阅读说明：本技术 一类噻唑酰肼类化合物及其制备方法和应用 (Thiazole hydrazide compounds and preparation method and application thereof ) 是由 王培义 朱建军 黄正春 陈亚珍 宿芬 邵明政 程祖红 李楚楚 于 2021-06-29 设计创作，主要内容包括：本申请涉及一类噻唑酰肼类化合物及其制备方法和应用。该化合物具有如通式(I)所示的结构：该化合物对致病病原真菌和细菌具有较好的抑制作用,针对如：小麦赤霉病菌、马铃薯晚疫病菌、蓝莓根腐病菌、辣椒枯萎病菌、油菜菌核病菌、油菜炭疽病菌、葡萄座腔菌病菌、水稻纹枯病菌、水稻白叶枯病菌、烟草青枯病菌、柑桔溃疡病菌、猕猴桃溃疡病菌、黄瓜白叶枯病菌、魔芋白叶枯病菌、葡萄溃疡病菌、番茄溃疡病菌、苹果溃疡病菌等均具有较好的抑制效果。(The application relates to thiazole hydrazide compounds, a preparation method and application thereof. The compound has a structure shown as a general formula (I):)

1. A thiazole hydrazide compound or a stereoisomer thereof, or a salt or solvate thereof, wherein: the compound has a structure shown as a general formula (I):

wherein the content of the first and second substances,

R₁and R₂Each independently selected from one or more of optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl.

2. A thiazole hydrazide compound according to claim 1, or a stereoisomer thereof, or a salt or solvate thereof, wherein: r₁And R₂Each independently selected from one or more of hydrogen, deuterium, alkyl, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a heterocycle.

3. A thiazole hydrazide compound according to claim 1, or a stereoisomer thereof, or a salt or solvate thereof, wherein: r₁And R₂Each independently selected from hydrogen, deuterium, C₁-C₆Alkyl radical, C₁-C₆Alkenyl, substituted or unsubstituted C₆-C₁₅Aryl, substituted or unsubstituted C₆-C₁₀One or more of heteroaryl, wherein said substituted refers to being substituted by C₁-C₆Alkyl, halogen, phenyl, difluoromethyl, trifluoromethyl substituted; most preferably, R₁And R₂Each independently selected from the group consisting of hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, propenyl, allyl, butenyl, pentenyl, hexenyl, methoxy, ethoxy, propoxy, butoxy, phenyl, n-pentyl, n-hexyl, n-pentyl, n-hexyl, n-hexyl, n-butyl, n-hexyl, n-butyl, n-pentyl, n, benzyl, o-fluorobenzyl, m-fluorobenzyl, p-fluorobenzyl, o-bromobenzyl, m-bromobenzyl, p-bromobenzyl, o-chlorobenzyl, m-chlorobenzyl, p-chlorobenzyl, naphthyl, phenanthryl, pyridyl, o-fluoropyridyl, m-fluoropyridyl, o-bromopyridyl, o-chloropyridyl, o-fluorothienyl, m-fluorothienyl, o-fluorofuryl, o-fluorotetrahydrofuryl, m-fluorotetrahydrofuryl, o-bromothienyl, m-bromothienyl, o-bromofuryl, m-bromofuryl, o-bromotetrahydrofuryl, m-bromotetrahydrofuryl, o-chlorothioenyl, m-chlorothiofuryl, o-chlorofuryl, m-chlorofuryl, o-hydroxybenzyl, m-hydroxybenzyl, p-hydroxybenzyl, o-aminobenzyl, m-aminobenzyl, p-aminobenzyl, o-methylbenzyl, m-methylbenzyl, o-chlorobenzyl, One or more of p-methylbenzyl, o-hydroxypyridine, m-hydroxypyridine, p-hydroxypyridine, o-aminothiophene, m-aminothiophene, o-hydroxyfuran, m-hydroxyfuran, o-hydroxytetrahydrofuran, m-hydroxytetrahydrofuran, o-methylfuran, m-methylfuran, o-methyltetrahydrofuran, m-methyltetrahydrofuran, o-furanmethylene, m-furanmethylene, o-tetrahydrofurmethylene, and m-tetrahydrofurmethylene.

