CN107827815A

CN107827815A - Fluoroquinolones aminoderivative and its purposes for preventing and treating citrus disease

Info

Publication number: CN107827815A
Application number: CN201711102891.1A
Authority: CN
Inventors: 胡军华; 杨大成; 范莉; 龙艳玲; 冯计周; 黄敏; 王帆; 刘�文; 刘洁; 陈菲菲; 刘晋宇; 张泽朝; 杨真; 张金坤; 谌阳; 陈思雅
Original assignee: Southwest University
Current assignee: Southwest University
Priority date: 2017-11-10
Filing date: 2017-11-10
Publication date: 2018-03-23
Anticipated expiration: 2037-11-10
Also published as: CN107827815B

Abstract

Citrus bacterial canker disease and brown spot are citrus Common Diseases, and it is few to prevent and treat the medicine of both diseases at present, and all have the defects of certain.The bit amino of FQNS 7 is connected to obtain the compound as shown in Formulas I or Formula II by the present invention with active fragment by attachment structure, and experiment shows, compound of the invention has preventing and treating citrus bacterial canker disease and the effect with brown spot, has extraordinary application prospect.

Description

Fluoroquinolones aminoderivative and its purposes for preventing and treating citrus disease

Technical field

The present invention relates to fluoroquinolones aminoderivative and application thereof, more particularly to fluoroquinolones aminoderivative to exist Prevent and treat the purposes in citrus bacterial canker disease and citrus brown spot.

Background technology

Citrus determines it in whole fruits industry as the first big fruit in the world, its yield and economic value Leading position.In recent years, China's Aspects In The Development of Citrus Industry is rapid, has been increasingly becoming and has promoted national rural economic development and guarantee agriculture The mainstay industry that the people increase income.However, citrusfruit is usually vulnerable to pest and disease damage during growing and storing transport etc. Infect, produce and accumulate various biotoxins, have a strong impact on the yield and quality of citrus, greatly reduce the economic valency of citrus Value.

Citrus bacterial canker disease (Citrus canker) is by carpetweed Xanthomonas campestris citrus pvs oryzae and oryzicola (Xanthomonas Axonopodis pv.citri, Xac) caused by cause harm the popularity bacteriosis of whole world citrus planting industry, mainly infect rue Fragrant section's both citrus, Poncirus and Fortunella plant.Xac mainly infects the overground parts such as Citrus leaf, treetop, fruit, prickle, trunk Point, it can cause ulcer and fruit or blade surface necrosis that sallow ring surrounds, the water soaking mode lesion on blade, 2~5mm of diameter, Blade suberification, rough surface, taupe, ftractures in crateriform；In addition to leaf symptom, moreover it is possible to cause fruit abscission, fruit Tree aging, and infection fruit is lost commodity value.

Citrus brown spot (Citrus brown spot) is by Alternaria alternata bacterium tangerine pathological form (Alternaria Alternata pathotype tangerine) caused by fungal disease.Citrus alternaric bacteria mainly infect citrus blade, Spray and fruit, growing for citrus is not only influenceed, reduce fruit yield, but also fruit quality can be reduced, had a strong impact on The production of citrus.In recent years, citrus brown spot occurs successively for the Orange Producing area such as Yunnan Province of China, Chongqing, Zhejiang, Hunan, danger Evil aggravates year by year, has caused the great attention of each side.China is the important original center of citrus, at present citriculture area and Annual production ranks first in the world, and Citrus Cultivars are various, and probability of catching an illness is larger, red tangerine, bowl mandarin orange, tribute mandarin orange and Ponkan in citrus It is all easily susceptible, and proportion of these kinds shared by China's citrus is larger, therefore brown spot is to the potential of the wide skin citrus in China Danger can not be ignored.

It is costly due to what is prevented and treated and eradicate for citrus bacterial canker disease, and eradicate DeGrain, it is external at present and , in the nursery of non-citrus bacterial canker disease region, copper agent and farm antibiotics are sprayed to prevent and reduce in the country mainly by putting prevention first The sprawling of canker.Long-term use of copper agent is also easy to produce drug resistance, causes heavy metal tolerance by the horizontal transfer between germ The shortcomings of with making copper ion be accumulated in soil as potential phytotoxin and influence environment, and copper agent is for fruit It is a kind of harm, is particularly used under arid and hot environment.The use of nearest agricultural streptomycin is prohibited, effective to ulcer bacteria Medicament famine is controlled, there is an urgent need to new compound to replace.

Citrus brown spot belongs to neopathy evil in China, lacks relevant art deposit and system research, especially for not The cause of disease species that causes to cause harm with producing region, infect regularty of epidemic, effective Prevention Technique and efficient pesticide control etc. and all lack research And accumulation, therefore, effective reliable Prevention Technique is had no at present.Therefore, exploitation preventing and treating citrus rod method brown spot is efficiently anti- Control medicament be particularly important with it is urgent.

The content of the invention

Purpose provided by the invention is to provide a series of compounds with quinolone structure, its raceme, three-dimensional different Structure body, dynamic isomer, nitrogen oxides or their pharmaceutically acceptable salt and its preventing and treating citrus bacterial canker disease and brown spot in Purposes.The structure of compound is as follows shown in formula I：

Wherein X is selected from：C1-C6 alkyl；C3-C6 cycloalkyl；Substituted or unsubstituted C6-C10 aryl, on the aryl Substituent for one or more, be independently selected from：Halogen；Amino；Hydroxyl；C1-C6 alkyl；C3-C6 cycloalkyl；

Z is selected from：N or C-R₇；R₇Selected from H；C1-C6 alkoxy or halogens；

R₁And R₂It is each independently selected from：H；C1-C6 alkyl；C1-C6 haloalkyls；C1-C6 alkoxies；Halogen；Hydroxyl；Ammonia Base or cyano group；

Q₁Selected from H；Halogen；

R₃Or R₄It is each independently selected from H；C1-C6 alkyl, the C1-C6 alkyl can be optionally by hydroxyls；Amino；Halogen；Cyanogen Base；Urea groups；Ghiourea group substitutes；

Or R₃, R₄5-8 circle heterocycles are collectively forming with N, the heterocycle optionally can be taken by one or more following substituents Generation：

Amino；Hydroxyl；Tertbutyloxycarbonyl；Benzyl or C1-C6 alkyl, the C1-C6 alkyl can be optionally by hydroxyls；Amino；

Halogen；C1-C4 alkoxies substitute；

A₁, A₂, A₃, A₄It is independently selected from C-R₅Or N, and A₁, A₂In at least one be N；

R₅Selected from H；C1-C4 alkyl；C1-C4 alkoxies；Amino；Acylamino-；Hydroxyl；Halogen；Phenyl or benzyl；

R₆For 1-4, H is independently selected from, C1-C6 alkyl, the C1-C6 alkyl can be optionally by hydroxyl；Amino；Halogen or

Cyano group substitutes；C1-C6 alkoxies, the C1-C6 alkoxies can be optionally optionally substituted by halogen；

B₁Selected from S or NH；

Het is the 5-7 member hetero-aromatic rings containing at least one nitrogen-atoms；

R₈Selected from H, C1-C6 alkyl；

N, k is respectively 0 to 3 integer.

The present invention also provides the compound of the structure as shown in Formula II：

R₈Selected from H, C1-C6 alkyl；

Q₂It is selected fromOr halogen；

N, k is respectively 0 to 3 integer；

M is 1 or 2.

In compound described in above-mentioned Formulas I or Formula II, substituent can be carried out as follows preferably, and independently carry out independent assortment：

Het is selected from

5-8 circle heterocycles are selected from：

X is selected from：Methyl；Ethyl；Cyclopropyl or 4- fluorophenyls；Claim elements are without this sentence and next sentence

Z is selected from：N or C-R₇；R₇Selected from H；Methoxyl group；Fluorine or chlorine；The present invention also provides the compound of following structure：

The present invention also provides a kind of pharmaceutical composition, including above-claimed cpd, its raceme, mutually stereoisomer, variation Structure body, nitrogen oxides or their pharmaceutically acceptable salt.

The present invention also provides a kind of pharmaceutical preparation, including above-claimed cpd, its raceme, stereoisomer, tautomerism Body, nitrogen oxides or their pharmaceutically acceptable salt, and pharmaceutically acceptable carrier and/or auxiliary agent.

The present invention also provides a kind of compound medicine, it is characterised in that including above-claimed cpd, its raceme, alloisomerism Body, dynamic isomer, nitrogen oxides or their pharmaceutically acceptable salt and other active components.

The present invention also provide above-claimed cpd, its raceme, stereoisomer, dynamic isomer, nitrogen oxides or they Pharmaceutically acceptable salt prepare preventing and treating citrus correlation disease medicine in purposes.The preferred citrus of citrus correlation disease is burst Ulcer disease or citrus brown spot.

The present invention also provides a kind of method for treating citrus correlation disease, including applies and contain to citrus fruit tree and/or fruit There are above-claimed cpd of the present invention, its raceme, stereoisomer, dynamic isomer, nitrogen oxides or theirs is pharmaceutically acceptable The medicament of salt.Term is defined and explained：

Unless otherwise indicated, the group described in present specification and claims and term definition, can be each other Between any combination and combine.Group definition and compound structure after such combination and combination, should belong to the application and say In the range of bright secretary carries.

Term " dynamic isomer " refer to because in molecule a certain atom in two rapid movements in position and caused by functional group Isomers.The compounds of this invention can show tautomerism.Tautomeric compound may have two or more can The species mutually converted.The migration of prototropic tautomeric body hydrogen atom of covalent bonding between two atoms.Change Isomers typically exists with equilibrium form, attempts to generally produce a kind of mixture when separating single dynamic isomer, its physics and chemistry The mixture of matter and compound is consistent.The position of balance depends on the chemical characteristic of intramolecular.For example, in many aliphatic aldehydes In ketone such as acetaldehyde, ketone type is dominant；And in phenol, enol form is dominant.All tautomerisms of inclusion compound of the present invention Form.

