CN104098549A - Piperazinedione derivative and preparation and application thereof - Google Patents

Piperazinedione derivative and preparation and application thereof Download PDF

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CN104098549A
CN104098549A CN201410378163.3A CN201410378163A CN104098549A CN 104098549 A CN104098549 A CN 104098549A CN 201410378163 A CN201410378163 A CN 201410378163A CN 104098549 A CN104098549 A CN 104098549A
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CN104098549B (en
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宋恭华
孙海洋
王佳毅
黄瑾
李晖
张小灵
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East China University of Science and Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/60—1,4-Diazines; Hydrogenated 1,4-diazines
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
    • A01N47/30—Derivatives containing the group >N—CO—N aryl or >N—CS—N—aryl
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
    • A01N47/36—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N< containing the group >N—CO—N< directly attached to at least one heterocyclic ring; Thio analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Dentistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Plant Pathology (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Pest Control & Pesticides (AREA)
  • Agronomy & Crop Science (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

The invention discloses a piperazinedione derivative and preparation and application thereof. Specifically, the invention discloses a compound with structure as shown in formula I, or pharmaceutically acceptable salt or agrochemically acceptable salt thereof. The compound has excellent insecticidal activity and can be used as the human 5-HT2a receptor stimulant, and detailed definition of the compound of the formula I refers to specification.

Description

Piperazinedione derivatives, their preparation and use
Technical Field
The invention belongs to the field of pesticides and medicines. Specifically, the invention relates to a piperazinedione derivative and preparation and application thereof.
Background
Pesticides are the primary means of controlling pests and play a very important role in modern agriculture. The insecticides currently used are mostly nerve agents, such as: the organophosphorus pesticide and carbamate pesticide have the main effects of inhibiting the activity of acetylcholinesterase in the insect body and causing insect poisoning and death; pyrethroid insecticides are used as nerve toxicants, and the toxicity mechanism of the pyrethroid insecticides is considered to be that the pyrethroid insecticides directly interact with sodium ion channels on nerve membranes to generate toxic effects; neonicotinoid insecticides are well known as acetylcholine receptor poisons, which are insecticides acting on acetylcholine receptors.
However, over the last two to thirty years, the market for insecticides has changed greatly and a large number of insecticides have been pushed out of the market. The reason for this is twofold:
firstly, the safety problem of the pesticide is solved, some traditional pesticides are eliminated due to the toxicity and the influence on the environment ecology, the frequency of banning organophosphorus pesticides with high toxicity and high residue, such as methamidophos, parathion, omethoate and the like, and carbamate pesticides with high toxicity, such as aldicarb, carbofuran, methomyl and the like, is increasing in the 90 s, and at present, the important pesticide varieties are banned or about to be banned worldwide.
Secondly, the drug resistance of the pests to the pesticide is improved due to the long-term abuse of the chemical pesticide, so that on one hand, the dosage of the pesticide is continuously increased, a vicious circle is formed, and the environment and the ecology are greatly damaged; on the other hand, the cost for controlling pests is continuously increased.
On one hand, the market demand is continuously expanded, and on the other hand, the varieties of the pesticides are continuously eliminated, so that the development of novel environment-friendly pesticides is very important.
Disclosure of Invention
The invention aims to provide a piperazinedione derivative which has a novel structure and good insecticidal activity.
Another object of the present invention is to provide a process for the preparation and use of the piperazinedione derivatives described above, for example for the preparation of a composition for combating pests, or for the preparation of a human 5-HT2a receptor ligand or agonist.
The invention provides a compound with a structure shown in a formula (I) or a pharmaceutically acceptable salt or an agriculturally pharmaceutically acceptable salt thereof,
wherein R is1Is substituted or unsubstituted C1～C10Alkyl, substituted or unsubstituted C1～C10Alkoxy, substituted or unsubstituted C2～C10Alkenyl, substituted or unsubstituted C2～C10Alkenyloxy, substituted or unsubstituted C2～C10Alkynyl, substituted or unsubstituted C2～C10Alkynyloxy, substituted or unsubstituted C1～C10Ester group, substituted or unsubstituted C1～C10Alkylcarbonyl, substituted or unsubstituted C1～C10Alkoxycarbonyl, substituted or unsubstituted C5～C10Aryl, substituted or unsubstituted C2～C8Heteroaryl, substituted or unsubstituted C3～C8Heterocycloalkyl, substituted or unsubstituted-C1～C6alkylene-C5～C10Aryl, or substituted or unsubstituted-C1～C6alkylene-C2～C8A heteroaryl group; wherein substituted means substituted with one or more (preferably 1,2, 3 or 4) substituents selected from the group consisting of: nitro, halogen, cyano, amino, hydrazino, C1～C6Acylamino, hydroxy, C1～C6Alkyl, hydroxy C1～C6Alkyl radical, C1～C6Alkoxy, halo C1～C6Alkyl, halo C1～C6Alkoxy radical, C2～C6Alkenyl radical, C2～C6Alkenyloxy radical, C1～C6Alkoxy radical, C2～C6Alkenyl radical, C2～C6Alkynyl, C1～C6Ester group, C1～C6Alkylcarbonyl group, C1～C6Alkoxycarbonyl group, C5～C10Aryl, halo C5～C10Aryl and C3～C8A heterocycloalkyl group;
n is an integer from 1 to 3 (i.e., 1,2, or 3); x is carbonyl (C ═ O), thiocarbonyl (C ═ S) or CH2(ii) a Y is absent, or NH;
R2is substituted or unsubstituted C1～C10Alkyl, substituted or unsubstituted C1～C10Ester radicals, substituted orUnsubstituted C1～C10Alkylcarbonyl, substituted or unsubstituted C1～C10Alkoxycarbonyl, substituted or unsubstituted C5～C10Aryl, substituted or unsubstituted C3～C8Heterocycloalkyl, substituted or unsubstituted C5～C10Aryl, or substituted or unsubstituted C2～C8A heteroaryl group; wherein substituted means substituted with one or more (preferably 1,2, 3 or 4) substituents selected from the group consisting of: nitro, halogen, cyano, amino, hydrazino, C1～C6Acylamino, hydroxy, C1～C6Alkyl, hydroxy C1～C6Alkyl, -O-C1～C6alkylene-O-, C1～C6Alkoxy, halo C1～C6Alkyl, halo C1～C6Alkoxy radical, C2～C6Alkenyl radical, C2～C6Alkenyloxy radical, C1～C6Alkoxy radical, C2～C6Alkenyl radical, C2～C6Alkynyl, C1～C6Ester group, C1～C6Alkylcarbonyl group, C1～C6Alkoxycarbonyl group, C5～C10Aryl, halo C5～C10Aryl and C3～C8A heterocycloalkyl group.
In another preferred embodiment, C is3～C8Heterocycloalkyl or said C2～C8Heteroaryl contains one or more (preferably 1-4 or 1-3) heteroatoms selected from N, S and O.
In another preferred embodiment, the compound has a structure represented by formula 10, formula 11, formula 14, or formula 15,
in the formula, n and R1、R2The definition is the same as before.
In another preferred embodiment, R1Is substituted or unsubstituted C1～C10Alkyl, substituted or unsubstituted C1～C10Alkoxy, substituted or unsubstituted-CH2-indolyl, substituted or unsubstituted-CH2-phenyl, substituted or unsubstituted-CH2-pyridyl, substituted or unsubstituted-CH2-benzopyridyl, substituted or unsubstituted-CH2-pyrrolyl, substituted or unsubstituted-CH2-thienyl, substituted or unsubstituted-CH2-benzothienyl, substituted or unsubstituted-CH2-furyl, substituted or unsubstituted-CH2-a benzofuranyl group; wherein substituted means substituted with one or more (preferably 1,2, 3 or 4) substituents selected from the group consisting of: nitro, halogen, cyano, amino, hydrazino, C1～C6Acylamino, hydroxy, C1～C6Alkyl, hydroxy C1～C6Alkyl radical, C1～C6Alkoxy, halo C1～C6Alkyl, halo C1～C6Alkoxy radical, C2～C6Alkenyl radical, C2～C6Alkenyloxy radical, C1～C6Alkoxy radical, C2～C6Alkenyl radical, C2～C6Alkynyl, C1～C6Ester group, C1～C6Alkylcarbonyl group, C1～C6Alkoxycarbonyl group, C5～C10Aryl, halo C5～C10Aryl and C3～C8A heterocycloalkyl group.
