Amide thiazole compound as well as preparation method and application thereof

Abstract

The invention relates to the technical field of agricultural protection, in particular to an amide thiazole compound as well as a preparation method and application thereof. The amide nitrothiazole compound shown in the formula (1) is provided by carrying out proper structural modification on nitazoxanide, and the compound has good biological activity, can be applied to prevention and treatment of cryptosporidiosis and has a certain inhibition effect on florae such as rice streak, rice bacterial leaf blight, rice ralstonia solanacearum, cabbage soft rot and citrus ulcer. Formula (1): # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the technical field of agricultural protection, and in particular to an amide thiazole compound, a preparation method and an application thereof. Background Art

[0002] Cryptosporidiosis is a foodborne and waterborne infectious disease caused by Cryptosporidium parvum infection, which infects a variety of mammals (J Parasit Dis, 2022, 46(3), 923-939). More than 800 cases of human cryptosporidiosis have been reported each year (Int J Parasitol, 2018, 48(1), 1-12), which has a huge impact worldwide. Currently, more than 40 different Cryptosporidium species have been confirmed, of which Cryptosporidium hominis and Cryptosporidium parvum are the main causes of disease (Pak Vet J, 2023, 43(2), 213-223). The main host of Cryptosporidium is livestock, and cases can be found in most livestock species on all continents except Antarctica, resulting in a decline in livestock production and economic downturn (EST, 2017, 51(15), 8663-8671).

[0003] Currently, nitazoxanide is still the only FDA-approved drug for the treatment of cryptosporidiosis in the world (Expert Rev Anti-infe, 2023, 21(2), 167-173). The therapeutic mechanism is still unclear. Studies have shown that its metabolite, nitazoxanide, may inhibit the growth of Cryptosporidium oocysts by blocking the reaction of pyruvate-ferredoxin oxidoreductase (PFOR enzyme) (IJBM, 2023, 247, 125823). Nitazoxanide is only effective for patients with normal immune function, and its efficacy will be greatly reduced for patients with immune deficiency and children (Expert Opin Pharmaco, 2021, 22(17), 2337-2342). Therefore, the development of new veterinary insecticides targeting Cryptosporidium has become an urgent need and research hotspot. In this context, we selected nitazoxanide as the research object to guide the design and synthesis of new drugs.

[0004] Since its development in the last century, nitazoxanide (NTZ) has been widely commercialized worldwide. As the first US Food and Drug Administration (FDA)-approved treatment for Cryptosporidium infection and currently the only commercially available treatment for the disease, NTZ has developed a certain degree of drug resistance after long-term use. Furthermore, due to incomplete research on NTZ, no complete structure-activity relationship has been reported for Cryptosporidium infection. In addition, no such products are currently marketed or imported in my country. Therefore, the development of new and highly effective drug molecules has become a research hotspot both domestically and internationally. Therefore, research on nitazoxanide derivatives holds great promise.

[0005] The inventors discovered that when nitazoxanide is appropriately structurally modified, the resulting derivatives often exhibit good biological activity. By appropriately transforming and modifying the benzene ring portion, testing the anti-Cryptosporidium activity after obtaining the target product and studying the corresponding structure-activity relationship, a more optimal derivative structure can be found. Summary of the Invention

[0006] The purpose of the present invention is to overcome the problems of nitazoxanide resistance and unclear complete structure-activity relationship of Cryptosporidium in the prior art, and to provide an amide thiazole compound with good biological activity and can be used for the prevention and treatment of cryptosporidiosis.

[0007] In order to achieve the above object, the present invention provides an amide thiazole compound, which is a compound represented by formula (1);

[0008] Formula (1):

[0009] wherein R1 is selected from substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C6-C 20 aryl and substituted or unsubstituted C3-C 20 At least one of the heterocyclic groups;

[0010] Substituted C1-C 20 Alkyl, substituted C6-C 20 Aryl and substituted C3-C 20 The substituents of the heterocyclic group are selected from C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 haloalkyl, hydroxyl, halogen, C3-C 10 At least one of an alkylene oxide and R4; the heteroatom in the heterocyclic group is selected from at least one of O, N and S, and the number of heteroatoms is 1-4;

[0011] R2 is selected from H, substituted or unsubstituted C1-C12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl and substituted or unsubstituted C3-C 20 At least one of the cycloalkyl groups; substituted C1-C 12 Alkyl, substituted C2-C 12 Alkenyl and substituted C3-C 12 The substituent of the cycloalkyl group is selected from at least one of a C1-C6 alkyl group, a C2-C6 alkenyl group, and a C3-C8 cycloalkyl group;

[0012] Each R3 is independently selected from H, C1-C 12 At least one of an alkyl group, a nitro group, and a cyano group;

[0013] R4 is R5 is substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C6-C 12 Aryl and substituted or unsubstituted C1-C 12 At least one of the alkoxy groups, substituted C1-C 12 Alkyl, substituted C6-C 12 Aryl and substituted C1-C 12 The substituent of the alkoxy group is at least one selected from a hydroxy group, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a C2-C8 acyloxy group.

[0014] The second aspect of the present invention provides a method for preparing the amide thiazole compound according to the first aspect of the present invention, the method comprising:

[0015] The compound represented by formula (A) is contacted with the compound represented by formula (B) to prepare an amide thiazole compound;

[0016] Formula (A): Formula (B):

[0017] Wherein, R is selected from at least one of C1-C6 alkoxy, halogen and hydroxyl.

[0018] A third aspect of the present invention provides a method for preparing an amide thiazole compound, the method comprising: subjecting a compound represented by formula (C) to a first acylation reaction with a first acylating agent to prepare an amide thiazole compound;

[0019] Formula (C):

[0020] The fourth aspect of the present invention provides a use of the amide thiazole compound described in the first aspect of the present invention in preventing and controlling plant pathogens.

[0021] The present invention modifies the structure of nitazoxanide, specifically includes performing appropriate structural modification on the benzene ring, so that the obtained amide thiazole compound can have good biological activity and has a good effect in preventing and controlling plant pathogens. DETAILED DESCRIPTION

[0022] The endpoints of the ranges and any values disclosed herein are not limited to the precise ranges or values, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, the endpoints of each range, the endpoints of each range and individual point values, and the individual point values can be combined with each other to obtain one or more new numerical ranges, which should be considered to be specifically disclosed herein.

[0023] In one aspect, the present invention provides an amide thiazole compound, which is a compound represented by formula (1);

[0024] Formula (1):

[0025] wherein R1 is selected from substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C6-C 20 aryl and substituted or unsubstituted C3-C 20 At least one of the heterocyclic groups;

[0026] Substituted C1-C 20 Alkyl, substituted C6-C 20 Aryl and substituted C3-C 20 The substituents of the heterocyclic group are selected from C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 haloalkyl, hydroxyl, halogen, C3-C 10 At least one of an alkylene oxide and R4; the heteroatom in the heterocyclic group is selected from at least one of O, N and S, and the number of heteroatoms is 1-4;

[0027] R2 is selected from H, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl and substituted or unsubstituted C3-C 20 At least one of the cycloalkyl groups; substituted C1-C 12 Alkyl, substituted C2-C 12 Alkenyl and substituted C3-C 12 The substituent of the cycloalkyl group is selected from at least one of a C1-C6 alkyl group, a C2-C6 alkenyl group, and a C3-C8 cycloalkyl group;

[0028] Each R3 is independently selected from H, C1-C 12 At least one of an alkyl group, a nitro group, and a cyano group;

[0029] R4 is R5 is substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C6-C 12 Aryl and substituted or unsubstituted C1-C 12 At least one of the alkoxy groups, substituted C1-C 12 Alkyl, substituted C6-C 12 Aryl and substituted C1-C 12 The substituent of the alkoxy group is at least one selected from a hydroxy group, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a C2-C8 acyloxy group.

