A heterocyclic imidazole-2-oxazoline compound, a preparation method and application thereof

Abstract

The application provides a kind of heterocyclic imidazole-2-oxazoline compound and its preparation method and application, belong to chemical synthesis technical field.The heterocyclic imidazole-2-oxazoline compound provided by the application has the structure shown in formula A, which includes heterocyclic and oxazoline fragment in structure, has certain inhibitory effect on various plant pathogenic fungi (such as rice sheath blight fungus, oilseed rape sclerotinia, tomato botrytis cinerea, wheat scab fungus, pepper pythium disease fungus), is expected to be used as a new type of fungicide candidate compound or directly as fungicide, at the same time, heterocyclic imidazole-2-oxazoline skeleton as ligand molecule with chemical catalytic activity, has important significance for biological and chemical research field.The preparation method of the above compound is provided, which is synthesized by using simple and easy-to-synthesize heterocyclic imidazole-2-carboxylic acid as starting material, the synthesis route is short, the raw material is easy to obtain, and industrialized batch production is easy to realize.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of chemical synthesis, in particular to a kind of heterocyclic imidazole-2-oxazoline compound and its preparation method and application. BACKGROUND

[0002] The global food loss caused by fungi each year leads to serious economic losses directly. Chemical pesticides are commonly used to control agricultural harmful pathogens. Currently, the commonly used chemical pesticides mainly include fenhexamid, thiabendazole, carbendazim and tricyclazole.

[0003] The use of chemical pesticides can ensure food production safety. However, chemical pesticides are often used unreasonably, which can easily lead to pesticide residues and make the toxicity of pesticides to non-target organisms rise sharply. In the long run, it can cause crops to develop drug resistance. Therefore, it is crucial to develop eco-friendly pesticides with good activity, high selectivity and new crop protection mechanisms. SUMMARY

[0004] Therefore, the present application aims to provide a kind of heterocyclic imidazole-2-oxazoline compound and its preparation method and application. The heterocyclic imidazole-2-oxazoline compound provided by the present application shows excellent inhibitory activity against agricultural harmful pathogens.

[0005] In order to achieve the above-mentioned application purposes, the present application provides the following technical solutions:

[0006] The present application provides a kind of heterocyclic imidazole-2-oxazoline compound or its stereoisomer, pharmaceutically acceptable salt, with formula A shown structure:

[0007]

[0008] In formula A, is

[0009] R1 is one of hydrogen, C1-C8 alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl, hydroxymethylene, carboxyl, C1-C6 carboxyalkyl ester, C1-C6 alkylcarbonyl, phenylcarbonyl or substituted phenylcarbonyl, hydroxymethyl or substituted hydroxymethyl;

[0010] R2 is one of hydrogen, C1-C8 alkyl, hydroxymethylene, C1-C6 carboxyalkyl ester, aryl and aryl methylene;

[0011] or R1+R2 jointly constitutes one of ; and

[0012] R3 is one of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, ester and halogen.

[0013] Preferably, in R1, the C1-C8 alkyl is one of methyl, ethyl, isopropyl, sec-butyl and isobutyl.

[0014] In the substituted phenyl, the substituent is one or more of C1-C6 alkyl, alkoxy, halogenated alkyl, and the number of substituents is 1-5.

[0015] In the substituted benzyl, the substituent is one or more of C1-C6 alkyl, alkoxy, halogenated alkyl, and the number of substituents is 1-5.

[0016] In the substituted phenylcarbonyl, the substituent on the phenyl is one or more of C1-C6 alkyl, alkoxy, halogenated alkyl, and the number of substituents is 1-5.

[0017] In the substituted hydroxymethyl, the substituent is one of C1-C6 alkyl, phenyl, substituted phenyl, and the substitution site of the substituent is the ortho position of the hydroxyl group.

[0018] In R2, the aromatic group is phenyl or substituted phenyl, and the aromatic group methylene is benzyl or substituted benzyl.

[0019] Preferably, the heterocyclic fused imidazole-2-oxazoline compound has a structure represented by any one of formula A1 to formula A16:

[0020]

[0021] Preferably, the heterocyclic fused imidazole-2-oxazoline compound has a structure represented by any one of formula A5 to formula A11.

[0022] The present application provides a preparation method of the above-mentioned heterocyclic fused imidazole-2-oxazoline compound or its stereoisomer, pharmaceutically acceptable salt, comprising the following steps:

[0023] In the presence of a condensing agent, a heterocyclic fused imidazole-2-carboxylic acid having a structure represented by formula i is subjected to a condensation reaction with an amino alcohol having a structure represented by formula ii to obtain a compound having a structure represented by formula iii;

[0024]

[0025] Under the action of diethylaminosulfur trifluoride, the compound having a structure represented by formula iii is subjected to a cyclization reaction to obtain a compound having a structure represented by formula A.

[0026] Preferably, the condensing agent comprises a first condensing agent and a second condensing agent.

[0027] the first condensing agent is one or more of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate and O-benzotriazol-tetramethyluronium hexafluorophosphate;

[0028] the second condensing agent is 1-hydroxybenzotriazole.

[0029] Preferably, the temperature of the condensation reaction is 0-40℃, and the time is 12-96h.

[0030] The temperature of the cyclization reaction is 25℃-78℃, and the time is 3h-12h.

[0031] The application provides application of the above-mentioned heterocyclic imidazole-2-oxazoline compound or its stereoisomer, pharmaceutically acceptable salt or the heterocyclic imidazole-2-oxazoline compound or its stereoisomer, pharmaceutically acceptable salt prepared by the preparation method in any one of claims 5-7 in preventing and treating plant pathogenic fungi.

[0032] Preferably, the plant pathogenic fungi include one or more of Rhizoctonia solani, Rhizoctonia cerealis, Sclerotinia sclerotiorum, Fusarium graminearum, Gaeumannomyces graminis, Botrytis cinerea, Phytophthora infestans, Phytophthora capsici, Alternaria solani, Pythium arrhenomanes, Botrytis cinerea, Botrytis cinerea and Magnaporthe grisea.

[0033] The application provides a pharmaceutical composition for preventing and treating plant pathogenic fungi, which comprises one or more of the above-mentioned heterocyclic imidazole-2-oxazoline compound or its stereoisomer, pharmaceutically acceptable salt and acceptable adjuvant.

[0034] The application provides a heterocyclic imidazole-2-oxazoline compound with the structure shown in formula A. The heterocyclic imidazole-2-oxazoline compound provided by the application has a heterocyclic ring and an oxazoline fragment, and shows excellent inhibitory activity on agricultural harmful pathogenic fungi. The results of examples show that the heterocyclic imidazole-2-oxazoline compound provided by the application has certain inhibitory effect on various plant pathogenic fungi (such as Rhizoctonia solani, Sclerotinia sclerotiorum, Botrytis cinerea, Fusarium graminearum and Phytophthora capsici), and is expected to be used as a new type of fungicide candidate compound or directly used as a fungicide, which has important significance for new pesticide creation.

[0035] The application provides a preparation method of the above-mentioned heterocyclic imidazole-2-oxazoline compound, which is synthesized by using a simple and easily synthesized heterocyclic imidazole-2-carboxylic acid as a starting material, has a short synthesis route, and is easy to obtain raw materials and realize industrialized batch production. BRIEF DESCRIPTION OF DRAWINGS

[0036] Figure 1 A synthetic route map of the heterocyclic imidazo-2-oxazoline compound. DETAILED DESCRIPTION

[0037] The present application provides a heterocyclic imidazo-2-oxazoline compound or its stereoisomer, pharmaceutically acceptable salt, having the structure shown in Formula A:

[0038]

[0039] In Formula A,

[0040] R1 is one of hydrogen, C1-C8 alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl, hydroxymethylene, carboxyl, C1-C6 carboxyalkyl ester, C1-C6 alkylcarbonyl, phenylcarbonyl or substituted phenylcarbonyl, hydroxymethyl or substituted hydroxymethyl;

[0041] R2 is one of hydrogen, C1-C8 alkyl, hydroxymethylene, C1-C6 carboxyalkyl ester, aryl and arylmethylene;

[0042] or R1+R2 together form one of

[0043] R3 is one of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkylamino, ester and halogen.