Term " halogen " refers to F, Cl, Br and I.In other words, F, Cl, Br and I can be described as " halogen " in this manual.

Term " C1-C6 " is interpreted as the preferred direct-connected or side chain saturation monovalent hydrocarbon for representing to have 1-6 carbon atom, example Such as methyl, ethyl, propyl group, butyl, amyl group, hexyl, isopropyl, isobutyl group, sec-butyl, the tert-butyl group, isopentyl, 2- methyl fourths Base, 1- methyl butyls, 1- ethyl propyls, 1,2- dimethyl propyls, neopentyl, 1,1- dimethyl propyls, 4- methyl amyls, 3- first Base amyl group, 2- methyl amyls, 1- methyl amyls, 2- ethyl-butyls, 1- ethyl-butyls, 3,3- dimethylbutyls, 2,2- dimethyl Butyl, 1,1- dimethylbutyls, 2,3- dimethylbutyls, 1,3- dimethylbutyls or 1,2- dimethylbutyls etc. or theirs is different Structure body.

The number range that present specification and claims are recorded, when the number range is defined as " integer ", Each integer in the range of should be understood to describe two end points of the scope and being somebody's turn to do.It is for example, " any whole in 0-4 Number " should be understood to describe 0,1,2,3,4 each integer.

Compound pharmaceutically acceptable salt mentioned by the present invention can be ackd salt or basic salt.Pharmacy Upper acceptable salt can be the acid with compound of the invention alkaline enough with nitrogen-atoms for example in chain or ring Addition salts, such as the acid-addition salts formed with following inorganic acid：Such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, burnt sulphur Acid, phosphoric acid or nitric acid, or disulfate, or the acid-addition salts formed with following organic acid：Such as formic acid, acetic acid, acetyl second Acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, enanthic acid, hendecanoic acid, laurate, benzoic acid, salicylic acid, 2- (4- hydroxyls Base benzoyl) benzoic acid, camphoric acid, cinnamic acid, pentamethylene propionic acid, gluconic acid, 3- hydroxy-2-naphthoic acids, nicotinic acid, flutter acid, Pectinic acid, persulfuric acid, 3- phenylpropionic acids, picric acid, pivalic acid, 2- ethylenehydrinsulfonic acids, itaconic acid, sulfamic acid, fluoroform Sulfonic acid, dodecyl sulphate, ethyl sulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, methanesulfonic acid, 2- naphthalene sulfonic acids, naphthalenedisulfonic acid, camphorsulfonic acid, Citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, butanedioic acid, malic acid, adipic acid, alginic acid, maleic acid, rich horse Acid, D- gluconic acids, mandelic acid, ascorbic acid, glucoheptose, phosphoglycerol, aspartic acid, sulfosalicylic acid, hemisulfic acid or sulphur cyanogen Acid.

In addition, the pharmaceutically acceptable salt that the another kind with compound of the invention acid enough is adapted to is alkali gold Belong to salt (such as sodium salt or sylvite), alkali salt (such as calcium salt or magnesium salts), ammonium salt, or with providing the acceptable sun of physiology The salt that the organic base of ion is formed, such as the salt formed with following material：Sodium ion, potassium ion, N-METHYL-ALPHA-L-GLUCOSAMINE, dimethyl Aminoglucose, ethyl aminoglucose, lysine, dicyclohexylamine, 1,6- hexamethylene diamines, monoethanolamine, aminoglucose, meglumine, methyl amimoacetic acid, silk Ammonia alcohol, trishydroxymethylaminomethane, amino-propanediol, 1- amino -2,3,4- butantriols.

Embodiment

Embodiment 1

Raw material gatifloxacin (GAT) 1mmol, NaHCO is sequentially added into 100mL round-bottomed flasks₃ 2.5mmol、DCM 5mL, chloracetyl chloride 2mmol and DCM 2mL mixed solution is added dropwise under ice bath.Drop finishes, and continues stirring reaction, TLC under ice bath Monitor reaction process.After reaction terminates, adding a little ice-cold saturation NaCl solution makes solid dissolving, and ice-cold 2N HCl solutions adjust pH For 4-5, separatory funnel liquid separation is moved into after stirring, DCM is extracted twice, and merges organic phase, and the washing of saturation NaCl solution is anhydrous Na₂SO₄Dry, revolving removes solvent.Recrystallization or column chromatography obtain sterling, dry, weigh, obtain product, [M+H]⁺453.1342。

Embodiment 2

Raw material GAT 1mmol, NaHCO are sequentially added into 100mL round-bottomed flasks₃2.5mmol, DCM 5mL, in ice bath Lower dropwise addition chlorpromazine chloride 2mmol and DCM 2mL mixed solution.Drop finish, under ice bath continue stirring reaction, TLC monitoring react into Journey.After reaction terminates, adding a little ice-cold saturation NaCl solution makes solid dissolving, and it is 4-5 that ice-cold 2N HCl solutions, which adjust pH, stirring Separatory funnel liquid separation is moved into after uniformly, DCM is extracted twice, and merges organic phase, the washing of saturation NaCl solution, anhydrous Na₂SO₄Dry, Revolving removes solvent.Recrystallization or column chromatography obtain sterling, dry, weigh, obtain product, [M+H]⁺467.1453。

Embodiment 3

Raw material GAT 1mmol, NaHCO are sequentially added into 100mL round-bottomed flasks₃2.5mmol, DCM 4mL, in ice bath Lower dropwise addition 4- chlorobutanoylchlorides 2.5mmol and 2mL DCM mixed solution.Drop finishes, and continues stirring reaction under ice bath, and TLC monitorings are anti- Answer process.After reaction terminates, adding a little ice-cold saturation NaCl solution makes solid dissolving, and it is 4-5 that ice-cold 2N HCl solutions, which adjust pH, Separatory funnel liquid separation is moved into after stirring, DCM is extracted twice, and merges organic phase, the washing of saturation NaCl solution, anhydrous Na₂SO₄ Dry, revolving removes solvent.Sterling is recrystallized to obtain, is dried, is weighed, obtain product, [M+H]⁺481.1679。

Embodiment 4

100mL round-bottomed flasks sequentially add GAT 1.880g (5mmol), DCM 20mL, succinic anhydride 0.601g (6mmol).Na is added after 30min₂CO₃0.635g(6mmol).Reaction, TLC monitoring reaction process is stirred at room temperature.Reaction terminates There are a large amount of yellow oils at reaction bulb bottom afterwards.Revolving removes solvent DCM, adds H₂O 20mL, insoluble matter dissolving.It is molten with 2N HCl It is 2 that liquid, which adjusts pH value,, there are a large amount of yellow oils again in bottom of bottle, is put into refrigerator cold-storage, and grease is changed into solid, filters, obtains yellow Solid.Product is spontaneously dried to obtain, [M+H]⁺476.1834。

Embodiment 5

1mmol sarafloxacins and 2mL DCM are added in 100mL round-bottomed flasks, ice bath cooling, magnetic agitation, adds 3mmol NaHCO₃, after 20min, DCM (2mL) solution of 2.5mmol 4- chlorobutanoylchlorides is added dropwise with constant pressure funnel, and (rate of addition is About 1d/2s), drip and finish sustained response under ice bath, TLC tracking and monitorings to reaction terminate.Stop stirring, add H₂O15mL and DCM 20mL, the lower 1N HCl solutions regulation pH=3-4 of stirring, stands if having solid, filters, filter cake is washed 3 times with DCM, and filter cake stays Wait to be further purified；Filtrate moves to separatory funnel, liquid separation, and aqueous phase is extracted (15mL × 1) with DCM, merges organic phase, saturation NaCl Solution washs (15mL × 1), collects organic phase, anhydrous Na₂SO₄Dry.Rotary Evaporators are spin-dried for obtaining crude product, and column chromatography obtains To sterling, vacuum drying, product is obtained, [M+H]⁺491.1238。

Embodiment 6

1mmol Clinafloxacins and 2mL DCM are added in 100mL round-bottomed flasks, ice bath cooling, magnetic agitation, adds 3mmol NaHCO₃, after 20min, DCM (2mL) solution of 2.5mmol 2- chloracetyl chlorides is added dropwise with constant pressure funnel, and (rate of addition is About 1d/2s), drip and finish sustained response under ice bath, TLC tracking and monitorings to reaction terminate.Stop stirring, add H₂O15mL and DCM 20mL, the lower 1N HCl solutions regulation pH=3-4 of stirring, stands if having solid, filters, filter cake is washed 3 times with DCM, and filter cake stays Wait to be further purified；Filtrate moves to separatory funnel, liquid separation, and aqueous phase is extracted (15mL × 1) with DCM, merges organic phase, saturation NaCl Solution washs (15mL × 1), collects organic phase, anhydrous Na₂SO₄Dry.Rotary Evaporators are spin-dried for obtaining crude product, and column chromatography obtains To sterling, vacuum drying, product is obtained, [M+H]⁺443.0635。

Embodiment 7

1mmol Clinafloxacins and 2mL DCM are added in 100mL round-bottomed flasks, ice bath cooling, magnetic agitation, adds 3mmol NaHCO₃, after 20min, DCM (2mL) solution of 2.5mmol 3- chlorpromazine chlorides is added dropwise with constant pressure funnel, and (rate of addition is About 1d/2s), drip and finish sustained response under ice bath, TLC tracking and monitorings to reaction terminate.Stop stirring, add H₂O 15mL and DCM 20mL, the lower 1N HCl solutions regulation pH=3-4 of stirring, stands if having solid, filters, filter cake is washed 3 times with DCM, and filter cake stays Wait to be further purified；Filtrate moves to separatory funnel, liquid separation, and aqueous phase is extracted (15mL × 1) with DCM, merges organic phase, saturation NaCl Solution washs (15mL × 1), collects organic phase, anhydrous Na₂SO₄Dry.Rotary Evaporators are spin-dried for obtaining crude product, and column chromatography obtains To sterling, vacuum drying, product is obtained, [M+H]⁺457.0814。

