The resulting compound D45 is 1-(2-chlorophenyl)-1-(4,5-dimethylthiazol-2-yl)-2-(1H-imidazol-1-yl)ethanol-1-ol, with the following structural formula:

[0310]

[0311] Compound D45 is a white solid with a yield of 78%; mp, 142-143 °C.

[0312] 1 H NMR (600 MHz, Chloroform-d) δ 7.63 (d, J = 7.8 Hz, 1H), 7.35 (d, J= 7.9 Hz, 1H), 7.28 (s, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.19 (t, J = 7.7 Hz,1H), 6.72 (s, 1H), 6.65 (s, 1H), 5.17 (d, J = 14.4 Hz, 1H), 5.01 (d, J = 14.4Hz, 1H), 2.32 (d, J = 13.8 Hz, 6H). 13 C NMR (126 MHz, Chloroform-d) δ 167.9,147.4, 138.4, 131.8, 131.1, 130.0, 129.1, 128.4, 127.7, 127.1, 120.6, 76.6,53.3, 14.8, 11.4. HRMS (ESI) calculated for C 16 H17 ClN3OS [M+H] + , 334.0775;found, 334.0785.

[0313] Example 46: Preparation of compound D46

[0314] The only difference from Example 13 is that 1,2,4-triazole in step (4) is replaced with 1,2,3-triazole. The resulting compound D46 is 1-(2-chlorophenyl)-1-(4,5-dimethylthiazol-2-yl)-2-(1H-1,2,3-triazol-1-yl)ethanol, with the following structural formula:

[0315]

[0316] Compound D46 is a yellow solid with a yield of 68%; mp, 173-174 °C.

[0317] 1 H NMR (600 MHz, Chloroform-d) δ 7.59 (d, J = 7.9 Hz, 1H), 7.51 (s,1H), 7.44 (s, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 7.7 Hz, 1H), 7.20(d, J = 7.8 Hz, 1H), 5.74 (d, J = 16.6 Hz, 1H), 5.49 (d, J = 15.8 Hz, 1H), 4.78 (s, 1H), 2.32 (d, J = 13.5 Hz, 6H). 13 C NMR (126 MHz, Chloroform-d) δ166.6, 147.5, 137.8, 133.3, 132.0, 131.3, 130.2, 128.9, 128.8, 127.1, 125.4,76.9, 55.8, 14.8, 11.4. HRMS (ESI) calculated for C 15 H 16 ClN4OS [M+H] + ,335.0728; found, 335.0735.

[0318] Example 47: Preparation of compound D47

[0319] The only difference from Example 13 is that 1,2,4-triazole in step (4) is replaced with 1,2,3,4-tetraazole. The resulting compound D47 is 1-(2-chlorophenyl)-1-(4,5-dimethylthiazol-2-yl)-2-(1H-tetrazole-1-yl)ethanol-1-ol, with the following structural formula:

[0320]

[0321] Compound D47 is a yellow solid with a yield of 69%; mp, 192-193 °C.

[0322] 1 H NMR (600 MHz, Chloroform-d) δ 7.75 (d, J = 7.4 Hz, 1H), 7.38 (d, J= 7.5 Hz, 1H), 7.33 (d, J = 7.9 Hz, 2H), 7.26 (s, 1H), 5.15 (d, J = 12.8 Hz,1H), 4.16 (d, J = 12.9 Hz, 1H), 2.32 (s, 3H), 2.30 (s, 3H). 13 HRMS (ESI) calculated for C 14 H 15 ClN5OS [M+H] + , 336.0400; found, 336.0406.

[0323] Example 48: Preparation of compound D48

[0324] The only difference from Example 13 is that 1,2,4-triazole in step (4) is replaced with benzimidazole. The resulting compound D48 is 2-(1H-benzo[d]imidazol-1-yl)-1-(2-chlorophenyl)-1-(4,5-dimethylthiazol-2-yl)ethanol, with the following structural formula:

[0325]

[0326] Compound D48 is a yellow solid with a yield of 71%; mp, 186-187 °C.

[0327] 1H NMR (400 MHz, Chloroform-d) δ 7.80 (s, 1H), 7.55 (dt, J = 7.9, 2.1Hz, 2H), 7.35 (dd, J = 7.9, 1.4 Hz, 1H), 7.32 – 7.27 (m, 1H), 7.19 (td, J =7.6, 1.7 Hz, 1H), 7.15 – 7.03 (m, 3H), 5.37 – 5.24 (m, 2H), 2.30 (d, J = 13.3Hz, 6H). 13 C NMR (126 MHz, Chloroform-d) δ 167.9, 147.5, 144.6, 142.5, 138.5,134.9, 132.0, 131.2, 130.1, 129.0, 128.8, 127.1, 122.6, 121.7, 119.6, 110.2,77.3, 51.3, 14.8, 11.4. HRMS (ESI) calculated for C 20 H 19 ClN3OS [M+H] + ,384.0932; found, 384.0942.