4. A thiazole hydrazide compound or a stereoisomer thereof, or a salt or solvate thereof according to claim 1, wherein said compound is selected from the following specific compounds:

5. an intermediate compound for preparing the compound of claim 1 or a stereoisomer thereof, or a salt or solvate thereof, characterized by the following:

wherein R is₁As claimed in claim 1.

6. A process for preparing a compound of claim 1 or a stereoisomer thereof, or a salt or solvate thereof, which comprises: compound (I)A step of producing a compound represented by the general formula (I) in the presence of various substituted hydrazines; further preferably comprising the steps of:

wherein R is₁And R₂As claimed in claim 1.

7. A composition characterized by comprising a compound of claim 1 or a stereoisomer thereof, or a salt or solvate thereof, and an agriculturally acceptable adjuvant or fungicide, insecticide or herbicide; preferably, the formulation of the composition is selected from Emulsifiable Concentrates (EC), Dusts (DP), Wettable Powders (WP), Granules (GR), Aqueous Solutions (AS), Suspension Concentrates (SC), ultra low volume sprays (ULV), Soluble Powders (SP), Microcapsules (MC), smoking agents (FU), aqueous Emulsions (EW), water dispersible granules (WG).

8. Use of a compound of claim 1 or a stereoisomer thereof, or a salt or solvate thereof, or a composition of claim 7, for controlling an agricultural pest, preferably a fungal or bacterial disease of a plant; more preferably, the agricultural pests are plant scab and plant leaf blight; most preferably, the agricultural pests are fusarium graminearum, potato late blight, blueberry root rot, pepper wilt, sclerotinia sclerotiorum, colletotrichum colza, botrytis cinerea, rhizoctonia solani, fusarium solani, tobacco ralstonia solani, citrus canker, kiwi canker, cucumber leaf blight, konjac leaf blight, grape canker, tomato canker and apple canker.

9. A method for controlling agricultural pests is characterized in that: allowing the compound according to claim 1 or a stereoisomer thereof, or a salt or solvate thereof, or the composition according to claim 7 to act on harmful substances or their living environments; preferably, the agricultural pest is a fungal or bacterial disease of a plant; more preferably, the agricultural pests and diseases are fusarium graminearum, potato late blight, blueberry root rot, pepper wilt, sclerotinia sclerotiorum, colletotrichum colza, botrytis cinerea, rhizoctonia solani, fusarium solani, tobacco ralstonia solani, citrus canker, kiwi canker, cucumber leaf blight, konjac leaf blight, grape canker, tomato canker, apple canker and eggplant verticillium wilt.

10. A method for protecting a plant from an agricultural pest comprising a method step wherein the plant is contacted with a compound of claim 1 or a stereoisomer thereof, or a salt or solvate thereof, or a composition of claim 7.

Technical Field

The invention relates to the technical field of medicinal chemistry, in particular to a thiazole-containing hydrazide compound and a preparation method and application thereof.

Background

In recent years, plant fungi and bacteria seriously affect the yield and quality of crops all over the world, and plant fungal diseases directly cause the yield reduction and the quality reduction of the crops, thereby bringing huge economic loss to farmers. For example, Gibberella saubinetii (Gibberella saubinetii) is a filamentous ascomycete, a disease caused by infection with many fusarium species, which occurs in wheat. The germs can cause seedling rot, stem rot, stalk rot and ear rot of wheat, and bring about 10-20% of yield reduction to the wheat planting countries every year. In addition, rice leaf blight (Xanthomonas oryzae, Oryzae) is a rod-shaped gram-negative bacterium that causes withering and whitening of rice leaves, which causes at least 10-50% reduction in yield per year in rice-growing countries. Citrus canker pathogen (Xanthomonas axonopodis pv. citri) causes decay of citrus, affecting citrus yield on a global scale. In the agricultural production process, due to the long-term use of the traditional medicament, phytopathogens have certain resistance to the traditional medicament. Therefore, the creation of novel, efficient, low-toxicity and safe green pesticide has very important significance.

Thiazole derivatives have been reported in the literature to exhibit a broad spectrum of biological activities, such as: antibacterial, antifungal, insecticidal, herbicidal, plant growth regulating, antitumor, and antiinflammatory etc. According to the previous work in this center, thiazole compounds showed better activity against phytopathogens. The nitrogen-containing heterocyclic compound has the characteristics of structural diversity and biological activity diversity, and draws wide attention in the fields of medicinal chemistry, pesticide chemistry and organic chemistry. On the other hand, molecules containing a hydrazide (-CO-NH-) skeleton exhibit biological activities such as bactericidal, insecticidal, antiviral, etc.