Embodiment 8

1mmol Clinafloxacins and 2mL DCM are added in 100mL round-bottomed flasks, ice bath cooling, magnetic agitation, adds 3mmol NaHCO₃, after 20min, DCM (2mL) solution of 2.5mmol 4- chlorobutanoylchlorides is added dropwise with constant pressure funnel, and (rate of addition is About 1d/2s), drip and finish sustained response under ice bath, TLC tracking and monitorings to reaction terminate.Stop stirring, add H₂O15mL and DCM 20mL, the lower 1N HCl solutions regulation pH=3-4 of stirring, stands if having solid, filters, filter cake is washed 3 times with DCM, and filter cake stays Wait to be further purified；Filtrate moves to separatory funnel, liquid separation, and aqueous phase is extracted (15mL × 1) with DCM, merges organic phase, saturation NaCl Solution washs (15mL × 1), collects organic phase, anhydrous Na₂SO₄Dry.Rotary Evaporators are spin-dried for obtaining crude product, and column chromatography obtains To sterling, vacuum drying, product is obtained, [M+H]⁺471.0927。

Embodiment 9

1mmol Norfloxacins and 2mL DCM are added in 100mL round-bottomed flasks, ice bath cooling, magnetic agitation, adds 3mmol NaHCO₃, after 20min, DCM (2mL) solution of 2.5mmol 2- chloracetyl chlorides is added dropwise with constant pressure funnel, and (rate of addition is About 1d/2s), drip and finish sustained response under ice bath, TLC tracking and monitorings to reaction terminate.Stop stirring, add H₂O 15mL and DCM 20mL, the lower 1N HCl solutions regulation pH=3-4 of stirring, stands if having solid, filters, filter cake is washed 3 times with DCM, and filter cake stays Wait to be further purified；Filtrate moves to separatory funnel, liquid separation, and aqueous phase is extracted (15mL × 1) with DCM, merges organic phase, saturation NaCl Solution washs (15mL × 1), collects organic phase, anhydrous Na₂SO₄Dry.Rotary Evaporators are spin-dried for obtaining crude product, and column chromatography obtains To sterling, vacuum drying, product is obtained, [M+H]⁺397.1021。

Embodiment 10

1mmol Barnes ＆ Noble sand stars and 2mL DCM are added in 100mL round-bottomed flasks, ice bath cooling, magnetic agitation, adds 3mmol NaHCO₃, after 20min, DCM (2mL) solution of 2.5mmol 2- chloracetyl chlorides is added dropwise with constant pressure funnel, and (rate of addition is About 1d/2s), drip and finish sustained response under ice bath, TLC tracking and monitorings to reaction terminate.Stop stirring, add H₂O15mL and DCM 20mL, the lower 1N HCl solutions regulation pH=3-4 of stirring, stands if having solid, filters, filter cake is washed 3 times with DCM, and filter cake stays Wait to be further purified；Filtrate moves to separatory funnel, liquid separation, and aqueous phase is extracted (15mL × 1) with DCM, merges organic phase, saturation NaCl Solution washs (15mL × 1), collects organic phase, anhydrous Na₂SO₄Dry.Rotary Evaporators are spin-dried for obtaining crude product, and column chromatography obtains To sterling, vacuum drying, product is obtained, [M+H]⁺467.1428。

Embodiment 11

1mmol sarafloxacins and 2mL DCM are added in 100mL round-bottomed flasks, ice bath cooling, magnetic agitation, adds 3mmol NaHCO₃, after 20min, DCM (2mL) solution of 2.5mmol 3- chlorpromazine chlorides is added dropwise with constant pressure funnel, and (rate of addition is About 1d/2s), drip and finish sustained response under ice bath, TLC tracking and monitorings to reaction terminate.Stop stirring, add H₂O15mL and DCM 20mL, the lower 1N HCl solutions regulation pH=3-4 of stirring, stands if having solid, filters, filter cake is washed 3 times with DCM, and filter cake stays Wait to be further purified；Filtrate moves to separatory funnel, liquid separation, and aqueous phase is extracted (15mL × 1) with DCM, merges organic phase, saturation NaCl Solution washs (15mL × 1), collects organic phase, anhydrous Na₂SO₄Dry.Rotary Evaporators are spin-dried for obtaining crude product, and column chromatography obtains To sterling, vacuum drying, product is obtained, [M+H]⁺477.1173。

Embodiment 12

Sequentially added into 100mL round-bottomed flasks2mmol、CHCl₃ 3mL、K₂CO₃2mmol, room temperature Stir 30min.The compound 1mmol of INTERMEDIATES Example 1 is added, and is moved in 35 DEG C of water-baths, TLC monitoring reaction process.Instead After should terminating, DCM 15mL, H are added₂O 10mL, 1N HCl solution adjust pH value 7~8, liquid separation.Saturation NaCl solution 10mL is washed Wash, liquid separation, organic phase anhydrous Na₂SO₄Dry, rotate to obtain crude product, column chromatography obtains sterling, [M+H]⁺521.2406。

Embodiment 13

2- ethylaminoethanols 1mmol, CHCl are sequentially added into 100mL round-bottomed flasks₃3mL, add the compound of embodiment 3 1.2mmol, and move in 60 DEG C of water-bath back flow reactions, TLC monitoring reaction process.When the compound of example 3 to be performed is no longer reduced, stop Reaction.Revolving removes solvent, and column chromatography obtains sterling, [M+H]⁺505.2466。

Embodiment 14

Sequentially added into 100mL round-bottomed flasks1mmol、CHCl₃3mL, add the chemical combination of embodiment 3 Thing 1.2mmol, and move in 60 DEG C of water-bath back flow reactions, TLC monitoring reaction process.When the compound of example 3 to be performed is no longer reduced, stop Only react.Revolving removes solvent, and column chromatography obtains sterling, [M+H]⁺549.2726。

Embodiment 15

2- amion acetic acids (50mmol), methanol 100mL are added in reaction bulb, SOCl is slowly added dropwise under ice bath₂ (125mmol), drop finish, and are transferred to 60 DEG C of stirred in water bath back flow reactions, TLC monitorings are until reaction terminates.Vacuum rotary steam removes first Alcohol and most SOCl₂, methanol 20mL is added, is rotated again to eliminate SOCl as far as possible₂, vacuum drying, obtain corresponding 2- Methyl aminoacetate hydrochloride.

INA (isonicotinic acid 20mmol), HOBt (24mmol), DCC (24mmol), DCM are sequentially added in reaction bulb (20mL), Et is added after stirring 10min₃2- methyl aminoacetates hydrochloride (22mmol) is added after N (60mmol), 0.5~1h, TLC, which is monitored to reaction, to be terminated.Refrigerator freezing 2h is put into, is filtered, filter cake washs with DCM, and filtrate is with saturation Na₂CO₃The aqueous solution is washed (20mL × 2), aqueous phase are extracted (30mL × 3) with DCM, merge organic phase, anhydrous Na₂SO₄1h is dried, Rotary Evaporators are spin-dried for, post Chromatography obtains 4- pyridylcarbonylamino methyl acetates.

4- pyridylcarbonylaminos methyl acetate (15mmol), CH are sequentially added in reaction bulb₃OH-H₂O(V _CH3OH:V_H2O=3:1) solution (15mL), LiOHH is added under ice bath₂O (45mmol), stirring, TLC, which is monitored to reaction, to be terminated.Rotation is steamed Instrument is sent out by CH₃OH is removed, and with 4N HCl solutions regulation pH=3 or so under ice bath, is had a large amount of white solids to separate out, is filtered, filter cake Washed 2 times with filtrate, acetone is washed 2 times, 50 DEG C of drying, obtains 4- pyridylcarbonylamino acetic acid.

4- pyridylcarbonylaminos acetic acid (1mmol), HBTU/TBTU (1.2mmol), DCM are sequentially added in reaction bulb (3mL)、Et₃N (3mmol), Clinafloxacin (1mmol), temperature control stirring, TLC, which is monitored to reaction, to be terminated.DCM 20mL are added, are moved To separatory funnel, saturation Na₂CO₃The aqueous solution is washed (20mL × 1), and 0.5N HCl solutions are washed (20mL × 1), saturated common salt washing (20mL × 1), anhydrous Na₂SO₄1h is dried, Rotary Evaporators are spin-dried for, and column chromatography obtains sterling, [M+H]⁺528.1445。

Embodiment 16

Formula is added in 100mL round-bottomed flasks and implements 9 compound 1mmol, 5mL toluene, 2mmol Et₃N, stir 20- 30min, add after 2mmol INA, 10min and move to back flow reaction in 110 DEG C~120 DEG C oil bath pans, TLC is monitored to having reacted Entirely.Reaction solution is spin-dried for Rotary Evaporators Rotary Evaporators, adds 30mL DCM stirring and dissolvings, is filtered, filter cake washes 3 with DCM Secondary, filtrate is washed (15mL × 1) with 10% citric acid solution, collects organic phase, anhydrous Na₂SO₄Dry.Rotary Evaporators are spin-dried for To crude product, column chromatography obtains sterling, [M+H]⁺483.1642。

Embodiment 17

1mmol Norfloxacins and 2mL DCM are added in 100mL round-bottomed flasks, ice bath cooling, magnetic agitation, adds 3mmol NaHCO₃, after 20min, DCM (2mL) solution of 2.5mmol 4- chlorobutanoylchlorides is added dropwise with constant pressure funnel, and (rate of addition is About 1d/2s), drip and finish sustained response under ice bath, TLC tracking and monitorings to reaction terminate.Stop stirring, add H₂O15mL and DCM 20mL, the lower 1N HCl solutions regulation pH=3-4 of stirring, stands if having solid, filters, filter cake is washed 3 times with DCM, and filter cake stays Wait to be further purified；Filtrate moves to separatory funnel, liquid separation, and aqueous phase is extracted (15mL × 1) with DCM, merges organic phase, saturation NaCl Solution washs (15mL × 1), collects organic phase, anhydrous Na₂SO₄Dry.Rotary Evaporators are spin-dried for obtaining crude product, and column chromatography obtains To sterling, vacuum drying, intermediate is obtained.