[0044] ​​In the present application, R1 is one of hydrogen, C1-C8 alkyl, phenyl or substituted phenyl, benzyl or substituted benzyl, hydroxymethylene, carboxyl, C1-C6 carboxylic acid alkyl ester, C1-C6 alkyl carbonyl, phenyl carbonyl or substituted phenyl carbonyl, hydroxymethyl or substituted hydroxymethyl; in the R1, the C1-C8 alkyl is preferably one of methyl, ethyl, isopropyl, sec-butyl and isobutyl; in the substituted phenyl, the substituent on the phenyl is preferably one or more of C1-C6 alkyl, alkoxyl, halogenated alkyl, the number of substituents is 1-5, in the substituted benzyl, the substituent on the benzyl is one or more of C1-C6 alkyl, alkoxyl, halogenated alkyl, the number of substituents is 1-5; in the substituted phenyl carbonyl, the substituent on the phenyl is one of C1-C6 alkyl, alkoxyl, halogenated alkyl, the number of substituents is 1-5; in the substituted hydroxymethyl, the substituent is one of C1-C6 alkyl, phenyl, substituted phenyl, the substitution site of the substituent is the ortho position of the hydroxyl; in the above substituents, the C1-C6 alkyl is preferably one of methyl, ethyl, isopropyl, sec-butyl and isobutyl, the alkoxyl is preferably one of methoxyl and ethoxyl, and the halogenated alkyl is preferably I or Br substituted C1-C3 alkane.

[0045] In the present application, R2 is one of hydrogen, C1-C8 alkyl, hydroxymethylene, C1-C6 carboxylic acid alkyl ester, aryl and aryl methylene; wherein the C1-C8 alkyl is preferably one of methyl, ethyl, isopropyl, sec-butyl and isobutyl, the C1-C6 carboxylic acid alkyl ester is preferably carboxylic acid methyl ester or carboxylic acid ethyl ester, the aryl is preferably phenyl, and the aryl methylene is preferably benzyl.

[0046] Or R1+R2 together form one of .

[0047] In the present application, R3 is one of hydrogen, C1-C6 alkyl, C1-C6 alkoxyl, C1-C6 alkylamino, ester and halogen; wherein the C1-C6 alkyl is preferably one of methyl, ethyl, isopropyl, sec-butyl and isobutyl, the C1-C6 alkoxyl is preferably one of methoxyl and ethoxyl, and the C1-C6 alkylamino is preferably one of methylamino and ethylamino; the halogen is preferably one of F, Cl, Br and I.

[0048] In the present application, the substituted carbon center configuration of R1 and R2 is independently R type or S type.

[0049] In the present application, the heterocyclic imidazole-2-oxazoline compound has a structure represented by any one of formula A1 to formula A11:

[0050]

[0051] In the present application, the heterocyclic imidazo-2-oxazoline compound more preferably has a structure represented by any one of Formula A5 to Formula A11.

[0052] In the present application, the pharmaceutically acceptable salt preferably includes one or more of potassium salt, sodium salt, ammonium salt, calcium salt, pyridine salt, hydrochloride, acetate, benzenesulfonate, oxalate, sulfate, phosphate, malonate, succinate, malate, lactate, maleate, fumarate, salicylate, and aminobenzoate.

[0053] The present application provides a preparation method of the above-mentioned heterocyclic imidazo-2-oxazoline compound, comprising the following steps:

[0054] In the presence of a condensing agent, the heterocyclic imidazo-2-carboxylic acid having a structure represented by Formula I is subjected to condensation reaction with a chiral amino alcohol having a structure represented by Formula II to obtain a compound having a structure represented by Formula III.

[0055]

[0056] In the presence of a condensing agent, the heterocyclic imidazo-2-carboxylic acid having a structure represented by Formula I is subjected to condensation reaction with a chiral amino alcohol having a structure represented by Formula II to obtain a compound having a structure represented by Formula III.

[0057] In the presence of a condensing agent, the heterocyclic imidazo-2-carboxylic acid having a structure represented by Formula I is subjected to condensation reaction with a chiral amino alcohol having a structure represented by Formula II to obtain a compound having a structure represented by Formula III. In the present application, the condensing agent preferably includes a first condensing agent and a second condensing agent.

[0058] The first condensing agent is one or more of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate, and O-benzotriazol-tetramethyluronium hexafluorophosphate; and the second condensing agent is 1-hydroxybenzotriazole.

[0059] In the present application, the condensation reaction is carried out in an organic solvent; and the organic solvent used in the condensation reaction is preferably one or more of dichloromethane, tetrahydrofuran, dioxane, toluene, and chlorobenzene.

[0060] In the present application, the molar ratio of the heterocyclic imidazo-2-carboxylic acid having a structure represented by Formula I to the chiral amino alcohol having a structure represented by Formula II is preferably 1 to 3:1, and more preferably 2:1.

[0061] In the present application, the molar ratio of the heterocyclic imidazo-2-carboxylic acid having a structure represented by Formula I to the first condensing agent and the second condensing agent is preferably 1:1.2 to 3:1.3 to 2.

[0062] In the present application, the mixing method is preferably mixing the heterocyclic imidazole-2-carboxylic acid with formula I with an organic solvent, adding a condensing agent under ice bath conditions, and then adding a chiral amino alcohol.

[0063] In the present application, the condensation reaction is preferably carried out under stirring. In the present application, the condensation reaction is preferably carried out at a temperature of 0-40℃, more preferably at room temperature, and preferably for 12-96h, more preferably for 24-48h.

[0064] After the condensation reaction, the present application preferably carries out post-treatment on the obtained condensation reaction solution, and the post-treatment preferably comprises the following steps:

[0065] Mixing an aqueous solution of a quenching agent with the condensation reaction solution to carry out a quenching reaction, thereby obtaining a quenching reaction solution;

[0066] Carrying out water washing, desolventizing, and column chromatography separation on the quenching reaction solution in sequence, thereby obtaining a pure compound with formula III.

[0067] In the present application, the quenching agent is preferably one or more of sodium bicarbonate, ammonium chloride, and sodium carbonate, more preferably sodium bicarbonate. In the present application, the concentration of the aqueous solution of the quenching agent is preferably 10-50wt%, more preferably 20-40wt%. In the present application, the molar ratio of the heterocyclic imidazole-2-carboxylic acid with formula I to the volume of the aqueous solution of the quenching agent is preferably 1mmol:2-10mL.

[0068] The present application does not have special requirements for the specific operation method of the water washing and desolventizing, and the operation method known to those skilled in the art can be used. In the present application, the filler of the column chromatography separation includes silica gel, and the eluent includes ethyl acetate, petroleum ether, gradient elution, and the volume ratio of ethyl acetate: petroleum ether is 1:0.5-15.

[0069] In the present application, the compound with formula III undergoes a cyclization reaction under the action of diethylaminosulfur trifluoride, thereby obtaining a compound with formula A. In the present application, the cyclization reaction is preferably carried out under N2 conditions.

[0070] In the present application, the molar ratio of the compound with formula III to diethylaminosulfur trifluoride is preferably 1:3-6, more preferably 1:4-5. In the present application, the diethylaminosulfur trifluoride plays a role in promoting cyclization.

[0071] In the present application, the cyclization reaction is preferably carried out at a temperature of -78℃, and preferably for 3-12h, more preferably for 5-10h.

[0072] After the cyclization reaction, the cyclization reaction liquid obtained is preferably post-treated according to the present application, and the post-treatment preferably comprises the following steps:

[0073] The cyclization reaction liquid is sequentially quenched with water, washed, dried, concentrated and purified by column chromatography to obtain a pure compound having the structure shown in Formula A.

[0074] In the present application, the washing agent used in the washing is preferably water; and the drying agent used in the drying is preferably anhydrous sodium sulfate. In the present application, the column used in the column chromatography purification is preferably a silica gel column, and the length thereof is preferably 200-300 m.

[0075] The present application provides the use of the above-mentioned heterocyclic and imidazole-2-oxazoline compound in the prevention and treatment of plant pathogenic fungi.

