Beta-carboline derivative as well as preparation method and application thereof

Abstract

The invention discloses a beta-carboline derivative as well as a preparation method and application thereof. The structural formula of the compound is shown as a formula (1). The compounds disclosed by the invention have a good inhibition effect on pathogenic plant pathogenic bacteria and plant pathogenic fungi, the EC50 of part of the compounds to Xanthomonas oryzae pv. Oryzae is in the range of 1.12-1.45 mu g / mL, the EC50 of part of the compounds to Xanthomonas citri is in the range of 2.91-4.85 mu g / mL, the EC50 of part of the compounds to Pseudomonas syringae pv. Chinensis is in the range of 7.61-20.08 mu g / mL, and the EC50 of part of the compounds to Pseudomonas syringae pv. The activity of the compound is far better than that of field common medicaments such as thiediazole copper and bismerthiazol; besides, under the concentration of 50 mu g / mL, the compound III-6 and the compound III-14 have good inhibition rates on rhizoctonia solani and fusarium graminearum, the preparation method is simple, and the reaction conditions are mild. (1).

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to a class of... β - Carboline derivatives, their preparation methods, and applications. Background Technology

[0002] Plant diseases are a major factor affecting global agricultural production, severely impacting the yield and quality of agricultural products, causing not only enormous economic losses but also threatening human health. Diseases such as rice bacterial blight, citrus canker, kiwifruit canker, tobacco bacterial wilt, apple ring rot, wheat scab, and rice sheath blight break out to varying degrees every year, causing huge economic losses to farmers. Long-term use of traditional fungicides, such as tebuconazole, streptomycin sulfate, and carbendazim, has not only increased the drug resistance of pathogens but also had harmful effects on the ecological environment and plant safety. Therefore, there is an urgent need to develop new pesticides with high activity, high selectivity, and novel structures.

[0003] β The following is a summary of the research progress on the bioactivity of carboline compounds: In 2006, Volk et al [Volk, R. -B.; Furkert, FH Antialgal, antibacterial and antifungal activity of two metabolites produced and excreted by cyanobacteria during growth [ J ]. Microbiol. Res .,2006, 161( 2 ), 180–186.] From cyanobacteria ( Cyanobacterial Separate from ) to obtain a β -Carboline alkaloids—Norharmane. Bioactivity assessment results show that norharmane possesses significant antifungal and antibacterial activity. Specifically, it exhibits activity against *Escherichia coli* (…). Escherichia coli ), Pseudomonas aeruginosa ( Pseudomonas aeruginosa ), Bacillus cereus ( Bacillus cereus Bacillus subtilis ( Bacillus subtilis ) and Staphylococcus aureus ( Staphylococcus aureus The MICs for these products are 32, 32, 160, 128, and 16, respectively. μ g / mL; against Candida albicans ( Candida albicans The MIC of ) is 40 μ g / mL.

[0004] In 2009, Chen et al. [Chen, J.; Yan, X. -H.; Dong, J. -H.; Sang, P.; Fang, X.; Di, Y. -T.; Zhang, Z. -K.; Hao, X. -J. Tobacco mosaic virus (TMV) inhibitors from Picrasma quassioides Benn [ J ]. J. Agric. Food Chem. , 2009, 57 , 6590-6595] isolated eight Picrasma quassioides -carboline alkaloids from β Benn. The bioassay results showed that the obtained β -carboline alkaloids exhibited excellent inhibitory activities against Tobacco Mosaic Virus (TMV), and some of the compounds were more active than the control drug, Nanaomycin.

[0005] In 2014, Song et al. [Song, H. J.; Liu, Y. X.; Liu, Y. X.; Wang, L. Z.; Wang, Q. M. Synthesis and Antiviral and Fungicidal Activity Evaluation of β -Carboline, Dihydro- β -carboline, Tetrahydro- β -carboline Alkaloids, and Their Derivatives [ J ]. J. Agric. Food Chem. , 2014, 62( 5 ), 1010-1018.] reported a series of β -carboline derivatives. The bioassay results showed that most of the obtained compounds exhibited excellent inhibitory activities against plant pathogenic fungi and viruses.

[0006] In 2018, Suzuki et al. [Suzuki, K.; Nomura, I.; Ninomiya, M.; Tanaka, K.; Koketsu, M. Synthesis and antimicrobial activity of β -carboline derivatives with N 2-alkyl modifications [ J ]. Bioorg. Med. Chem. Lett. ,2018, 28( 17 ), 2976–2978.] synthesized a series of N 2-substituted β -carboline salts, and the bioassay results showed that the synthesized β -carboline salts exhibited excellent inhibitory activity against drug-resistant bacteria such as Methicillin-resistant Staphylococcus aureus Staphylococcus aureus (MRSA) and fungi such as Candida intermedia Candida intermedia . Among them N 2 -benzyl- β -carboline dimer salts had a MIC as low as 0.01 μmol / mL against MRSA and C. intermedia.