[0030] In the present invention, in order to improve the activity of the thiazole amide compound, preferably, in the compound represented by formula (1), R1 is selected from substituted or unsubstituted C1-C 15 Alkyl, substituted or unsubstituted C6-C 15 aryl and substituted or unsubstituted C3-C 15 At least one of the heterocyclic groups;

[0031] Substituted C1-C 15 Alkyl, substituted C6-C 15 Aryl and substituted C3-C 15 The substituent of the heterocyclic group is selected from at least one of C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, hydroxy, halogen, C3-C8 epoxyalkyl and R4; the heteroatom in the heterocyclic group is selected from at least one of O, N and S, and the number of heteroatoms is 1-4;

[0032] R2 is selected from H, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C2-C 10 Alkenyl and substituted or unsubstituted C3-C 10 At least one of the cycloalkyl groups; substituted C1-C 10 Alkyl, substituted C2-C 10 Alkenyl and substituted C3-C 10 The substituent of the cycloalkyl group is selected from at least one of a C1-C6 alkyl group, a C2-C6 alkenyl group, and a C3-C8 cycloalkyl group;

[0033] Each R3 is independently selected from at least one of H, C1-C6 alkyl and nitro;

[0034] In R4, R5 is a substituted or unsubstituted C1-C 10Alkyl, substituted or unsubstituted C6-C 10 Aryl and substituted or unsubstituted C1-C 10 At least one of the alkoxy groups, substituted C1-C 10 Alkyl, substituted C6-C 10 Aryl and substituted C1-C 10 The substituent of the alkoxy group is at least one selected from a hydroxy group, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a C2-C8 acyloxy group.

[0035] In the present invention, preferably, R1 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted quinolinone, substituted or unsubstituted C1-C 10 at least one of substituted or unsubstituted alkyl, substituted or unsubstituted anthracenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted C3-C8 epoxyalkyl, substituted or unsubstituted C3-C8 episulfanyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted quinolinyl and substituted or unsubstituted benzofuranyl, substituted phenyl, substituted quinolinone, substituted C1-C8 10 The substituents of the alkyl, substituted anthracenyl, substituted pyridyl, substituted pyridazinyl, substituted C3-C8 epoxyalkyl, substituted C3-C8 episulfanyl, substituted benzothiophenyl, substituted quinolinyl and substituted benzofuranyl are selected from CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -CH2CH2CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)CH2CH3, -C(CH3)2CH2CH3, -CH2CH2CH2CH2 At least one of CH2CH3, -CH2CH(CH3)CH2CH2CH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2, -OCH(CH3)CH2CH3, -OC(CH3)3, -CF3, -CCl3, -CH2F, -CH2Cl, -CH2Br, -CH2I, -CH2CH2F, -CH2CH2Cl, -CH2CH2Br, -CH2CH2I, hydroxyl, F, Cl, Br, I, C3-C6 alkylene oxide and R4;

[0036] R2 is selected from at least one of H, CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)CH2CH3, -C(CH3)2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH(CH3)CH2CH3, -C(CH3)2CH2CH3, -CH2CH2CH2CH2CH2CH3 and -CH2CH(CH3)CH2CH2CH3;

[0037] each R3 is independently selected from at least one of H, CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, and nitro;

[0038] In R4, R5 is CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, or a substituted or unsubstituted phenyl group; the substituent of the substituted phenyl group is selected from at least one of hydroxyl, acetoxy, propionyloxy, butyryloxy, CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3 and -OCH(CH3)2.

[0039] In the present invention, the modification of the nitazoxanide structure can be carried out from three aspects. First, the aromatic structure in the nitazoxanide structure can be modified with an acyloxy group to achieve the purpose of improving the biological activity of the amide thiazole compound. For this purpose, preferably, case 1: in the compound represented by formula (1), R1 is

[0040] wherein R6 is selected from substituted or unsubstituted phenylene, and the substituent of the substituted phenylene is selected from at least one of CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CF3, -CCl3, -CH2F, -CH2Cl, -CH2Br, -CH2I, -CH2CH2F, -CH2CH2Cl, -CH2CH2Br, -CH2CH2I, hydroxyl, F, Cl, Br and I;

[0041] Preferably, the amide thiazole compound is a compound represented by formula (1-1);

[0042] Formula (1-1):

[0043] In the present invention, preferably, the compound represented by formula (1) is selected from at least one of the following formulae:

[0044] Formula (d1): Formula (d2):

[0045] Formula (d3): Formula (d4):

[0046] Formula (d5): Formula (d6):

[0047] Formula (d7): Formula (d8):

[0048] Formula (d9): Formula (d10):

[0049] Formula (d11): Formula (d12):

[0050] Formula (d13): Formula (d14):

[0051] In the present invention, in order to improve the biological activity of the amide thiazole compound, the nitazoxanide structure can also be modified with a corresponding quinolinone group. According to a preferred implementation method, case 2: in the compound represented by formula (1), R1 is a substituted or unsubstituted quinolinone group; the substituent of the substituted quinolinone group is selected from at least one of CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)CH2CH3, -C(CH3)2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH(CH3)CH2CH2CH, F, Cl, Br, I and hydroxyl;

[0052] In the present invention, preferably, the amide thiazole compound is a compound represented by formula (1-2);

[0053] Formula (1-2):

[0054] Wherein, R7 is H, CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)CH2CH3, -C(CH3)2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH(CH3)CH2CH3, -C(CH3)2CH2CH3, -CH2CH2CH2CH2CH2CH3 or -CH2CH(CH3)CH2CH2CH, and each R8 is independently selected from at least one of H, F, Cl, Br, I and hydroxyl.

[0055] In the present invention, preferably, the compound represented by formula (1) is selected from at least one of the following compounds:

[0056] Formula (h1): Formula (h2):

[0057] Formula (h3): Formula (h4):

[0058] According to another preferred embodiment, case three: in the compound represented by formula (1), R1 is at least one selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted anthracenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted C3-C8 epoxyalkyl, substituted or unsubstituted C3-C8 episulfanyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted quinolyl and substituted or unsubstituted benzofuranyl;

[0059] The substituents of the substituted C1-C6 alkyl, substituted phenyl, substituted anthracenyl, substituted pyridyl, substituted pyridazinyl, substituted C3-C8 epoxyalkyl, substituted C3-C8 episulfanyl, substituted benzothiophenyl, substituted quinolinyl and substituted benzofuranyl are selected from CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -OCH3, -OCH2CH3, -OCH2CH 2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2, -OCH(CH3)CH2CH3, -OC(CH3)3, -CF3, -CCl3, -CH2F, -CH2Cl, -CH2Br, -CH2I, -CH2CH2F, -CH2CH2Cl, -CH2CH2Br, -CH2CH2I, hydroxyl, F, Cl, Br, I, C3-C6 epoxyalkyl and hydroxybenzoyl; the hydroxybenzoyl is optionally substituted by a C1-C6 alkyl.

[0060] In the present invention, preferably, R1 is selected from at least one of the following j1-j30 groups:

[0061]

[0062]

[0063] In the present invention, preferably, the compound represented by formula (1) is selected from at least one of the following compounds; Formula (j1): Formula (j2): Formula (j3): Formula (j4): Formula (j5): Formula (j6): Formula (j7): Formula (j8): Formula (j9): Formula (j10): Formula (j11): Formula (j12): Formula (j13): Formula (j14): Formula (j15): Formula (j16):

[0064] Formula (j17): Formula (j18):

[0065] Formula (j19): Formula (j20):

[0066] Formula (j21): Formula (j22):

[0067] Formula (j23): Formula (j24):

[0068] Formula (j25): Formula (j26):

[0069] Formula (j27): Formula (j28):

[0070] Formula (j29): Formula (j30):

[0071] In the present invention, the inventors have found that by limiting the R1 group in the compound represented by formula (1), a compound with better performance can be obtained. Preferably, in the compound represented by formula (1), R1 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted quinolinone and substituted or unsubstituted benzothiophenyl, and the substituents of the substituted phenyl, substituted quinolinone and substituted benzothiophenyl are selected from at least one of F, C1-C6 alkyl, hydroxyl, C2-C6 acyloxy and C1-C6 alkoxy; more preferably, the substituents are selected from F, CH3, -CH2CH3, -CH2CH2CH3, At least one of -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)CH2CH3, -C(CH3)2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH(CH3)CH2CH2CH, hydroxyl, acetoxy, propionyloxy, butyryloxy, -OCH3, -OCH2CH3, -OCH2CH2CH3 and -OCH(CH3)2.