[0076] In the present application, the plant pathogenic fungi preferably include one or more of Rhizoctonia solani, Rhizoctonia cerealis, sclerotinia scleotiorum, Fusarium graminearum, Gaeumanomyce graminis, Botrytis cinerea, Phytophthora infestans, Phytophthora capsici, Alternaria solani, Fusarium fujikuroi, Fusarium sulphureum, Colletotrichum lagenarium, Pyricularia oryzac, and the like.

[0077] The present application provides a composition comprising one or more of the above-mentioned heterocyclic and imidazole-2-oxazoline compound or its stereoisomer, pharmaceutically acceptable salt, and acceptable adjuvant.

[0078] In the present application, the acceptable adjuvant preferably includes one or more of an emulsifier, a solubilizer, a wetting agent, a dispersing agent, a crystal growth inhibitor, and a water hardness reducing agent.

[0079] The heterocyclic and imidazole-2-oxazoline compound provided by the present application, the preparation method and the application thereof will be described in detail below in conjunction with examples, but they should not be understood as limiting the scope of protection of the present application.

[0080] Synthesis of compound (S)-2-(1H-benzo[d]imidazol-2-yl)-4-isopropyl-4,5- dihydrooxazole A1

[0081]

[0082] (1) Benzimidazole-2-carboxylic acid A-1 (162 mg, 1 mmol) was dissolved in anhydrous dichloromethane (5 mL), and condensing agent 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI, 250 mg, 1.3 mmol) was added under ice bath condition, stirred for 10 min, then 1-hydroxybenzotriazole (HOBt, 178 mg, 1.3 mmol) was added, followed by (s)-valinol (144 mg, 1.2 mmol), the reaction was stirred at room temperature, quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (5 mL x 2), the solvent was evaporated under reduced pressure, and the intermediate (S)-N-(1-hydroxy-3-methylbutan-2-yl)-1H- benzo[d]imidazole-2-carboxamide B-1 was isolated as a white solid by silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1:1), 200 mg, yield 81%.

[0083] (2) The intermediate (S)-N-(1-hydroxy-3-methylbutan-2-yl)-1H-benzo[d]imidazole-2- carboxamide B-1 (247 mg, 1 mmol) was dissolved in a Schlenk tube, replaced with N2 for three times, dissolved in dichloromethane (3 mL) and transferred to -78 °C, diethylaminosulfur trifluoride (DAST, 368 μL, 3 mmol) was added dropwise slowly, the reaction was stirred at -78 °C after the addition was completed, TLC tracking monitoring, the reaction was complete after 8 h, quenched with water, washed with saturated sodium carbonate solution (10 mL x 3), the organic phase was dried with anhydrous sodium sulfate, and the mixture was concentrated. (S)-2-(1H-benzo[d]imidazol-2-yl)-4-isopropyl-4,5-dihydrooxazole A1 was isolated as a white solid by silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1:1), 130 mg, yield 50%.

[0084] 1 H NMR (400 MHz, CDC13) δ 12.19 (s, 1H), 7.87 (d, J = 7.3 Hz, 1H), 7.45 - 7.42 (m, 1H), 7.37 - 7.28 (m, 2H), 4.67 (dd, J = 9.5, 8.3 Hz, 1H), 4.39 - 4.27 (m, 2H), 1.86 (h, J = 6.7 Hz, 1H), 0.96 (dd, J = 20.4, 6.7 Hz, 6H).

[0085] 13C NMR (101 MHz, CDC13) δ 157.93, 143.62, 140.49, 134.12, 125.31, 123.30, 121.40, 111.56, 72.49, 71.70, 33.10, 18.61, 18.56.

[0086] Example 2 Synthesis of (S)-2-(lH-benzo[d]imidazol-2-yl)-4-((R)-sec-butyl)-4,5- dihydrooxazole A2

[0087]

[0088] (1) Dissolve benzimidazole-2-carboxylic acid A-l (162 mg, 1 mmol) in anhydrous dichloromethane (5 mL), add condensing agent l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI, 250 mg, 1.3 mmol) under ice bath condition, stir for 10 min, then add l-hydroxybenzotriazole (HOBt, 178 mg, 1.3 mmol), followed by (s)-leucinol (144 mg, 1.2 mmol), stir the reaction at room temperature, quench the reaction with saturated sodium bicarbonate solution, extract with dichloromethane (5 mL x 2), evaporate the solvent under reduced pressure, isolate the intermediate N-((2S,3R)-l-hydroxy-3-methylpentan-2-yl)-lH- benzo[d]imidazole-2-carboxamide B-2, white solid, 151 mg, yield 58% by silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1: 1).

[0089] (2) Dissolve the intermediate N-((2S,3R)-l-hydroxy-3-methylpentan-2-yl)-lH- benzo[d]imidazole-2-carboxamide B-2 (261 mg, 1 mmol) in a Schlenk tube, replace with N2 for three times, dissolve in dichloromethane (3 mL) and transfer to -78 °C, slowly add diethylaminosulfur trifluoride (DAST, 368 μL, 3 mmol), add dropwise and stir the reaction at -78 °C, monitor by TLC, the reaction is complete after 8 h, quench the reaction with water, wash with saturated sodium carbonate solution (10 mL x 3), dry the organic phase with anhydrous sodium sulfate, concentrate the mixture. Isolate (S)-2-(lH-benzo[d]imidazol-2-yl)-4-((R)-sec-butyl)-4,5- dihydrooxazole A2, white solid, 80 mg, yield 33% by silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1:4).

[0090] 1H NMR (500 MHz, CDC13) δ 11.97 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 7.36 - 7.28 (m, 2H), 4.74 - 4.67 (m, 1H), 4.55 - 4.45 (m, 1H), 4.20 (t, J = 8.2 Hz, 1H), 1.79 (dd, J = 13.6, 6.8 Hz, 1H), 1.70 - 1.65 (m, 1H), 1.46 - 1.40 (dt, J = 13.9, 7.3 Hz, 1H), 0.90 (dd, J = 11.0, 6.5 Hz, 6H).

[0091] 13 C NMR (126 MHz, CDC13) δ 157.68, 143.57, 140.59, 134.06, 125.28, 123.28, 121.35, 111.58, 74.29, 64.96, 45.56, 25.43, 22.94, 22.46.

[0092] Example 3 Synthesis of (S)-2-(lH-benzo[d]imidazol-2-yl)-4-(tert-butyl)-4,5- dihydrooxazole A3

[0093]

[0094] (1) Dissolve benzimidazole-2-carboxylic acid A-l (162 mg, 1 mmol) in anhydrous dichloromethane (5 mL), add condensing agent l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI, 250 mg, 1.3 mmol) at 0 °C, stir for 10 min, then add l-hydroxybenzotriazole (HOBt, 178 mg, 1.3 mmol), and then add (s)-tert-leucinol (144 mg, 1.2 mmol), stir the reaction at room temperature, quench the reaction with saturated sodium bicarbonate solution, extract with dichloromethane (5 mL x 2), evaporate the solvent under reduced pressure, and separate the intermediate (S)-N-(l-hydroxy-3,3-dimethylbutan-2-yl)-lH- benzo[d]imidazole-2-carboxamide B-3 as a white solid by silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1: 1), 200 mg, yield 77%.

[0095] (2) Intermediate (S)-N-(l-hydroxy-3,3-dimethylbutan-2-yl)-lH- benzo[d]imidazole-2-carboxamide B-3 (261 mg, 1 mmol) was taken in a Schlenk tube, N2was replaced three times, dichloromethane (3 mL) was added to dissolve and transfer to -78 °C, diethylaminosulfur trifluoride (DAST, 368 μL, 3 mmol) was added dropwise slowly, after the addition was completed and the reaction was stirred at -78 °C, TLC tracking monitoring, after 8 h the reaction was complete, the reaction was quenched with water, and washed with saturated sodium carbonate solution (10 mL x 3), the organic phase was dried with anhydrous sodium sulfate, the mixture was concentrated. Silica gel column chromatography (200-300 mesh, dichloromethane / ethyl acetate = 1:4) was separated to obtain (S)-2-(lH-benzo[d]imidazol-2-yl)-4-(tert-butyl)-4,5-dihydrooxazole A3, white solid, 187 mg, yield 77%.