[0007] In 2024, He et al. [He, X. D.; Sun, S. X.; Kong, W. L.; Li, M. Y.; Li, S. K. Eudistomins Y-Inspired Design and Divergent Optimization of Heteroaryl Ketones for New Antifungal Leads [ J ]. J. Agric. Food Chem. ,2024, 72(21),11928–11937.] reported a β -carboline derivative containing an oxime structure. The bioactivity evaluation results showed that the obtained β -carboline derivative had good inhibitory activity against plant pathogenic fungi such as Rhizoctonia solani Rhizoctonia solani , Sclerotinia sclerotiorum Sclerotinia sclerotiorum , and Phytophthora capsici Phytophthora capsici .

[0008] However, the current bioactivity research on β -carboline derivatives mainly focuses on medicinal activity, and there are very limited reports on their research in pesticide bioactivity. Therefore, comprehensive evaluation of the agricultural antifungal and antibacterial potential of such compounds can promote the practical application of such compounds in the agricultural field. SUMMARY

[0009] In view of the above problems, one of the purposes of the present application is to provide a β -carboline derivative. β-Carbline derivatives are novel pesticide active molecules with high activity, broad spectrum, and novel structure. These compounds are synthesized by using tryptamines and their derivatives as starting materials, undergoing a Pictet-Spengler ring-closing reaction with aldehydes under acidic conditions, followed by aromatization of elemental sulfur to obtain a series of 1-, 3-, 6-, 7-, and 9- compounds with different substituted groups. β -Carboline compounds. These compounds exhibit good inhibitory activity against pathogenic plant bacteria, specifically targeting pathogens such as *Bacillus thuringiensis*, the causal agent of rice bacterial blight. Xanthomonas oryzae pv . oryzae , Xoo ), Citrus canker pathogen ( Xanthomonas axonopodis pv . citri , Xac ) and kiwifruit canker pathogen ( Pseudomonas syringae pv. actinidiae , Psa ) etc.] and fungi [such as rice sheath blight fungus ( Rhizoctonia solani [ ) etc.] all have good inhibitory effects.

[0010] To achieve the above objectives, the following technical solutions can be adopted: This invention provides one aspect β -Carboline derivatives or compounds with the structural formula shown in formula (1), (1) R1, R2, R3, R4 and R5 are each independently selected from one or more of hydrogen, carboxyl, amide, halogen, any substituted formate, any substituted or unsubstituted alkyl, any substituted or unsubstituted alkenyl, any substituted or unsubstituted alkynyl, any substituted or unsubstituted cycloalkyl, any substituted or unsubstituted aryl, any substituted or unsubstituted heteroaryl, and any substituted or unsubstituted benzyl.

[0011] Another aspect of the present invention provides the above-mentioned β The preparation method of -carboline derivatives includes the following steps: The present invention also provides a composition comprising one of the above-described components. β -Carboline derivatives.

[0012] The present invention also provides a drug comprising one of the above-described components. β - Carboline derivatives or the above-described compositions; and diluents or excipients.

[0013] This invention provides the above-mentioned β- the use of the carboline derivatives or the above-mentioned compositions or the above-mentioned medicaments in the prevention and treatment of agricultural fungal and bacterial diseases.

[0014] Compared with the prior art, the present application has the following advantages: (1) the present application provides β - the carboline derivatives have good inhibitory effect on pathogenic plant pathogens, and have good inhibitory effect on pathogenic bacteria [such as Xanthomonas oryzae pv. oryzae, Xanthomonas axonopodis pv. citri and Pseudomonas syringae pv. actinidiae, etc.] and plant pathogenic fungi [such as Rhizoctonia solani, etc.]. Among them, the EC 50 values of the compounds III-9, III-11, III-41 and III-44 against Xanthomonas oryzae pv. oryzae are 1.12, 1.32, 1.45 and 1.23 μ g / mL respectively, the EC 50 values of the compounds III-2, III-3, III-9 and III-42 against Xanthomonas axonopodis pv. citri are 4.32, 2.91, 4.85 and 3.22 μ g / mL respectively, the EC 50 values of the compounds III-1, III-2, III-3 and III-9 against Pseudomonas syringae pv. actinidiae are 7.61, 19.39, 18.61 and 20.08 μ g / mL respectively, and the activity is much higher than that of the commonly used field agents copper oxychloride and flutolanil (the EC 50 values of the three tested plant pathogenic bacteria are all higher than 37.23 μ g / mL); in addition, at a concentration of 50 μ g / mL, the inhibition rate of the compound III-6 against Rhizoctonia solani is 52.90%, and the inhibition rates of the compound III-14 against Rhizoctonia solani and Gibberella saubinetii are 50.48% and 50.09% respectively, and the activity is lower than that of the commercial agent carbendazim (the inhibition rates of the three tested plant pathogenic fungi are 100%, 100% and 94.18% respectively).

[0015] (2) the present application provides β - the preparation method of the carboline derivatives is simple and the reaction conditions are mild. DETAILED DESCRIPTION

[0016] The examples are provided to better illustrate the present application, but are not intended to limit the present application to only the examples. Therefore, the skilled in the art can make non-essential improvements and adjustments to the embodiments according to the above description, which still belong to the protection scope of the present application.