Above-mentioned intermediate 1mmol, 5mL toluene, 2mmol Et are added in 100mL round-bottomed flasks₃N, 20-30min is stirred, is added Enter 2mmol INA, back flow reaction in 110 DEG C~120 DEG C oil bath pans is moved to after 10min, TLC monitors complete to reaction.Will reaction Liquid is spin-dried for Rotary Evaporators Rotary Evaporators, adds 30mL DCM stirring and dissolvings, is filtered, and filter cake is washed 3 times with DCM, and filtrate is used 10% citric acid solution is washed (15mL × 1), collects organic phase, anhydrous Na₂SO₄Dry.Rotary Evaporators are spin-dried for obtaining crude product, Column chromatography obtains sterling, [M+H]⁺411.1956。

Embodiment 18

1mmol Enoxacins and 2mL DCM are added in 100mL round-bottomed flasks, ice bath cooling, magnetic agitation, adds 3mmol NaHCO₃, after 20min, DCM (2mL) solution (rate of addition of 2.5mmol 2- chloro-acetyl chlorides is added dropwise with constant pressure funnel It is about 1d/2s), drip and finish sustained response under ice bath, TLC tracking and monitorings to reaction terminate.Stop stirring, add H₂O 15mL and DCM 20mL, the lower 1N HCl solutions regulation pH=3-4 of stirring, stand if having solid, filter, filter cake is washed 3 times with DCM, filter Cake remains to be further purified；Filtrate moves to separatory funnel, liquid separation, and aqueous phase is extracted (15mL × 1) with DCM, merges organic phase, saturation NaCl solution washs 15mL × 1), collect organic phase, anhydrous Na₂SO₄Dry.Rotary Evaporators are spin-dried for obtaining crude product, column chromatography Sterling is obtained, is dried in vacuo, obtains intermediate.

Above-mentioned intermediate 1mmol, 5mL toluene, 2mmol Et are added in 100mL round-bottomed flasks₃N, 20-30min is stirred, is added Enter 2mmol INA, back flow reaction in 110 DEG C~120 DEG C oil bath pans is moved to after 10min, TLC monitors complete to reaction.Will reaction Liquid is spin-dried for Rotary Evaporators Rotary Evaporators, adds 30mL DCM stirring and dissolvings, is filtered, and filter cake is washed 3 times with DCM, and filtrate is used 10% citric acid solution is washed (15mL × 1), collects organic phase, anhydrous Na₂SO₄Dry.Rotary Evaporators are spin-dried for obtaining crude product, Column chromatography obtains sterling, [M+H]⁺484.1616。

Embodiment 19

1mmol Enoxacins and 2mL DCM are added in 100mL round-bottomed flasks, ice bath cooling, magnetic agitation, adds 3mmol NaHCO₃, after 20min, DCM (2mL) solution (rate of addition of 2.5mmol 4- chlorobutyroyl chlorides is added dropwise with constant pressure funnel It is about 1d/2s), drip and finish sustained response under ice bath, TLC tracking and monitorings to reaction terminate.Stop stirring, add H₂O 15mL and DCM 20mL, the lower 1N HCl solutions regulation pH=3-4 of stirring, stand if having solid, filter, filter cake is washed 3 times with DCM, filter Cake remains to be further purified；Filtrate moves to separatory funnel, liquid separation, and aqueous phase is extracted (15mL × 1) with DCM, merges organic phase, saturation NaCl solution washs (15mL × 1), collects organic phase, anhydrous Na₂SO₄Dry.Rotary Evaporators are spin-dried for obtaining crude product, post layer Analysis obtains sterling, is dried in vacuo, obtains intermediate.

Above-mentioned intermediate 1mmol, 5mL toluene, 2mmol Et are added in 100mL round-bottomed flasks₃N, 20-30min is stirred, is added Enter 2mmol pyrazine carboxylic acids (POA), move to back flow reaction in 110 DEG C~120 DEG C oil bath pans after 10min, TLC is monitored to having reacted Entirely.Reaction solution is spin-dried for Rotary Evaporators Rotary Evaporators, adds 30mL DCM stirring and dissolvings, is filtered, filter cake washes 3 with DCM Secondary, filtrate is washed (15mL × 1) with 10% citric acid solution, collects organic phase, anhydrous Na₂SO₄Dry.Rotary Evaporators are spin-dried for To crude product, column chromatography obtains sterling, [M+H]⁺513.1892。

Embodiment 20

Compound 1mmol, the 5mL toluene of embodiment 10,2mmol Et are added in 100mL round-bottomed flasks₃N, stir 20- 30min, 2mmol pyrazine carboxylic acids (POA) are added, back flow reaction in 110 DEG C~120 DEG C oil bath pans, TLC monitorings are moved to after 10min It is complete to reaction.Reaction solution is spin-dried for Rotary Evaporators Rotary Evaporators, adds 30mL DCM stirring and dissolvings, is filtered, filter cake Washed 3 times with DCM, filtrate is washed (15mL × 1) with 10% citric acid solution, collects organic phase, anhydrous Na₂SO₄Dry.Rotary evaporation Instrument is spin-dried for obtaining crude product, and column chromatography obtains sterling, [M+H]⁺554.2046。

Embodiment 21

1mmol Barnes ＆ Noble sand stars and 2mL DCM are added in 100mL round-bottomed flasks, ice bath cooling, magnetic agitation, adds 3mmol NaHCO₃, after 20min, DCM (2mL) solution (rate of addition of 2.5mmol 4- chlorobutyroyl chlorides is added dropwise with constant pressure funnel It is about 1d/2s), drip and finish sustained response under ice bath, TLC tracking and monitorings to reaction terminate.Stop stirring, add H₂O 15mL and DCM 20mL, the lower 1N HCl solutions regulation pH=3-4 of stirring, stand if having solid, filter, filter cake is washed 3 times with DCM, filter Cake remains to be further purified；Filtrate moves to separatory funnel, liquid separation, and aqueous phase is extracted (15mL × 1) with DCM, merges organic phase, saturation NaCl solution washs (15mL × 1), collects organic phase, anhydrous Na₂SO₄Dry.Rotary Evaporators are spin-dried for obtaining crude product, post layer Analysis obtains sterling, is dried in vacuo, obtains intermediate.

Above-mentioned intermediate 1mmol, 5mL toluene, 2mmol Et are added in 100mL round-bottomed flasks₃N, 20-30min is stirred, is added Enter 2mmol pyrazine carboxylic acids (POA), move to back flow reaction in 110 DEG C~120 DEG C oil bath pans after 10min, TLC is monitored to having reacted Entirely.Reaction solution is spin-dried for Rotary Evaporators Rotary Evaporators, adds 30mL DCM stirring and dissolvings, is filtered, filter cake washes 3 with DCM Secondary, filtrate is washed (15mL × 1) with 10% citric acid solution, collects organic phase, anhydrous Na₂SO₄Dry.Rotary Evaporators are spin-dried for To crude product, column chromatography obtains sterling, [M+H]⁺582.2359。

Embodiment 22

2mmol isoniazid, 4mmol NaHCO are sequentially added in 100mL round-bottomed flasks₃With 5mL DCM, stir under the conditions of -5 DEG C After mixing 20min, 3mmol chloracetyl chlorides solution (rate of addition is about 1d/2s) is added dropwise with constant pressure funnel, is held under the conditions of -5 DEG C Continuous reaction, TLC tracking and monitorings to reaction terminate.Under stirring state, DCM-CH is added₃OH solution (V_DCM:V_CH3OH=2：1) to anti- Answer solid in bottle no longer to reduce, stand, filter, filter cake DCM-CH₃OH solution washs 3 times, filtrate anhydrous Na₂SO₄Dry, Rotary Evaporators are spin-dried for obtaining crude product, then add 5mL DCM stirring 20min, filter, filter cake washes 3 times, and vacuum with DCM Dry, it is standby to obtain intermediate.

1mmol Norfloxacins, 4mmol Et are sequentially added in 100mL round-bottomed flasks₃N and 2mL DMF, after stirring 20min Above-mentioned intermediate is added, stirring reaction under the conditions of 60 DEG C are moved to after 10min, TLC, which is monitored to reaction, to be terminated.Added under stirring state The saturated common salt aqueous solution ice-cold 10mL, and pH=8 or so is adjusted with 1N HCl solutions, filter, filtrate extracts (10mL with DCM × 2), merge organic phase, use anhydrous Na₂SO₄Dry, Rotary Evaporators are spin-dried for, and column chromatography purifies to obtain product, [M+ together with filter cake H]⁺497.1943。

Embodiment 23

Alanine (50mmol), methanol 100mL are added in reaction bulb, SOCl is slowly added dropwise under ice bath₂(125mmol), Drop finishes, and is transferred to 60 DEG C of stirred in water bath back flow reactions, TLC monitorings are until reaction terminates.Vacuum rotary steam removes methanol and major part SOCl₂, methanol 20mL is added, is rotated again to eliminate SOCl as far as possible₂, vacuum drying, obtain corresponding methyl lactamine salt Hydrochlorate.