[0096] 1 HNMR (400 MHz, CDC13) δ 12.64 (s, 1H), 7.91 - 7.80 (m, 1H), 7.43 - 7.40 (m, 1H), 7.36 - 7.28 (m, 2H), 4.64 (dd, J = 10.2, 9.0 Hz, 1H), 4.49 (dd, J = 9.0, 7.8 Hz, 1H), 4.30 (dd, J = 10.3, 7.8 Hz, 1H), 0.94 (s, 9H).

[0097] 13 C NMR (101 MHz, CDC13) δ 158.09, 143.61, 140.39, 134.17, 125.35, 123.32, 121.40, 111.57, 70.13, 34.32, 25.88.

[0098] Example 4. Synthesis of (S)-2-(lH-benzo[d]imidazol-2-yl)-4-phenyl-4,5- dihydrooxazole A4.

[0099]

[0100] (1) Benzimidazole-2-carboxylic acid A-1 (162 mg, 1 mmol) was dissolved in anhydrous dichloromethane (5 mL), and a condensing agent 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI, 250 mg, 1.3 mmol) was added under ice bath conditions, stirred for 10 minutes, then 1-hydroxybenzotriazole (HOBt, 178 mg, 1.3 mmol) was added, followed by (s)-phenylglycinol (164 mg, 1.2 mmol), and the reaction was stirred at room temperature. The reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (5 mL x 2), and the solvent was evaporated under reduced pressure. The intermediate (S)-N-(2-hydroxy-1-phenylethyl)-1H-benzo[d]imidazole-2-carboxamide B-4 was isolated as a white solid by silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1:1), 169 mg, yield 60%.

[0101] (2) The intermediate (S)-N-(2-hydroxy-1-phenylethyl)-1H-benzo[d]imidazole-2- carboxamide B-4 (281 mg, 1 mmol) was dissolved in a Schlenk tube, and N2 was replaced three times. Dichloromethane (3 mL) was added to dissolve and transfer to -78 °C. Diethylaminosulfur trifluoride (DAST, 368 μL, 3 mmol) was slowly added dropwise, and the reaction was stirred at -78 °C. TLC tracking showed that the reaction was complete after 8 h. The reaction was quenched with water and washed with saturated sodium carbonate solution (10 mL x 3). The organic phase was dried with anhydrous sodium sulfate, and the mixture was concentrated. (S)-2-(1H-benzo[d]imidazol-2-yl)-4-phenyl-4,5-dihydrooxazole A4 was isolated as a white solid by silica gel column chromatography (200-300 mesh, dichloromethane / ethyl acetate = 1:4), 118 mg, yield 45%.

[0102] 1 H NMR (400 MHz, CDCl3) δ 12.36 - 11.95 (m, 1H), 7.82 (dd, J = 6.1, 3.2 Hz, 1H), 7.33 - 7.14 (m, 8H), 5.46 (dd, J = 10.2, 8.0 Hz, 1H), 4.91 (dd, J = 10.2, 8.7 Hz, 1H), 4.44 (t, J = 8.4 Hz, 1H).

[0103] 13 C NMR (126 MHz, CDCl3) δ 158.65, 143.50, 140.99, 140.21, 133.96, 129.17, 128.32, 126.79, 125.42, 123.38, 121.32, 111.67, 69.97.

[0104] Example 5 Synthesis of (4R, 5R)-2-(lH-benzo[d]imidazol-2-yl)-4, 5-diphenyl-4, 5- dihydrooxazole A5

[0105]

[0106] (1) Benzimidazole-2-carboxylic acid A-l (162 mg, 1 mmol) was dissolved in anhydrous dichloromethane (5 mL), and the condensing agent l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI, 250 mg, 1.3 mmol) was added under ice bath condition. After stirring for 10 min, l-hydroxybenzotriazole (HOBt, 178 mg, 1.3 mmol) was added, followed by the addition of (lS,2R)-2-amino-l,2-diphenylethan-l-ol (213 mg, 1 mmol). The reaction was stirred at room temperature, quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (5 mL x 2), and the solvent was evaporated under reduced pressure. The intermediate N-((lR,2S)-2-hydroxy-l,2-diphenylethyl)-lH- benzo[d]imidazole-2-carboxamide B-5 was isolated as a white solid by silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1: 1), 146 mg, 41% yield.

[0107] (2) The intermediate N-((lR,2S)-2-hydroxy-l,2-diphenylethyl)-lH-benzo[d]imidazole-2- carboxamide B-5 (357 mg, 1 mmol) was dissolved in dichloromethane (3 mL) in a Schlenk tube, and the solution was transferred to -78 °C. Diethylaminosulfur trifluoride (DAST, 368 μL, 3 mmol) was added dropwise slowly. After the addition was completed, the reaction was stirred at -78 °C. TLC tracking showed that the reaction was complete after 8 h. The reaction was quenched with water and washed with saturated sodium carbonate solution (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, and the mixture was concentrated. (4R, 5R)-2-(lH-benzo[d]imidazol-2-yl)-4, 5-diphenyl-4, 5-dihydrooxazole A5 was isolated as a white solid by silica gel column chromatography (200-300 mesh, dichloromethane / ethyl acetate = 1:4), 153 mg, 45% yield.

[0108] 1 H NMR (500 MHz, CDC13) δ 11.98 (s, 1H), 7.99 - 7.76 (m, 1H), 7.39 (d, J = 3.2 Hz, 5H), 7.35 - 7.31 (m, 3H), 7.29 - 7.24 (m, 4H), 7.23 - 7.19 (m, 1H), 5.61 (d, J = 7.9 Hz, 1H), 5.36 (d, J = 7.6 Hz, 1H).

[0109] 13 C NMR (126 MHz, CDC13) δ 158.19, 143.54, 140.60, 140.07, 139.11, 134.06, 129.21, 129.12, 128.95, 128.41, 126.75, 125.84, 125.45, 123.37, 121.35, 111.65, 90.13, 78.35.

[0110] Example 6 Synthesis of (4S,5S)-2-(lH-benzo[d]imidazol-2-yl)-4,5-diphenyl-4,5- dihydrooxazole A6

[0111]

[0112] (1) Dissolve benzimidazole-2-carboxylic acid A-l (162 mg, 1 mmol) in anhydrous dichloromethane (5 mL), add condensing agent l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI, 250 mg, 1.3 mmol) under ice bath condition, stir for 10 min, then add l-hydroxybenzotriazole (HOBt, 178 mg, 1.3 mmol), add (lR,2S)-2-amino-l,2-diphenylethan-l-ol (213 mg, 1 mmol), stir the reaction at room temperature, quench the reaction with saturated sodium bicarbonate solution, extract with dichloromethane (5 mL x 2), evaporate the solvent under reduced pressure, isolate the intermediate N-((lS,2R)-2-hydroxy-l,2-diphenylethyl)-lH- benzo[d]imidazole-2-carboxamide B-6, white solid, 123 mg, yield 34% by silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1: 1).

[0113] (2) Dissolve the intermediate N-((lS,2R)-2-hydroxy-l,2-diphenylethyl)-lH- benzo[d]imidazole-2-carboxamide B-6 (357 mg, 1 mmol) in a Schlenk tube, replace with N2for three times, dissolve in dichloromethane (3 mL) and transfer to -78 °C, slowly add diethylaminosulfur trifluoride (DAST, 368 μL, 3 mmol), add dropwise at -78 °C, TLC track monitoring, complete after 8 h, quench the reaction with water, wash with saturated sodium carbonate solution (10 mL x 3), dry the organic phase with anhydrous sodium sulfate, concentrate the mixture. Isolate (4S,5S)-2-(lH-benzo[d]imidazol-2-yl)-4,5-diphenyl-4,5- dihydrooxazole A6, white solid, 158 mg, yield 47% by silica gel column chromatography (200-300 mesh, dichloromethane / ethyl acetate = 1:4).