Therefore, in order to search for an active compound with high-efficiency sterilization, the thiazole hydrazide structure is used as a connecting chain to synthesize a series of thiazole hydrazide compounds with novel structures, and the biological activity of the thiazole hydrazide compounds is tested, so that an important scientific basis is provided for the research and development of new pesticides.

The study of the biological activity of thiazole derivatives has progressed as follows:

2019, Zuo et al [ Zuo, z.p.; chen, m.m.; shao, x.n.; qian, x.y.; liu, x.c.; zhou, x.; xiang, j.w.; deng, p.d.; li, Y.; jie, h.; liu, c.q.; cen, x.b.; xie, y.m.; ZHao, Y.L.design and biological evaluation of tetrahydropyridine derivatives as novel human GPR119 aginsts [ J].Bioorg.Med.Chem.Lett.，2019，126855.]A series of novel thiazole-containing tetrahydropyridine derivatives were prepared and evaluated by a cell method. Discovery of Compound 20 (EC)₅₀4.9nM) had high GPR119 agonistic activity and moderate clogP. Through single and long-term pharmacodynamic experiments, the compound 20 is found to have the effect of reducing blood sugar and possibly improving the basal metabolic rate of DIO mice. Both in vitro and in vivo experiments indicate that compound 20 is a potentially potent GPR119 agonist for the treatment of T2 DM.

The research on the biological activity based on hydrazide compounds has progressed as follows:

2017, Wang et al [ Wang, X.; dai, z.c.; chen, y.f.; cao, l.l.; yan, w.; li, s.k.; wang, j.x.; zhang, z.g.; ye, Y.H., Synthesis of 1, 2, 3-triazole hydrate derivative inhibiting-phytopathogenic activity, Eur.J.Med.chem.2017, 126, 171-.]The triazole hydrazide derivative is designed and synthesized, and preliminary biological activity tests show that the compound 14 has good antibacterial activity and EC for rice sheath blight fungus (R.solani) and wheat gibberella (F.graminearum)₅₀Respectively 0.18 +/-0.01 and 0.37 +/-0.020 mu g/mL, and has antibacterial activity superior to that of commercial bactericide carbendazim (EC)₅₀1.32. + -. 0.18, 0.60. + -. 0.050. mu.g/mL) respectively.

Disclosure of Invention

One of the purposes of the invention is to provide a thiazole hydrazide compound or a stereoisomer thereof, or a salt or a solvate thereof.

Another object of the present invention is to provide an intermediate compound for preparing the above compound or a stereoisomer thereof, or a salt or solvate thereof, and a preparation method thereof.

It is still another object of the present invention to provide a composition comprising the above compound or a stereoisomer thereof, or a salt or solvate thereof.

It is a further object of the present invention to provide the above compounds or stereoisomers thereof, or salts or solvates thereof, or the use of said compositions.

Another object of the present invention is to provide a method for controlling agricultural pests using the above compound or a stereoisomer thereof, or a salt or solvate thereof, or the composition.

In order to realize the purpose, the invention adopts the following technical scheme:

a thiazole hydrazide compound or a stereoisomer thereof, or a salt or a solvate thereof, wherein the compound has a structure shown as a general formula (I):

wherein the content of the first and second substances,

R₁one or more selected from the group consisting of optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl;

R₂one or more selected from the group consisting of hydrogen, deuterium, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkoxy, optionally substituted or unsubstituted aryl, and optionally substituted or unsubstituted heteroaryl;