[0328] Example 49: Preparation of compound D49

[0329] The only difference from Example 13 is that 1,2,4-triazole in step (4) is replaced with ethanolamine. The resulting compound D49 is 1-(2-chlorophenyl)-1-(4,5-dimethylthiazol-2-yl)-2-((2-hydroxyethyl)amino)ethanol-1-ol, with the following structural formula:

[0330]

[0331] Compound D49 is a yellow solid with a yield of 69%; mp, 85-86 ℃.

[0332] 1H NMR (400 MHz, Chloroform-d) δ 7.91 (dd, J = 8.1, 1.8 Hz, 1H), 7.36– 7.28 (m, 2H), 7.27 – 7.21 (m, 1H), 4.16 (d, J = 12.1 Hz, 1H), 3.73 – 3.62(m, 2H), 3.12 (d, J = 12.2 Hz, 1H), 2.89 (ddd, J = 12.8, 5.9, 3.9 Hz, 1H), 2.79 (ddd, J = 12.8, 6.6, 4.1 Hz, 1H), 2.30 (d, J = 6.4 Hz, 6H). 13 C NMR (126MHz, Chloroform-d) δ 170.6, 146.7, 140.9, 132.5, 131.1, 129.4, 128.4, 127.8,126.8, 75.5, 61.4, 54.9, 51.4, 14.8, 11.4. HRMS (ESI) calculated forC 15 H 20 ClN2O2S [M+H] + , 327.0929; found, 327.0926.

[0333] Example 50: Preparation of compound D50

[0334] The only difference from Example 42 is that 2-chlorobenzaldehyde in step (1) is replaced with 2,4-dichlorobenzaldehyde. The resulting compound D50 is 1-(2,4-dichlorophenyl)-1-(5-methylthiazolyl-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the following structural formula:

[0335]

[0336] Compound D50 is a yellow solid with a yield of 81%; mp, 183-184 °C.

[0337] 1H NMR (400 MHz, Chloroform-d) δ 7.98 (s, 1H), 7.84 (s, 1H), 7.59 (d,J = 8.6 Hz, 1H), 7.36 (d, J = 2.2 Hz, 1H), 7.20 (dd, J = 8.6, 2.2 Hz, 1H), 6.90 (s, 1H), 5.57 – 5.46 (m, 2H), 5.31 (d, J = 14.3 Hz, 1H), 2.45 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 170.53, 152.25, 151.90, 144.65, 136.62,135.51, 132.73, 131.09, 129.96, 127.35, 115.69, 77.3, 54.69, 17.13. HRMS(ESI) calculated for C 14 H 13 Cl2N4OS [M+H] + , 355.0182; found, 355.0193.

[0338] Example 51: Preparation of compound D51

[0339] The only difference from Example 42 is that 2-chlorobenzaldehyde in step (1) is replaced with 2,4-dibromobenzaldehyde. The resulting compound D51 is 1-(2,4-dibromophenyl)-1-(5-methylthiazolyl-2-yl)-2-(1H-1,2,4-triazol-1-yl)ethanol-1-ol, with the following structural formula:

[0340]

[0341] Compound D51 is a white solid with a yield of 77%; mp, 174-175 °C.

[0342] 1H NMR (400 MHz, Chloroform-d) δ 7.98 (s, 1H), 7.84 (s, 1H), 7.59 (d,J = 8.6 Hz, 1H), 7.36 (d, J = 2.2 Hz, 1H), 7.20 (dd, J = 8.6, 2.2 Hz, 1H), 6.90 (s, 1H), 5.57 – 5.46 (m, 2H), 5.31 (d, J = 14.3 Hz, 1H), 2.45 (s, 3H). 13 C NMR (101 MHz, Chloroform-d) δ 170.6, 152.30, 151.84, 144.63, 138.48,137.20, 130.72, 130.50, 123.52, 122.00, 115.90, 77.8, 54.59, 17.14. HRMS(ESI) calculated for C 14 H 13 Br2N4OS [M+H] + , 442.9171; found, 442.9182.

[0343] Example of effect verification:

[0344] The antifungal activity of the 1,2,4-triazole derivatives containing thiazole / oxazole groups prepared in the embodiments of the present invention was studied:

[0345] Experimental subjects: compounds D1-D51, with tebuconazole as a positive control.

[0346] Experimental methods:

[0347] The in vitro inhibitory activity of eight plant pathogenic fungi was determined using the mycelial linear growth rate method.

[0348] The measurement results are shown in Table 1.

[0349]

[0350]

[0351]

[0352] The inhibitory activity of all target compounds at a concentration of 20 mg / L against eight plant pathogenic fungi / oomycetes was evaluated in vitro using the linear hyphal growth rate method. The results are listed in Table 1. The commercial triazole fungicide tebuconazole was used as a positive control. Bioactivity tests showed that almost all target compounds exhibited moderate to excellent inhibitory activity against the tested fungi and oomycetes, preliminarily validating the rationality of the structural design of this class of triazole fungicides.