[0114] 1H NMR (500 MHz, CDC13) δ 11.98 (s, 1H), 7.99 - 7.76 (m, 1H), 7.39 (d, J = 3.2 Hz, 5H), 7.35 - 7.31 (m, 3H), 7.29 - 7.24 (m, 4H), 7.23 - 7.19 (m, 1H), 5.61 (d, J = 7.9 Hz, 1H), 5.36 (d, J = 7.6 Hz, 1H).

[0115] 13 C NMR (126 MHz, CDC13) δ 158.19, 143.54, 140.60, 140.07, 139.11, 134.06, 129.21, 129.12, 128.95, 128.41, 126.75, 125.84, 125.45, 123.37, 121.35, 111.65, 90.13, 78.35.

[0116] Example 7 Synthesis of (4R, 5R)-2-(benzo[d]thiazol-2-yl)-4, 5-diphenyl-4, 5- dihydrox yloxazole A7

[0117]

[0118] (1) Benzimidazole-2-carboxylic acid A-1 (162 mg, 1 mmol) was dissolved in anhydrous dichloromethane (5 mL), and condensing agent l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI, 250 mg, 1.3 mmol) was added under ice bath condition, stirred for 10 minutes, followed by the addition of l-hydroxybenzotriazole (HOBt, 178 mg, 1.3 mmol), and then (1S, 2R)-2-amino-1, 2-diphenylethan-1-ol (213 mg, 1 mmol) was added. The reaction was stirred at room temperature, quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (5 mL x 2), and the solvent was evaporated under reduced pressure. The intermediate N-((1R, 2S)-2-hydroxy-1, 2-diphenylethyl)benzo[d]thiazole-2-carboxamide B-7 was isolated as a white solid by silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1: 1), 189 mg, yield 51%.

[0119] (2) Intermediate N-((lR,2S)-2-hydroxy-l,2-diphenylethyl)benzo[d]thiazole-2- carboxamide B-7 (374 mg, 1 mmol) was taken in a Schlenk tube, N2was replaced three times, dichloromethane (3 mL) was added to dissolve and transfer to -78 °C, diethylaminosulfur trifluoride (DAST, 368 μL, 3 mmol) was added dropwise slowly, after dropwise addition was completed and stirring reaction at -78 °C, TLC tracking monitoring, 8 h after the reaction was complete, quenched with water, and washed with saturated sodium carbonate solution (10 mL x 3), the organic phase was dried over anhydrous sodium sulfate, the mixture was concentrated. Silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1:4) separation obtained (4R,5R)-2-(benzo[d]thiazol-2-yl)-4,5-diphenyl-4,5-dihydroxoxazole A7, white solid, 249 mg, yield 70%.

[0120] 1 H NMR (400 MHz, CDC13) δ 8.24 (dd, J = 7.7, 1.4 Hz, 1H, aromatic H in phenyl ring), 7.99 (dd, J = 8.2, 1.2 Hz, 1H), 7.64 - 7.50 (m, 2H), 7.53 - 7.25 (m, 11H), 5.60 (d, J = 8.3 Hz, 1H), 5.38 (d, J = 8.3 Hz, 1H).

[0121] 13 C NMR (101 MHz, CDC13) δ 159.32, 155.63, 153.44, 140.69, 139.10, 136.19, 129.10, 129.07, 128.97, 128.25, 127.26, 127.05, 126.92, 126.23, 125.04, 122.00, 90.71, 79.03.

[0122] Example 8 Synthesis of (4R,5R)-2-(imidazo[l,2-a]pyrazin-2-yl)-4,5-diphenyl-4,5- dihydroxoxazole A8

[0123]

[0124] (1) Pyrazinoimidazole-2-carboxylic acid A-1 (162 mg, 1 mmol) was dissolved in dry dichloromethane (5 mL), and condensing agent l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI, 250 mg, 1.3 mmol) was added under ice bath condition. After stirring for 10 min, l-hydroxybenzotriazole (HOBt, 178 mg, 1.3 mmol) was added, followed by the addition of (1S,2R)-2-amino-1,2-diphenylethan-1-ol (213 mg, 1 mmol). The reaction was stirred at room temperature. The reaction was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (5 mL x 2). The solvent was evaporated under reduced pressure. The intermediate, N-((1R,2S)-2-hydroxy-1,2-diphenylethyl)imidazo[1,2-a]pyrazine-2-carboxamide B-8, was isolated as a white solid by silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1:1), 232 mg, 65% yield.

[0125] (2) The intermediate, N-((1R,2S)-2-hydroxy-1,2-diphenylethyl)imidazo[1,2-a]pyrazine-2- carboxamide B-8 (358 mg, 1 mmol), was dissolved in dichloromethane (3 mL) in a Schlenk tube and transferred to -78 °C. Diethylaminosulfur trifluoride (DAST, 368 μL, 3 mmol) was added dropwise slowly. The reaction was stirred at -78 °C. TLC tracking showed that the reaction was complete after 8 h. The reaction was quenched with water and washed with saturated sodium carbonate solution (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate. The mixture was concentrated. (4R,5R)-2-(imidazo[1,2-a]pyrazin-2-yl)-4,5-diphenyl-4,5-dihydrooxazole A8 was isolated as a white solid by silica gel column chromatography (200-300 mesh, dichloromethane / ethyl acetate = 1:4), 136 mg, 40% yield.

[0126] 1 HNMR (500 MHz, CDC13) δ 9.14 (d, J = 1.5 Hz, 1H), 8.26 (s, 1H), 8.04 (dd, J = 4.6, 1.6 Hz, 1H), 7.88 (d, J = 4.6 Hz, 1H), 7.35 - 7.23 (m, 10H), 5.44 (d, J = 8.0 Hz, 1H), 5.26 (d, J = 8.1 Hz, 1H).

[0127] Example 9 Synthesis of (4R,5R)-2-(imidazo[1,2-a]pyrimidin-2-yl)-4,5-diphenyl-4,5- dihydrooxazole A9

[0128]

[0129] (1) Imidazo[l,2-a]pyrimidine-2-carboxylic acid A-4 (163 mg, 1 mmol) was dissolved in anhydrous dichloromethane (5 mL), and condensing agent l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI, 250 mg, 1.3 mmol) was added under ice bath condition, stirred for 10 min, then l-hydroxybenzotriazole (HOBt, 178 mg, 1.3 mmol) was added, followed by (lS,2R)-2-amino-l,2-diphenylethan-l-ol (213 mg, 1 mmol). The reaction was stirred at room temperature, quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (5 mL x 2), and the solvent was evaporated under reduced pressure. The intermediate N-((lR,2S)-2-hydroxy-l,2-diphenylethyl)imidazo[l,2-a]pyrimidine-2-carboxamide B-9 was isolated as a white solid by silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1:1), 145 mg, 40% yield.

[0130] (2) The intermediate N-((lR,2S)-2-hydroxy-l,2-diphenylethyl)imidazo[l,2-a]pyrimidine-2- carboxamide B-9 (358 mg, 1 mmol) was dissolved in a Schlenk tube, and N2 was replaced three times. Dichloromethane (3 mL) was added to dissolve and transfer to -78 °C. Diethylaminosulfur trifluoride (DAST, 368 μL, 3 mmol) was added dropwise slowly. After the addition was completed, the reaction was stirred at -78 °C. TLC tracking showed that the reaction was complete after 8 h. The reaction was quenched with water and washed with saturated sodium carbonate solution (10 mL x 3). The organic phase was dried with anhydrous sodium sulfate, and the mixture was concentrated. (4R,5R)-2-(imidazo[l,2-a]pyrimidin-2-yl)-4,5-diphenyl-4,5-dihydrooxazole A9 was isolated as a white solid by silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1:3), 190 mg, 56% yield.

[0131] 1 H NMR (400 MHz, CDC13) δ 9.82 (dd, J = 6.8, 2.0 Hz, 1H), 8.66 (dd, J = 4.2, 2.1 Hz, 1H), 8.39 (s, 1H), 7.42 - 7.21 (m, 10H), 7.03 (dd, J = 6.8, 4.1 Hz, 1H), 5.34 (d, J = 7.7 Hz, 1H), 5.24 (d, J = 7.7 Hz, 1H).