In another preferred embodiment, R2Is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted 1, 3, 4-thiadiazole, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted thienyl, substituted or unsubstituted benzothienyl, substituted or unsubstituted furyl, substituted or unsubstituted benzofuryl(ii) a Wherein substituted means substituted with one or more (preferably 1,2, 3 or 4) substituents selected from the group consisting of: nitro, halogen, cyano, amino, hydrazino, C1～C6Acylamino, hydroxy, C1～C6Alkyl, hydroxy C1～C6Alkyl, -O-C1～C6alkylene-O-, C1～C6Alkoxy, halo C1～C6Alkyl, halo C1～C6Alkoxy radical, C2～C6Alkenyl radical, C2～C6Alkenyloxy radical, C1～C6Alkoxy radical, C2～C6Alkenyl radical, C2～C6Alkynyl, C1～C6Ester group, C1～C6Alkylcarbonyl group, C1～C6Alkoxycarbonyl group, C5～C10Aryl, halo C5～C10Aryl and C3～C8A heterocycloalkyl group.
In another preferred embodiment, said substituted means substituted with one or more (preferably 1,2, 3 or 4) substituents selected from the group consisting of: nitro, fluoro, chloro, bromo, iodo, cyano, methyl, -O-C1～C3alkylene-O-, methoxy, trifluoromethyl, carbomethoxy, carboethoxy, methylcarbonyl, ethylcarbonyl, phenyl, chlorophenyl.
In a second aspect, the present invention provides a composition comprising (a) a compound according to the first aspect of the present invention, or a pharmaceutically or agriculturally acceptable salt thereof, (b) a pharmaceutically or agriculturally acceptable carrier.
In another preferred embodiment, the composition is a pharmaceutical composition or an agricultural composition.
In another preferred embodiment, the composition further comprises an additional active selected from the group consisting of: an insecticide, a bait, a bactericide, an acaricide, a nematicide, a fungicide or a growth control agent.
In a third aspect, the present invention provides the use of a compound according to the first aspect of the invention, or a pharmaceutically or agriculturally acceptable salt thereof, or a composition according to the second aspect of the invention, for combating or preventing an agricultural pest; or for preparing pesticides for killing or preventing agricultural pests.
In another preferred embodiment, the compound or pharmaceutically or agriculturally acceptable salt thereof or the composition is administered at a concentration of 0.05 to 5000 ppm; preferably, 0.1 to 1000 ppm; more preferably, 0.5 to 500 ppm; more preferably, it is 0.5 to 100ppm or 0.5 to 50 ppm.
In another preferred embodiment, the composition is used for preparing an insecticide for killing or preventing lepidoptera insects, for preparing an insecticide for inhibiting feeding and growth of the lepidoptera insects, or for preparing an insecticide for killing or preventing nematodes.
In a fourth aspect, the invention provides the use of a compound according to the first aspect of the invention, or a pharmaceutically or agriculturally acceptable salt thereof, or a composition according to the second aspect of the invention, for the preparation of a human 5-HT2a receptor ligand or a human 5-HT2a receptor agonist.
The fifth aspect of the invention provides a preparation method of the compound or the pharmaceutically acceptable salt or the agriculturally pharmaceutically acceptable salt thereof,
(a) the method comprises the following steps: reacting compound 7 and compound 5 in an inert solvent in the presence of a base to give compound 10;
(b) the method comprises the following steps: reacting compound 9 and compound 5 in an inert solvent in the presence of a base to give compound 10;
(c) the method comprises the following steps: reacting compound 12 and compound 5 in an inert solvent in the presence of a condensing agent to obtain compound 10;
(d) the method comprises the following steps: reacting compound 13 and compound 5 in an inert solvent in the presence of a reducing agent to give compound 10;
in the formula, n and R1、R2The definition is the same as before.
In a sixth aspect, the invention provides a pesticidal and/or pesticidal method which comprises applying a compound according to the first aspect of the invention or a pharmaceutically or agriculturally acceptable salt thereof or a composition according to the second aspect of the invention to a plant suffering from, or likely to suffer from, insect pests or to the soil or environment surrounding the plant.
In another preferred embodiment, the compound or pharmaceutically or agriculturally acceptable salt thereof or the composition is administered at a concentration of 0.05 to 5000 ppm; preferably, 0.1 to 1000 ppm; more preferably, 0.5 to 500 ppm; more preferably, it is 0.5 to 100ppm or 0.5 to 50 ppm.
It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.
Detailed Description
The inventor of the invention has conducted extensive and intensive studies, and synthesized for the first time a series of piperazinedione derivatives with novel structures, which have excellent effects of killing agricultural pests (such as lepidoptera insects, for example armyworm, or nematodes, for example, meloidogyne incognita, and the like) or inhibiting feeding and growth of the agricultural pests, and the compounds can also be used as agonists of human 5-HT2a receptor. On this basis, the inventors have completed the present invention.
Term(s) for
The term "C1～C10Alkyl "means a straight or branched chain alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl or the like. It may preferably be a C1-C6 alkyl group or a C1-C3 alkyl group.
The term "C1～C10The alkoxy group "means a straight or branched alkoxy group having 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, 1-butoxy, 2-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy or the like. C1-C6 alkoxy or C1-C3 alkoxy may be preferred.
The term "C2～C10Alkenyl "means a straight or branched chain alkenyl group having 2 to 10 carbon atoms, such as ethenyl, propenyl, isopropenyl, 1-butenyl, 2-butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl or the like. C2-C6 alkenyl or C2-C3 alkenyl may be preferable.
The term "C2～C10Alkenyloxy "means a straight-chain or branched alkenyloxy group having 2 to 6 carbon atoms, such as ethyleneoxy, propyleneoxy, isopropenyloxy, 1-buteneoxy, 2-buteneoxy, penteneoxyHexenyloxy, heptenyloxy, octenyloxy, nonenyloxy, decenyloxy or the like. It may preferably be C2-C6 alkenyloxy or C2-C3 alkenyloxy.
The term "C2～C10Alkynyl "means straight-chain or branched alkynyl having 2 to 10 carbon atoms, such as ethynyl, propynyl, isopropynyl, 1-butynyl, 2-butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl or the like. C2 to C6 alkynyl or C2 to C3 alkynyl may be preferred.
The term "C5～C10Aryl "means a group having an aromatic character having 5 to 10 carbon atoms, such as phenyl, naphthyl, or the like.
The term "C2～C8Heteroaryl "refers to an aromatic group having 2 to 8 carbon atoms having one or more heteroatoms selected from nitrogen, oxygen, and sulfur, such as pyridyl, benzopyridyl, pyrrolyl, benzopyrryl, benzothienyl, thienyl, benzofuranyl, furanyl, thiazolyl, benzothiazolyl, imidazolyl, oxazolyl, indolyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, acridinyl, or the like.
The term "C1～C6The "acyl group" means an acyl group having 1 to 6 carbon atoms, such as formyl group, acetyl group, propionyl group, isopropionyl group, 1-butyryl group, 2-butyryl group, or the like. The acyl group may preferably be a C1 to C3 acyl group.
The term "C3～C8Heterocycloalkyl "refers to a cyclic group having 3 to 8 carbon atoms having one or more heteroatoms selected from nitrogen, oxygen, and sulfur, such as piperidinyl, piperazinyl, ethylene oxide, propylene oxide, tetrahydrofuranyl, or the like.
The term "halogen" is fluorine, chlorine, bromine, iodine. The 'halo' is fluoro, chloro, bromo, iodo.
Preparation method
The following describes more specifically the processes for the preparation of the compounds of formula (I) according to the invention, but these particular processes do not constitute any limitation of the invention. The compounds of the present invention may also be conveniently prepared by optionally combining various synthetic methods described in the present specification or known in the art, and such combinations may be readily carried out by those skilled in the art to which the present invention pertains.
Generally, in the preparative schemes, each reaction is typically in an inert solvent. Each reaction is carried out at a temperature ranging from room temperature to reflux temperature (e.g., from 0 ℃ to 80 ℃, preferably from 0 ℃ to 50 ℃). The reaction time is usually 0.1 to 60 hours, preferably 0.5 to 48 hours.
One particularly preferred preparation scheme is as follows:
(5) triphosgene (BTC) is dissolved in an inert solvent (e.g., dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, DMF, etc.), compound 6 and an organic base are dissolved in an inert solvent (e.g., dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, etc.), and a solution of triphosgene in an inert solvent (e.g., dichloromethane) is added at low temperature to give compound 7.
(6) The compound 7 is dropped into a solution of the compound 5 and an inert solvent (e.g., dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, DMF, etc.) for the organic base to obtain a compound 10.