INA (20mmol), HOBt (24mmol), DCC (24mmol), DCM (20mL) are sequentially added in reaction bulb, is stirred DIPEA is added after 10min under ice bath, alanine methyl ester hydrochloride (22mmol) is added after 0.5~1h, TLC is monitored to reaction and tied Beam.Refrigerator freezing 2h is put into, is filtered, filter cake washs with DCM, and filtrate is with saturation Na₂CO₃The aqueous solution is washed (20mL × 2), and aqueous phase is used DCM extracts (30mL × 3), merges organic phase, anhydrous Na₂SO₄1h is dried, Rotary Evaporators are spin-dried for, and column chromatography obtains intermediate.

Intermediate (15mmol), CH are sequentially added in reaction bulb₃OH-H₂O(V _CH3OH:V _H2O=3:1) solution (15mL), LiOHH is added under ice bath₂O (45mmol), stirring, TLC, which is monitored to reaction, to be terminated.Rotary Evaporators are by CH₃OH is removed Going, with 4N HCl solutions regulation pH=3 or so under ice bath, there are a large amount of white solids to separate out, filter, filter cake washes 2 times with filtrate, and third Ketone is washed 2 times, 50 DEG C of drying, obtains intermediate.

Above-mentioned midbody compound (1mmol), HBTU/TBTU (1.2mmol), DCM are sequentially added in reaction bulb DIPEA3mmol, gatifloxacin (1mmol) are added under (3mL), ice bath, temperature control stirring, TLC, which is monitored to reaction, to be terminated.Add DCM20mL, move to separatory funnel, saturation Na₂CO₃The aqueous solution is washed (20mL × 1), and 0.5N HCl solutions wash (20mL × 1), saturation Salt washes (20mL × 1), anhydrous Na₂SO₄1h is dried, Rotary Evaporators are spin-dried for, and column chromatography obtains sterling, [M+H]⁺552.2217。

Embodiment 24

3- alanines (50mmol), methanol 100mL are added in reaction bulb, SOCl is slowly added dropwise under ice bath₂ (125mmol), drop finish, and are transferred to 60 DEG C of stirred in water bath back flow reactions, TLC monitorings are until reaction terminates.Vacuum rotary steam removes first Alcohol and most SOCl₂, methanol 20mL is added, is rotated again to eliminate SOCl as far as possible₂, vacuum drying, obtain corresponding 3- Aminopropanoate hydrochloride.

INA (20mmol), HOBt (24mmol), DCC (24mmol), DCM (20mL) are sequentially added in reaction bulb, is stirred DIPEA is added after 10min under ice bath, adds 3- aminopropanoates hydrochloride (22mmol) after 0.5~1h, TLC is monitored to anti- It should terminate.Refrigerator freezing 2h is put into, is filtered, filter cake washs with DCM, and filtrate is with saturation Na₂CO₃The aqueous solution washes (20mL × 2), water Mutually extracted (30mL × 3) with DCM, merge organic phase, anhydrous Na₂SO₄1h is dried, Rotary Evaporators are spin-dried for, and column chromatography obtains centre Body.

Above-mentioned midbody compound (1mmol), HBTU/TBTU (1.2mmol), DCM are sequentially added in reaction bulb DIPEA3mmol, gatifloxacin (1mmol) are added under (3mL), ice bath, temperature control stirring, TLC, which is monitored to reaction, to be terminated.Add DCM20mL, move to separatory funnel, saturation Na₂CO₃The aqueous solution is washed (20mL × 1), and 0.5N HCl solutions wash (20mL × 1), saturation Salt washes (20mL × 1), anhydrous Na₂SO₄1h is dried, Rotary Evaporators are spin-dried for, and column chromatography obtains sterling, [M+H]⁺552.2253。

Embodiment 25

4-Aminobutanoicacid (50mmol), methanol 100mL are added in reaction bulb, SOCl is slowly added dropwise under ice bath₂ (125mmol), drop finish, and are transferred to 60 DEG C of stirred in water bath back flow reactions, TLC monitorings are until reaction terminates.Vacuum rotary steam removes first Alcohol and most SOCl₂, methanol 20mL is added, is rotated again to eliminate SOCl as far as possible₂, vacuum drying, obtain corresponding 4- Aminobutyric acid methyl ester hydrochloride.

INA (20mmol), HOBt (24mmol), DCC (24mmol), DCM (20mL) are sequentially added in reaction bulb, is stirred DIPEA is added after 10min under ice bath, adds 4-Aminobutanoicacid methyl ester hydrochloride (22mmol) after 0.5~1h, TLC is monitored to anti- It should terminate.Refrigerator freezing 2h is put into, is filtered, filter cake washs with DCM, and filtrate is with saturation Na₂CO₃The aqueous solution washes (20mL × 2), water Mutually extracted (30mL × 3) with DCM, merge organic phase, anhydrous Na₂SO₄1h is dried, Rotary Evaporators are spin-dried for, and column chromatography obtains centre Body.

Above-mentioned midbody compound (1mmol), HBTU/TBTU (1.2mmol), DCM are sequentially added in reaction bulb DIPEA3mmol, gatifloxacin (1mmol) are added under (3mL), ice bath, temperature control stirring, TLC, which is monitored to reaction, to be terminated.Add DCM20mL, move to separatory funnel, saturation Na₂CO₃The aqueous solution is washed (20mL × 1), and 0.5N HCl solutions wash (20mL × 1), saturation Salt washes (20mL × 1), anhydrous Na₂SO₄1h is dried, Rotary Evaporators are spin-dried for, and column chromatography obtains sterling, [M+H]⁺566.2409。

Embodiment 26

Glycine (50mmol), methanol 100mL are added in reaction bulb, SOCl is slowly added dropwise under ice bath₂(125mmol), Drop finishes, and is transferred to 60 DEG C of stirred in water bath back flow reactions, TLC monitorings are until reaction terminates.Vacuum rotary steam removes methanol and major part SOCl₂, methanol 20mL is added, is rotated again to eliminate SOCl as far as possible₂, vacuum drying, obtain corresponding glycine methyl ester salt Hydrochlorate.

INA (20mmol), HOBt (24mmol), DCC (24mmol), DCM (20mL) are sequentially added in reaction bulb, is stirred DIPEA is added after 10min under ice bath, glycine methyl ester hydrochloride (22mmol) is added after 0.5~1h, TLC is monitored to reaction and tied Beam.Refrigerator freezing 2h is put into, is filtered, filter cake washs with DCM, and filtrate is with saturation Na₂CO₃The aqueous solution is washed (20mL × 2), and aqueous phase is used DCM extracts (30mL × 3), merges organic phase, anhydrous Na₂SO₄1h is dried, Rotary Evaporators are spin-dried for, and column chromatography obtains intermediate.

Above-mentioned midbody compound (1mmol), HBTU/TBTU (1.2mmol), DCM are sequentially added in reaction bulb (3mL), add Et₃N 3mmol, Norfloxacin (1mmol), temperature control stirring, TLC, which is monitored to reaction, to be terminated.DCM 20mL are added, Move to separatory funnel, saturation Na₂CO₃The aqueous solution is washed (20mL × 1), and 0.5N HCl solutions are washed (20mL × 1), saturated common salt washing (20mL × 1), anhydrous Na₂SO₄1h is dried, Rotary Evaporators are spin-dried for, and column chromatography obtains sterling, [M+H]⁺482.1853。

Embodiment 27

Above-mentioned midbody compound (1mmol), HBTU/TBTU (1.2mmol), DCM are sequentially added in reaction bulb DIPEA3mmol, Norfloxacin (1mmol) are added under (3mL), ice bath, temperature control stirring, TLC, which is monitored to reaction, to be terminated.Add DCM20mL, move to separatory funnel, saturation Na₂CO₃The aqueous solution is washed (20mL × 1), and 0.5N HCl solutions wash (20mL × 1), saturation Salt washes (20mL × 1), anhydrous Na₂SO₄1h is dried, Rotary Evaporators are spin-dried for, and column chromatography obtains sterling, [M+H]⁺496.2015。

Embodiment 28

Above-mentioned midbody compound (1mmol), HBTU/TBTU (1.2mmol), DCM are sequentially added in reaction bulb DIPEA3mmol, Norfloxacin (1mmol) are added under (3mL), ice bath, temperature control stirring, TLC, which is monitored to reaction, to be terminated.Add DCM20mL, move to separatory funnel, saturation Na₂CO₃The aqueous solution is washed (20mL × 1), and 0.5N HCl solutions wash (20mL × 1), saturation Salt washes (20mL × 1), anhydrous Na₂SO₄1h is dried, Rotary Evaporators are spin-dried for, and column chromatography obtains sterling, [M+H]⁺496.2064。

Embodiment 29

Above-mentioned midbody compound (1mmol), HBTU/TBTU (1.2mmol), DCM are sequentially added in reaction bulb DIPEA3mmol, Norfloxacin (1mmol) are added under (3mL), ice bath, temperature control stirring, TLC, which is monitored to reaction, to be terminated.Add DCM20mL, move to separatory funnel, saturation Na₂CO₃The aqueous solution is washed (20mL × 1), and 0.5N HCl solutions wash (20mL × 1), saturation Salt washes (20mL × 1), anhydrous Na₂SO₄1h is dried, Rotary Evaporators are spin-dried for, and column chromatography obtains sterling, [M+H]⁺510.2148。

Embodiment 30

Above-mentioned midbody compound (1mmol), HBTU/TBTU (1.2mmol), DCM are sequentially added in reaction bulb (3mL), add Et₃N 3mmol, Enoxacin (1mmol), temperature control stirring, TLC, which is monitored to reaction, to be terminated.DCM 20mL are added, Move to separatory funnel, saturation Na₂CO₃The aqueous solution is washed (20mL × 1), and 0.5N HCl solutions are washed (20mL × 1), saturated common salt washing (20mL × 1), anhydrous Na₂SO₄1h is dried, Rotary Evaporators are spin-dried for, and column chromatography obtains sterling, [M+H]⁺483.1754。