[0132] 13C NMR (101 MHz, CDC13) δ 156.37, 151.72, 150.75, 141.52, 140.25, 139.60, 136.22, 129.06, 128.99, 128.77, 128.08, 126.69, 125.84, 112.07, 110.10, 88.19, 78.88, 60.44.

[0133] Example 10 Synthesis of (4R, 5R)-4, 5-diphenyl-2-(pyrazolo[l, 5-a]pyrimidin-3-yl)-4, 5- dihydrooxazole A10

[0134]

[0135] (1) Imidazo[l, 5-a]pyrimidine-2-carboxylic acid A-5 (163 mg, 1 mmol) was dissolved in anhydrous dichloromethane (5 mL), and the condensing agent l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI, 250 mg, 1.3 mmol) was added under ice bath condition, stirred for 10 min, then l-hydroxybenzotriazole (HOBt, 178 mg, 1.3 mmol) was added, followed by the addition of (lS, 2R)-2-amino-l, 2-diphenylethan-l-ol (213 mg, 1 mmol), and the reaction was stirred at room temperature. The reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (5 mL x 2), and the solvent was evaporated under reduced pressure. The intermediate N-((lR, 2S)-2-hydroxy-l, 2-diphenylethyl)imidazo[l, 2-a]pyrimidine-2-carboxamide B-10 was isolated as a white solid by silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1: 1) with a yield of 160 mg (51%).

[0136] (2) The intermediate N-((lR, 2S)-2-hydroxy-l, 2-diphenylethyl)imidazo[l, 2-a]pyrimidine-2- carboxamide B-10 (358 mg, 1 mmol) was dissolved in dichloromethane (3 mL) in a Schlenk tube, and N2was replaced three times. Diethylaminosulfur trifluoride (DAST, 368 μL, 3 mmol) was added slowly dropwise at -78 °C. The reaction was stirred at -78 °C after the dropwise addition was completed. TLC tracking showed that the reaction was complete after 8 h. The reaction was quenched with water and washed with saturated sodium carbonate solution (10 mL x 3). The organic phase was dried with anhydrous sodium sulfate, and the mixture was concentrated. (4R, 5R)-4, 5-diphenyl-2-(pyrazolo[l, 5-a]pyrimidin-3-yl)-4, 5-dihydrooxazole A10 was isolated as a white solid by silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1:4) with a yield of 170 mg (50%).

[0137] 1 HNMR (500 MHz, CDC13) δ 8.73 - 8.60 (m, 3H), 7.36 - 7.16 (m, 10H), 6.86 (dd, J = 7.0, 4.1 Hz, 1H), 5.39 (d, J = 7.4 Hz, 1H), 5.24 (d, J = 7.3 Hz, 1H).

[0138] 13 C NMR (126 MHz, CDC13) δ 158.31, 151.83, 146.65, 146.25, 142.06, 140.32, 135.77, 128.64, 128.52, 128.16, 127.44, 126.71, 125.58, 109.15, 99.45, 88.10, 78.89.

[0139] Example 11 Synthesis of (4R, 5R)-2-(6-chloroimidazo[l,2-b]pyridazin-2-yl)-4,5- diphenyl-4,5-dihydrooxazole A11

[0140]

[0141] (1) 6-chloroimidazo[l,2-b]pyridazine-2-carboxylic acid A-6 (162 mg, 1 mmol) was dissolved in anhydrous dichloromethane (5 mL), and condensing agent l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI, 250 mg, 1.3 mmol) was added under ice bath condition, stirred for 10 minutes, then l-hydroxybenzotriazole (HOBt, 178 mg, 1.3 mmol) was added, followed by (lS,2R)-2-amino-l,2-diphenylethan-l-ol (213 mg, 1 mmol), and the reaction was stirred at room temperature for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (5 mL x 2), and the solvent was evaporated under reduced pressure. The intermediate 6-chloro-N-((lR,2S)-2-hydroxy-l,2-diphenylethyl)imidazo[l,2-b]pyridazine-2- carboxamide B-11 was isolated as a white solid by silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1:1), 181 mg, yield 50%.

[0142] (2) Intermediate 6-chloro-N-((lR,2S)-2-hydroxy-l,2-diphenyl ethyl)imidazo[l,2- b]pyridazine-2-carboxamide B-11 (392 mg, 1 mmol) was taken in a Schlenk tube, purged with N2three times, dichloromethane (3 mL) was added to dissolve and transfer to -78 °C, diethylaminosulfur trifluoride (DAST, 368 μL, 3 mmol) was added dropwise slowly, the reaction was stirred at -78 °C, TLC was used to monitor the reaction, after 8 h the reaction was complete, the reaction was quenched with water, washed with saturated sodium carbonate solution (10 mL x 3), the organic phase was dried over anhydrous sodium sulfate, the mixture was concentrated. Silica gel column chromatography (200-300 mesh, dichloromethane / ethyl acetate = 1:4) was used to isolate to obtain (4R,5R)-2-(6-chloroimidazo[l,2-b]pyridazin-2-yl)-4,5-diphenyl-4,5- dihydrooxazole Al 1, white solid, 210 mg, yield 55%.

[0143] 1 H NMR (500 MHz, CDC13) δ 8.46 (s, 1H), 7.91 (d, J = 9.6 Hz, 1H), 7.33 - 7.20 (m, 10H), 7.02 (d, J = 9.5 Hz, 1H), 5.42 (d, J = 8.2 Hz, 1H), 5.26 (d, J = 8.2 Hz, 1H).

[0144] 13 C NMR (126 MHz, CDC13) δ 148.17, 141.17, 139.52, 137.76, 134.48, 128.74, 128.66, 128.46, 127.68, 126.60, 125.85, 120.59, 118.97, 89.17, 78.67.

[0145] Example 12. Synthesis of (S)-2-(benzo[d]thiazol-2-yl)-5-(tert-butyl)-4,5- dihydrooxazole A12

[0146]

[0147] (1) Benzothiazole-2-carboxylic acid A-2 (176 mg, 1 mmol) was dissolved in anhydrous dichloromethane (5 mL), and condensing agent 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI, 250 mg, 1.3 mmol) was added under ice bath condition, stirred for 10 min, followed by the addition of 1-hydroxybenzotriazole (HOBt, 178 mg, 1.3 mmol), and then S-tert-leucinol (144 mg, 1.2 mmol). The reaction was stirred at room temperature, quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (5 mL x 2), and the solvent was evaporated under reduced pressure. The intermediate (S)-N-(1-hydroxy-3,3-dimethylbutan-2-yl)benzo[d]thiazole-2- carboxamide B-12 was isolated as a white solid by silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1:1), 186 mg, yield 67%.

[0148] (2) The intermediate (S)-N-(1-hydroxy-3,3-dimethylbutan-2-yl)benzo[d]thiazole-2- carboxamide B-12 (278 mg, 1 mmol) was dissolved in dichloromethane (3 mL) in a Schlenk tube, and N2was replaced three times. Diethylaminosulfur trifluoride (DAST, 368 μL, 3 mmol) was added slowly dropwise at -78 °C. After the addition was completed, the reaction was stirred at -78 °C. TLC tracking showed that the reaction was complete after 8 h. The reaction was quenched with water and washed with saturated sodium carbonate solution (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, and the mixture was concentrated. (S)-2-(benzo[d]thiazol-2-yl)-5-(tert-butyl)-4,5-dihydrooxazole A12 was isolated as a white solid by silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1:4), 200 mg, yield 77%.

[0149] 1 H NMR (500 MHz, CDCl3) δ 8.17 (d, J = 7.7 Hz, 1H), 7.93 (dd, J = 8.1, 1.2 Hz, 1H), 7.56 - 7.44 (m, 2H), 4.51 (dd, J = 10.4, 8.8 Hz, 1H), 4.39 (t, J = 8.6 Hz, 1H), 4.17 (dd, J = 10.3, 8.1 Hz, 1H), 0.98 (s, 9H).

[0150] 13 C NMR (126 MHz, CDCl3) δ 158.54, 156.14, 153.43, 136.06, 126.98, 126.89, 124.88, 121.90, 70.19, 34.25, 26.02.