(7) Dissolving compound 6, carbon disulfide and organic base in inert solvent (such as THF, toluene, dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, etc.) to obtain compound 8, and adding triphosgene to obtain compound 9.
(8) Dissolving compound 9 in inert solvent (such as methanol, DMF, DMSO, toluene, dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, etc.), and adding compound 5 and appropriate amount of organic base to obtain compound 11.
(9) Dissolving compound 5 and compound 12 in inert solvent (such as DMF, DMSO, acetonitrile, dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride, etc.), adding condensing agent (such as EDCI) and catalyst (such as HoBt, DMAP, etc.), and reacting to obtain compound 14.
(10) Dissolving the compound 5 and the compound 13 in an inert solvent (such as DMF, DMSO, acetonitrile, dichloromethane, 1, 2-dichloroethane, chloroform, carbon tetrachloride and the like), adding a reducing agent (such as sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride and the like), and reacting to obtain a compound 15.
In another preferred embodiment, the compound 5 can be prepared by the following method:
(1) compound 1, di-tert-butyl dicarbonate ((Boc)2O) is taken as a raw material, dissolved in an inert solvent (such as acetone, water, acetonitrile, water, ethyl acetate and the like) and the compound 2 is obtained under the alkaline condition.
(2) Dissolving the compound 2 and amino acid methyl ester hydrochloride in an inert solvent (such as dichloromethane, acetonitrile, acetone, chloroform and the like), adding a condensing agent (such as EDCI and the like) and a catalyst (such as HoBt, DMAP and the like), and reacting to obtain a compound 3.
(3) The compound 3 is dissolved in an inert solvent (e.g., dichloromethane, acetonitrile, acetone, chloroform, etc.), and an acid (e.g., trifluoroacetic acid, hydrochloric acid, etc.) is added to give a compound 4.
(4) Dissolving the compound 4 in an inert solvent (such as n-butanol, n-propanol, toluene, etc.), and performing reflux reaction to obtain a compound 5.
In the reaction, the organic base is triethylamine, triethylene diamine, pyridine and the like. Under basic conditions is meant in the presence of a base selected from the group consisting of various organic and inorganic bases known in the art.
Pesticide composition
The term "active substance according to the invention" or "active compound according to the invention" means a compound according to the invention or an agriculturally pharmaceutically acceptable salt thereof.
The agriculturally pharmaceutically acceptable salts may include inorganic salts, organic acid salts, basic amino acids, or salts of acidic amino acids. Inorganic acid salts in the present invention include, for example: hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, or phosphoric acid. Organic acids in the present invention include, for example: lactic acid, formic acid, acetic acid (i.e., acetic acid), trifluoroacetic acid, fumaric acid, oxalic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid. Acidic amino acids include, for example: glycine, aspartic acid, or glutamic acid.
The active substance of the present invention can be used for controlling and exterminating a wide range of agricultural and forestry plant pests, pests of stored cereals, pests harmful to the health of animals, public health pests, and the like. In the present specification, "pesticide" is a general term for a substance having an effect of controlling all the pests mentioned above.
Examples of pests include, but are not limited to: lepidopteran insects (such as gypsy moth (Lymantria dispar)), tsetnamese (Malacosoma neustria tetracea), yellow poplar wild borer (Diaphania persica), bagworm (claniaviridiae), yellow spiny moth (cnidocapa fiangensis), red tail pine moth (Dendrolimus punctatus), ancient moth (Orgyia goniothrix), poplar Paranthrene (parathrina tabformis), prodenia litura (Spodoptera litura), Chilo supressalis (Chilo supressalis), corn borer (Ostrinia nubilalis), pink borer (Ephestia caudatus), cotton leafworm (Adoxophyes orana), pymetrozine (pysorethe granulosa), Ostrinia (Ostrinia), cabbage moth (Ostrinia nubilalis), Ostrinia nubilalis (Ostrinia), cabbage moth (Ostrinia nubilalis), cabbage moth (Ostrinia nubila, Ostrinia nubila (Ostrinia nubila, Ostrinia nubila, or (ostr.
The active substances according to the invention can be prepared in a customary manner to give pesticide compositions. The active compounds can be formulated in conventional preparations such as solutions, emulsions, suspensions, powders, foams, pastes, granules, aerosols and the like.
These formulations can be produced by known methods, for example by mixing the active compounds with extenders, that is, liquid or liquefied gas or solid diluents or carriers, and optionally surfactants, that is, emulsifiers and/or dispersants and/or foam formers. Organic solvents may also be used as adjuvants, for example when water is used as extender.
When a liquid solvent is used as the diluent or carrier, it is basically suitable, for example: aromatic hydrocarbons such as xylene, toluene or alkylnaphthalene; chlorinated aromatic or chlorinated aliphatic hydrocarbons, such as chlorobenzene, vinyl chloride or dichloromethane; aliphatic hydrocarbons, such as cyclohexane or paraffins, for example mineral oil fractions; alcohols, such as ethanol or ethylene glycol and their ethers and lipids; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone; or less commonly polar solvents such as dimethylformamide and dimethylsulfoxide, and water.
By a diluent or carrier for liquefied gases is meant a liquid which will become gaseous at ambient temperature and pressure, for example aerosol propellants such as halogenated hydrocarbons as well as butane, propane, nitrogen and carbon dioxide.
Solid carriers which may be used are ground natural minerals, such as kaolin, clay, talc, quartz, attapulgite, montmorillonite or kieselguhr, and ground synthetic minerals, such as highly dispersed silicic acid, alumina and silicates. Solid carriers for granules are ground and classified natural marble, such as calcite, marble, pumice, sepiolite and dolomite, as well as synthetic granules of inorganic and organic meals, and granules of organic materials, such as sawdust, coconut shells, corn cobs and tobacco stalks, etc.
Nonionic and anionic emulsifying trains may be used as emulsifiers and/or foam formers. Such as polyoxyethylene-fatty acid esters, polyoxyethylene-fatty alcohol ethers, such as alkylaryl polyethylene glycol ethers, alkyl sulfonates, alkyl sulfates, aryl sulfonates and albumin hydrolysates. Dispersants include, for example, lignin sulfite waste liquor and methyl cellulose.
Binders such as carboxymethylcellulose and natural and synthetic polymers in the form of powders, granules or emulsions, for example gum arabic, polyvinyl alcohol and polyvinyl acetate, can be used in the formulations.
Colorants such as inorganic dyes, e.g., iron oxide, cobalt oxide and prussian blue; organic dyes, such as organic dyes, e.g., azo dyes or metallotitanyl cyanine dyes; and with trace nutrients such as salts of iron, manganese, boron, copper, cobalt, aluminum, and zinc, and the like.
These formulations generally contain from 0.001 to 99.99% by weight, preferably from 0.01 to 99.9% by weight, more preferably from 0.05 to 90% by weight, of the active compounds according to the invention, based on the pesticide composition. The concentration of the active compound in the dosage form prepared from commercial preparations for use can vary within wide limits. The concentration of active compound in the dosage form to be used may be from 0.0000001 to 100% (g/v), preferably between 0.0001 and 1% (g/v).
Pharmaceutical composition
The term "active substance according to the invention" or "active compound according to the invention" means a compound according to the invention or a pharmaceutically acceptable salt thereof.
The pharmaceutically acceptable salt may include inorganic salts, organic acid salts, basic amino acids, or salts of acidic amino acids. Inorganic acid salts in the present invention include, for example: hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, or phosphoric acid. Organic acids in the present invention include, for example: lactic acid, formic acid, acetic acid (i.e., acetic acid), trifluoroacetic acid, fumaric acid, oxalic acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, or p-toluenesulfonic acid. Acidic amino acids include, for example: glycine, aspartic acid, or glutamic acid.
The compound of the present invention and the pharmaceutically acceptable salts thereof, as well as the pharmaceutical composition containing the compound as a main active ingredient, are useful for treating or preventing 5-HT2a receptor-related diseases, such as inflammation diminishing, pain relieving, psychosis prevention or treatment of depression, and the like, because the compound of the present invention has excellent agonistic activity to the 5-HT2a receptor.
The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmacologically acceptable salt thereof in a safe and effective amount range and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000mg of a compound of the invention per dose, more preferably, 10-200mg of a compound of the invention per dose. Preferably, said "dose" is a capsule or tablet.
"pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances which are suitable for human use and must be of sufficient purity and sufficiently low toxicity. By "compatible" is meant herein that the components of the composition are capable of intermixing with and with the compounds of the present invention without significantly diminishing the efficacy of the compounds. Examples of pharmaceutically acceptable carrier moieties are cellulose and its derivatives (e.g. sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g. stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g. soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g. propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (e.g. tween, etc.)) Wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
The 5-HT2a receptor is a Gq-coupled receptor, linked to the phosphoinositide signaling pathway. The activity screening method of the compound of the present invention may be a luciferase reportA method for detecting a gene. The principle is that extracellular signal molecules are combined with a cell surface G protein coupled receptor (such as a 5-HT2a receptor) in a phosphatidylinositol signal pathway, phospholipase C (PLC-beta) on a plasma membrane is activated, phosphatidylinositol 4, 5-diphosphate (PIP2) on the plasma membrane is hydrolyzed into two second messengers, namely inositol 1,4, 5-triphosphate (IP3) and Diacylglycerol (DG), and the extracellular signal is converted into an intracellular signal, which is also called a double messenger system. IP3 binds to the IP3 ligand portal calcium channel on the endoplasmic reticulum, opening the calcium channel and allowing intracellular Ca2+The ion concentration increases. Calcium flux through CaMKII and CaMKIV leads to phosphorylation of CREB, resulting in expression of downstream genes (e.g., luciferase reporter gene, pcr-luc). Thus receptor activation can be detected by the luciferase reporter gene pCRE-luc.
The main advantages of the invention include:
1. the compound of the invention has excellent insecticidal activity, can especially effectively kill lepidoptera insects or inhibit feeding and growth of the lepidoptera insects, and can be used for preventing and controlling nematodes, such as meloidogyne incognita.
2. The compounds of the present invention not only facilitate further studies of insect 5-HT receptors, but also act as human 5-HT2a receptor ligands.
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally followed by conventional conditions, such as Sambrook et al, molecular cloning: the conditions described in the Laboratory Manual (New York: Cold Spring Harbor Laboratory Press,1989), or according to the manufacturer's recommendations. Unless otherwise indicated, percentages and parts are by weight.
Example 1: synthesis of piperazinedione intermediate 5a
(1) Ornithine hydrochloride 1a (337mg, 2mmol), di-tert-butyl dicarbonate ((Boc)2O) (1310mg, 6mmol), triethylamine (Et)3N) (404mg, 4mmol) was dissolved in 6ml acetone and 6ml water, stirred at room temperature and TCL followed the reaction. After the reaction, acetone was distilled off under reduced pressure, followed by extraction with dichloromethane 3 times. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed by rotary evaporation under reduced pressure to obtain a crude product of compound 2 a.
(2) The crude compound 2a obtained in the first reaction, tryptophan methyl ester hydrochloride (1019mg,4mmol), triethylamine (6mmol), HOBt (297mg, 2.2mmol) and EDCl (460mg,2.4mmol) were added to a 100ml round-bottom flask, and 30ml dichloromethane was added thereto, followed by stirring in ice bath for 1 hour and further stirring at room temperature for 15 hours. After the reaction is finished, the reaction solution is washed by water, separated, subjected to organic phase vacuum distillation to remove dichloromethane, and the obtained crude product is purified by a column to obtain a compound 3 a.
(3) The compound 3a is dissolved in dichloromethane, 5 times of equivalent weight of trifluoroacetic acid is added, after 12 hours of stirring at room temperature, the trifluoroacetic acid and the dichloromethane are removed by reduced pressure rotary evaporation, and a tan liquid, namely a crude product of 4a is obtained. The crude product of 4a was dissolved in 20ml of n-butanol and slowly added dropwise to 20ml of refluxing n-butanol, and the progress of the reaction was followed by TLC. After the reaction, n-butanol was removed by distillation under reduced pressure to obtain a crude product of compound 5 a. The crude product was washed with dichloromethane-methanol 95:5 and filtered to afford pure compound 5a in 47% overall reaction yield.1HNMR(400MHz,DMSO)δ11.15(s,1H),8.15(d,J＝1.7Hz,1H),8.06(s,1H),7.91(s,2H),7.57(d,J＝7.9Hz,1H),7.33(d,J＝8.0Hz,1H),7.06-6.93(m,3H),6.94(t,J＝7.2Hz,1H),4.12(t,J＝7.9Hz,1H),3.53(s,1H),3.40(s,1H),3.23(dd,J＝14.4,4.2Hz,1H),3.05(dd,J＝14.4,4.4Hz,1H),2.31(t,J＝7.4Hz,2H),1.14-0.82(m,3H),0.72-0.54(m,1H)。
Example 2: synthesis of piperazinedione urea compound 10a-1
Triphosgene (BTC) (223mg,0.75mmol) was added to a 50mL round bottom flask and dissolved in 5mL dichloromethane. Aniline 6a (140mg,1.5mmol) and triethylamine (152mg, 1.5mmol) were dissolved in 5ml dichloromethane and added dropwise to the previous flask, stirred in an ice bath for about half an hour, and stirred at room temperature (TLC tracing reaction) to give compound 7 a. A50 ml round bottom flask was taken, Compound 5a (300mg,1mmol) was dissolved in 1ml DMF and triethylamine (101mg, 1mmol) was added and stirred magnetically. The previous reaction was slowly added dropwise to the flask and allowed to react at room temperature. After the addition was complete, the reaction was complete (follow-up by TLC). The solvent in the reaction system was removed by distillation under the reduced pressure, and the reaction system was washed with water, and the obtained crude product was purified by column chromatography (dichloromethane/methanol (V/V ═ 10:1) elution) to obtain compound 10a in a yield of 70%.1H NMR(400MHz,DMSO)δ10.86(d,J＝14.6Hz,1H),8.36(s,1H),8.00(dd,J＝24.5,13.8Hz,2H),7.58(d,J＝7.8Hz,1H),7.44-6.82(m,9H),5.83(t,J＝5.3Hz,1H),4.12(t,J＝7.8Hz,1H),3.55(t,J＝7.8Hz,1H),3.14(ddd,J＝84.7,14.5,4.2Hz,2H),2.78-2.55(m,2H),1.12-0.57(m,4H).13C NMR(101MHz,DMSO)δ167.60,167.43,155.52,141.03,136.42,129.08,128.28,125.03,121.34,121.24,119.42(2C),118.81,117.98(2C),111.56,109.15,55.90,54.18,38.96,31.39,29.49,25.01.
Example 3: synthesis of piperazinedione thiourea compound 11a-1
In a 50mL round-bottom flask, aniline 6a (140mg,1.5mmol), 1, 4-diazabicyclo [2.2.2]Octane DABCO (336mg,3mmol) was added to the THF solution and CS was slowly added dropwise2(228mg,3mmol), stirring at room temperature for 24h, filtering, washing the solid with THF for 3 times, suspending the solid in THF solvent, cooling to below 0 ℃, dissolving BTC (150mg, 0.75mmol) in the solvent, dripping, reacting at room temperature for 2h, stirring at room temperature for 5h, filtering the reaction solution, drying the filtrate by spinning, dissolving with petroleum ether, filtering off insoluble substances, and obtaining crude product of isothiocyanate. Dissolving the crude product of isothiocyanate in methanol, adding 5a (300mg,1mmol) and triethylamine (152mg, 1.5mmol), stirring at room temperature, tracking the reaction process by TLC, evaporating the solvent after the reaction is finished, and carrying out column chromatography separation and purification to obtain the target compound 11a with the yield of 64%.1H NMR(400MHz,DMSO)δ10.88(d,J＝1.6Hz,1H),9.46(s,1H),8.08-7.95(m,2H),7.58(d,J＝7.9Hz,1H),7.49-7.26(m,6H),7.14-6.88(m,4H),4.12(d,J＝1.3Hz,1H),3.58(d,J＝7.9Hz,1H),3.25(dd,J＝14.4,4.5Hz,1H),3.16-2.98(m,3H),1.13-0.85(m,3H),0.72-0.53(m,1H).13CNMR(101MHz,DMSO)δ180.64,167.67,167.48,139.75,136.41,129.04(2C),128.25,125.02,124.51,123.40(2C),121.28,119.40,118.83,111.61,109.16,55.91,54.09,43.64,31.43,29.57,23.93.