[0017] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit this disclosure. Singular expressions include plural expressions unless they have a clearly different meaning in the context. As used herein, it should be understood that terms such as “comprising,” “having,” “including” are intended to indicate the presence of features, numbers, operations, components, parts, elements, materials, or combinations thereof. The terminology of the invention is disclosed in the specification and is not intended to exclude the possibility that one or more other features, numbers, operations, components, parts, elements, materials, or combinations thereof may be present or added.

[0018] The term "alkyl" as used in this invention refers to branched and straight-chain saturated hydrocarbon groups having a specific number of carbon atoms. For example, "C 1-10 Alkyl (or alkylene) refers to C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. Additionally, for example, "C 1-6 "Alkyl" means an alkyl group having 1 to 6 carbon atoms. Alkyl groups can be unsubstituted or substituted, such that one or more of their hydrogen atoms are replaced by other chemical groups. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as n-butyl, isobutyl, tert-butyl), pentyl (such as n-pentyl, isopentyl, neopentyl) and the like.

[0019] The term "alkenyl" as used in this invention refers to hydrocarbons that include both straight-chain and branched structures and have one or more carbon-carbon double bonds present at any stable point in the chain. For example, "C..." 2-6 The term "alkenyl" (or "alkenylidene") aims to include C2, C3, C4, C5, and C6 alkenyl groups. Examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-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 their analogues.

[0020] The term "alkynyl" as used in this invention refers to hydrocarbons that include both straight-chain and branched structures and have one or more carbon-carbon triple bonds present at any stable point in the chain. For example, "C 2-6 The purpose of "alkynyl" (or ynylene) is to include C2, C3, C4, C5 and C6 alkynyl groups; such as ethynyl, propynyl, butynyl, pentylyl, hexynyl and their analogues.

[0021] The term "substituted" as used herein means that any one or more hydrogen atoms on the designated atom or group is replaced with a selection of the designated group, provided that the designated atom's normal valence is not exceeded. Unless otherwise indicated, substituents are named to the point of attachment 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 portion. When substitution is referred to, especially multiple substitution, it is meant that multiple substituents are substituted on each position on the designated group, as in dichlorophenyl which refers to 1,2-dichlorophenyl, 1,3-dichlorophenyl, 1,4-dichlorophenyl and 2,4-dichlorophenyl. 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 is one which does not undergo spontaneous transformation at a useful rate under working conditions of the application. Preferably, the compounds do not contain N-halogen, S(O)2H or S(O)H groups.

[0022] The term "aryl" as used herein means a monocyclic or bicyclic aromatic hydrocarbon group having from 6 to 12 carbon atoms in the ring portion, such as phenyl and naphthyl, each of which can be substituted.

[0023] The term "halogen" or "halogen atom" as used herein means chlorine, bromine, fluorine and iodine.

[0024] The term "haloalkyl" as used herein means a substituted alkyl group having one or more halogen substituents. For example, "haloalkyl" includes mono, di and tri-fluoromethyl; even though the halo in haloalkyl is specifically stated to be fluorine, chlorine, bromine, iodine, it also refers to a substituted alkyl group having one or more fluorine, chlorine, bromine, iodine substituents.

[0025] The term "heteroaryl" as used herein 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, preferably having 1, 2, or 3 heteroatoms selected from O, S, and N. Each ring of the heteroaryl group containing a heteroatom can contain one or two oxygen or sulfur atoms 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 can contain only carbon atoms and can be saturated, partially saturated, or unsaturated. Nitrogen and sulfur atoms can be optionally oxidized and nitrogen atoms can be optionally quaternized. The bicyclic or tricyclic heteroaryl must include at least one fully aromatic ring, and the other fused ring(s) can be aromatic or nonaromatic. The heteroaryl group can be attached at any available nitrogen or carbon atom of any ring. When valence permits, if the other ring is a cycloalkyl or heterocycloalkyl, it is additionally optionally substituted with =0 (oxo). Exemplary monocyclic heteroaryl groups include pyrrolyl, pyrazolyl, pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, furanyl, thiophenyl, oxadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, and the like. Exemplary bicyclic heteroaryl groups include indolyl, benzothiazolyl, benzodioxolyl, benzoxazolyl, benzothiophenyl, quinolyl, tetrahydroisoquinolyl, isoquinolyl, benzimidazolyl, benzofuranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzofuranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, fluoropyridyl, dihydroisoindolyl, tetrahydroquinolinyl, and the like.

[0026] The term "compound" as used herein, if not otherwise specified, is understood to include the free form and salts thereof. "Salts" refer to acidic and / or basic salts formed with inorganic and / or organic acids and bases; additionally, "salts can include zwitterions (inner salts), such as when a compound of Formula A contains both a basic fragment, such as an amine or pyridine or imidazole ring, and an acidic fragment, 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 significant toxicity or biological activity to the salt.