[0151] Example 13. Synthesis of (S)-2-(benzo[d]imidazol-2-yl)-5-(tert-butyl)-4,5- dihydrooxazole A13

[0152]

[0153] (1) Dissolve benzimidazole-2-carboxylic acid A-2 (162 mg, 1 mmol) in anhydrous dichloromethane (5 mL), add condensing agent l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI, 250 mg, 1.3 mmol) under ice bath condition, stir for 10 min, then add l-hydroxybenzotriazole (HOBt, 178 mg, 1.3 mmol), followed by S-tert-leucinol (144 mg, 1.2 mmol), stir the reaction at room temperature, quench the reaction with saturated sodium bicarbonate solution, extract with dichloromethane (5 mL x 2), evaporate the solvent under reduced pressure, isolate the intermediate (S)-N-(l-hydroxy-3,3-dimethylbutan-2-yl)benzo[d]imidazole-2- carboxamide B-13 as a white solid, 209 mg, 80% yield, by silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1: 1).

[0154] (2) Dissolve the intermediate (S)-N-(l-hydroxy-3,3-dimethylbutan-2-yl)benzo[d]imidazole- 2-carboxamide B-13 (261 mg, 1 mmol) in a Schlenk tube, replace with N2for three times, dissolve in dichloromethane (3 mL) and transfer to -78 °C, slowly add diethylaminosulfur trifluoride (DAST, 368 μL, 3 mmol), add dropwise and stir the reaction at -78 °C, monitor by TLC, the reaction is complete after 8 h, quench the reaction with water, wash with saturated sodium carbonate solution (10 mL x 3), dry the organic phase with anhydrous sodium sulfate, concentrate the mixture. Isolate (S)-2-(benzo[d]imidazol-2-yl)-5-(tert-butyl)-4,5-dihydrooxazole A13 as a white solid, 176 mg, 72% yield, by silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1:4).

[0155] 1 H NMR (400 MHz, CDC13) δ 12.64 (s, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.41 (dt, J = 8.3, 1.0 Hz, 1H), 7.39 - 7.25 (m, 2H), 4.64 (dd, J = 10.2, 9.0 Hz, 1H), 4.49 (dd, J = 9.0, 7.8 Hz, 1H), 4.30 (dd, J = 10.3, 7.8 Hz, 1H), 0.94 (s, 9H).

[0156] 13C NMR (101 MHz, CDC13) δ 158.09, 143.61, 140.39, 134.17, 125.35, 123.32, 121.40, 111.57, 70.13, 34.32, 25.88.

[0157] Example 14. Synthesis of (S)-4-(tert-butyl)-2-(pyrazolo[l,5-a]pyrimidin-3-yl)-4,5- dihydrooxazole A14

[0158]

[0159] (1) Imidazo[l,5-a]pyrimidine-2-carboxylic acid A-5 (163 mg, 1 mmol) was dissolved in anhydrous dichloromethane (5 mL), and condensing agent l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI, 250 mg, 1.3 mmol) was added under ice bath condition, stirred for 10 min, then l-hydroxybenzotriazole (HOBt, 178 mg, 1.3 mmol) was added, followed by (lS,2R)-2-amino-l,2-diphenylethan-l-ol (213 mg, 1 mmol). The reaction was stirred at room temperature, quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (5 mL x 2), and the solvent was evaporated under reduced pressure. The intermediate (S)-N-(l-hydroxy-3,3-dimethylbutan-2-yl)pyrazolo[l,5-a]pyrimidine-3- carboxamide B-14 was isolated as a white solid by silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1: 1), 160 mg, 51% yield.

[0160] (2) The intermediate (S)-N-(l-hydroxy-3,3-dimethylbutan-2-yl)pyrazolo[l,5-a]pyrimidine-3- carboxamide B-14 (262 mg, 1 mmol) was dissolved in dichloromethane (3 mL) in a Schlenk tube, and N2was replaced three times. Diethylaminosulfur trifluoride (DAST, 368 μL, 3 mmol) was added slowly dropwise at -78 °C. After the addition was completed, the reaction was stirred at -78 °C. TLC tracking showed that the reaction was complete after 8 h. The reaction was quenched with water and washed with saturated sodium carbonate solution (10 mL x 3). The organic phase was dried over anhydrous sodium sulfate, and the mixture was concentrated. (S)-4-(tert-Butyl)-2-(pyrazolo[l,5-a]pyrimidin-3-yl)-4,5-dihydrooxazole A14 was isolated as a white solid by silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1:4), 170 mg, 50% yield.

[0161] 1H NMR (500 MHz, CDC13) δ 8.76 - 8.67 (m, 2H), 8.62 (s, 1H), 6.94 (dd, J = 6.9, 4.1 Hz, 1H), 4.40 (dd, J = 10.0, 8.6 Hz, 1H), 4.29 (dd, J = 8.7, 7.5 Hz, 1H), 4.06 (dd, J = 10.0, 7.6 Hz, 1H), 0.96 (s, 9H).

[0162] 13 C NMR (126 MHz, CDC13) δ 158.05, 151.79, 146.75, 146.41, 136.03, 109.01, 100.43, 75.76, 68.81, 34.17, 26.03.

[0163] Example 15. Synthesis of (S)-6-chloro-N-(l-hydroxy-3,3-dimethylbutan-2-yl)imidazo[l,2- b]pyridazine-2-carboxamide A15.

[0164]

[0165] (1) 6-chloroimidazo[l,2-b]pyridazine-2-carboxylic acid A-6 (162 mg, 1 mmol) was dissolved in anhydrous dichloromethane (5 mL), and condensing agent l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI, 250 mg, 1.3 mmol) was added under ice bath condition, stirred for 10 minutes, then l-hydroxybenzotriazole (HOBt, 178 mg, 1.3 mmol) was added, followed by (lS,2R)-2-amino-l,2-diphenylethan-l-ol (213 mg, 1 mmol), and the reaction was stirred at room temperature for 1 hour. The reaction was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (5 mL x 2), and the solvent was evaporated under reduced pressure. The intermediate (S)-6-chloro-N-(l-hydroxy-3,3-dimethylbutan-2-yl)imidazo[l,2-b]pyridazine-2-carboxamide B-15 was isolated as a white solid by silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1: 1), 162 mg, 55% yield.

[0166] (2) Intermediate (S)-6-chloro-N-(l-hydroxy-3,3-dimethylbutan-2-yl)imidazo[l,2- b]pyridazine-2-carboxamide B15 (296 mg, 1 mmol) was taken in a Schlenk tube, N2was replaced three times, dichloromethane (3 mL) was added to dissolve and transfer to -78 °C, diethylaminosulfur trifluoride (DAST, 368 μL, 3 mmol) was added dropwise slowly, after the addition was completed and the reaction was stirred at -78 °C, TLC tracking monitoring, after 8 h the reaction was complete, the reaction was quenched with water, and washed with saturated sodium carbonate solution (10 mL x 3), the organic phase was dried over anhydrous sodium sulfate, the mixture was concentrated. Silica gel column chromatography (200-300 mesh, dichloromethane / ethyl acetate = 1:4) was separated to obtain (S)-4-(tert-butyl)-2-(6-chloroimidazo[l,2-b]pyridazin-2-yl)-4,5- dihydrooxazole A15, white solid, 192 mg, yield 69%.

[0167] 1 H NMR (500 MHz, CDC13) δ 8.35 (s, 1H), 7.92 (d, J = 9.4 Hz, 1H), 7.09 (d, J = 9.4 Hz, 1H), 4.40 (dd, J = 10.2, 8.5 Hz, 1H), 4.26 (t, J = 8.5 Hz, 1H), 4.10 (dd, J = 10.1, 8.3 Hz, 1H), 0.96 (s, 9H).

[0168] 13 C NMR (126 MHz, CDC13) δ 158.58, 148.21, 137.82, 135.23, 127.80, 120.58, 118.62, 69.06, 34.03, 26.04.