preferably, R₁One or more selected from hydrogen, deuterium, alkyl, alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or heterocycle; more preferably, R₁Selected from hydrogen, deuterium, C₁-C₆Alkyl radical, C₁-C₆Alkenyl, substituted or unsubstituted C₆-C₁₅Aryl, substituted or unsubstituted C₆-C₁₀One or more of heteroaryl, wherein said substituted refers to being substituted by C₁-C₆Alkyl, phenyl, difluoromethyl, trifluoromethyl substituted; most preferably, R₁Selected from the group consisting of hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, propenyl, allyl, butenyl, pentenyl, hexenyl, methoxy, ethoxy, propoxy, butoxy, phenyl, chlorophenyl, bromophenyl, fluorophenyl, tolyl, aminophenyl, hydroxyphenyl, benzyl, o-fluorobenzyl, m-fluorobenzyl, p-fluorobenzyl, o-bromobenzyl, m-bromobenzyl, p-chlorobenzyl, o-chlorobenzyl, m-chlorobenzyl, p-chlorobenzyl, naphthyl, phenanthryl, pyridyl, o-fluoropyridyl, m-fluoropyridyl, o-bromopyridyl, m-bromopyridyl, o-chloropyridyl, m-fluoropyridyl, o-fluorothienyl, m-fluorothienyl, o-fluorofuryl, o-fluorotetrahydrofuryl, m-fluorofuryl, m-fluorotetrahydrofuryl, o-bromothienyl, m-bromothienyl, O-bromofuryl, m-bromofuryl, o-bromotetrahydrofuryl, m-bromotetrahydrofuryl, o-chlorothienyl, m-chlorothienyl, o-chlorofuryl, m-chlorofuryl, o-chlorotetrafuryl, o-hydroxybenzyl, m-hydroxybenzyl, p-hydroxybenzyl, o-aminobenzyl, m-aminobenzyl, p-aminobenzyl, o-methylbenzyl, m-methylbenzyl, p-methylbenzyl, o-hydroxypyridine, m-hydroxypyridinyl, p-hydroxypyridinyl, o-aminothienyl, m-aminothienyl, o-hydroxyfuryl, m-hydroxyfuryl, o-hydroxytetrahydrofuryl, m-hydroxytetrahydrofuryl, o-methylfuryl, m-methylfuryl, o-methyltetrahydrofuryl, m-methyltetrahydrofuryl, o-methyltetrahydrofuryl, m-tetrahydrofuryl, 2-indolyl, o-methylfuryl, o-methyltetrahydrofuryl, m-methyltetrahydrofuryl, o-methylfuryl, m-methyltetrahydrofuryl, o-tetrahydrofuryl, m-tetrahydrofuryl, 2-indolyl, One or more of N-methyl-2-pyrrolyl, 2-thiazolyl, 1-phenyl-3-trifluoromethyl-1H-pyrazolyl, 1-methyl-3-difluoromethyl-1H-pyrazolyl, benzimidazolyl;

preferably, R₂One or more selected from the group consisting of hydrogen, deuterium, alkyl, alkenyl, alkoxy, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; more preferablyEarth, R₂Selected from hydrogen, deuterium, C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Alkenyl, substituted or unsubstituted C₆-C₁₅Aryl, substituted or unsubstituted C₆-C₁₀One or more of heteroaryl, wherein said substituted refers to being substituted by C₁-C₆Alkyl radical, C₁-C₆Alkoxy radical, C₁-C₆Alkenyl, halogen substitution; most preferably, R₂Selected from the group consisting of hydrogen, deuterium, nitro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, propenyl, allyl, butenyl, pentenyl, hexenyl, propynyl, butynyl, pentynyl, hexynyl, methoxy, ethoxy, propoxy, butoxy, phenyl, chlorophenyl, bromophenyl, fluorophenyl, tolyl, aminophenyl, hydroxyphenyl, benzyl, o-fluorobenzyl, m-fluorobenzyl, p-fluorobenzyl, o-bromobenzyl, m-bromobenzyl, p-bromobenzyl, o-chlorobenzyl, m-chlorobenzyl, p-chlorobenzyl, naphthyl, phenanthryl, pyridyl, o-fluoropyridinyl, m-fluoropyridinyl, o-bromopyridyl, m-chloropyridyl, o-fluorothienyl, m-fluorothienyl, o-fluorofuryl, m-fluorofuryl, o-fluorotetrahydrofuryl, m-fluorotetrahydrofuryl, n-fluorofuryl, p-chlorobenzyl, p-fluorophenyl, o-chlorobenzyl, o-bromopyridyl, p-bromopyridyl, o-bromomethyl, o-bromopyridyl, o-bromofuryl, o-bromothienyl, m-bromothienyl, o-bromofuryl, m-bromofuryl, o-bromotetrahydrofuryl, m-bromotetrahydrofuryl, o-chlorothioenyl, m-chlorothioenyl, o-chlorofuryl, m-chlorofuryl, o-chlorotetrahydroffuryl, m-chlorotetrahydroffuryl, o-hydroxybenzyl, m-hydroxybenzyl, p-hydroxybenzyl, o-aminobenzyl, m-aminobenzyl, p-aminobenzyl, o-methylbenzyl, m-methylbenzyl, p-methylbenzyl, o-hydroxypyridine, m-hydroxypyridinyl, p-hydroxypyridinyl, o-aminothienyl, m-aminothienyl, o-hydroxyfuryl, m-hydroxyfuryl, o-hydroxytetrahydrofuryl, m-hydroxytetrahydrofuryl, o-methylfuryl, m-methylfuryl, o-methyltetrahydrofuryl, m-methyltetrahydrofuryl, o-furanmethylene, m-furanmethylene, o-tetrahydrofurmethylene, m-tetrahydrofurfuryl.One or more of methylene 2-indolyl, N-methyl-2-pyrrolyl, 2-thiazolyl, 1-phenyl-3-trifluoromethyl-1H-pyrazolyl, 1-methyl-3-difluoromethyl-1H-pyrazolyl, and benzimidazolyl.