[0027] In the present application, C1-C 10 Alkyl refers to methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and isomers thereof; C1-C 10 Alkoxy refers to methoxy, ethoxy, propyloxy, butyloxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, and isomers thereof; C2-C5 alkenyl refers to ethenyl, propenyl, allyl, butenyl, pentenyl, and isomers thereof.

[0028] In the present invention, when it is mentioned that a substituent is alkenyl, alkynyl, alkyl, halogen, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxyl, amino, thiol, phosphino, or the substituent is specifically one of alkenyl, alkynyl, alkyl, halogen, aryl, heteroaryl, alkoxy, cycloalkyl, hydroxyl, amino, thiol, phosphino, it means one to three of the above substituents. For example, methylphenyl means one to three methyl-substituted phenyl.

[0029] In one aspect, the present invention provides a 1,2,3,4-tetrahydro- β -quinoline derivative, having a structure as shown in formula (1) (1) wherein R1, R2, R3, R4and R5are each independently selected from one or more of hydrogen, carboxyl, amido, halogen, optionally substituted formate, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heteroaryl, and optionally substituted benzyl.

[0030] In some embodiments, the above-mentioned β -quinoline derivative is characterized in that R1, R2, R3, R4and R5are each independently selected from hydrogen, optionally substituted or unsubstituted C 1-6 alkyl, optionally substituted or unsubstituted C 2-6 alkenyl, optionally substituted or unsubstituted C 5-10 cycloalkyl, optionally substituted or unsubstituted C 5-10 aryl, optionally substituted or unsubstituted C 5-10 heteroaryl, and optionally substituted benzyl; or R1and R2are connected to form an optionally substituted 5-10 membered ring or a heteroatom-containing ring.

[0031] In some embodiments, the above-mentioned β -quinoline derivative is characterized in that R1, R2, R3, R4and R5are each independently selected from hydrogen, carboxyl, amido, halogen, methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, heptyl, octyl, haloalkyl, alkenyl, alkynyl, phenyl, benzyl, fluorophenyl, chlorophenyl, bromophenyl, nitrophenyl, N,N-diethylaminophenyl, N,N-dimethylaminophenyl, trifluoromethylphenyl, dichlorophenyl, difluorophenyl, methylphenyl, methoxyphenyl, furanyl, thienyl, benzothiazolyl, naphthyl, quinolinyl, indolyl, pyrrolyl, pyrimidinyl, pyrazolyl, imidazolyl.

[0032] In some embodiments, the above-mentioned β ​The carboline derivative can be selected from any one of the following structures: Another aspect of the present application provides a method for preparing the above-mentioned β The method for preparing the carboline derivative of formula (III) comprises: In some embodiments, the above-mentioned β In the method for preparing the carboline derivative, the method for preparing the compound of formula (II) comprises: ; More specifically, condition a is applicable to the method for preparing the compound of formula (II) wherein R1 is a carboxyl group, which comprises: Condition b is applicable to the method for preparing the compound of formula (II) wherein R1 is an ester group or the compound of formula (I) is a salt of a strong inorganic acid (such as sulfuric acid, hydrochloric acid, etc.), which comprises: Condition c is applicable to the method for preparing the compound of formula (II) wherein R2 is an acid-sensitive group such as indole group or pyrrolopyridine group, which comprises: Condition d is applicable to the method for preparing the compound of formula (II) other than the compounds of conditions a, b and c, which comprises: The method for preparing the target compound by synthesizing the intermediate II is as follows: .

[0033] Another aspect of the present application provides a composition, which in some embodiments can comprise the above-mentioned β carboline derivative or a stereoisomer thereof or a salt thereof or a solvate thereof. Specifically, the above-mentioned compound can be used alone to prevent and treat fungal and bacterial diseases, or can be combined with other effective ingredients of pesticides to form a composition for preventing and treating fungal and bacterial diseases.

[0034] Another aspect of the present application provides a medicine, which in some embodiments can comprise the above-mentioned β carboline derivative or the above-mentioned composition; and a diluent or an excipient. Specifically, the above-mentioned compound can be added to a diluent or an excipient to prepare various dosage forms for use in different environments.

[0035] In some embodiments, the above-mentioned medicine, diluent or excipient is applicable to emulsifiable concentrate, powder, wettable powder, granule, aqueous solution, suspension concentrate, ultra-low volume spray, soluble powder, microcapsule, smoke agent, emulsion in water or water dispersible granule.

[0036] In still another aspect, the present application provides a use of the above-mentioned β - the carboline derivative or a stereoisomer thereof or a salt thereof or a solvate thereof or the above-mentioned composition or the above-mentioned medicament in preventing and treating agricultural diseases.

[0037] In some embodiments, the agricultural disease is a bacterial or fungal disease of a plant; in some specific embodiments, the agricultural disease is any one or more of a leaf blight disease, a bacterial blight disease, a bacterial wilt disease, a bacterial leaf streak disease, a gray mold disease, a late blight disease, a wilt disease, and a root rot disease of a plant; in some specific embodiments, the agricultural disease is one or more of a bacterial blight disease of rice, a bacterial wilt disease of citrus, a bacterial wilt disease of kiwifruit, a bacterial blight disease of tobacco, a bacterial blight disease of cucumber, a bacterial blight disease of konjac, a bacterial wilt disease of grape, a bacterial wilt disease of tomato, a bacterial wilt disease of apple, a bacterial leaf streak disease of rice, a bacterial wilt disease of tree, a scab disease of wheat, a gray mold disease of cucumber, a wilt disease of pepper, a sclerotinia rot disease of rape, a late blight disease of potato, and a root rot disease of blueberry.