Embodiment 31

Above-mentioned midbody compound (1mmol), HBTU/TBTU (1.2mmol), DCM are sequentially added in reaction bulb DIPEA3mmol, Lomefloxacin (1mmol) are added under (3mL), ice bath, temperature control stirring, TLC, which is monitored to reaction, to be terminated.Add DCM20mL, move to separatory funnel, saturation Na₂CO₃The aqueous solution is washed (20mL × 1), and 0.5N HCl solutions wash (20mL × 1), saturation Salt washes (20mL × 1), anhydrous Na₂SO₄1h is dried, Rotary Evaporators are spin-dried for, and column chromatography obtains sterling, [M+H]⁺528.2053。

Embodiment 32

GAT 5mmol, DCM 15mL, NaHCO are sequentially added into 100mL round-bottomed flasks₃7.5mmol, stir Afterwards, solid phosgene 2.5mmol dichloromethane (DCM) 5mL solution is slowly added dropwise under ice bath.After being added dropwise, move into room temperature and stir Mix reaction, TLC monitoring reaction process.After reaction terminates, the ice-cold saturation NaCl solutions of 10mL are added, 2N HCl solutions adjust pH value 4~5, liquid separation.Saturation NaCl solution 10mL is washed, liquid separation, organic phase anhydrous Na₂SO₄Dry, revolving removes solvent and obtains intermediate.

Piperidines 2mmol, CHCl are sequentially added into 100mL round-bottomed flasks₃ 3mL、K₂CO₃2mmol, it is stirred at room temperature 30min.Intermediate 1mmol is added, and is moved in 35 DEG C of water-baths, TLC monitoring reaction process.After reaction terminates, if product is easy Water is dissolved in, is filtered, filter cake DCM and CH₃OH mixed liquors are washed.Filtrate adjusts pH value 7~8, Na with HCl-EA solution₂SO₄Dry；If The water solubility of product is smaller, adds 15mL DCM, 10mL H₂O, 2N HCl solution adjust pH value 7~8, liquid separation.Saturation NaCl solution 10mL is washed, liquid separation, organic phase anhydrous Na₂SO₄Dry；Revolving removes solvent afforded crude material, column chromatography (DCM/CH₃OH sterling) is obtained, [M+Na]⁺509.2171。

Embodiment 33

1- methyl piperazines 2mmol, CHCl are sequentially added into 100mL round-bottomed flasks₃ 3mL、K₂CO₃2mmol, room temperature are stirred Mix 30min.Intermediate 1mmol is added, and is moved in 35 DEG C of water-baths, TLC monitoring reaction process.After reaction terminates, if product It is soluble in water, filter, filter cake DCM and CH₃OH mixed liquors are washed.Filtrate adjusts pH value 7~8, Na with HCl-EA solution₂SO₄Dry； If the water solubility of product is smaller, 15mL DCM, 10mL H are added₂O, 2N HCl solution adjust pH value 7~8, liquid separation.Saturation NaCl is molten Liquid 10mL is washed, liquid separation, organic phase anhydrous Na₂SO₄Dry；Revolving removes solvent afforded crude material, column chromatography (DCM/CH₃OH) obtain pure Product, [M+H]⁺502.2460。

Embodiment 34

GAT 5mmol, DCM 15mL, NaHCO are sequentially added into 100mL round-bottomed flasks₃7.5mmol, stir Afterwards, solid phosgene 2.5mmol DCM 5mL solution is slowly added dropwise under ice bath.After being added dropwise, reaction, TLC is stirred at room temperature in immigration Monitor reaction process.After reaction terminates, the ice-cold saturation NaCl solutions of 10mL are added, 2N HCl solutions adjust pH value 4~5, liquid separation. Saturation NaCl solution 10mL is washed, liquid separation, organic phase anhydrous Na₂SO₄Dry, revolving removes solvent and obtains intermediate.

Thiosemicarbazides 2mmol, CHCl are sequentially added into 100mL round-bottomed flasks₃ 3mL、K₂CO₃2mmol, it is stirred at room temperature 30min.Intermediate 1mmol is added, and is moved in 35 DEG C of water-baths, TLC monitoring reaction process.After reaction terminates, if product is easy Water is dissolved in, is filtered, filter cake DCM and CH₃OH mixed liquors are washed.Filtrate adjusts pH value 7~8, Na with HCl-EA solution₂SO₄Dry；If The water solubility of product is smaller, adds 15mL DCM, 10mL H₂O, 2N HCl solution adjust pH value 7~8, liquid separation.Saturation NaCl solution 10mL is washed, liquid separation, organic phase anhydrous Na₂SO₄Dry；Revolving removes solvent afforded crude material, column chromatography (DCM/CH₃OH sterling) is obtained, [M+H]⁺493.1673。

Embodiment 35

4- benzyl diethylenediamines 2mmol, CHCl are sequentially added into 100mL round-bottomed flasks₃ 3mL、K₂CO₃2mmol, room temperature are stirred Mix 30min.Intermediate 1mmol is added, and is moved in 35 DEG C of water-baths, TLC monitoring reaction process.After reaction terminates, if product It is soluble in water, filter, filter cake DCM and CH₃OH mixed liquors are washed.Filtrate adjusts pH value 7~8, Na with HCl-EA solution₂SO₄Dry； If the water solubility of product is smaller, 15mL DCM, 10mL H are added₂O, 2N HCl solution adjust pH value 7~8, liquid separation.Saturation NaCl is molten Liquid 10mL is washed, liquid separation, organic phase anhydrous Na₂SO₄Dry；Revolving removes solvent afforded crude material, column chromatography (DCM/CH₃OH) obtain pure Product, [M+H]⁺578.2773。

Embodiment 36

2- ethylaminoethanols 2mmol, CHCl are sequentially added into 100mL round-bottomed flasks₃ 3mL、K₂CO₃2mmol, room temperature are stirred Mix 30min.The compound 1mmol of embodiment 1 is added, and is moved in 35 DEG C of water-baths, TLC monitoring reaction process.After reaction terminates, Add DCM 15mL, H₂O 10mL, 1N HCl solution adjust pH value 7~8, liquid separation.Saturation NaCl solution 10mL is washed, and liquid separation, is had Machine phase anhydrous Na₂SO₄Dry, rotate to obtain crude product, column chromatography obtains sterling, [M+H]⁺477.2144。

Embodiment 37

Sequentially added into 100mL round-bottomed flasks2mmol、CHCl₃ 3mL、K₂CO₃2mmol, room temperature Stir 30min.The compound 1mmol of embodiment 1 is added, and is moved in 35 DEG C of water-baths, TLC monitoring reaction process.Reaction terminates Afterwards, DCM 15mL, H are added₂O 10mL, 1N HCl solution adjust pH value 7~8, liquid separation.Saturation NaCl solution 10mL is washed, liquid separation, Organic phase anhydrous Na₂SO₄Dry, rotate to obtain crude product, column chromatography obtains sterling, [M+H]⁺521.2406。

Embodiment 38

2- (methylamino) ethyl -1- alcohol 2mmol, CHCl are sequentially added into 100mL round-bottomed flasks₃ 3mL、K₂CO₃ 2mmol, 30min is stirred at room temperature.Add the compound 1mmol of embodiment 1, and move in 35 DEG C of water-baths, TLC monitorings react into Journey.After reaction terminates, DCM 15mL, H are added₂O 10mL, 1N HCl solution adjust pH value 7~8, liquid separation.Saturation NaCl solution 10mL is washed, liquid separation, organic phase anhydrous Na₂SO₄Dry, rotate to obtain crude product, column chromatography obtains sterling, [M+H]⁺491.2300。

Embodiment 39

Sequentially added into 100mL round-bottomed flasks2mmol、、CHCl₃ 3mL、NaHCO₃5mmol, room Temperature stirring 30min.The compound 1mmol of embodiment 2 is added, and is moved in 50 DEG C of water-baths, TLC monitoring reaction process.Reaction knot Shu Hou, add DCM 15mL, H₂O 10mL, 2N HCl solution adjust pH value 7~8, liquid separation.Saturation NaCl solution 10mL is washed, point Liquid, anhydrous Na₂SO₄Dry, rotate to obtain crude product, column chromatography obtains sterling, [M+H]⁺535.2563。

Embodiment 40

Sequentially added into 100mL round-bottomed flasks 1- methyl piperazines 2mmol, CHCl₃ 3mL、NaHCO₃5mmol, room temperature Stir 30min.The compound 1mmol of embodiment 2 is added, and is moved in 50 DEG C of water-baths, TLC monitoring reaction process.Reaction terminates Afterwards, DCM 15mL, H are added₂O 10mL, 2N HCl solution adjust pH value 7~8, liquid separation.Saturation NaCl solution 10mL is washed, liquid separation, Anhydrous Na₂SO₄Dry, rotate to obtain crude product, column chromatography obtains sterling, [M+H]⁺530.2773。

Embodiment 41

Sequentially added into 100mL round-bottomed flasks piperidines 2mmol, CHCl₃ 3mL、NaHCO₃5mmol, it is stirred at room temperature 30min.The compound 1mmol of embodiment 2 is added, and is moved in 50 DEG C of water-baths, TLC monitoring reaction process.After reaction terminates, add Enter DCM 15mL, H₂O 10mL, 2N HCl solution adjust pH value 7~8, liquid separation.Saturation NaCl solution 10mL is washed, and liquid separation is anhydrous Na₂SO₄Dry, rotate to obtain crude product, column chromatography obtains sterling, [M+H]⁺543.2613。