Example 4: synthesis of piperazinedionamide compounds 14a-1
In a 50ml round bottom flask, 4-cyanobenzoic acid 12a (177mg,1.2mmol), compound 5a (300mg,1mmol), 1-hydroxybenzotriazole (HOBt) (162mg,1.2mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (230mg,1.2mmol), triethylamine (152mg, 1.5mmol) were dissolved in 2ml DMF, stirred magnetically, reacted at room temperature for 12h to completion (TLC follow-up). And (3) distilling under reduced pressure to remove DMF in the reaction system, washing the obtained crude product with deionized water, then washing with dichloromethane, and carrying out column chromatography separation and purification to obtain the compound 14a with the yield of 72%.1H NMR(400MHz,DMSO)δ10.87(s,1H),8.49(s,1H),8.03(d,J＝16.3Hz,2H),7.95(s,4H),7.57(d,J＝7.8Hz,1H),7.29(d,J＝8.0Hz,1H),7.07(s,1H),7.02(t,J＝7.4Hz,1H),6.93(t,J＝7.4Hz,1H),4.13(t,J＝5.4Hz,1H),3.59(t,J＝5.4Hz,1H),3.23(dd,J＝14.3,4.0Hz,1H),3.06(dd,J＝14.3,3.9Hz,1H),2.93(ddd,J＝30.1,12.9,6.3Hz,2H),1.18-0.90(m,3H),0.75-0.51(m,1H).13C NMR(101MHz,DMSO)δ167.71,167.54,165.11,139.10,136.41,132.82(2C),128.47(2C),128.23,124.99,121.26,119.36,118.85,118.81,113.88,111.58,109.17,55.85,54.12,39.28,31.39,29.49,24.39.
Example 5: synthesis of piperazinedione secondary amine compound 15a-6
In a 50ml round bottom flask, compound 5a (300mg,1mmol), benzaldehyde 13a (145mg, 1.2mmol) was dissolved in 1ml DMF, and after stirring at room temperature for 2h, sodium triacetoxyborohydride (318mg, 1.5mmol) was added, and stirring at room temperature overnight, purification by column chromatography was carried out in 65% yield.1H NMR(400MHz，DMSO)δ10.96(d,J＝1.7Hz,1H),8.12(d,J＝2.1Hz,1H),8.03(d,J＝2.2Hz,1H),7.57(d,J＝7.8Hz,1H),7.35-7.21(m,5H),7.07(d,J＝2.2Hz,1H),7.02-6.90(m,2H),4.13(d,J＝1.3Hz,1H),3.95-3.83(m,2H),3.56(t,J＝4.9Hz,1H),3.24(dd,J＝14.4,4.3Hz,1H),3.05(dd,J＝14.4,4.6Hz,1H),2.44-2.35(m,2H),2.33(s,3H),1.21-1.00(m,2H),0.99-0.82(m,1H),0.63-0.43(m,1H).13C NMR(101MHz,DMSO)δ167.75,167.32,138.74,136.34,130.23(2C),129.70,129.64(2C),128.24,125.17,121.29,119.44,118.88,111.56,109.14,55.89,53.75,50.14,46.22,31.01,29.40,21.56,21.31.
Example 6: synthesis of piperazinedionamide compounds 14b-1
In a 50ml round bottom flask, 4-bromobenzoic acid 12b (240mg,1.2mmol), compound 5b (300mg,1mmol), 1-hydroxybenzotriazole (HOBt) (162mg,1.2mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (230mg,1.2mmol), triethylamine (152mg, 1.5mmol) were dissolved in 2ml DMF and reacted at room temperature with magnetic stirring for 12h completion (TLC follow-up). And (3) distilling under reduced pressure to remove DMF in the reaction system, washing the obtained crude product with deionized water, then washing with dichloromethane, and carrying out column chromatography separation and purification to obtain the compound 14b with the yield of 79%.1HNMR(400MHz,DMSO)δ8.38(t,J＝5.4Hz,1H),8.13(s,1H),8.05(s,1H),7.79(d,J＝8.5Hz,2H),7.68(d,J＝8.4Hz,2H),7.14(qd,J＝14.7,7.4Hz,5H),4.19(s,1H),3.63(s,1H),3.14(dd,J＝13.4,3.6Hz,1H),2.97(d,J＝6.1Hz,2H),2.85(dd,J＝13.5,4.8Hz,1H),1.15-0.87(m,3H),0.77(d,J＝7.1Hz,1H).13C NMR(100MHz,DMSO)δ166.9,166.1,164.9,136.0,133.7,131.2(2C),130.2(2C),129.2(2C),127.9(2C),126.4,124.6,55.2,53.6,38.8,38.0,30.7,23.9.
Example 7: synthesis of piperazinedione urea compound 15b-1
Triphosgene (BTC) (223mg,0.75mmol) was added to a 50mL round bottom flask and dissolved in 5mL dichloromethane. 4-Trifluoromethylaniline 6a (240mg,1.5mmol) and triethylamine (152mg, 1.5mmol) were dissolved in 5ml of dichloromethane, and the solution was added dropwise to the previous flask, stirred in an ice bath for about half an hour, and stirred at room temperature (TLC tracing reaction) to obtain Compound 7 b. A50 ml round bottom flask was taken, Compound 5b (300mg,1mmol) was dissolved in 1ml DMF and triethylamine (101mg, 1mmol) was added and stirred magnetically. The previous reaction was slowly added dropwise to the flask and allowed to react at room temperature. The dropping is finishedAfter that, the reaction was complete (TLC followed the reaction). The solvent in the reaction system was removed by distillation under the reduced pressure, and the reaction system was washed with water, and the obtained crude product was purified by column chromatography (dichloromethane/methanol (V/V ═ 10:1) elution) to obtain compound 10a in a yield of 70%.1H NMR(400MHz,DMSO)δ8.85(s,1H),8.13(s,1H),8.06(s,1H),7.58(q,J＝8.9Hz,4H),7.30-7.10(m,5H),6.08(t,J＝5.6Hz,1H),4.20(s,1H),3.62(s,1H),3.14(d,J＝3.8Hz,1H),2.90-2.80(m,3H),1.11(dd,J＝10.1,4.8Hz,1H),1.02-0.84(m,2H),0.79-0.63(m,1H).13C NMR(100MHz,DMSO)δ166.9,166.2,154.6,144.2,136.0,130.2(2C),127.9(2C),125.9(q,J＝4Hz),126.5,124.6(q,J＝270Hz),120.8(q,J＝31Hz),117.1(2C),55.3,53.6,48.5,38.6,38.1,30.6,24.4.
According to the preparation method (as in examples 1 to 7), the following compounds are adopted as different raw materials.
1H NMR(400MHz,DMSO)δ10.89(s,1H),8.26(s,1H),8.01(d,J＝26.4Hz,2H),7.58(d,J＝7.9Hz,1H),7.26(dt,J＝24.7,12.3Hz,3H),7.11-6.87(m,5H),5.79(t,J＝5.2Hz,1H),4.12(t,J＝7.8Hz,1H),3.55(t,J＝7.8Hz,1H),3.14(ddd,J＝84.8,14.4,4.2Hz,2H),2.75-2.55(m,2H),2.21(s,3H),1.09-0.57(m,4H).13C NMR(100MHz,DMSO)δ167.6,167.4,155.6,138.4,136.4,130.0,129.4(2C),128.2,125.0,121.2,119.4,118.8,118.1(2C),111.5,109.1,55.9,54.1,38.9,31.4,29.4,25.0,20.7.
1H NMR(400MHz,DMSO)δ10.88(s,1H),8.16(s,1H),8.04(s,1H),7.98(s,1H),7.57(s,1H),7.26(d,J＝8.9Hz,2H),7.00(d,J＝48.7Hz,4H),6.80(d,J＝8.8Hz,2H),5.72(t,J＝5.3Hz,1H),4.12(s,1H),3.69(s,3H),3.53(t,J＝5.3Hz,1H),3.25-2.98(m,2H),2.73-2.56(m,2H),1.06-0.58(m,4H).13C NMR(100MHz,DMSO)δ167.7,167.5,155.6,138.5,136.4,130.0,128.28,126.23(2C),125.0,121.2,119.4,118.8,114.1(2C),111.6,109.1,55.9,55.6，54.2,38.9,31.4,29.5,25.1
1H NMR(400MHz,DMSO)δ10.80(d,J＝69.9Hz,1H),8.20(s,1H),8.02(d,J＝26.8Hz,2H),7.58(d,J＝7.9Hz,1H),7.32(d,J＝8.1Hz,1H),7.10-6.85(m,5H),6.52(s,1H),5.80(t,J＝7.8Hz,1H),4.12(t,J＝7.8Hz,1H),3.55(t,J＝7.8Hz,1H),3.34-3.04(m,2H),2.78-2.54(m,2H),2.19(s,6H),1.09-0.57(m,4H).13C NMR(100MHz,DMSO)δ167.6,167.4,155.5,140.8,137.9(2C),136.4,128.2,125.0,123.0,121.2,119.4,118.8,115.8(2C),111.5,109.1,55.9,54.2,38.9,31.4,29.4,25.0,21.6(2C).