[0038] It should be noted that the above-mentioned β - the carboline derivative or a stereoisomer thereof or a salt thereof or a solvate thereof or the above-mentioned composition is directly contacted with a plant or a pathogen when used in preventing and treating agricultural diseases.

[0039] It should be noted that natural products are widely available and have diverse structures, and are an important source of ideas for the creation of new pesticides. Natural products are not only diverse in type and diverse in biological activity, but also unique in action, and more importantly, are easily degradable or have good environmental compatibility, and therefore have been widely used by people for thousands of years; however, most natural product compounds are complex in structure and difficult to synthesize, are mostly unstable to light or extremely volatile, and therefore cannot be directly used as pesticides. The starting material in the present application, tryptamine and its derivatives, are common natural alkaloids that exist widely in plants, animals, microorganisms, and marine organisms. According to literature reports, β - carboline compounds have excellent anticancer, antifungal, and antiviral activities, and are a hot skeleton for current new drug research and development. However, most of the researches are biased towards the medical field, and there are few research reports in the field of agricultural chemicals. In order to find high-efficiency antibacterial compounds, the present application takes tryptamine and its derivatives as starting materials, and a series of 1-, 3-, 6-, 7-, and 9- carboline compounds containing different groups are synthesized through Pictet-Spengler ring-closing reaction of aldehyde under acidic conditions and subsequent aromatization reaction, and the biological activities thereof are evaluated, thereby providing scientific data for the research and development of new pesticides. β - carboline compounds, and evaluate the biological activities thereof, thereby providing scientific data for the research and development of new pesticides.

[0040] In order to better understand the present application, the content of the present application is further illustrated below in combination with specific examples, but the content of the present application is not limited only to the following examples.