[0072] In the present invention, preferably, R1 is selected from at least one of the following groups;

[0073]

[0074] The second aspect of the present invention provides a method for preparing the amide thiazole compound according to the first aspect of the present invention, the method comprising:

[0075] The compound represented by formula (A) is contacted with the compound represented by formula (B) to prepare an amide thiazole compound;

[0076] Formula (A): Formula (B):

[0077] Wherein, R is selected from at least one of C1-C6 alkoxy, halogen and hydroxyl.

[0078] In the present invention, preferably, when R is selected from halogen, the conditions of the contact reaction include: temperature of 0-40°C and time of 6-24h; more preferably, the conditions of the contact reaction include: temperature of 0-30°C and time of 10-20h.

[0079] In the present invention, when R is selected from halogen, the above preparation method can prepare the amide thiazole compound described in Case 1. Preferably, the contact reaction is a first condensation reaction, which is achieved by combining the acyl halide carbonyl carbon in the compound represented by formula (A) with the amino group in the compound represented by formula (B) to form an amide bond to prepare the amide thiazole compound.

[0080] In the present invention, to ensure efficient formation of the amide bond, the first condensation reaction is preferably carried out in the presence of a first catalyst, wherein the first catalyst is selected from at least one of 4-dimethylaminopyridine (DMAP), 4-pyrrolidinylpyridine, and imidazole. More preferably, the molar ratio of the compound represented by formula (A) to the first catalyst is 1:0.01-1, preferably 1:0.02-0.5, for example, 1:0.02, 1:0.04, 1:0.1, 1:0.5, and any range therebetween.

[0081] In the present invention, to neutralize the acid released by the formation of the amide bond, the first condensation reaction is carried out in the presence of a first alkaline agent. Preferably, the first alkaline agent is selected from at least one of triethylamine (Et3N), N,N-diisopropylethylamine (DIPEA), and pyridine. More preferably, the molar ratio of the compound represented by formula (A) to the first alkaline agent is 1:0.5-4, preferably 1:1-3, for example, 1:1, 1:2, 1:3, and any range therebetween.

[0082] In the present invention, preferably, the first condensation reaction is carried out in the presence of a first solvent, wherein the first solvent is selected from at least one of tetrahydrofuran (THF), diethyl ether, and dichloromethane (DCM). More preferably, the mass ratio of the compound represented by formula (A) to the first solvent is 1:10-40, preferably 1:15-25, for example, 1:15, 1:18, 1:20, 1:25, and any range therebetween.

[0083] In the present invention, preferably, when R is selected from halogen, the first condensation reaction further includes post-treatment; the post-treatment includes: after the reaction is completed, the reaction solution is filtered, extracted with EA, washed with 1-3M hydrochloric acid, saturated NaHCO3 and saturated brine, dried with anhydrous sodium sulfate, desolvated under reduced pressure, and purified by column chromatography (the purification solution can be, for example, PE:EA:THF=5:1:1) to obtain the compound shown in formula (1).

[0084] In the present invention, R is a halogen. When preparing the amide thiazole compound described in the first embodiment, preferably, the compound represented by formula (A) can be prepared by the following method, comprising: sequentially subjecting the compound represented by formula (a) to a second acylation reaction with a second acylating agent, and then to an acyl halide reaction with an acyl halide agent;

[0085] Formula (a):

[0086] In the present invention, preferably, the second acylation reaction is carried out by reacting the hydroxyl group in the compound represented by formula (a) with a second acylating agent to obtain the compound represented by formula (b), so as to ensure the stability of subsequent reactions;

[0087] Formula (b):

[0088] In the present invention, preferably, the conditions for the second acylation reaction include: temperature of 20-40°C, time of 3-24h; more preferably, the conditions for the second acylation reaction include: temperature of 25-35°C, time of 10-20h.

[0089] In the present invention, preferably, the second acylating agent is selected from at least one of acetic anhydride, propionic anhydride, and butyric anhydride. More preferably, the molar ratio of the compound represented by formula (a) to the second acylating agent is 1:5-20, preferably 1:8-15, for example, 1:8, 1:9, 1:10, 1:12, 1:15, and any range therebetween.

[0090] In the present invention, preferably, the second acylation reaction is carried out in the presence of a second alkaline agent, wherein the second alkaline agent is selected from at least one of triethylamine (Et3N), N,N,N',N'-tetramethylethylenediamine (TMEDA), pyridine, and N,N-diisopropylethylamine (DIPEA). More preferably, the molar ratio of the compound represented by formula (a) to the second alkaline agent is 1:0.5-5, preferably 1:1-3, for example, 1:1, 1:2, 1:3, and any range therebetween.

[0091] In the present invention, preferably, the second acylation reaction is carried out in the presence of a second solvent, wherein the second solvent is selected from at least one of tetrahydrofuran (THF), diethyl ether, and dichloromethane (DCM). More preferably, the mass ratio of the compound represented by formula (a) to the first solvent is 1:10-30, preferably 1:15-25, for example, 1:15, 1:19, 1:20, 1:23, 1:25, and any range therebetween.

[0092] In the present invention, preferably, the second acylation reaction further includes a purification treatment; the purification treatment includes: after the reaction is completed, acidifying with hydrochloric acid (for example, 1M hydrochloric acid), extracting with EA, washing with saturated brine, adding anhydrous sodium sulfate for drying, desolvating under reduced pressure, and recrystallizing with EA-PE to obtain a white solid, thereby preparing a compound represented by formula (b).

[0093] In the present invention, preferably, the acyl halide reaction comprises: reacting the compound represented by formula (b) with an acyl halide reagent in the presence of a second catalyst to produce the compound represented by formula (A). Specifically, the ester group in the compound represented by formula (b) is converted into an acyl halide group by the acyl halide reagent.

[0094] In the present invention, preferably, the conditions for the acyl halide reaction include: temperature of 20-40° C., and time of 1-5 h; more preferably, the conditions for the acyl halide reaction include: temperature of 25-35° C., and time of 2-4 h.

[0095] In the present invention, preferably, the second catalyst is selected from at least one of N,N-dimethylformamide (DMF), dimethyl sulfoxide, and hexamethylphosphoramide. More preferably, the molar ratio of the compound represented by formula (b) to the second catalyst is 1:0.01-0.5, preferably 1:0.01-0.2, for example, 1:0.01, 1:0.05, 1:0.2, and any range therebetween.

[0096] In the present invention, preferably, the acyl halide reagent is selected from at least one of oxalyl chloride, thionyl chloride, and phosphorus trichloride. More preferably, the molar ratio of the compound represented by formula (b) to the acyl halide reagent is 1:0.5-5, preferably 1:1.5-3.5, for example, 1:1.5, 1:2, 1:3, 1:3.5, and any range therebetween.

[0097] In the present invention, preferably, the acyl halide reaction is carried out in the presence of a third solvent, wherein the third solvent is selected from at least one of tetrahydrofuran (THF), diethyl ether, and dichloromethane (DCM). More preferably, the mass ratio of the compound represented by formula (b) to the third solvent is 1:10-30, preferably 1:15-25, for example, 1:15, 1:20, 1:25, and any range therebetween.

[0098] In the present invention, preferably, the acyl halide reaction includes purifying the reaction solution; the purification process includes: after the reaction is completed, desolventizing and preparing the compound represented by formula (A).

[0099] In the present invention, when R is selected from halogen, the specific reaction process for preparing the amide thiazole compound described in the first embodiment is as follows:

[0100]

[0101] R1-R3 in the compound represented by the reaction product formula (1) are provided by corresponding groups in the compound represented by formula (a), the compound represented by formula (b), the compound represented by formula (A) and the compound represented by formula (B), and the reagents, reaction conditions and amounts of each raw material involved in the reaction formula can be appropriately selected from the reagents, reaction conditions and amounts of each raw material described in the preparation method of the amide thiazole compound described in the above-mentioned case 1, and the present invention will not be repeated here.