An intermediate compound for preparing the compound or a stereoisomer thereof, or a salt or solvate thereof, as shown below:

wherein R is₁As described above.

A process for preparing the compound or a stereoisomer thereof, or a salt or solvate thereof, comprising: compound (I)A step of generating the compound shown in the general formula (I) in the presence of different substituted hydrazines.

The preparation method also comprises the following specific steps:

wherein R is₁And R₂As described above.

A composition comprising said compound or a stereoisomer thereof, or a salt or solvate thereof, and an agriculturally acceptable adjuvant or fungicide, insecticide or herbicide; preferably, the formulation of the composition is selected from Emulsifiable Concentrates (EC), Dusts (DP), Wettable Powders (WP), Granules (GR), Aqueous Solutions (AS), Suspension Concentrates (SC), ultra low volume sprays (ULV), Soluble Powders (SP), Microcapsules (MC), smoking agents (FU), aqueous Emulsions (EW), water dispersible granules (WG).

The compound or the stereoisomer thereof, or the salt or the solvate thereof, or the composition can be used for controlling agricultural pests, preferably fungal or bacterial plant diseases; more preferably, the agricultural pests are plant scab and plant leaf blight; most preferably, the agricultural pests are fusarium graminearum, potato late blight, blueberry root rot, pepper wilt, sclerotinia sclerotiorum, colletotrichum colza, botrytis cinerea, rhizoctonia solani, fusarium solani, tobacco ralstonia solani, citrus canker, kiwi canker, cucumber leaf blight, konjac leaf blight, grape canker, tomato canker and apple canker.

A method for controlling agricultural pests by allowing said compound or a stereoisomer thereof, or a salt or solvate thereof, or said composition to act on the pests or their living environment; preferably, the agricultural pest is a fungal or bacterial disease of a plant; more preferably, the agricultural pests and diseases are fusarium graminearum, potato late blight, blueberry root rot, pepper wilt, sclerotinia sclerotiorum, colletotrichum colza, botrytis cinerea, rhizoctonia solani, rice leaf blight, tobacco ralstonia solani, citrus canker, kiwi canker, cucumber leaf blight, konjac leaf blight, grape canker, tomato canker and apple canker.

A method for protecting a plant from an agricultural pest comprising the method step wherein a plant is contacted with the compound or stereoisomer thereof, or salt or solvate thereof, or the composition.

The term "alkyl" as used herein is intended to include both branched and straight chain saturated hydrocarbon radicals having the specified number of carbon atoms. E.g. "C_1-10Alkyl "(or alkylene) groups are intended to be C1, C2, C3, C4, C5, C6, C7, C8, C9 and C10 alkyl groups. In addition, for example "C_1-6Alkyl "denotes an alkyl group having 1 to 6 carbon atoms. Alkyl groups may be unsubstituted or substituted such that one or more of its hydrogen atoms are replaced with another chemical group. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl), and the like.

"alkenyl" is a hydrocarbon group that includes both straight and branched chain structures and has one or more carbon-carbon double bonds that occur at any stable point in the chain. E.g. "C_2-6Alkenyl "(or alkenylene) is intended to include C2, C3, C4, C5, and C6 alkenyl. Examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.