[0041] I. Preparation and characterization of compounds Example 1 Preparation of intermediate 1-methyl-2,3,4,9-tetrahydro-1 H - pyrido [3, 4- b ] indole-3-carboxylic acid Tryptamine acid (2.08 g, 10.0 mmol), 40 wt% acetaldehyde solution (1.21 g, 11.0 mmol) and water (50 mL) were added into a reaction bottle in turn, and then concentrated sulfuric acid (200 μ L) was added dropwise into the reaction system, and the reaction was carried out at room temperature for 15 h. Then, the pH of the system was adjusted to 6-7 with saturated NaHC03solution, and a large amount of solid was precipitated, which was filtered to obtain 1-methyl-2,3,4,9-tetrahydro-1 H - pyrido [3, 4- b ] indole-3-carboxylic acid with high purity. White solid, yield: 82.72%. 1 H NMR (500 MHz, DMSO- d 6) δ 11.20 (s, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.31 (d, J = 8.1 Hz,1H), 7.04 (t, J = 7.0 Hz, 1H), 6.95 (t, J = 7.0 Hz, 1H), 4.52 (q, J = 6.3 Hz, 1H),3.61 (dd, J = 12.0, 4.8 Hz, 1H), 3.14 (dd, J = 15.7, 4.4 Hz, 1H), 2.83 – 2.70 (m,1H), 1.60 (d, J = 6.7 Hz, 3H); 13 C NMR (126 MHz, DMSO- d 6) δ 170.2, 136.9, 132.6,126.6, 121.9, 119.4, 118.6, 111.8, 107.2, 58.1, 49.6, 23.7, 17.4; HRMS (ESI)[M+H] + calcd for C 13 H 15 O2N2: 231.1128, found: 231.1122. Example 2 Intermediate 1-methyl-2,3,4,9-tetrahydro-1 H -pyridine[3,4- b Preparation of methyl indole-3-carboxylate Will L methyl tryptophan hydrochloride (1.30 g, 5.0 mmol), 40 wt% acetaldehyde solution (0.63 g, 5.5 mmol), and a methanol-acetonitrile mixture (CH3CH2OH: CH3CN = 1:1, V / V, 15 mL) were added to the reaction flask, and the reaction was refluxed. TLC monitoring was performed (CH2Cl2: MeOH = 100: 1, V / V). L The reaction of methyl tryptophan hydrochloride was complete, and direct filtration yielded 1-methyl-2,3,4,9-tetrahydro- ... H -pyridine[3,4- b Methyl indole-3-carboxylate (white solid, 0.72 g); the filtrate was evaporated to dryness and then subjected to column chromatography (CH₂Cl₂: MeOH = 100: 1; V / V) to give another fraction of 1-methyl-2,3,4,9-tetrahydro-1-carboxylate. H -pyridine[3,4- b Methyl indole-3-carboxylate (white solid, 0.45 g). Overall yield: 96.00%. 1 H NMR (400 MHz, DMSO-) d 6) δ 11.47 (s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.13 (dt, J = 8.0, 1.1 Hz, 1H), 7.03 (dt, J = 7.8, 1.0 Hz, 1H), 4.76 (d, J =6.3 Hz, 1H), 4.62 (dd, J = 11.8, 4.9 Hz, 1H), 3.86 (s, 3H), 3.28 (dd, J = 15.7,4.4 Hz, 1H), 3.12 – 3.03 (m, 1H), 1.75 (d, J = 6.8 Hz, 3H); 13 C NMR (101 MHz, DMSO- d 6) δ169.5, 136.9, 131.4, 126.1, 122.3, 119.6, 118.6, 111.9, 104.7, 55.0,53.5, 50.1, 22.8, 17.0; HRMS (ESI) [M+H] + calcd for C 14 H 17 O2N2: 245.1285, found:245.1279. Example 3 Intermediate 1-(1 H (-indol-3-yl)-2,3,4,9-tetrahydro-1 H -pyridine[3,4- b Preparation of indole Tryptophan / tryptophan derivative (2.1 mmol), indole-3-carboxaldehyde with different substitutions (2.0 mmol), and toluene (8 mL) were added sequentially to a reaction flask, and the mixture was refluxed for 12 h. The solvent was evaporated to dryness, and the residue was redissolved with chloroform (5 mL). TFA diluted with chloroform (5 mL) (1.8 mL, 20.0 mmol) was slowly added dropwise to the system, and the reaction was carried out at room temperature for 24 h. Then, the pH of the system was adjusted to 7-8 with saturated NaHCO3 solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phase was collected, dried over anhydrous Na2SO4, dissolved, and subjected to column chromatography (eluent ratio: CH2Cl2: MeOH = 20: 1, V / V) to obtain 1-(1 H (-indol-3-yl)-2,3,4,9-tetrahydro-1 H -pyridine[3,4- b Indole. Yellow solid, yield: 78.82%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.47 (s, 1H), 10.83 (s, 1H), 7.53 (d, J = 7.5 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 2.1 Hz, 1H), 7.28 (d, J = 12.4 Hz, 1H), 7.26 (d, J = 12.2 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.08 (t, J= 7.3 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 6.96(t, J = 7.5 Hz, 1H), 6.02 (s, 1H), 3.39 (dt, J = 12.5, 5.7 Hz, 2H), 3.01 (dt, J =22.5, 5.9 Hz, 2H); 13 C NMR (101 MHz, DMSO- d 6) δ 136.9, 136.6, 131.8, 127.4,126.6, 126.5, 122.0, 121.8, 119.6, 119.5, 119.1, 118.4, 112.3, 111.9, 110.7,107.2, 49.5, 41.2, 19.9; HRMS (ESI) [M+H] + calcd for C 19 H 18 N3: 288.1495, found:288.1487. This example is applicable to the synthesis of intermediates where R2is an indole group or similar scaffold groups (e.g. pyrrolopyridine, pyrimidopyrrolo).

[0042] Example 4 Preparation of intermediate 1-methyl-2,3,4,9-tetrahydro-1 H H b indole Trifluoroacetic acid (495 μL, 6 mmol) was added slowly dropwise into the reaction system after the trifluoroacetic acid (495 μL, 6 mmol) was diluted with DCM (3 mL) under ice bath condition, and stirred for 30 min. Then, the reaction was refluxed, and TLC was used to monitor the reaction (CH2Cl2: MeOH = 40: 1, V / V). When the reaction of tryptamine / 2-amino-3-(1 μ H H After the reaction of tryptamine / 2-amino-3-(1 H Hb ]indole. White solid, yield: 59.75%. 1 H NMR (400 MHz, DMSO- d 6) δ 10.76 (s, 1H), 7.35(d, J = 7.7 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.01 (dt, 6.9, 1.2 Hz, 1H), 6.93(dt, 6.8, 1.0 Hz, 1H), 4.09 (q, J = 6.6 Hz, 1H), 3.03 (m, 2H), 2.62 (dt, J =11.4, 4.2 Hz, 2H), 1.39 (d, J = 6.7 Hz, 3H); 13 C NMR (101 MHz, DMSO- d 6) δ 138.0,136.05, 127.4, 120.9, 118.7, 117.9, 111.3, 107.0, 48.4, 42.5, 22.4, 20.6;HRMS (ESI) [M+H] + calcd for C 12 H 15 N2: 187.1230, found: 187.1223. This example is applicable to the preparation of all other intermediates except for Examples 1, 2 and 3.