1H NMR(400MHz,DMSO)δ10.88(s,1H),8.95(s,1H),8.02(d,J＝29.2Hz,2H),7.71-7.50(m,5H),7.32(d,J＝8.1Hz,1H),6.98(ddd,J＝33.1,19.8,12.4Hz,3H),6.08(t,J＝5.2Hz,1H),4.12(t,J＝7.8Hz,1H),3.54(t,J＝7.8Hz,1H),3.29-2.97(m,2H),2.82-2.56(m,2H),0.98-0.51(m,4H).13C NMR(100MHz,DMSO)δ167.6,167.4,154.9,145.4,136.4,133.6(2C),128.2,125.0,121.2,119.9,119.4,118.8,117.8(2C),111.5,109.1,102.6,55.8,54.1,38.9,31.2,29.4,24.7.
1H NMR(400MHz,DMSO)δ10.88(s,1H),9.40(s,1H),8.15(s,1H),8.06(s,1H),8.01-7.91(m,2H),7.63(dd,J＝38.6,8.1Hz,2H),7.31(d,J＝8.1Hz,1H),7.09-6.87(m,3H),6.27(t,J＝5.2Hz,1H),4.12(t,J＝7.8Hz,1H),,3.56(t,J＝7.8Hz,1H),3.30-2.97(m,2H),2.81-2.58(m,2H),0.98-0.51(m,4H).13C NMR(100MHz,DMSO)δ167.6,167.4,154.6,145.9,136.6,136.4,132.1(t,J＝31Hz),128.2,125.0,123.5(t,J＝273Hz),121.2,120.5,119.4,118.7,116.6,115.1(t,J＝6Hz),111.5,109.1,99.1,55.8,54.1,39.0,31.2,29.4,24.6.
1H NMR(400MHz,DMSO)δ10.88(s,1H),8.64(s,1H),8.13-7.94(m,3H),7.58(d,J＝7.9Hz,1H),7.31(d,J＝8.1Hz,1H),7.08-6.89(m,3H),6.43(t,J＝5.2Hz,1H),4.12(s,1H),3.55(s,1H),3.30-2.95(m,2H),2.71-2.56(m,2H),1.10-0.47(m,4H).13C NMR(100MHz,DMSO)δ167.6,166.5(d,J＝214Hz),167.3,154.7,136.4,128.3,126.9(d,J＝206Hz),125.5(d,J＝106Hz),125.0,121.2,120.3(d,J＝206Hz),119.4,118.8,111.5,110.3(d,J＝288Hz),109.1,102.1(d,J＝25Hz),55.9,54.1,38.9,31.3,29.4,24.5.
1H NMR(400MHz,DMSO)δ10.92(s,1H),8.06(s,1H),7.99(s,1H),7.87(s,1H),7.59(d,J＝7.8Hz,1H),7.44(s,1H),7.34(d,J＝8.1Hz,1H),7.13-7.00(m,4H),6.95(t,J＝7.4Hz,1H),6.12(t,J＝5.0Hz,1H),4.12(t,J＝7.8Hz,1H),3.55(t,J＝7.8Hz,1H),3.25(dd,J＝14.4,3.9Hz,1H),3.04(dd,J＝14.2,4.2Hz,1H),2.73-2.51(m,2H),1.11-0.51(m,4H).13C NMR(100MHz,DMSO)δ167.6,167.44,159.5(d,J＝5Hz),157.1(d,J＝5Hz),155.3,136.4,128.2,126.6(t,J＝10Hz),125.0,121.2,119.1,118.8,116.5(t,J＝8Hz),112.1,111.9,111.5,109.1,55.9,54.1,39.4,31.4,29.4,25.0.
1H NMR(400MHz,DMSO)δ10.92(s,1H),9.35(s,1H),8.13(d,J＝9.0Hz,2H),8.07(s,1H),7.99(s,1H),7.60(t,J＝9.5Hz,3H),7.32(d,J＝8.0Hz,1H),7.10-6.88(m,3H),6.23(t,J＝5.2Hz,1H),4.13(t,J＝7.8Hz,1H),3.57(t,J＝7.8Hz,1H),3.28-3.18(m,1H),3.11-2.99(m,1H),2.82-2.58(m,2H),1.12-0.54(m,4H).13C NMR(100MHz,DMSO)δ167.5,167.3,154.7,147.7,140.7,136.4,128.2,125.6(2C),125.0,121.2,119.4,118.8,117.1(2C),111.5,109.2,55.8,54.1,39.0,31.2,29.4,24.6.
1H NMR(400MHz,DMSO)δ10.80(d,J＝68.3Hz,1H),8.91(s,1H),8.54(s,1H),8.02(d,J＝28.6Hz,2H),7.58(d,J＝7.9Hz,1H),7.51-7.41(m,3H),7.32(d,J＝8.5Hz,1H),7.11-6.89(m,3H),5.90(t,J＝5.2Hz,1H),4.12(t,J＝7.82Hz,1H),3.55(t,J＝7.8Hz,1H),3.25(dd,J＝14.3,4.1Hz,1H),3.04(dd,J＝14.4,4.3Hz,1H),2.79-2.55(m,2H),1.11-0.43(m,4H).13C NMR(100MHz,DMSO)δ167.6,167.4,155.3,140.4,136.4,131.9,131.7,128.2,125.0,121.2,120.6,119.8,119.4,118.8,112.5,111.5,109.1,55.9,54.1,38.9,31.3,29.4,24.9.
1H NMR(400MHz,DMSO)δ10.95(s,1H),8.28(s,1H),8.12-7.93(m,3H),7.58(d,J＝7.9Hz,1H),7.32(d,J＝8.0Hz,1H),7.28-7.17(m,1H),7.06-6.87(m,4H),6.42(t,J＝5.0Hz,1H),4.12(t,J＝7.82Hz,1H),3.55(t,J＝7.82Hz,1H),3.26(dd,J＝14.4,3.8Hz,1H),3.03(dd,J＝14.4,3.8Hz,1H),2.74-2.57(m,2H),1.07-0.59(m,4H).13C NMR(100MHz,DMSO)δ167.5,167.3,156.4(dd,J＝239,11Hz),155.2,151.2(dd,J＝243,12Hz)136.4,128.2,125.4(dd,J＝10,4Hz),125.02,121.6(t,J＝7,4Hz),121.2,119.4,118.7,111.5,111.2(dd,J＝224Hz),109.0,103.9(t,J＝27,23Hz),55.9,54.1,39.0,31.4,29.4,24.8.
1H NMR(400MHz,DMSO)δ10.88(s,1H),8.84(s,1H),8.01(dd,J＝27.6,2.1Hz,2H),7.62-7.49(m,5H),7.32(d,J＝8.1Hz,1H),7.09-6.89(m,3H),6.02(t,J＝5.5Hz,1H),4.12(t,J＝5.5Hz,1H),3.55(t,J＝5.5Hz,1H),3.25(dd,J＝14.4,4.3Hz,1H),3.04(dd,J＝14.4,4.6Hz,1H),2.76-2.58(m,2H),1.10-0.49(m,4H).13C NMR(100MHz,DMSO)δ167.6,167.4,155.1,144.7,136.4,128.2,126.4,126.3,125.0(q,J＝267Hz),125.0,121.2(q,J＝32Hz),121.2,119.4,118.8,117.5(2C),111.5,109.1,55.8,54.1,38.9,31.3,29.4,24.8.
1H NMR(400MHz,DMSO)δ10.93(s,1H),9.02(s,1H),8.05(s,1H),7.97(s,1H),7.84(d,J＝8.6Hz,2H),7.58(d,J＝7.9Hz,1H),7.50(d,J＝8.6Hz,2H),7.31(d,J＝8.0Hz,1H),6.99(ddd,J＝33.0,12.6,4.4Hz,3H),6.12(t,J＝5.4Hz,1H),4.12(t,J＝5.4Hz,1H),3.56(t,J＝5.4Hz,1H),3.25(dd,J＝14.4,4.2Hz,1H),3.03(dd,J＝14.5,4.5Hz,1H),2.77-2.55(m,2H),1.08-0.50(m,4H).13C NMR(100MHz,DMSO)δ196.6,167.5,167.3,155.0,145.7,136.4,130.1(2C),128.2,125.0,121.2,119.4,118.7,116.8(2C),111.5,109.1,99.9,55.9,54.1,39.0,31.3,29.4,26.7,24.8.