[0102] In the present invention, when R is selected from halogen, the preparation method can also prepare some of the amide thiazole compounds described in situation 3. For example, the compounds represented by formula (j5) to (j8) can be prepared. The specific process is as follows:

[0103]

[0104] The R1-R3 in the compound represented by the reaction product formula (1) are provided by the corresponding groups in the compound represented by the formula (A) and the compound represented by the formula (B), and the reagents, reaction conditions and amounts of each raw material involved in the reaction formula can be appropriately selected from the reagents, reaction conditions and amounts of each raw material described in the preparation method of the amide thiazole compound when R is selected from halogen, and the present invention will not be repeated here.

[0105] In the present invention, preferably, when R is selected from C1-C6 alkoxy, the contact reaction conditions include: temperature of 120-180°C and time of 10-24h; more preferably, the contact reaction conditions include: temperature of 140-160°C and time of 11-14h.

[0106] In the present invention, when R is selected from a C1-C6 alkoxy group, the above preparation method can prepare the amide thiazole compound described in the second case.

[0107] In the present invention, when R is selected from a C1-C6 alkoxy group, the contact reaction is a second condensation reaction, which is prepared by replacing the hydroxyl group in the compound represented by formula (A") with the amide group in the compound represented by formula (B);

[0108] Formula (A"):

[0109] In the present invention, preferably, the second condensation reaction is carried out in the presence of a fourth solvent, wherein the fourth solvent is selected from at least one of dimethylformamide (DMF), N-methylpyrrolidone (NMP), and N,N-dimethylacetamide (DMAC). More preferably, the mass ratio of the compound represented by formula (A") to the fourth solvent is 1:5-35, preferably 1:15-30, for example, 1:15, 1:20, 1:25, 1:30, and any range therebetween.

[0110] In the present invention, preferably, the compound represented by formula (A") can be prepared by the following method:

[0111] (1) alkylating the compound represented by formula (a') with the compound represented by formula (b') to prepare the compound represented by formula (c');

[0112] (2) deprotecting the ester protecting group in the compound represented by formula (c') to restore the hydroxyl group to prepare the compound represented by formula (A");

[0113] Formula (a'): Formula (b'): R7-X; Formula (c'):

[0114] Wherein, X is a halogen.

[0115] In the present invention, the alkylation reaction is a nucleophilic substitution reaction of the nitrogen atom of the amide group in the compound represented by formula (a') to form an alkylated amino group, thereby connecting the R6 group in the compound represented by formula (b') with the compound represented by formula (a') to prepare the compound represented by formula (c).

[0116] In the present invention, preferably, the conditions for the alkylation reaction include: temperature of 0-40° C., and time of 15-30 h; more preferably, the conditions for the alkylation reaction include: temperature of 0-30° C., and time of 10-25 h.

[0117] In the present invention, the alkylation reaction is preferably carried out in the presence of a third alkaline agent, wherein the third alkaline agent is selected from at least one of NaH, NaOH, and KOH. More preferably, the molar ratio of the compound represented by formula (a') to the third alkaline agent is 1:0.5-4, preferably 1:1-3, for example, 1:1, 1:2, 1:3, and any range therebetween.

[0118] In the present invention, the alkylation reaction is preferably carried out in the presence of a fifth solvent, wherein the fifth solvent is selected from at least one of dimethylformamide (DMF), N-methylpyrrolidone (NMP), and N,N-dimethylacetamide (DMAC). More preferably, the mass ratio of the compound represented by formula (a') to the fifth solvent is 1:5-15, for example, 1:8-12, for example, 1:8, 1:9, 1:10, 1:12, and any range therebetween.

[0119] In the present invention, preferably, the alkylation reaction includes a purification treatment; the purification treatment includes: after the reaction is completed, adding water to the reaction solution and extracting with ethyl acetate, washing the organic phase with saturated brine, drying over anhydrous sodium sulfate, and separating by column chromatography (the eluent can be, for example, a mixed solvent of petroleum ether PE / ethyl acetate EA with a volume ratio of 2-6:1, preferably a mixed solvent of petroleum ether PE / ethyl acetate EA with a volume ratio of 5:1) to obtain the compound represented by formula (c').

[0120] In the present invention, preferably, the conditions for the deprotection reaction include: temperature of 0-10°C, time of 5-12 h; more preferably, the conditions for the deprotection reaction include: temperature of 0-5°C, time of 6-10 h.

[0121] In the present invention, preferably, the deprotecting agent used in the deprotection reaction is selected from at least one of diethyl malonate, acetic anhydride, acetyl chloride, acetyl bromide, and chloroformate. More preferably, the molar ratio of the compound represented by formula (c') to the deprotecting agent is 1:5-15, preferably 1:8-12, for example, 1:8, 1:9, 1:10, 1:12, and any range therebetween.

[0122] In the present invention, the deprotection reaction is carried out in the presence of a fourth alkaline agent. Preferably, the fourth alkaline agent is selected from at least one of NaH, NaOH, and KOH. More preferably, the molar ratio of the compound represented by formula (c') to the fourth alkaline agent is 1:0.8-2, preferably 1:1-1.5, for example, 1:1, 1:1.2, 1:1.5, and any range therebetween.

[0123] In the present invention, preferably, the deprotection reaction is carried out in the presence of a sixth solvent, wherein the sixth solvent is selected from at least one of dimethylformamide (DMF), N-methylpyrrolidone (NMP), and N,N-dimethylacetamide (DMAC). More preferably, the mass ratio of the compound represented by formula (c') to the sixth solvent is 1:4-20, preferably 1:6-15, for example, 1:6, 1:7, 1:10, 1:15, and any range therebetween.

[0124] In the present invention, preferably, the deprotection reaction includes a purification treatment; the purification treatment includes: after the reaction is completed, quenching with water, acidifying by dropwise addition of concentrated hydrochloric acid, extracting with ethyl acetate, washing with saturated brine, adding anhydrous sodium sulfate for drying, and purifying by column chromatography (the eluent can be, for example, a mixed solvent of petroleum ether PE / ethyl acetate EA with a volume ratio of 2-6:1, preferably a mixed solvent of petroleum ether PE / ethyl acetate EA with a volume ratio of 5:1) to obtain the compound represented by formula (A").

[0125] In the present invention, when R is selected from a C1-C6 alkoxy group, the specific reaction process for preparing the amide thiazole compound described in the second scenario is as follows:

[0126]

[0127] R7 and R8 in the compound represented by the reaction product formula (1-2) are provided by the corresponding groups in the compound represented by formula (a') and the compound represented by formula (b'), and the reagents, reaction conditions and amounts of each raw material involved in the reaction formula can be appropriately selected from the reagents, reaction conditions and amounts of each raw material described in the preparation method of the amide thiazole compound described in the above-mentioned case 2, and the present invention will not be repeated here.

[0128] In the present invention, preferably, when R is a hydroxyl group, the contact reaction conditions include: temperature of 20-40°C and time of 3-8 hours; more preferably, the contact reaction conditions include: temperature of 25-35°C and time of 4-7 hours.

[0129] In the present invention, when R is a hydroxyl group, the above preparation method can prepare the amide thiazole compound described in the third situation. Preferably, the contact reaction is the third condensation reaction.

[0130] In the present invention, the third condensation reaction is to connect the hydroxy acid group in the compound represented by formula (A'') with the amide group in the compound represented by formula (B) in the presence of a third catalyst to prepare the amide thiazole compound;

[0131] Formula (A'):

[0132] In the present invention, the third catalyst is selected from at least one of 4-dimethylaminopyridine (DMAP), 4-pyrrolidinylpyridine, and imidazole. More preferably, the molar ratio of the compound represented by formula (B) to the third catalyst is 1:1-5, preferably 1:2-4, for example, 1:2, 1:3, 1:4, and any range therebetween.

[0133] In the present invention, to promote the third condensation reaction, the third condensation reaction is carried out in the presence of a fifth alkaline agent. Preferably, the fifth alkaline agent is selected from at least one of triethylamine, N,N-diisopropylethylamine (DIPEA), and pyridine. More preferably, the molar ratio of the compound represented by formula (B) to the fifth alkaline agent is 1:1-5, preferably 1:2-4, for example, 1:2, 1:3, 1:4, and any range therebetween.