The term "substituted" as used herein means that any one or more hydrogen atoms on the designated atom or group is replaced with the designated group of choice, provided that the general valence of the designated atom is not exceeded. If not otherwise stated, substituents are named to the central structure. For example, it is understood that when (cycloalkyl) alkyl is a possible substituent, the point of attachment of the substituent to the central structure is in the alkyl moiety. As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C ═ C, C ═ N or N ═ N).

Combinations of substituents and or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure implies that the compound is sufficiently stable to be isolated in useful purity from the reaction mixture and subsequently formulated to form an effective therapeutic agent. Preferably, the compounds described so far do not contain N-halogen, S (O)₂H or S (O) H group.

The term "cycloalkyl" refers to cycloalkyl groups, including mono-, bi-or polycyclic ring systems. C_3-7Cycloalkyl groups are intended to include C3, C4, C5, C6 and C7 cycloalkyl groups. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. As used herein, "carbocycle" or "carbocycle residue" refers to any stable 3, 4, 5, 6 or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12 or 13-membered bi-or tricyclic ring which may be saturated, partially unsaturated, unsaturated or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, penteneCyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadiene, [3.3.0]Bicyclo-octane, [4.3.0]Bicyclo nonane, [4.4.0]Bicyclo decane, [2.2.2]Bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl and tetrahydronaphthyl (tetralin). As mentioned above, bridged rings are also included in carbocyclic rings (e.g. [2.2.2 ]]Bicyclooctane). Preferred carbocycles, if not otherwise stated, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl. When the term "carbocycle" is used, it is intended to include "aryl". A bridged ring occurs when one or more carbon atoms connects two non-adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is pointed out that the bridge always converts a single ring into a double ring. When the rings are bridged, substituents of the rings are also present on the bridge.

The term "aryl" refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, such as phenyl and naphthyl, each of which may be substituted.

The term "halogen" or "halogen atom" refers to fluorine, chlorine, bromine and iodine.

The term "heteroaryl" refers to substituted and unsubstituted aromatic 5 or 6 membered monocyclic groups, 9-or 10-membered bicyclic groups, and 11 to 14 membered tricyclic groups having at least one heteroatom (O, S or N) in at least one ring, said heteroatom containing ring preferably having 1, 2 or 3 heteroatoms selected from O, S and N. The heteroatom-containing heteroaryl groups can contain one or two oxygen or sulfur atoms per ring and/or from 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is 4 or less and each ring has at least one carbon atom. The fused rings completing the bicyclic and tricyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. The nitrogen and sulfur atoms may optionally be oxidized and the nitrogen atoms may optionally be quaternized. Bicyclic or tricyclic heteroaryl groups must include at least one fully aromatic ring, and the other fused rings may be aromatic or non-aromatic. The heteroaryl group may be attached at any available nitrogen or carbon atom of any ring. If the other ring is cycloalkyl or heterocyclic, it is additionally optionally substituted with ═ O (oxygen), as valency permits.

Exemplary monocyclic heteroaryls include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furanyl, thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like.

Exemplary bicyclic heteroaryls include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothienyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzofuranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzofuranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, fluoropyridinyl, dihydroisoindolyl, tetrahydroquinolinyl, and the like.

The compounds of the invention are understood to include both the free form and salts thereof, unless otherwise indicated. The term "salt" means an acid and/or base salt formed from an inorganic and/or organic acid and a base. In addition, the term "salt" may include zwitterions (internal salts), such as when the compound of formula I contains a basic moiety, such as an amine or pyridine or imidazole ring, and an acidic moiety, such as a carboxylic acid. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, such as acceptable metal and amine salts, wherein the cation does not contribute significantly to the toxicity or biological activity of the salt. However, other salts may be useful, such as separation or purification steps in the preparation process, and are therefore included within the scope of the present invention. Salts of the compounds of formula I may be formed, for example, by combining a compound of formula I with an amount of acid or base, for example, in equal amounts, in a vehicle, for example, in which the salt precipitates or in which it is present in an aqueous vehicle, and then lyophilizing.

When reference is made to substituents being alkenyl, alkynyl, alkyl, halo, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxy, amino, mercapto, phosphino, or when these substituents are specifically alkenyl, alkynyl, alkyl, halo, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxy, amino, mercapto, phosphino as specified, one to three of the above substituents are meant. Such as methylphenyl refers to phenyl substituted with one to three methyl groups.