1H NMR(400MHz,DMSO)δ10.86(s,1H),8.50(s,1H),8.00(dd,J＝25.9,1.9Hz,2H),7.58(d,J＝7.8Hz,1H),7.44-7.20(m,5H),7.10-6.85(m,3H),5.87(t,J＝5.5Hz,1H),4.10(t,J＝5.2Hz,1H),3.55(t,J＝5.2Hz,1H),3.24(dd,J＝14.4,4.4Hz,1H),3.04(dd,J＝14.4,4.5Hz,1H),2.79-2.56(m,2H),1.11-0.59(m,4H).13C NMR(100MHz,DMSO)δ167.6,167.4,155.3,140.0,136.4,128.8(2C),128.2,125.0,124.7,121.2,119.4(2C),119.4,118.8,111.5,109.1,55.8,54.1,38.9,31.3,29.4,24.9.
1H NMR(400MHz,DMSO)δ10.88(s,1H),8.77(s,1H),8.07-7.91(m,3H),7.57(t,J＝7.0Hz,1H),7.49-7.40(m,2H),7.32(d,J＝8.0Hz,1H),7.21(d,J＝7.0Hz,1H),7.10-6.99(m,2H),6.98-6.89(m,1H),5.97(t,J＝5.6Hz,1H),4.12(t,J＝5.6Hz,1H),3.56(t,J＝5.6Hz,1H),3.25(dd,J＝14.4,4.3Hz,1H),3.04(dd,J＝14.4,4.6Hz,1H),2.78-2.55(m,2H),1.10-0.53(m,4H).13C NMR(100MHz,DMSO)δ167.6,167.4,155.3,141.8,136.4,130.1,129.8(q,J＝31Hz),128.2,125.0,124.7(q,J＝270Hz),121.4,121.2,119.4,118.8,117.5(q,J＝3Hz),113.8(q,J＝4Hz),111.6,109.1,55.9,54.1,38.9,31.3,29.4,24.8.
1H NMR(400MHz,DMSO)δ10.88(s,1H),8.77(s,1H),8.07-7.91(m,3H),7.57(t,J＝7.0Hz,1H),7.49-7.40(m,2H),7.32(d,J＝8.0Hz,1H),7.21(d,J＝7.0Hz,1H),7.10-6.99(m,2H),6.98-6.89(m,1H),5.97(t,J＝5.6Hz,1H),4.12(t,J＝5.6Hz,1H),3.56(t,J＝5.6Hz,1H),3.25(dd,J＝14.4,4.3Hz,1H),3.04(dd,J＝14.4,4.6Hz,1H),2.78-2.55(m,2H),1.10-0.53(m,4H).13C NMR(100MHz,DMSO)δ167.6,167.4,155.3,141.8,136.4,130.1,129.8(q,J＝31Hz),128.2,125.0,124.7(q,J＝270Hz),121.4,121.2,119.4,118.8,117.5(q,J＝3Hz),113.8(q,J＝4Hz),111.6,109.1,55.9,54.1,38.9,31.3,29.4,24.8.
1H NMR(400MHz,DMSO)δ10.88(d,J＝1.6Hz,1H),8.44(d,J＝8.8Hz,1H),8.30(s,1H),8.06(d,J＝2.0Hz,1H),7.98(d,J＝2.1Hz,1H),7.78(d,J＝1.7Hz,1H),7.60(dd,J＝11.4,4.7Hz,2H),7.32(d,J＝8.1Hz,1H),7.08-6.89(m,4H),4.12(s,1H),3.55(s,1H),3.30-2.99(m,2H),2.80-2.58(m,2H),1.10-0.51(m,4H).13C NMR(100MHz,DMSO)δ167.6,167.3,154.5,141.0,136.4,128.2,126.5(q,J＝4Hz),125.1(q,J＝4Hz),125.0(q,J＝270Hz),122.5(q,J＝32Hz),121.2,120.9,120.0,119.4,118.8,111.5,109.1,100.0,55.9,54.1,39.0,31.4,29.4,24.5.
1H NMR(400MHz,DMSO)δ10.98(s,1H),8.33(s,1H),8.15-8.04(m,2H),7.98(s,1H),7.58(d,J＝7.9Hz,1H),7.32(d,J＝8.0Hz,1H),7.20-6.87(m,6H),6.55(t,J＝5.1Hz,1H),4.12(t,J＝5.4Hz,1H),3.57(t,J＝5.4Hz,1H),3.25(dd,J＝14.4,4.3Hz,1H),3.04(dd,J＝14.4,4.5Hz,1H),2.78-2.63(m,2H),1.10-0.53(m,4H).13C NMR(100MHz,DMSO)δ167.5,167.4,155.2,152.0(d,J＝239Hz),136.4,128.9(d,J＝10Hz),128.3,125.0,124.7(d,J＝4Hz),121.8(d,J＝8Hz),121.2,120.6,119.4,118.7,115.1(d,J＝9Hz),111.5,109.0,55.9,54.1,39.0,31.4,29.4,24.8.
1H NMR(400MHz,DMSO)δ10.87(s,1H),9.11(s,1H),8.17(dd,J＝5.0,1.1Hz,1H),8.00(dd,J＝20.2,2.0Hz,3H),7.71-7.54(m,2H),7.31(d,J＝8.0Hz,2H),7.08-6.86(m,4H),4.11(t,J＝5.4Hz,1H),3.54(t,J＝5.4Hz,1H),3.25(dd,J＝14.4,4.2Hz,1H),3.03(dd,J＝14.4,4.6Hz,1H),2.74(dd,J＝12.7,6.7Hz,2H),1.15-0.43(m,4H).13C NMR(100MHz,DMSO)δ167.6,167.4,155.1,153.9,147.1,138.5,136.4,128.2,125.0,121.2,119.4,118.8,117.1,111.9,111.5,109.1,55.9,54.1,38.9,31.5,29.5,24.9.
1H NMR(400MHz,DMSO)δ10.86(d,J＝10.3Hz,1H),10.27(d,J＝10.0Hz,1H),8.02(dd,J＝32.1,10.4Hz,2H),7.64-7.48(m,1H),7.30(dd,J＝13.8,10.2Hz,2H),7.10-6.80(m,4H),6.24(s,1H),4.11(s,1H),3.55(s,1H),3.24(d,J＝8.9Hz,1H),3.04(d,J＝11.5Hz,1H),2.68(s,2H),1.06-0.96(m,1H),0.77(s,2H),0.56(s,1H).13C NMR(100MHz,DMSO)δ167.6,167.3,160.5,154.1,137.7,136.4,128.2,125.0,121.2,119.5,118.8,112.1,111.5,109.1,55.9,541,39.1,31.2,29.5,24.7.
1H NMR(400MHz,DMSO)δ10.89(s,1H),8.85(s,1H),8.01(dd,J＝19.1,15.3Hz,2H),7.89(d,J＝5.7Hz,1H),7.58(d,J＝7.8Hz,1H),7.32(d,J＝8.1Hz,1H),7.10-6.82(m,5H),6.07(s,1H),4.12(s,1H),3.79(s,3H),3.55(s,1H),3.25(dd,J＝14.3,4.1Hz,1H),3.03(dd,J＝14.4,4.4Hz,1H),2.72-2.60(m,2H),1.04-1.02(m,1H),0.79-0.76(m 2H),0.58-0.57(m,1H).13C NMR(100MHz,DMSO)δ167.6,167.4,164.9,154.8,147.1,136.4,134.6,128.2,125.0,121.2,119.4,118.8,111.5,109.1,107.5,96.6,55.8,54.1,53.4,38.9,31.2,29.4,24.7.
1H NMR(400MHz,DMSO)δ10.86(s,1H),10.05(s,1H),8.05(s,1H),7.97(s,1H),7.58(d,J＝7.8Hz,1H),7.31(d,J＝8.0Hz,1H),7.11-6.86(m,4H),6.22(s,1H),4.11(s,1H),3.54(s,1H),3.25(dd,J＝14.3,4.1Hz,1H),3.03(dd,J＝14.4,4.4Hz,1H),2.78-2.61(m,2H),2.27(s,3H),1.10-0.95(m,1H),0.78-0.75(m,2H),0.59-0.54(m,1H).13C NMR(100MHz,DMSO)δ167.5,167.3,158.8,154.0,136.4,134.6,128.2,125.0,124.7,121.2,119.4,118.8,111.5,109.1,55.8,54.0,39.1,31.2,29.4,24.7,11.5.