[0134] In the present invention, preferably, the third condensation reaction is carried out in the presence of a seventh solvent, wherein the seventh solvent is selected from at least one of dimethylformamide (DMF), N-methylpyrrolidone (NMP), and N,N-dimethylacetamide (DMAC). More preferably, the mass ratio of the compound represented by formula (B) to the seventh solvent is 1:5-30, preferably 1:10-25, for example, 1:10, 1:13, 1:20, 1:25, and any range therebetween.

[0135] In the present invention, preferably, the third condensation reaction includes post-treatment; the post-treatment includes: after the reaction is completed, extracting the reaction solution with EA, washing it with HCl solution (for example, 1-3M HCl solution), saturated NaHCO3 solution and saturated NaCl solution respectively, adding Na2SO4 to dry, desolvating under reduced pressure, recrystallizing it with ethyl acetate, and filtering to obtain the compound represented by formula (1).

[0136] In the present invention, preferably, the compound represented by formula (A') is activated before the third condensation reaction. The activation treatment comprises: reacting the carboxylic acid group in the compound represented by formula (A') with a condensation reagent to form an active ester intermediate, and then adding a stabilizer to prevent its decomposition.

[0137] In the present invention, preferably, the activation treatment conditions include: temperature of 20-40°C, time of 0.3-2h; more preferably, the activation treatment conditions include: temperature of 25-35°C, time of 0.5-1h.

[0138] In the present invention, preferably, the condensation reagent is selected from at least one of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), dicyclohexylcarbodiimide (DCC), and diisopropylcarbodiimide (DIC). More preferably, the molar ratio of the compound represented by formula (A') to the condensation reagent is 1:0.5-5, preferably 1:1-3, for example, 1:1:1:1.5, 1:3, and any range therebetween.

[0139] In the present invention, preferably, the stabilizer is 1-hydroxybenzotriazole (HOBT); more preferably, the molar ratio of the compound represented by formula (A') to the stabilizer is 1:0.5-5, preferably 1:1-3, for example, it can be 1:1:1:1.5, 1:3 and the like and any range therebetween.

[0140] In the present invention, preferably, the activation reaction is carried out in the presence of an eighth solvent, wherein the eighth solvent is selected from at least one of dimethylformamide (DMF), N-methylpyrrolidone (NMP), and N,N-dimethylacetamide (DMAC). More preferably, the mass ratio of the compound represented by formula (A'") to the eighth solvent is 1:5-40, preferably 1:15-25, for example, 1:15, 1:18, 1:20, 1:25, and any range therebetween.

[0141] In the present invention, when R is a hydroxyl group, the specific reaction process for preparing the amide thiazole compound described in the third embodiment is as follows:

[0142]

[0143] The R1-R3 in the compound represented by the reaction product formula (1) are provided by the corresponding groups in the compound represented by the formula (A') and the compound represented by the formula (B), and the reagents, reaction conditions and amounts of each raw material involved in the reaction formula can be appropriately selected from the reagents, reaction conditions and amounts of each raw material described in the preparation method of the amide thiazole compound described in the above situation three, and the present invention will not be repeated here.

[0144] In the present invention, preferably, the preparation of R1 is C1-C 20 When the compound represented by formula (1) is alkyl, it can be obtained by replacing the compound represented by formula (A'') with a halogenated acyl salicylic acid and performing a third condensation reaction with the compound represented by formula (B). In this reaction, the reagents, reaction conditions and amounts of each raw material involved can be appropriately selected from the reagents, reaction conditions and amounts of each raw material described in the aforementioned third condensation reaction, and the present invention will not repeat them here. For example, the method for preparing the compound represented by formula (j1) may include: performing a third condensation reaction on p-fluoroacetylsalicylic acid and the compound represented by formula (B) to prepare the compound represented by formula (j1).

[0145] A third aspect of the present invention provides a method for preparing an amide thiazole compound, the method comprising: subjecting a compound represented by formula (C) to a first acylation reaction with a first acylating agent to prepare an amide thiazole compound;

[0146] Formula (C):

[0147] In the present invention, the method is applicable to the preparation of the amide thiazole compound described in Case 1, and is prepared by attacking the carbonyl carbon group in the first acylating agent with the hydroxyl group in the compound represented by formula (C) to obtain the amide thiazole compound.

[0148] In the present invention, preferably, the conditions for the first acylation reaction include: temperature: 20-40°C, time: 2-10h; more preferably, the conditions for the first acylation reaction include: temperature: 25-35°C, time: 3-6h.

[0149] In the present invention, preferably, the first acylating agent is selected from at least one of acetic anhydride, acetyl chloride, acetyl bromide, benzoyl chloride, and chloroformates. More preferably, the molar ratio of the compound represented by formula (C) to the first acylating agent is 1:2-10, preferably 1:5-8, for example, 1:5, 1:7, 1:8, and any range therebetween.

[0150] In the present invention, to improve the efficiency of the first acylation reaction, the first acylation reaction is carried out in the presence of a sixth alkaline reagent, wherein the sixth alkaline reagent is selected from at least one of triethylamine (Et3N), N,N,N',N'-tetramethylethylenediamine (TMEDA), pyridine, and N,N-diisopropylethylamine (DIPEA). More preferably, the molar ratio of the compound represented by formula (C) to the sixth alkaline reagent is 1:1-5, preferably 1:1.2-4, for example, 1:1.2, 1:1.3, 1:1.5, 1:4, and any range therebetween.

[0151] In the present invention, preferably, the first acylation reaction is carried out in the presence of a ninth solvent, wherein the ninth solvent is selected from at least one of tetrahydrofuran (THF), diethyl ether, and dichloromethane. More preferably, the mass ratio of the compound represented by formula (C) to the ninth solvent is 1:10-40, preferably 1:15-30, for example, 1:15, 1:20, 1:29, 1:30, and any range therebetween.

[0152] In the present invention, preferably, the first acylation reaction further includes post-treatment; the post-treatment includes: filtering the reaction solution, desolventizing the filtrate under reduced pressure, washing with dilute hydrochloric acid, extracting with ethyl acetate and then washing with saturated brine, adding anhydrous sodium sulfate for drying, and desolventizing to obtain the compound represented by formula (1).

[0153] In the present invention, preferably, the preparation method of the amide thiazole compound provided in the third aspect of the present invention has the following specific preparation process:

[0154]

[0155] The R1-R3 in the compound represented by the reaction product formula (1) are provided by the corresponding groups in the compound represented by the formula (C), and the reagents, reaction conditions and amounts of each raw material involved in the reaction formula can be appropriately selected from the reagents, reaction conditions and amounts of each raw material described in the method for preparing amide thiazole compounds provided in the third aspect of the present invention, and the present invention will not repeat them here.

[0156] In the present invention, each reaction raw material, acidic reagent, alkaline reagent, catalyst, etc. can be obtained by purchasing commercial products.

[0157] The fourth aspect of the present invention provides a use of the amide thiazole compound described in the first aspect of the present invention in preventing and controlling plant pathogens.

[0158] In the present invention, preferably, the plant pathogenic bacteria include at least one of Brassica rapa, Xanthomonas oryzae var. oryzae, Ralstonia solani, Angular leaf spot of cucumber, Xanthomonas citri var. citri and Pseudomonas syringae pv. oryzae bacterial leaf streak.

[0159] The amide thiazole compounds obtained by the above technical scheme have excellent biological activity. According to some preferred embodiments, the amide thiazole compounds have a certain anti-Cryptosporidium effect, and the inhibition rate of some compounds is higher than 70%; at a concentration of 50 mg / L, most amide thiazole compounds have a certain inhibitory effect on bacteria such as rice streak, rice bacterial blight, rice wilt, cabbage soft rot and citrus ulcer, and the fungicidal activity of some compounds can be higher than 90%.

[0160] The present invention will be described in detail below through examples.