By adopting the technical scheme, the invention takes thiazole hydrazide compounds as the basis, introduces nitrogen heterocyclic groups capable of improving the bioactivity of a target compound into the system to synthesize a series of thiazole hydrazide compounds, finds that the compounds have good inhibition effect on pathogenic fungi, and provides important scientific basis for research, development and creation of new pesticides aiming at pathogenic fungi such as verticillium wilt of eggplant (V.dahliae), fusarium wilt of pepper (F.oxysporum), sclerotinia sclerotiorum (S.sclerotiorum), fusarium graminearum (G.saubinetii), potato blight (P.infestans), rice sheath blight (T.cucumeris) and the like.

Examples

The invention is further illustrated by the following examples. It should be understood that the method described in the examples is only for illustrating the present invention and not for limiting the present invention, and that simple modifications of the preparation method of the present invention based on the concept of the present invention are within the scope of the claimed invention. All starting materials and solvents used in the examples are commercially available products of the corresponding purity.

Example 1: preparation of 4-methyl-2-phenylthiazole-5-carboxylic acid ethyl ester

Adding 5g (36.44mmol) of thiobenzamide into a 150mL round-bottom flask, adding 6.05mL (43.73mmol) of ethyl 2-chloroacetoacetate and 60mL of ethanol, heating to 100 ℃, carrying out reflux reaction for about 6 hours, monitoring the reaction process by TLC, and stopping the reaction after the reaction is finished; the ethanol was removed by distillation under the reduced pressure, 200mL of EA-dissolved system was washed with 100mL of water 3 times, the organic phase was dried over anhydrous sodium sulfate, filtered by suction, and subjected to distillation under the reduced pressure to remove the solvent, followed by column chromatography (PE/EA: 30/1) to obtain 5.69g of a yellow liquid with a yield of 63.2%.

Other ester intermediate compounds were synthesized by following the procedure of example 1 using the corresponding starting materials or substituents.

Example 2: preparation of 4-methyl-2-phenylthiazole-5-carboxylic acid

1g (36.44mmol) of ethyl 4-methyl-2-phenylthiazole-5-carboxylate was charged in a 100mL round-bottomed flask, and a 2-fold amount of sodium hydroxide solution was added thereto using 20mL of methanol as a solvent. Reacting for about 6 hours, monitoring the reaction process by TLC, and stopping the reaction after the reaction is finished; and (3) distilling under reduced pressure to remove methanol, adding concentrated hydrochloric acid into the system, adjusting the pH to 2-3, performing suction filtration, washing 3 times (5mL x 3) with ice water, and drying a filter cake under an infrared lamp to obtain 0.61g of white solid with the yield of 68.8%.

Other carboxylic acid intermediate compounds were synthesized according to the procedure of example 2 using the corresponding starting materials or substituents.

Example 3: preparation of 4-methyl-2-phenylthiazole-N' -phenyl-5-formylhydrazine

Adding 0.2g (0.91mmol) of 4-methyl-2-phenylthiazole-5-carboxylic acid into a 15mL pressure-resistant bottle, adding 0.35g (1.83mmol) of EDCI, 0.15g (1.09mmol) of HOBT and 3mL of DCM to dissolve a system, finally adding 0.14g (0.92mmol) of phenylhydrazine, stirring at normal temperature for reaction for about 5h, monitoring the reaction process by TLC, and stopping the reaction after the reaction is finished; 150mL of a compound in a DCM dissolution system is washed for 3 times by 50mL of water, the organic phase is added with anhydrous sodium sulfate for drying, suction filtration and decompression distillation desolventizing to obtain a light yellow solid, anhydrous ethanol is added for recrystallization to separate out the light yellow solid, the light yellow solid is suction filtered and washed by a small amount of anhydrous ethanol, the compound is placed under an infrared lamp for drying, and then 0.08g is weighed, and the yield is 28.4%. Melting point 166.5-167.8 ℃.

The thiazole hydrazide target compound is synthesized by the steps of reference example 3 by adopting corresponding raw materials or substituent groups.

The structure, nuclear magnetic resonance hydrogen spectrum and carbon spectrum data of the synthesized part of thiazole hydrazide compounds are shown in table 1, and the physicochemical properties are shown in table 2.