Embodiment 42

4- benzyl piepridines 2mmol, CHCl are sequentially added into 100mL round-bottomed flasks₃ 3mL、NaHCO₃5mmol, room temperature are stirred Mix 30min.The compound 1mmol of embodiment 2 is added, and is moved in 50 DEG C of water-baths, TLC monitoring reaction process.After reaction terminates, Add DCM 15mL, H₂O 10mL, 2N HCl solution adjust pH value 7~8, liquid separation.Saturation NaCl solution 10mL is washed, liquid separation, nothing Water Na₂SO₄Dry, rotate to obtain crude product, column chromatography obtains sterling, [M+H]⁺634.3035。

Embodiment 43

1H-1 is sequentially added into 100mL round-bottomed flasks, 2,4- triazole 3mmol, DMF 2mL, is stirred at room temperature, is added NaH 4mmol, 30min is stirred at room temperature, adds the compound 1mmol of embodiment 2, and move in 80 DEG C of water-baths.TLC monitoring reactions Process.After reaction terminates, add ice-cold saturation NaCl solution 20mL, 2N HCl solution and adjust pH value 5~6, there are a large amount of solids to analyse Go out.Filter, filter cake washs with ice-cold saturation NaCl solution, and frozen water washes secondary, dry crude product, and column chromatography and thin-layer chromatography obtain pure Product, [M+Na]⁺521.19192。

Embodiment 44

1H-1 is sequentially added into 100mL round-bottomed flasks, 2,4- triazole -3- amine 3mmol, DMF 2mL, is stirred at room temperature, NaH 4mmol are added, 30min is stirred at room temperature, add the compound 1mmol of embodiment 2, and move in 80 DEG C of water-baths.TLC is monitored Reaction process.After reaction terminates, add ice-cold saturation NaCl solution 20mL, 2N HCl solution and adjust pH value 5~6, have a large amount of solid Body separates out.Filter, filter cake washs with ice-cold saturation NaCl solution, and frozen water washes secondary, dry crude product, column chromatography and thin-layer chromatography Obtain sterling, [M+Na]⁺536.20282。

Embodiment 45

1H- tetrazole -5- amine 3mmol, DMF 2mL are sequentially added into 100mL round-bottomed flasks, is stirred at room temperature, adds NaH 4mmol, 30min is stirred at room temperature, adds the compound 1mmol of embodiment 2, and move in 80 DEG C of water-baths.TLC monitoring react into Journey.After reaction terminates, add ice-cold saturation NaCl solution 20mL, 2N HCl solution and adjust pH value 5~6, there are a large amount of solids to separate out. Filter, filter cake washs with ice-cold saturation NaCl solution, frozen water wash it is secondary, it is dry that crude product, column chromatography and thin-layer chromatography obtain sterling, [M+H]⁺515.2135。

Embodiment 46

Sequentially added into 100mL round-bottomed flasks 5- (difluoro-methoxy) -1H- benzos [d] imidazoles -2- mercaptan 3mmol, DMF 2mL, are stirred at room temperature, and add NaH 4mmol, and 30min is stirred at room temperature, and add the compound 1mmol of embodiment 2, and move in 80 DEG C water-bath.TLC monitors reaction process.After reaction terminates, add ice-cold saturation NaCl solution 20mL, 2N HCl solution and adjust PH value 5~6, there are a large amount of solids to separate out.Filter, filter cake washs with ice-cold saturation NaCl solution, frozen water wash it is secondary, it is slightly dry Product, column chromatography and thin-layer chromatography obtain sterling, [M+H]⁺646.1942。

Embodiment 47

Benzo [d] thiazol -2-thiol 3mmol, DMF 2mL are sequentially added into 100mL round-bottomed flasks, is stirred at room temperature, adds Enter NaH 4mmol, 30min is stirred at room temperature, add the compound 1mmol of embodiment 2, and move in 80 DEG C of water-baths.TLC monitorings are anti- Answer process.After reaction terminates, add ice-cold saturation NaCl solution 20mL, 2N HCl solution and adjust pH value 5~6, there are a large amount of solids Separate out.Filter, filter cake washs with ice-cold saturation NaCl solution, frozen water wash it is secondary, it is dry that crude product, column chromatography and thin-layer chromatography obtain Sterling, [M+H]⁺597.1636。

Embodiment 48

5- methyl isophthalic acids, 3,4- thiadiazoles -2- mercaptan 3mmol, DMF 2mL, room temperature are sequentially added into 100mL round-bottomed flasks Stirring, NaH 4mmol are added, 30min is stirred at room temperature, add the compound 1mmol of embodiment 2, and move in 80 DEG C of water-baths. TLC monitors reaction process.After reaction terminates, add ice-cold saturation NaCl solution 20mL, 2N HCl solution and adjust pH value 5~6, have A large amount of solids separate out.Filter, filter cake washs with ice-cold saturation NaCl solution, and frozen water washes secondary, dry crude product, column chromatography and thin Sterling is analysed to obtain layer by layer, [M+Na]⁺584.1408。

Embodiment 49

1H- imidazoles 0.204g (3mmol), toluene 10mL, the compound 0.484g of embodiment 3 are added in 100mL round-bottomed flasks (1mmol).Temperature control reacts, TLC detection reaction process.Reaction terminates, and revolving removes solvent toluene, solid column chromatography and thin layer Analyse (DCM:CH₃OH=30:1) sterling, [M+H] are obtained⁺512.2304。

Embodiment 50

2- methyl isophthalic acid H- imidazoles 3mmol, toluene 10mL, the compound 0.484g of embodiment 3 are added in 100mL round-bottomed flasks (1mmol).Temperature control reacts, TLC detection reaction process.Reaction terminates, and revolving removes solvent toluene, solid column chromatography and thin layer Analyse (DCM:CH₃OH=30:1) sterling, [M+H] are obtained⁺526.2460。

Embodiment 51

1H- pyrazoles 3mmol, toluene 10mL, the compound 0.484g (1mmol) of embodiment 3 are added in 100mL round-bottomed flasks. Temperature control reacts, TLC detection reaction process.Reaction terminates, and revolving removes solvent toluene, solid column chromatography and thin-layer chromatography (DCM: CH₃OH=30:1) sterling, [M+Na] are obtained⁺534.2123。

Embodiment 52

3,5- dimethyl -1H- pyrazoles 3mmol, toluene 10mL, the compound of embodiment 3 are added in 100mL round-bottomed flasks 0.484g(1mmol).Temperature control reacts, TLC detection reaction process.Reaction terminates, revolving remove solvent toluene, solid column chromatography and Thin-layer chromatography (DCM:CH₃OH=30:1) sterling, [M+H] are obtained⁺540.2617。

Embodiment 53

1H- benzo [d] imidazoles 3mmol, toluene 10mL, the compound 0.484g of embodiment 5 are added in 100mL round-bottomed flasks (1mmol).Temperature control reacts, TLC detection reaction process.Reaction terminates, and revolving removes solvent toluene, solid column chromatography and thin layer Analyse (DCM:CH₃OH=30:1) sterling, [M+H] are obtained⁺562.2460。

Embodiment 54

1H-1,2,3- triazoles 3mmol, toluene 10mL, the compound 0.484g of embodiment 5 are added in 100mL round-bottomed flasks (1mmol).Temperature control reacts, TLC detection reaction process.Reaction terminates, and revolving removes solvent toluene, solid column chromatography and thin layer Analyse (DCM:CH₃OH=30:1) sterling, [M+Na]+535.2076 are obtained.

Embodiment 55

1H-TETRAZOLE 3mmol, toluene 10mL, the compound 0.484g (1mmol) of embodiment 5 are added in 100mL round-bottomed flasks. Temperature control reacts, TLC detection reaction process.Reaction terminates, and revolving removes solvent toluene, solid column chromatography and thin-layer chromatography (DCM: CH₃OH=30:1) sterling, [M+Na] are obtained⁺536.2028。

Embodiment 56

5- methyl isophthalic acid H- tetrazoliums 3mmol, toluene 10mL, the compound 0.484g of embodiment 5 are added in 100mL round-bottomed flasks (1mmol).Temperature control reacts, TLC detection reaction process.Reaction terminates, and revolving removes solvent toluene, solid column chromatography and thin layer Analyse (DCM:CH₃OH=30:1) sterling, [M+Na] are obtained⁺550.2185。

Embodiment 57

5- amino -1H-TETRAZOLE 3mmol, toluene 10mL, the compound 0.484g of embodiment 5 are added in 100mL round-bottomed flasks (1mmol).Temperature control reacts, TLC detection reaction process.Reaction terminates, and revolving removes solvent toluene, solid column chromatography and thin layer Analyse (DCM:CH₃OH=30:1) sterling, [M+Na] are obtained⁺551.2137。

Embodiment 58

5- (difluoro-methoxy) -1H- benzos [d] imidazoles -2- mercaptan 3mmol, toluene are added in 100mL round-bottomed flasks 10mL, the compound 0.484g (1mmol) of embodiment 5.Temperature control reacts, TLC detection reaction process.Reaction terminates, and revolving removes molten Agent toluene, solid column chromatography and thin-layer chromatography (DCM:CH₃OH=30:1) sterling, [M+Na] are obtained⁺682.1918。

Embodiment 59

1- methyl isophthalic acid H- tetrazolium -5- mercaptan 3mmol, toluene 10mL, the compound of embodiment 5 are added in 100mL round-bottomed flasks 0.484g(1mmol).Temperature control reacts, TLC detection reaction process.Reaction terminates, revolving remove solvent toluene, solid column chromatography and Thin-layer chromatography (DCM:CH₃OH=30:1) sterling, [M+Na] are obtained⁺582.1905。