[0161] Example 1

[0162] This example is used to illustrate the preparation process of the compounds represented by formula (d1)-(d14), which is as follows:

[0163] Method 1:

[0164]

[0165] The specific preparation method is as follows:

[0166] (1) At room temperature (25°C), 3 mmol of the compound represented by formula (C), 20 mmol of acetic anhydride, and 4 mmol of N,N,N',N'-tetramethylethylenediamine (TMEDA) were placed in 20 mL of tetrahydrofuran (THF) for a first acylation reaction for 4 h;

[0167] (2) After the reaction of step (1) is completed, the reaction solution is filtered, the filtrate is desolvated under reduced pressure, washed with dilute hydrochloric acid, extracted with ethyl acetate, washed with saturated brine, added with anhydrous sodium sulfate for drying, and desolvated under reduced pressure to prepare the compound represented by formula (1-1);

[0168] Among them, the compounds of formula (1-1) prepared by using the compound of formula (C) shown in Table 1 correspond to compounds of formula (d1), formula (d2), formula (d5), formula (d6), formula (d8), formula (d9), formula (d12) and formula (d13), and the yield of step (2) is shown in the following table;

[0169] Table 1

[0170]

[0171]

[0172] Method 2:

[0173]

[0174] The specific preparation method includes:

[0175] (1) At room temperature, 10 mmol of the compound represented by formula (a), 100 mmol of acetic anhydride, and 20 mmol of triethylamine (Et3N) were placed in 30 mL of tetrahydrofuran (THF) for a second acylation reaction for 18 h. After the reaction was completed, the mixture was acidified with 1 M hydrochloric acid, extracted with EA three times, washed with saturated brine, dried over anhydrous sodium sulfate, and desolvated under reduced pressure with EA-PE to obtain a white solid, thereby preparing the compound represented by formula (b);

[0176] (2) At room temperature, 10 mmol of the compound represented by formula (b), 15 mmol of dichlorothionyl, and 0.1 mmol of N,N-dimethylformamide (DMF) were placed in 30 mL of dichloromethane (DCM) and subjected to an acyl halide reaction for 3 h. After the reaction was completed, the solution was removed under reduced pressure to obtain the compound represented by formula (A);

[0177] (3) 6 mmol of the compound represented by formula (B) was dissolved in 25 mL of tetrahydrofuran (THF) solution, cooled to 0°C, and 18 mmol of triethylamine was added dropwise. 18 mmol of the compound represented by formula (A) was dissolved in 20 mL of tetrahydrofuran (THF), reacted at room temperature for 0.5 h, and then 0.1 mmol of 4-dimethylaminopyridine (DMAP) was added and reacted for another 24 h.

[0178] (4) After the reaction is completed, the mixture is filtered, extracted with EA, washed with 1 M hydrochloric acid, saturated NaHCO3 and saturated brine, respectively, dried over anhydrous sodium sulfate, desolvated under reduced pressure, and purified by column chromatography (PE:EA:THF=5:1:1) to obtain the compound represented by formula (1);

[0179] Among them, the compounds of formula (1) prepared by using the compound of formula (a) shown in Table 2 correspond to compounds of formula (d3), formula (d4), formula (d7), formula (d10), formula (d11) and formula (d14), and the yield of step (4) is shown in the following table;

[0180] Table 2

[0181]

[0182]

[0183] Example 2

[0184] This example is used to illustrate the preparation process of the compounds represented by formula (h1)-(h4), which is as follows:

[0185]

[0186] (1) At 0°C, 10 mmol of the compound represented by formula (a') (all purchased from Bid Pharmaceuticals) was placed in 20 mL of tetrahydrofuran (THF) solution, and 10 mmol of NaH was slowly added in batches and stirred for 1 hour. Then, 15 mmol of the compound represented by formula (b') (all purchased from Xiens) was added dropwise at room temperature (25°C, the same below) and stirred for 24 hours to carry out alkylation reaction. After the reaction, water was added to the reaction solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and separated by column chromatography (the eluent was a mixed solvent of petroleum ether PE / ethyl acetate EA with a volume ratio of 5:1) to obtain the compound represented by formula (c').

[0187] (2) At 0°C, 7.24 mmol of the compound represented by formula (c') and 7.24 mmol of NaH were placed in 20 ml of N,N-dimethylformamide (DMF) solution, and 72.4 mmol of diethyl malonate was slowly added and stirred for 6 hours to carry out a deprotection reaction; after the reaction was completed, water was added to quench the reaction, concentrated hydrochloric acid was added dropwise to acidify the reaction, the reaction mixture was extracted with ethyl acetate, washed with saturated brine, dried with anhydrous sodium sulfate, and purified by column chromatography (PE:EA=5:1) to obtain the compound represented by formula (A");

[0188] (3) 3.67 mmol of the compound represented by formula (A") and 4.04 mmol of the compound represented by formula (B) were placed in 20 ml of N,N-dimethylformamide (DMF) solution and stirred at 150°C for 12 hours to perform a second condensation reaction; after the reaction was completed, water was added for recrystallization, washed with ethanol and then with dichloromethane, and dried to obtain the compound represented by formula (1-2);

[0189] Among them, the compounds represented by formula (a') and the compound represented by formula (b) shown in Table 3 are used to prepare the compounds represented by formula (h1) to formula (h4), and the yields of step (3) are shown in the following table:

[0190] Table 3

[0191]

[0192] Example 3

[0193] This example is used to illustrate the preparation of compounds represented by formula (j4) and formula (j9)-(j30). The specific process is as follows:

[0194]

[0195] Specific preparation method:

[0196] (1) At room temperature, 10 mmol of the compound represented by formula (A') (all purchased from Bidex Pharmaceuticals) was placed in 30 mL of dimethylformamide (DMF) with stirring, and the activation reaction was carried out for 30 min.

[0197] (2) At room temperature, 10 mmol of the compound represented by formula (B) and 30 mmol of N,N-diisopropylethylamine (DIPEA) were placed in 20 mL of dimethylformamide (DMF), stirred for 30 min, and then 30 mmol of 4-dimethylaminopyridine (DMAP) was added and mixed with the product of step (1) to carry out a third condensation reaction for 6 h. After the reaction, the reaction solution was extracted with EA three times and then washed with 1 M HCl solution, saturated NaHCO3 solution and saturated NaCl solution respectively, dried by adding Na2SO4, desolvated under reduced pressure, recrystallized with ethyl acetate, and filtered to obtain the compound represented by formula (1);

[0198] Among them, the compounds represented by formula (A'') as shown in Table 4 are used to prepare the compounds represented by formula (1), which correspond to the compounds represented by formula (j4), (j8)-(j30), and the yields of step (2) are shown in Table 4:

[0199] Table 4

[0200]

[0201]

[0202]

[0203] Example 4

[0204] This example is used to illustrate the preparation method of the compound represented by formula (j1);

[0205] A similar method to Example 3 was used, except that the same molar amount of p-fluoroacetylsalicylic acid was used instead of the compound represented by formula (A''), to prepare the compound represented by formula (j1) (yield: 60%).

[0206] Example 5

[0207] This example is used to illustrate the preparation of compounds represented by formula (j5)-(j8), and the specific process is as follows:

[0208]

[0209] The specific preparation method includes:

[0210] (1) 6 mmol of the compound represented by formula (B) was dissolved in 25 mL of tetrahydrofuran (THF) solution, cooled to 0°C, and 18 mmol of triethylamine (Et3N) was added dropwise. 18 mmol of the compound represented by formula (A) was dissolved in 20 mL of THF, reacted at room temperature for 0.5 h, and then 0.1 mmol of 4-dimethylaminopyridine (DMAP) was added and reacted for another 20 h.

[0211] (2) After the reaction is completed, the mixture is filtered, extracted with EA, washed with 1M hydrochloric acid, saturated NaHCO3 and saturated brine, respectively, dried over anhydrous sodium sulfate, desolvated under reduced pressure, and purified by column chromatography (PE:EA:THF=5:1:1) to obtain the compound represented by formula (1);

[0212] Among them, the compounds represented by formula (A) as shown in Table 5 are used to prepare the compounds represented by formula (1) corresponding to the compounds represented by formula (j5)-(j8), and the yields of step (2) are shown in Table 5;

[0213] Table 5

[0214]

[0215]

[0216] Test Example 1

[0217] The anti-Cryptosporidium activity of the amide thiazole compounds prepared in the above examples was determined. The specific anti-Cryptosporidium activity test results of the amide nitrothiazole compounds are shown in Table 6.