[0353] Preliminary SARs were performed based on the results of in vitro antifungal activity assays, as detailed below. As shown in Table 1, the inhibitory effects of the target compounds on plant pathogenic fungi and oomycetes were significantly influenced by changes in the R substituent structure. First, antifungal activity was generally more favorable when the R substituent was a benzene ring compared to heterocyclic rings (e.g., pyridine rings) or alkyl chains. For example, compound D1, with a benzene ring, showed significantly better primary screening activity than compounds with pyridine rings and compounds D33-D38 with alkyl chains. Compound D39, with a long-chain alkyl group, was a significant exception, exhibiting outstanding bioactivity. Initially, it was speculated that antifungal activity might be enhanced when the R substituent possessed significant steric resistance. The optimized D50 exhibited the best antifungal activity. Second, different substitutions on the benzene ring of the R group also significantly affected antifungal activity. The ortho-substituents of most compounds showed significantly higher antifungal efficacy than the meso- and para-substituents, and multiple substitutions on the benzene ring of the R group generally enhanced antifungal activity. These findings suggest that future development of these derivatives should prioritize enhancing the steric resistance of the R substituents and increasing the diversity of other positions in order to develop compounds with broader activities.

[0354] The embodiments described above are merely preferred embodiments of the present invention and are not intended to limit the scope of the present invention. Various modifications and improvements made by those skilled in the art to the technical solutions of the present invention without departing from the spirit of the present invention should fall within the protection scope defined by the claims of the present invention.

Claims

1. A 1,2,4-triazole derivative containing a thiazole / oxazole group, characterized in that... Its general structural formula is as follows: ； Among them, R 1 It is one of H, alkyl, aryl, or heteroaryl; R 2 It is one of H, alkyl, aryl, or heteroaryl; in addition, R 1 R 2 It can form saturated or unsaturated rings; R 3 It is one of substituted or unsubstituted alkyl groups or substituted or unsubstituted aryl groups; Y represents either a sulfur atom or an oxygen atom.

2. The method for preparing the 1,2,4-triazole derivative containing a thiazole / oxazole group as described in claim 1, characterized in that... Includes the following steps: Step 1: Using R 1 and R 2 Group-substituted thiazoles or oxazoles and R 3 Using aldehydes with substituted groups as raw materials, the reaction is carried out in an organic solvent in the presence of a base to give compound A; ； Step 2: Compound A and the oxidizing agent are added to an organic solvent to carry out an oxidation reaction, yielding compound B; ； Step 3: Dissolve compound B, the epoxidizing agent, and the base in an organic solvent to carry out an epoxidation reaction, yielding compound C; ； Step 4: Mix compound C, 1,2,4-triazole, base, and organic solvent to react and obtain the target product; Among them, R 1 It is one of H, alkyl, aryl, or heteroaryl; R 2 It is one of H, alkyl, aryl, or heteroaryl; in addition, R 1 R 2 It can form saturated or unsaturated rings; R 3 It is one of substituted or unsubstituted alkyl groups or substituted or unsubstituted aryl groups; Y represents either a sulfur atom or an oxygen atom.

3. The preparation method according to claim 2, characterized in that: The R 1 and R 2 The substituted thiazole or oxazole is one of 4,5-dimethylthiazole, 4,5-dimethyloxazole, 4-methylthiazole, 4-methyloxazole, 5-methylthiazole, 5-methyloxazole, benzothiazole, and benzoxazole. The R 3 The aldehydes with substituted groups are alkyl aldehydes, aryl aldehydes, or heteroaryl aldehydes; The alkali is one of n-butyllithium, tert-butyllithium, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide, potassium hydroxide, or potassium carbonate.

4. The preparation method according to claim 2, characterized in that: In step 2, the oxidant is one of manganese dioxide, perchlorate, permanganate, dichromate, sodium peroxide, oxygen, sodium dichromate, potassium dichromate, or potassium permanganate.

5. The preparation method according to claim 2, characterized in that: In step 3, the base is one of triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, lithium bis(trimethylsilylamine), potassium bis(trimethylsilylamine), or sodium hydride; the epoxidizing agent is trimethylsulfur iodide or trimethyl sulfoxide.

6. The preparation method according to claim 2, characterized in that: In step 4, the alkali is one of triethylamine, N,N-diisopropylethylamine, cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium ethoxide, lithium bis(trimethylsilylamine), potassium bis(trimethylsilylamine), or sodium hydride.

7. The use of the 1,2,4-triazole derivative containing a thiazole / oxazole group as described in claim 1 in the preparation of antifungal drug formulations.

8. The application according to claim 7, characterized in that: The fungi include one or more of the following: apple rot fungus, sclerotium rot fungus, gray mold fungus, rhizoctonia solani fungus, Alternaria alternata, wheat scab, Curvularia crescentis, and Phytophthora capsici.

9. An antifungal drug formulation, characterized in that: The active pharmaceutical ingredient of the antifungal drug formulation includes the 1,2,4-triazole derivative containing a thiazole / oxazole group as described in claim 1.

10. The antifungal drug formulation according to claim 9, characterized in that: The fungi include one or more of the following: apple rot fungus, sclerotium rot fungus, gray mold fungus, rhizoctonia solani fungus, Alternaria alternata, wheat scab, Curvularia crescentis, and Phytophthora capsici.

Images