TABLE 1 NMR hydrogen and carbon spectra data for some of the compounds

Table 2 physicochemical properties of the target compounds

Pharmacological example 1:

the antibacterial activity of the compound on plant pathogenic fungi such as wheat mildew (Gibberella saubinetii, G.s.), pepper wilt (Fusarium oxysporum, F.o.), Sclerotinia sclerotiorum (S.s.), rice sheath blight (Thanatephora cuperis, T.c.), Verticillium wilt (Verticillium dahliae, V.d.) and grape cavity (Botryosphaeria dothidea, B.d) is measured on a PDA culture medium by a mycelium growth rate inhibition method, and the strains are activated in advance. Weighing a compound to be detected by a ten-thousandth balance, adding 1mL of DMSO, dissolving, transferring to a 15m L sterilized centrifuge tube in a sterile operating platform, adding 9mL of water (Tween-20) for dissolving, pouring 10mL of water into a culture medium, uniformly mixing, and then evenly subpackaging into 9 culture dishes for cooling for later use; in a sterile operating table, with sterilized beatingAnd (3) preparing the normally grown bacterial colonies into bacterial cakes by a hole puncher (5mm), reversely buckling the bacterial cakes in the center of a culture medium by using a bacterial inoculating ring, culturing for 3-5 days at 28 ℃, measuring for 2 times by using a straight ruler according to a cross method when the contrast bacterial colonies grow to 2/3 of the diameter of the whole plate, and calculating the diameter of the bacterial colonies according to the average value. At the initial stage, 25 mu g/mL is selected as a primary screening concentration, and EC is carried out on the compound when the corresponding germ inhibition rate of the compound is more than 50% at the concentration₅₀The test was carried out to find the hypha growth inhibition rate according to the following formula. Hymexazol, carbendazim and fluopyram were tested together as control agents.

The calculation formula is as follows: inhibition ratio (%) - (C1-C)₂)/(C₁-0.4) x 100 formula wherein:

C₁-control colony diameter i.e. DMSO-treated colony diameter;

C₂-the diameter of the treated colony is the diameter of the dosed colony;

0.5-diameter of mother fungus cake.

The examples of the present invention are given to illustrate the technical solution of the present invention, but the contents of the examples are not limited thereto, and some experimental results of the target compounds are shown in table 4.

TABLE 4 inhibitory Activity of thiazole-containing hydrazide Compounds against phytopathogenic fungi

As can be seen from Table 4, the series of compounds are subjected to biological activity tests by adopting a growth rate method by taking Hymexazol (HM), Carbendazim (CB), Prochloraz (PC), Fluopyram (FP) and Boscalid (BS) as control medicaments and 6 pathogenic fungi as test objects, and the test results show that the series of compounds have excellent antifungal activity. Wherein, the compound 4 has higher antibacterial activity on wheat scab germs, the inhibition rates are respectively 92.7 percent and are close to 100 percent of a contrast medicament carbendazim; the compounds 2 and 12 have better activity for resisting pepper blight bacteria, the inhibition rates are respectively 63.0 percent and 63.7 percent, and the inhibition rates are superior to the control drugs of hymexazol, fluopyram and boscalid; the activity of the compounds 20 and 21 against rice sheath blight bacteria is 90.3 percent and 98.7 percent respectively, which are superior to those of contrast drugs of hymexazol, fluopyram and boscalid; the inhibition rates of the compounds such as the compounds 2 and 21 on sclerotinia sclerotiorum are respectively 88.9 percent and 85.5 percent; the inhibition rates of the compounds 4 and 22 against verticillium wilt of eggplants are respectively 88.6 percent and 80.8 percent; the compound 4 has good activity of resisting staphylococcus lumen bacteria, the inhibition rates of the compound 4 are respectively 92.7 percent and are close to the control drugs of carbendazim and prochloraz.

TABLE 5 EC50 of thiazole-containing hydrazide compounds against phytopathogenic fungi

As can be seen from Table 5, most of the target compounds tested had good antifungal activity, Compound B₄、B₆、B₉、B₁₁、B₁₇、B₁₉、B₂₁And B₂₂Anti-plasmodiophora EC₅₀The value range is 0.55-0.95. mu.g/mL; compound B₆，B₉And B₂₂Anti-wheat scab bacteria EC₅₀The values are 0.73, 0.75 and 0.69 mu g/mL respectively, which are equivalent to the activity of carbendazim; compound B₉Eggplant verticillium wilt resistant EC₅₀The value is 0.56. mu.g/mL, and the activity is far stronger than that of the control drug carbendazim.