[0043] Example 5 Preparation of the target compound 1-methyl-9 H pyrido[3,4- b ]indole Intermediate 1-methyl-2,3,4,9-tetrahydro-1 H pyrido[3,4- b ]indole (1.0 mmol), elemental sulfur S (66 mg, 2.0 mmol) and xylene (5 mL) were sequentially added into a 15 mL pressure tube. After heating under reflux for 24 h, the solvent was spun dry, and column chromatography was directly performed (eluent CH2Cl2and MeOH) to obtain the target compound 1-methyl-9 H pyrido[3,4- b ]indole. Brown solid, yield: 28.90%, melting point: 236.4 - 238.1 o C.1 H NMR (400 MHz, DMSO- d 6) δ 11.58 (s, 1H, N H), 8.27 – 8.13 (m, 2H, Carboline-3-H + Carboline-5-H), 7.92 (d, J = 5.2 Hz, 1H, Carboline-4-H), 7.60 (d, J = 8.2 Hz, 1H, Carboline-8-H), 7.53 (t, J = 7.6 Hz, 1H, Carboline-7-H), 7.22 (t, J = 7.4 Hz, 1H,Carboline-6-H), 2.76 (s, 3H, CH3); 13 C NMR (101 MHz, DMSO- d 6) δ 142.6, 140.8,138.0, 134.9, 128.3, 127.3, 122.2, 121.5, 119.6, 113.1, 112.4, 20.9; HRMS(ESI) [M+H] + calcd for C 12 H 11 N2: 183.0917, found: 183.0912. This example is applicable to the synthesis of all target compounds.

[0044] Table 1. NMR and high-resolution mass spectrometry data of the target compounds.

[0045] Table 2 Physicochemical properties of the target compounds

[0046] II. Applications of Compounds Example 6 EC of compounds against plant pathogenic bacteria 50 Measurement EC 50 Median effective concentration (EC50) is an important indicator for evaluating the effect of a compound on plant pathogens, and it is also a crucial parameter for setting the compound concentration when studying the mechanism of action. This example uses turbidimetry to determine the EC50 of the target compound against plant pathogens. 50 The test subject was determined to be *Bacillus thuringiensis*, the pathogen causing bacterial blight of rice. Xanthomonas oryzae pv. oryzae , Xoo ), Citrus canker pathogen ( Xanthomonas axonopodis pv. citri , Xac ) and kiwifruit canker bacteria ( Pseudomonas syringae pv. actinidiae, Psa DMSO was used as a blank control. The specific procedures are as follows: 1) The single clones (originally cultured in NA solid medium) were transferred to NB medium and cultured in a constant temperature shaker at 28℃ and 200 rpm until the logarithmic growth phase; 2) The reagent / compound was prepared into different concentrations (e.g., 100, 50, 25, 12.5, and 6.25) using the two-fold dilution method. μ Add 5 mL of NB-containing liquid culture medium (g / mL) to a test tube, and use an enzyme-linked immunosorbent assay (ELISA) reader to measure the OD of the corresponding concentration of the drug-containing culture medium. 595 Value (denoted as OD) A ); 3) Add 40 to each of the treated test tubes. µ The bacterial culture in L group was cultured to the logarithmic growth phase and then shaken at 28℃ and 200 rpm until the OD of the CK group was measured. 595 Once the value reaches 0.6-0.8, the OD of each treated sample is measured using an ELISA reader. 595 Value (denoted as OD) B ); 4) Calculate the inhibition rate (%) using the following formula: Corrected OD value = OD B -ODA ; inhibition rate = [(corrected control medium bacterial liquid OD value - corrected toxic medium OD value) / corrected control medium bacterial liquid OD value] x 100. Finally, the toxicity curve was fitted by Excel software and the EC 50 value was calculated.

[0047] According to the above method, the experimental results of the target compounds in Table 1 are shown in Table 3.

[0048] Table 3 EC 50

[0049] Example 7 Inhibitory activity of compounds on plant pathogenic fungi (50 μ g / mL) The mycelial growth rate method is the most commonly used method for evaluating the activity of agricultural antifungal agents. The principle is roughly as follows: the test agent is mixed with the culture medium, and the toxicity of the agent is measured by the speed of fungal colony growth on the surface of the drug-containing culture medium. In this example, Fusarium graminearum, Rhizoctonia solani and Botrytis cinerea were used as test objects, and DMSO was used as a blank control. The specific operation is as follows: 1) according to the test concentration, weigh an appropriate amount of drug, dissolve it with DMSO (the amount does not exceed 1% of the final toxic medium), then add 0.1% Tween 20 solution to make up to 10 mL, pour into 90 mL of melted PDA culture medium, mix well and pour into 9 culture dishes for standby; 2) use a sterilized puncher (inner diameter 0.5 cm) to punch the edge of the pre-activated strain, and use a inoculation needle to paste the mycelium to the center of the toxic medium, then invert and place in a 25°C biochemical incubator for incubation; 3) when the colony diameter of the control group reaches 5.5-6.6 cm, the colony diameters of all treatment groups are measured by cross method; 4) the inhibition rate (%) is calculated using the following formula: inhibition rate (%) = (C-T) / (C-0.5) x 100; where C is the colony diameter of the control group, T is the colony diameter of the agent treatment group, and 0.5 is the diameter of the inoculated fungus cake.

[0050] According to the above method, the experimental results of the target compounds in Table 1 are shown in Table 4.