[0169] Example 16 Synthesis of (4R,5R)-2-(5-chlorobenzo[d]thiazol-2-yl)-4,5-diphenyl-4,5- dihydrooxazole A16

[0170]

[0171] (1) 5-chlorobenzo[d]thiazole-2-carboxylic acid A-7 (212 mg, 1 mmol) was dissolved in anhydrous dichloromethane (5 mL), and condensing agent 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI, 250 mg, 1.3 mmol) was added under ice bath condition, stirred for 10 min, then 1-hydroxybenzotriazole (HOBt, 178 mg, 1.3 mmol) was added, followed by (1S,2R)-2-amino-1,2- diphenylethan-1-ol (213 mg, 1 mmol), the reaction was stirred at room temperature, quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (5 mL x 2), the solvent was evaporated under reduced pressure, and the intermediate 5-chloro-N-((1R,2S)-2-hydroxy-1,2-diphenylethyl)benzo[d]thiazole-2- carboxamide B-16 was isolated as a white solid by silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1:1), 279 mg, yield 68%.

[0172] (2) The intermediate 5-chloro-N-((1R,2S)-2-hydroxy-1,2-diphenylethyl)benzo[d]thiazole-2- carboxamide B-16 (408 mg, 1 mmol) was dissolved in a Schlenk tube, replaced with N2 for three times, dissolved in dichloromethane (3 mL) and transferred to -78 °C, diethylaminosulfur trifluoride (DAST, 368 μL, 3 mmol) was added dropwise slowly, the reaction was stirred at -78 °C after the addition was completed, TLC tracking showed that the reaction was complete after 8 h, quenched with water, washed with saturated sodium carbonate solution (10 mL x 3), the organic phase was dried with anhydrous sodium sulfate, and the mixture was concentrated. (4R,5R)-2-(5-chlorobenzo[d]thiazol-2-yl)-4,5-diphenyl-4,5-dihydrooxazole A16 was isolated as a white solid by silica gel column chromatography (200-300 mesh, petroleum ether / ethyl acetate = 1:1), 190 mg, yield 49%.

[0173] 1 H NMR (500 MHz, CDC13) δ 8.19 (s, 1H), 7.88 (t, J = 7.3 Hz, 1H), 7.49-7.30 (m, 11H), 5.60 (d, J = 8.7 Hz, 1H), 5.38 (d, J = 8.8 Hz, 1H).

[0174] 13 C NMR (126 MHz, CDC13) δ 158.95, 157.42, 154.18, 140.47, 138.88, 134.39, 133.10, 129.06, 129.00, 128.26, 127.82, 126.98, 126.85, 126.19, 124.52, 122.72, 90.79, 78.95.

[0175] Application Example 1

[0176]

[0177] Copper bromide (0.05 mol%) and ligand (0.05 mol%) were added to dry methanol (1 mL) at room temperature and the reaction stirred for 30 minutes. Methyl 3-hydroxy-2-naphthoate (0.1 mmol) was then added to the system and stirred for a further 24 hours to give the homo-coupled product after purification by flash chromatography (PE / EA, 20:1).

[0178] Table 1 Ligand screening

[0179]

[0180]

[0181] Application Example 2

[0182]

[0183] Palladium acetate (0.1 mol%) and A15 (0.1 mol%) were added to dry methanol (1 mL) at 60°C and the reaction stirred for 30 minutes. Phenylboronic acid (1.2 eq) 2,2,6,6-tetramethyl-l-oxopiperidine-l-tetrafluoroborate (1.1 eq) was added to the system and stirred for a further 24 hours to give the homo-coupled product after purification by flash chromatography (PE / EA, 20:1) in 47% yield with 90% ee.

[0184] Test Example Determination of the antibacterial activity of heterocyclic pyridine-2-oxazolines

[0185] The mycelial growth rate inhibition method was used to evaluate the in vitro antibacterial activity. The test strains were activated on PDA plates, including Rhizoctonia solani, Rhizoctonia cerealis, sclerotinia scleotiorum, Fusarium graminearum, Gaeumanomyce graminis, Botrytis cinerea, Phytophthora infestans, Phytophthora capsici, Alternaria solani, Fusarium fujikuroi, Fusarium sulphureum, Colletotrichum lagenarium, and Pyricularia oryzac. The compounds were configured into a series of gradient concentrations of PDA drug-containing plates, and the test strains were prepared into 5mm diameter fungus cakes and placed in the center of the drug-containing culture dish. The culture was incubated at 25℃ until the test strains in the blank control dish grew to the edge of the culture dish. The colony diameter of each drug-containing plate was measured by cross method, and the inhibition rate of the compound on mycelial growth was calculated. The inhibition rate of the disease was calculated according to the following formula:

[0186]

[0187] The statistical software SPSS 26.0 was used to calculate the concentration of the compound when the inhibition rate was 50%, i.e. EC50 value, which was repeated 3 times to take the average value. In the experiment, boscalid and thiabendazole were used as positive controls. The inhibition rates of examples 1-11 and positive controls on five kinds of agricultural fungi are shown in Table 1; the inhibition medium concentrations EC 50 As shown in Table 2.

[0188] Table 2 Inhibition rate (%) of examples 1-16 and positive controls on five kinds of agricultural fungi

[0189]

[0190] Table 3 Inhibition medium concentration EC 50

[0191]

[0192]

[0193] As can be seen from Table 1 and Table 2, the heterocyclic imidazole-2-oxazoline compounds have certain inhibitory effect on various plant pathogenic fungi. The type of oxazoline fragment and the diversity of heterocycle have significant influence on the fungicidal activity. The fungicidal activity is significantly improved when two phenyl groups are introduced as substituents on the oxazoline ring. Among them, Example 5 shows good fungicidal activity against Rhizoctonia solani and Gibberella zeae.

[0194] After structural optimization, the activity of Example 11 against Gibberella zeae is significantly higher than that of Example 5. The heterocyclic imidazole-2-oxazoline compounds are expected to be used as a new type of fungicide candidate compound or directly as a fungicide, which will have important significance for the creation of new pesticides.

[0195] The above only describes the preferred embodiments of the present application, and it should be pointed out that for ordinary skilled persons in the art, several improvements and refinements can be made without departing from the principles of the present application, and these improvements and refinements should also be considered as the protection scope of the present application.

Claims

1. A heterocyclic imidazole-2-oxazoline compound or a pharmaceutically acceptable salt thereof, having the structure shown in Formula A: Formula A; In formula A, for , , or ; R1 is a phenyl or substituted phenyl group, and R2 is one of an aromatic group and an aromatic methylene group, wherein the aromatic group is a phenyl or substituted phenyl group. In the substituted phenyl group, the substituent is selected from one or more of methyl, ethyl, isopropyl, sec-butyl, isobutyl, methoxy, ethoxy, I or Br substituted C1 to C3 alkyl groups, and the number of substituents is 1 to 5; R3 is one of hydrogen, methyl, ethyl, isopropyl, sec-butyl, isobutyl, methoxy, ethoxy, methylamino, ethylamino, and halogen; The carbon centers substituted by R1 and R2 have independent configurations of R or S.

2. The heterocyclic zimidazole-2-oxazoline compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The heterocyclic zimidazole-2-oxazoline compound has the structure shown in any one of formulas A8 to A11: 。 3. The use of the heterocyclic imidazole-2-oxazoline compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 2 in the control of plant pathogenic fungi.

4. The use of the heterocyclic fenimazole-2-oxazoline compound or a pharmaceutically acceptable salt thereof, or in the control of plant pathogenic fungi, according to claim 3, is characterized in that... The plant pathogenic fungi include one or more of the following: rice sheath blight fungus, wheat sheath blight fungus, rapeseed sclerotinia sclerotiorum fungus, wheat scab fungus, wheat take-all fungus, tomato gray mold fungus, potato late blight fungus, pepper phytophthora fungus, tomato early blight fungus, rice oxalis fungus, potato dry rot fungus, cucumber anthracnose fungus, and rice blast fungus.

5. A pharmaceutical composition for controlling plant pathogenic fungi, comprising one or more of the heterocyclic imidazole-2-oxazoline compounds as described in any one of claims 1 to 3, pharmaceutically acceptable salts, and acceptable excipients.

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