[0218] Test method:

[0219] 1. According to 2×10 4 cells and 10 4 The infection model was established with a dose of oocysts per well.

[0220] 2. 3 h after infection, the medium was changed to wash away the uninvaded parasites, and 200 μL of 2% FBS1640 medium (final concentration of compound 10 μM, paromomycin 160 μM, DMSO 0.5%) was added to each well. The cells were cultured in a 37°C incubator for 41 h.

[0221] 3. Extract RNA and perform qPCR analysis of human and Cryptosporidium 18S. Calculate the inhibition rate based on the results of three replicates.

[0222] 4. The remaining compounds were tested against Cryptosporidium according to the above procedure.

[0223] Table 6

[0224] serial number Inhibition rate (%) serial number Inhibition rate (%) serial number Inhibition rate (%) serial number Inhibition rate (%) Formula d1 65 Formula d14 0 Formula j13 70 Formula J21 23 Formula d2 56 Formula h1 76 Formula j14 0 Formula J27 30 Formula d3 37 Formula h2 71 Type J15 70 Type J28 61 Formula d4 10 Formula j1 27 Type J16 27 Formula J29 53 Formula d5 56 Formula j4 40 Type J17 0 Type J30 0 Formula d6 0 Formula j5 26 Type j18 0 Nitazoxanide 42 Formula d7 22 Formula j6 36 Formula J19 30 Formula d8 48 Formula j7 0 Type J20 0 Formula d9 0 Formula j8 0 Formula J22 32 Formula d10 66 Formula j9 60 Formula J23 0 Formula d11 0 Type j10 66 Formula J24 25 Formula d12 49 Formula j11 54 Type J25 0 Formula d13 0 Formula j12 50 Formula J26 61

[0225] As can be seen from Table 6, most of the compounds prepared in the examples of the present invention have a certain anti-Cryptosporidium effect, and some compounds have an inhibition rate of more than 70%. In particular, when R1 in the compound represented by formula (1) is a substituted or unsubstituted phenyl group, a substituted or unsubstituted quinolinone group, or a substituted or unsubstituted benzothiophenyl group (the substituent is at least one of F, CH3, acetoxy, and hydroxyl), the amide thiazole compounds provided by the present invention have even better anti-Cryptosporidium activity.

[0226] Test Example 2

[0227] The anti-plant pathogen activity of the amide thiazole compounds prepared in the above examples was determined. The specific anti-plant pathogen activity test results of the amide nitrothiazole compounds are shown in Table 7.

[0228] Test method:

[0229] 1. Activation of bacterial strains: Take out the bacterial strains stored at -80℃ and streak them on the prepared NA medium plates. Then, invert and culture them in a constant temperature box at 28℃ in the dark until good, pure and single colonies grow.

[0230] 2. Prepare bacterial suspension: Transfer a single activated colony to sterilized NB liquid medium that has been cooled to room temperature. Incubate in the dark on a shaker at 28°C and 180 rpm. Adjust the incubation time based on the growth characteristics of the individual bacteria. Measure the OD value using a spectrophotometer and adjust the suspension to 1.0 using liquid NB medium. Shake thoroughly and set aside.

[0231] 3. Preparation of the drug stock solution: Weigh 5 mg of the drug to be tested using an analytical balance, add 1000 μL of DMSO to dissolve it, and use a vortex to mix to make a 5000 mg / L drug stock solution for use.

[0232] 4. Experimental Preparation: Spray a sterile 24-well plate with alcohol and place it in a clean bench. Turn on the UV sterilizer for at least 30 minutes. Sterilize the required pipette tips and liquid NB culture medium in an autoclave at 121°C for 25 minutes. After sterilization, spray the plate with alcohol and place it in a clean bench under UV sterilization for at least 30 minutes.

[0233] 5. Primary Screening Inhibition Rate Determination: Add a bacterial suspension with an OD value of 1.0 to liquid NB medium at a 1% inoculum volume. Shake well, then pipette 990 μL into a 24-well plate. After pipetting, transfer 10 μL of the test drug stock solution to three parallel wells. Set up three blank wells per 24-well plate with DMSO alone. After addition, seal the wells and incubate in a shaker at 28°C, 180 rpm, in the dark. Incubate for varying times depending on the growth characteristics of different bacteria. After incubation, measure absorbance using a microplate reader. Calculate the inhibition rate based on three replicates.

[0234] 6. Data processing: Corrected OD value = OD value of bacterial culture medium - OD value of sterile culture medium

[0235] Inhibition rate = (corrected OD value of the control culture medium - corrected OD value of the toxic culture medium) / corrected OD value of the control culture medium × 100%.

[0236] Table 7

[0237]

[0238]

[0239] As can be seen from Table 7, at a concentration of 50 mg / L, most of the compounds prepared in the examples of the present invention have a certain inhibitory effect on bacteria such as rice leaf streak, rice bacterial blight, rice wilt, cabbage soft rot and citrus canker, and the fungicidal activity of some compounds can be higher than 90%. In particular, when R1 in the compound represented by formula (1) is a substituted or unsubstituted phenyl group (the substituent is at least one of F, CH3 and CHO), the amide thiazole compounds provided by the present invention have a more excellent antibacterial effect.

[0240] In order to intuitively illustrate the performance and characterization process of the amide thiazole compounds prepared by the method of the present invention, the present invention exemplarily provides the identification results of the amide thiazole compounds prepared in the examples, including H NMR spectrum, C NMR spectrum, F NMR spectrum, high-resolution data, ee value of single-configuration compound, appearance properties and melting point, as shown in Table 8.

[0241] Table 8

[0242]

[0243]

[0244]

[0245]

[0246]

[0247] The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, various simple variations of the technical solution of the present invention may be made, including combining the various technical features in any other appropriate manner. These simple variations and combinations should also be regarded as disclosed in the present invention and fall within the scope of protection of the present invention.

Claims

1. An amide thiazole compound, characterized in that: The compound is a compound represented by formula (1); Formula (1): wherein R1 is selected from substituted or unsubstituted C1-C 20 Alkyl, substituted or unsubstituted C6-C 20 aryl and substituted or unsubstituted C3-C 20 At least one of the heterocyclic groups; Substituted C1-C 20 Alkyl, substituted C6-C 20 Aryl and substituted C3-C 20 The substituents of the heterocyclic group are selected from C1-C 10 Alkyl, C1-C 10 Alkoxy, C1-C 10 haloalkyl, hydroxyl, halogen, C3-C 10 At least one of an alkylene oxide and R4; the heteroatom in the heterocyclic group is selected from at least one of O, N and S, and the number of heteroatoms is 1-4; R2 is selected from H, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl and substituted or unsubstituted C3-C 20 At least one of the cycloalkyl groups; substituted C1-C 12 Alkyl, substituted C2-C 12 Alkenyl and substituted C3-C 12 The substituent of the cycloalkyl group is selected from at least one of a C1-C6 alkyl group, a C2-C6 alkenyl group, and a C3-C8 cycloalkyl group; Each R3 is independently selected from H, C1-C 12 At least one of an alkyl group, a nitro group, and a cyano group; R4 is R5 is substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C6-C 12 Aryl and substituted or unsubstituted C1-C 12 At least one of the alkoxy groups, substituted C1-C 12 Alkyl, substituted C6-C 12 Aryl and substituted C1-C 12 The substituent of the alkoxy group is at least one selected from a hydroxy group, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a C2-C8 acyloxy group.