[0051] Table 4 Inhibitory activity of target compounds on plant pathogenic fungi (50 μ g / mL)

[0052] From Table 3, it can be seen that most of the target compounds have good inhibitory activities against plant pathogenic bacteria such as Xanthomonas oryzae pv. oryzae, Xanthomonas axonopodis pv. citri and Xanthomonas campestris pv. campestris. Among them, the compounds I-1, I-2, I-3, I-4, I-9, I-12, I-38, I-41, I-42, I-43 and I-44 have high inhibitory activities against Xanthomonas oryzae pv. oryzae, Xanthomonas axonopodis pv. citri and Xanthomonas campestris pv. campestris. The EC β - The activities of the carbazol derivatives against the three pathogenic bacteria tested are prominent. For example, the EC 50 of compounds III-1, III-2, III-3, III-4, III-9, III-12, III-38, III-41, III-42, III-43 and III-44 against Xanthomonas oryzae pv. oryzae, Xanthomonas axonopodis pv. citri and Xanthomonas campestris pv. campestris are 1.12, 1.32, 1.45, 1.23, 1.12, 1.32, 1.45, 1.23, 1.32, 1.45 and 1.23 μ g / mL, respectively. In particular, the EC 50 of compounds III-9, III-11, III-41 and III-44 against Xanthomonas oryzae pv. oryzae are 1.12, 1.32, 1.45 and 1.23 μ g / mL, respectively; the EC 50 of compounds III-2, III-3, III-9 and III-42 against Xanthomonas axonopodis pv. citri are 4.32, 2.91, 4.85 and 3.22 μ g / mL, respectively; the EC 50 of compounds III-1, III-2, III-3 and III-9 against Xanthomonas campestris pv. campestris are 7.61, 19.39, 18.61 and 20.08 μ g / mL, respectively. From Table 4, it can be seen that the target β - The carbazol derivatives also exhibit certain inhibitory activities against plant pathogenic fungi. At a concentration of 50 μ g / mL, the inhibitory rate of compound III-6 against Rhizoctonia solani is 52.90%, and the inhibitory rates of compound III-14 against Rhizoctonia solani and Gibberella saubinetii are 50.48% and 50.09%, respectively. In summary, β - The carbazol derivatives are potential active compounds against plant pathogenic bacteria and fungi, and have important research value and application prospects.

[0053] Finally, it should be noted that the above examples are only used to illustrate the technical solutions of the present application and not to limit the same. Although the present application has been described in detail with reference to the preferred embodiments, those skilled in the art should understand that the technical solutions of the present application can be modified or replaced equivalently without departing from the spirit and scope of the present application, and all of them should be covered in the scope of the claims of the present application.

Claims

1. A kind β -Carboline derivative, characterized by: The compound has a structure as shown in formula (1), （1） wherein R1, R2, R3, R4 and R5 are each independently selected from hydrogen, carboxyl, amido, halogen, optionally substituted formate, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted haloalkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted aryl, optionally substituted or unsubstituted heteroaryl, and optionally substituted or unsubstituted benzyl.

2. A compound according to claim 1 β - a carbazol derivative, characterized in that: R1, R2, R3, R4, and R5are each independently selected from the group consisting of hydrogen, carboxyl, amido, halogen, optionally substituted formate, optionally substituted or unsubstituted C 1-10 alkyl, optionally substituted or unsubstituted C 2-6 alkenyl, optionally substituted or unsubstituted C 5-10 cycloalkyl, optionally substituted or unsubstituted C 5-10 aryl, optionally substituted or unsubstituted benzyl, optionally substituted or unsubstituted C 5-10 heteroaryl.

3. A method according to claim 1 β - a carbazol derivative characterized in that: R1, R2, R3, R4and R5are each independently selected from the group consisting of hydrogen, carboxyl, amido, halogen, carboxymethyl ester, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, chloromethyl, chloroethyl, ethenyl, propenyl, ethynyl, propynyl, phenyl, benzyl, fluorophenyl, chlorophenyl, bromophenyl, nitrophenyl, N , N - dialkylaminophenyl, trifluoromethylphenyl, dichlorophenyl, difluorophenyl, methylphenyl, methoxyphenyl, furanyl, thienyl, benzothiazolyl, naphthyl, quinolinyl, indolyl, pyrrolyl, pyrimidinyl, pyrazolyl, imidazolyl.

4. A beta-carboline derivative according to claim 3, wherein: The compound is selected from one of the following structures: 。 5. A compound according to any one of claims 1 to 4 β Process for the preparation of a carbazol derivative, characterized in that: The method for preparing the compound comprises: 。 6. A composition characterized in that, A compound comprising any of claims 1 to 4 β - a carboline.

7. The composition of claim 6, wherein: Diluents or adjuvants can be added to the formulations, which are suitable for emulsifiable concentrates, dusts, wettable powders, granules, aqueous solutions, suspensions, ultra-low volume sprays, soluble powders, microencapsulations, smoke formulations, emulsions or water-dispersible granules.

8. A compound according to any one of claims 1 to 4 β - Use of a carboline derivative or a composition according to claim 6 for the control of fungal and bacterial diseases in agriculture.

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