Embodiment 60

Benzo [d] thiazol -2-thiol 3mmol, toluene 10mL, the compound of embodiment 5 are added in 100mL round-bottomed flasks 0.484g(1mmol).Temperature control reacts, TLC detection reaction process.Reaction terminates, revolving remove solvent toluene, solid column chromatography and Thin-layer chromatography (DCM:CH₃OH=30:1) sterling, [M+Na] are obtained⁺633.1612。

Embodiment 61

5- amino -1,3,4- thiadiazoles -2- mercaptan 3mmol, toluene 10mL, embodiment 5 is added in 100mL round-bottomed flasks to change Compound 0.484g (1mmol).Temperature control reacts, TLC detection reaction process.Reaction terminates, and revolving removes solvent toluene, solid column layer Analysis and thin-layer chromatography (DCM:CH₃OH=30:1) sterling, [M+H] are obtained⁺577.1698。

Embodiment 62

1mmol Clinafloxacins and 2mL DCM are added in 100mL round-bottomed flasks, ice bath cooling, magnetic agitation, adds 3mmol NaHCO₃, after 20min, DCM (2mL) solution of 2.5mmol chloroacetic chlorides is added dropwise with constant pressure funnel, and (rate of addition is about 1d/ 2s), drip and finish sustained response under ice bath, TLC tracking and monitorings to reaction terminate.Stop stirring, add H₂O 15mL and DCM 20mL, Stirring is lower to be extracted (15mL × 1) with DCM, is merged organic phase, saturation NaCl with 1N HCl solutions regulation pH=3-4, liquid separation, aqueous phase Solution washs (15mL × 1), collects organic phase, anhydrous Na₂SO₄Dry.Rotary Evaporators are spin-dried for obtaining crude product, and column chromatography obtains To sterling, vacuum drying, product is obtained, [M+H]⁺409.1119。

Embodiment 63

CF is sequentially added in reaction bulb₃COOH (1.2mmol), HBTU/TBTU (1.44mmol), DCM (3mL), addition Et₃N 3mmol, Clinafloxacin (1mmol), temperature control stirring, TLC, which is monitored to reaction, to be terminated.DCM 20mL are added, move to liquid separation leakage Bucket, saturation Na₂CO₃The aqueous solution is washed (20mL × 1), and 0.5N HCl solutions are washed (20mL × 1), saturated common salt washing (20mL × 1), Anhydrous Na₂SO₄Dry, Rotary Evaporators are spin-dried for, and column chromatography obtains sterling, [M+H]⁺462.0845。

Citrus processing Antibacterial Activity

Assay method：Weigh 1mg samples to dissolve in 50 μ L DMSO, being settled to 550 μ L by the use of ultra-pure water is used as sample mother liquor (1.82mg/mL).10 μ L mother liquors are taken to be used as sample solution a (0.0182mg/mL) in 1mL ultra-pure waters (0.02% tween), so Sample solution b (0.0091mg/mL), c (0.00455mg/mL), d (0.002275mg/ are prepared using coubling dilution successively afterwards mL)、e(0.0011375mg/mL)、f(0.00056875mg/mL)。

Under the ulcer bacteria for cultivating 3d in PDA culture medium is washed with 5mL LB fluid nutrient mediums, 195mL LB are added to In fluid nutrient medium, vibration mixes standby.450 μ L citrus ulcer bacterias bacterium solutions and above-mentioned are separately added into each 2mL centrifuge tubes The variant μ L of concentration (a~f) sample solution 50 so that sample ultimate density is respectively A (0.00182mg/ in each mixed bacteria liquid mL)、B(0.00091mg/mL)、C(0.000455mg/mL)、D(0.0002275mg/mL)、E(0.00011375mg/mL)、F (0.000056875mg/mL), 28 DEG C, 200rmin^-1OD is determined after constant-temperature shaking culture 14h₆₀₀Under each mixed bacteria liquid OD values simultaneously Calculate inhibiting rate (inhibiting rate %=(OD_Blank-OD_Sample)/OD_Blank× 100%).Each processing repeats three times.

Inhibition of the compound of table 1 to citrus ulcer bacteria

Statistical analysis is carried out to each pharmacy test result with PBT data handling systems, obtains each medicament to c itrus canker Inhibiting rate, virulence regression equation, the EC of germ₅₀、EC₉₀With coefficient correlation (r).

Inhibition of the compound of table 2 to citrus ulcer bacteria

Citrus brown patch germ Antibacterial Activity

Assay method：Under with 0.05% Tween 80, the brown patch germ conidium for cultivating 7d in PDA culture medium is washed, It is standby after four layers of sterile lens wiping paper filtering；Weigh 1mg compound samples to dissolve in 50 μ L DMSO, 550 are settled to ultra-pure water μ L are as sample mother liquor (1.82mg/mL).Take 2 μ L mother liquors in 1mL PDA (0.02% tween) as sample solution a (0.00364mg/mL), prepare sample solution b (0.00182mg/mL) successively using coubling dilution.And in 48 orifice plates are per hole Add 0.5mL sample solutions and 1.5mLPDA culture mediums so that test final concentration is respectively A (0.000910mg/mL) and B After (0.000455mg/mL), 2 μ L conidial suspensions are inoculated with, colony diameter is measured after 28 DEG C of illumination cultivation 3d.To be seeded in The bacterium colony being not added with the PDA culture medium of sample solution is blank control, calculates different samples and the inhibiting rate of disease fungus (is suppressed Rate %=(colony diameters_Blank- colony diameter_Sample)/colony diameter_Blank× 100%).

The anti-citrus brown patch germ Activity Results of the compound of table 3

From above table as can be seen that under than relatively low concentration (0.00182mg/mL), the embodiment of the present invention Compound still shows outstanding bacteriostatic activity to citrus processing, while the compound of the present invention also has necessarily brown Pinta bacterium bacteriostatic activity, play a part of certain preventing and treating citrus brown spot while citrus bacterial canker disease is prevented and treated.

Finally illustrate, the above embodiments are merely illustrative of the technical solutions of the present invention and it is unrestricted, although with reference to compared with The present invention is described in detail good embodiment, it will be understood by those within the art that, can be to the skill of the present invention Art scheme is modified or equivalent substitution, and without departing from the objective and scope of technical solution of the present invention, it all should cover at this Among the right of invention.

Claims

1. compound, its raceme, stereoisomer, dynamic isomer, nitrogen oxides or their pharmacy can connect shown in formula I By salt：

Wherein X is selected from：C1-C6 alkyl；C3-C6 cycloalkyl；Substituted or unsubstituted C6-C10 aryl, taking on the aryl Dai Jiwei is one or more, is independently selected from：Halogen；Amino；Hydroxyl；C1-C6 alkyl；C3-C6 cycloalkyl；

R₁And R₂It is each independently selected from：H；C1-C6 alkyl；C1-C6 haloalkyls；C1-C6 alkoxies；Halogen；Hydroxyl；Amino or Cyano group；

Q₁Selected from H；Halogen；

R₃Or R₄It is each independently selected from H；C1-C6 alkyl, the C1-C6 alkyl can be optionally by hydroxyls；Amino；Halogen；Cyano group；Urea Base；Ghiourea group substitutes；

Or R₃, R₄5-8 circle heterocycles are collectively forming with N, the heterocycle optionally can be substituted by one or more following substituents：

Amino；Hydroxyl；Tertbutyloxycarbonyl；Benzyl or C1-C6 alkyl, the C1-C6 alkyl can be optionally by hydroxyls；Amino；Halogen； C1-C4 alkoxies substitute；

R₆For 1-4, H is independently selected from, C1-C6 alkyl, the C1-C6 alkyl can be optionally by hydroxyl；Amino；Halogen or cyano group take Generation；C1-C6 alkoxies, the C1-C6 alkoxies can be optionally optionally substituted by halogen；

B₁Selected from S or NH；

R₈Selected from H, C1-C6 alkyl；

N, k is respectively 0 to 3 integer.

2. compound, its raceme, stereoisomer, dynamic isomer, nitrogen oxides or their pharmacy can as shown in Formula II Receive salt：

R₈Selected from H, C1-C6 alkyl；

Q₂It is selected fromOr halogen or H；

N, k is respectively 0 to 3 integer；

M is 1 or 2.

3. compound as claimed in claim 1 or 2, its raceme, stereoisomer, dynamic isomer, nitrogen oxides or they Pharmaceutically acceptable salt be characterized in that：

The het is selected from

The 5-8 circle heterocycles are selected from：

4. the compound of following structure, its raceme, stereoisomer, dynamic isomer, nitrogen oxides or their pharmacy can Receive salt：

5. a kind of pharmaceutical composition, it is characterised in that including compound, its raceme, alloisomerism described in claim 1-4 Body, dynamic isomer, nitrogen oxides or their pharmaceutically acceptable salt.

A kind of 6. pharmaceutical preparation, it is characterised in that including compound described in claim 1-4, its raceme, stereoisomer, Dynamic isomer, nitrogen oxides or their pharmaceutically acceptable salt, and pharmaceutically acceptable carrier and/or auxiliary agent.

A kind of 7. compound medicine, it is characterised in that including compound described in claim 1-4, its raceme, stereoisomer, Dynamic isomer, nitrogen oxides or their pharmaceutically acceptable salt and other active components.

8. compound, its raceme, stereoisomer, dynamic isomer, nitrogen oxides or them as described in claim 1-4 Purposes of the pharmaceutically acceptable salt in the medicine for preparing preventing and treating citrus correlation disease.

9. purposes as claimed in claim 8, it is characterised in that the citrus correlation disease is citrus bacterial canker disease or citrus foxiness Disease.

A kind of 10. method for treating citrus correlation disease, it is characterised in that contain including being applied to citrus fruit tree and/or fruit Compound, its raceme, stereoisomer, dynamic isomer, nitrogen oxides or their pharmacy can as described in claim 1-4 Receive the medicament of salt.