2. The amide thiazole compound according to claim 1, wherein In the compound represented by formula (1), R1 is selected from substituted or unsubstituted C1-C 15 Alkyl, substituted or unsubstituted C6-C 15 aryl and substituted or unsubstituted C3-C 15 At least one of the heterocyclic groups; Substituted C1-C 15 Alkyl, substituted C6-C 15 Aryl and substituted C3-C 15 The substituent of the heterocyclic group is selected from at least one of C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, hydroxy, halogen, C3-C8 epoxyalkyl and R4; the heteroatom in the heterocyclic group is selected from at least one of O, N and S, and the number of heteroatoms is 1-4; R2 is selected from H, substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C2-C 10 Alkenyl and substituted or unsubstituted C3-C 10 At least one of the cycloalkyl groups; substituted C1-C 10 Alkyl, substituted C2-C 10 Alkenyl and substituted C3-C 10 The substituent of the cycloalkyl group is selected from at least one of a C1-C6 alkyl group, a C2-C6 alkenyl group, and a C3-C8 cycloalkyl group; Each R3 is independently selected from at least one of H, C1-C6 alkyl and nitro; In R4, R5 is a substituted or unsubstituted C1-C 10 Alkyl, substituted or unsubstituted C6-C 10 Aryl and substituted or unsubstituted C1-C 10 At least one of the alkoxy groups, substituted C1-C 10 Alkyl, substituted C6-C 10 Aryl and substituted C1-C 10 The substituent of the alkoxy group is at least one selected from a hydroxyl group, a C1-C6 alkyl group, a C1-C6 alkoxy group, and a C2-C8 acyloxy group; Preferably, R1 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted quinolinone, substituted or unsubstituted C1-C 10 at least one of substituted or unsubstituted alkyl, substituted or unsubstituted anthracenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted C3-C8 epoxyalkyl, substituted or unsubstituted C3-C8 episulfanyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted quinolinyl and substituted or unsubstituted benzofuranyl, substituted phenyl, substituted quinolinone, substituted C1-C8 10 substituted alkyl, substituted anthracenyl, substituted pyridyl, substituted pyridazinyl, substituted C3-C8 epoxyalkyl, substituted C3-C8 episulfanyl, substituted benzothiophenyl, substituted quinolinyl and substituted benzofuranyl The group is selected from CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)CH2CH3, -C(CH3)2CH2C H3, -CH2CH2CH2CH2CH2CH3, -CH2CH(CH3)CH2CH2CH, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2, -OCH(CH3)CH2CH3, -OC(CH3) 3、 At least one of -CF3, -CCl3, -CH2F, -CH2Cl, -CH2Br, -CH2I, -CH2CH2F, -CH2CH2Cl, -CH2CH2Br, -CH2CH2I, hydroxyl, F, Cl, Br, I, C3-C6 alkylene oxide and R4; R2 is selected from at least one of H, CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)CH2CH3, -C(CH3)2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH(CH3)CH2CH3, -C(CH3)2CH2CH3, -CH2CH2CH2CH2CH2CH3 and -CH2CH(CH3)CH2CH2CH3; each R3 is independently selected from at least one of H, CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, and nitro; In R4, R5 is CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, or a substituted or unsubstituted phenyl group; the substituent of the substituted phenyl group is selected from at least one of hydroxyl, acetoxy, propionyloxy, butyryloxy, CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3 and -OCH(CH3)2.

3. The amide thiazole compound according to claim 1 or 2, wherein Case 1: In the compound represented by formula (1), R1 is wherein R6 is selected from substituted or unsubstituted phenylene, and the substituent of the substituted phenylene is selected from at least one of CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -CF3, -CCl3, -CH2F, -CH2Cl, -CH2Br, -CH2I, -CH2CH2F, -CH2CH2Cl, -CH2CH2Br, -CH2CH2I, hydroxyl, F, Cl, Br and I; Preferably, the amide thiazole compound is a compound represented by formula (1-1); Formula (1-1): More preferably, the compound represented by formula (1) is selected from at least one of the following formulae:

4. The amide thiazole compound according to claim 1 or 2, wherein Case 2: In the compound represented by formula (1), R1 is a substituted or unsubstituted quinolinone group; the substituent of the substituted quinolinone group is selected from at least one of CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)CH2CH3, -C(CH3)2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH(CH3)CH2CH2, F, Cl, Br, I and hydroxyl group; Preferably, the amide thiazole compound is a compound represented by formula (1-2); Formula (1-2): wherein R7 is H, CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)CH2CH3, -C(CH3)2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH(CH3)CH2CH3, -C(CH3)2CH2CH3, -CH2CH2CH2CH2CH2CH3, or -CH2CH(CH3)CH2CH2CH, and each R8 is independently selected from at least one of H, F, Cl, Br, I, and hydroxyl; More preferably, the compound represented by formula (1) is selected from at least one of the following compounds:

5. The amide thiazole compound according to claim 2, wherein Case 3: In the compound represented by formula (1), R1 is at least one selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted anthracenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted C3-C8 epoxyalkyl, substituted or unsubstituted C3-C8 episulfanyl, substituted or unsubstituted benzothiophenyl, substituted or unsubstituted quinolyl and substituted or unsubstituted benzofuranyl; The substituents of the substituted C1-C6 alkyl, substituted phenyl, substituted anthracenyl, substituted pyridyl, substituted pyridazinyl, substituted C3-C8 epoxyalkyl, substituted C3-C8 episulfanyl, substituted benzothiophenyl, substituted quinolinyl and substituted benzofuranyl are selected from CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2, -OCH(CH3)CH2CH3, -OC(CH3) 3、 -CF3, -CCl3, -CH2F, -CH2Cl, -CH2Br, -CH2I, -CH2CH2F, -CH2CH2Cl, -CH2CH2Br, -CH2CH2I, hydroxyl, F, Cl, Br, I, C3-C6 epoxyalkyl and hydroxybenzoyl; the hydroxybenzoyl is optionally substituted with a C1-C6 alkyl; Preferably, R1 is selected from at least one of the following j1-j30 groups: More preferably, the compound represented by formula (1) is selected from at least one of the following compounds:

6. The amide thiazole compound according to claim 1 or 2, wherein In the compound represented by formula (1), R1 is selected from substituted or unsubstituted phenyl, substituted or unsubstituted quinolinone and substituted or unsubstituted benzothiophenyl, and the substituents of the substituted phenyl, substituted quinolinone and substituted benzothiophenyl are selected from at least one of F, C1-C6 alkyl, hydroxy, C2-C6 acyloxy and C1-C6 alkoxy; Preferably, the substituent is selected from at least one of F, CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH2CH2CH3, -CH2CH(CH3)2, -CH(CH3)CH2CH3, -C(CH3)3, -CH2CH2CH2CH2CH3, -CH2CH(CH3)CH2CH3, -C(CH3)2CH2CH3, -CH2CH2CH2CH2CH2CH3, -CH2CH(CH3)CH2CH2CH, hydroxyl, acetoxy, propionyloxy, butyryloxy, -OCH3, -OCH2CH3, -OCH2CH2CH3 and -OCH(CH3)2; More preferably, R1 is selected from at least one of the following groups; 7. A method for preparing the amide thiazole compound according to any one of claims 1 to 6, wherein: The method includes: The compound represented by formula (A) is contacted with the compound represented by formula (B) to prepare an amide thiazole compound; Wherein, R is selected from at least one of C1-C6 alkoxy, halogen and hydroxyl.

8. The preparation method according to claim 7, wherein When R is selected from halogen, the contact reaction conditions include: temperature of 0-40°C and time of 6-24h; And / or, when R is selected from C1-C6 alkoxy, the contact reaction conditions include: temperature of 120-180°C and time of 10-24h; And / or, when R is a hydroxyl group, the contact reaction conditions include: a temperature of 20-40° C. and a time of 3-8 hours.

9. A method for preparing an amide thiazole compound, characterized in that: The method comprises: performing a first acylation reaction on a compound represented by formula (C) and a first acylating agent to prepare an amide thiazole compound; Formula (C):

10. The preparation method according to claim 9, wherein The first acylating agent is selected from at least one of acetic anhydride, acetyl chloride, acetyl bromide, benzoyl chloride and chloroformates; Preferably, the conditions of the first acylation reaction include: temperature of 20-40° C. and time of 2-10 h.

11. Use of the amide thiazole compound according to any one of claims 1 to 6 in controlling plant pathogens; Preferably, the plant pathogens include at least one of Brassica rapa, Xanthomonas oryzae var. oryzae, R. solanacearum, Angular leaf spot of cucumber, Xanthomonas citri var. citri and Psoralea corylifolia of rice.

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