1H NMR(400MHz,DMSO)δ10.86(s,1H),10.77(s,1H),8.97(s,1H),8.02(dd,J＝34.8,1.5Hz,2H),7.58(d,J＝7.8Hz,1H),7.31(d,J＝8.0Hz,1H),6.99(ddd,J＝31.8,13.7,4.6Hz,3H),6.33(s,1H),4.12(s,1H),3.56(s,1H),3.26(dd,J＝14.4,4.1Hz,1H),3.03(dd,J＝14.4,4.5Hz,1H),2.76-2.70(m,2H),1.06-0.99(m,1H),0.88-0.69(m,2H),0.63-0.54(m,1H).13C NMR(100MHz,DMSO)δ167.6,167.3,160.9,153.7,147.9,136.4,128.3,125.1,121.2,119.4,118.8,111.5,109.1,99.9,55.8,54.0,31.1,29.4,24.5.
1H NMR(400MHz,DMSO)δ10.87(s,1H),10.60(s,1H),8.07(s,1H),7.99(s,1H),7.86(d,J＝7.4Hz,1H),7.60(t,J＝7.5Hz,2H),7.33(d,J＝7.5Hz,2H),7.21(d,J＝6.9Hz,1H),7.13-6.87(m,3H),6.49(s,1H),4.13(s,1H),3.58(s,1H),3.27(d,J＝13.7Hz,1H),3.04(d,J＝11.6Hz,1H),2.73(s,2H),1.08-0.95(m,1H),0.89-0.70(m,2H),0.68-0.56(m,1H).13C NMR(100MHz,DMSO)δ167.6,167.3,160.2,154.0,149.5,136.4,131.8,128.3,126.1,125.1,123.0,121.7,121.2,120.0,119.4,118.8,111.5,109.1,55.9,54.1,39.2,31.2,29.4,24.5.
1H NMR(400MHz,DMSO)δ10.86(d,J＝9.0Hz,1H),9.17(d,J＝10.3Hz,1H),8.19-7.84(m,3H),7.82-7.69(m,1H),7.58(d,J＝8.4Hz,1H),7.39(s,1H),7.29(t,J＝19.6Hz,1H),7.15-6.84(m,3H),4.11(s,1H),3.80(s,3H),3.54(s,1H),3.24(s,1H),3.05(d,J＝9.9Hz,1H),2.68(dd,J＝17.2,9.8Hz,2H),1.10-0.95(m,1H),0.78-0.75(m,2H),0.59-0.54(m,1H).13C NMR(100MHz,DMSO)δ167.6,167.4,164.0,154.1,147.0,136.4,132.8,128.2,125.0,122.3,121.2,119.4,118.8,111.5,109.1,106.0,55.8,54.2,52.1,39.3,31.5,29.5,24.7.
1H NMR(400MHz,DMSO)δ10.93(s,1H),10.85(s,1H),7.95(dd,J＝44.3,19.3Hz,4H),7.59(s,3H),7.32(d,J＝7.2Hz,1H),7.17-6.87(m,3H),6.37(s,1H),4.12(s,1H),3.57(s,1H),3.24(d,J＝12.4Hz,1H),3.04(d,J＝12.4Hz,1H),2.74(s,2H),1.10-0.95(m,1H),0.78-0.75(m,2H),0.59-0.54(m,1H).13C NMR(100MHz,DMSO)δ167.6,167.3,136.4,135.2,129.8,129.7,128.7,128.2,125.0,123.7,121.2,119.4,118.8,111.5,111.4,109.1,99.9,55.8,54.0,39.2,31.1,29.4,24.5.
1H NMR(400MHz,DMSO)δ10.87(s,1H),8.43(s,1H),8.02(d,J＝16.3Hz,3H),7.77(dd,J＝22.1,8.4Hz,2H),7.57(d,J＝7.8Hz,1H),7.29(d,J＝8.0Hz,1H),7.13-6.88(m,3H),4.12(t,J＝5.4Hz,1H),3.59(t,J＝5.4Hz,1H),3.23(dd,J＝14.4,4.2Hz,1H),3.06(dd,J＝14.4,4.1Hz,1H),3.00-2.78(m,2H),1.18-0.90(m,3H),0.75-0.66(m,1H).13C NMR(100MHz,DMSO)δ167.7,167.5,164.2,136.4,135.4,134.2,131.6,131.0,129.5,128.2,127.9,124.9,121.2,119.5,118.8,111.5,109.1,55.8,54.1,39.2,31.4,29.4,24.3.
1H NMR(400MHz,DMSO)δ10.90(s,1H),8.50(t,J＝4.9Hz,1H),8.03(d,J＝20.0Hz,2H),7.84(s,2H),7.79(s,1H),7.57(d,J＝7.8Hz,1H),7.28(d,J＝8.0Hz,1H),7.13-6.86(m,3H),4.12(t,J＝5.4Hz,1H),3.59(t,J＝5.4Hz,1H),3.23(dd,J＝14.3,4.2Hz,1H),3.06(dd,J＝14.4,4.1Hz,1H),3.00-2.78(m,2H),1.18-0.90(m,3H),0.75-0.66(m,1H).13C NMR(100MHz,DMSO)δ167.7,167.5,163.7,138.2,136.4,134.6(2C),130.8,128.2,126.5(2C),124.9,121.2,119.3,118.7,111.5,109.1,55.8,54.0,39.2,31.3,29.4,24.2.
1H NMR(400MHz,DMSO)δ10.87(s,1H),8.47(s,1H),8.02(t,J＝10.3Hz,4H),7.84(d,J＝8.1Hz,2H),7.58(d,J＝7.8Hz,1H),7.29(d,J＝8.0Hz,1H),7.08(s,1H),6.98(dt,J＝33.4,7.2Hz,2H),4.13(t,J＝5.4Hz,1H),3.59(t,J＝5.4Hz,1H),3.24(dd,J＝14.4,4.2Hz,1H),3.06(dd,J＝14.4,4.1Hz,1H),3.02-2.84(m,2H),1.18-0.90(m,3H),0.75-0.66(m,1H).13CNMR(100MHz,DMSO)δ167.7,167.5,165.3,138.8,136.4,131.4(q,J＝32Hz),128.5(2C),128.2,125.7(q,J＝4Hz,2C),124.9,124.4(q,J＝270Hz),121.2,119.3,118.8,111.5,109.1,55.8,54.1,39.2,31.4,29.5,24.4.
1H NMR(400MHz,DMSO)δ10.88(s,1H),8.80(s,1H),8.51(s,1H),8.20(d,J＝7.9Hz,1H),8.03(d,J＝19.1Hz,2H),7.60(dd,J＝24.2,7.9Hz,2H),7.28(d,J＝7.9Hz,1H),7.16-6.82(m,3H),4.13(t,J＝4.2Hz,1H),3.59(t,J＝4.2Hz,1H),3.24(d,J＝10.7Hz,1H),3.06(d,J＝10.7Hz,1H),2.92(dd,J＝15.3,6.4Hz,2H),1.09-0.90(m,3H),0.75-0.64(m,1H).
13C NMR(100MHz,DMSO)δ167.7,167.5,163.9,152.8,149.3,138.9,136.4,129.9,128.2,125.0,124.5,121.2,119.3,118.8,111.5,109.1,55.8,54.1,39.2,31.3,29.4,24.3.
1H NMR(400MHz,DMSO)δ10.88(s,1H),8.13(t,J＝4.9Hz,1H),8.01(t,J＝10.5Hz,2H),7.72(d,J＝8.0Hz,2H),7.58(d,J＝7.9Hz,1H),7.30(d,J＝8.0Hz,1H),7.25(d,J＝7.9Hz,2H),7.08(s,1H),7.03(t,J＝7.5Hz,1H),6.94(t,J＝7.4Hz,1H),4.12(t,J＝4.9Hz,1H),3.59(t,J＝4.9Hz,1H),3.23(dd,J＝14.3,4.3Hz,1H),3.07(dd,J＝14.4,4.1Hz,1H),3.00-2.81(m,2H),1.21-0.95(m,3H),0.79-0.68(m,1H).13C NMR(100MHz,DMSO)δ167.7,167.5,166.3,141.2,136.4,132.3,129.1(2C),128.2,127.6(2C),124.9,121.2,119.3,118.8,111.6,109.1,55.8,54.2,39.0,31.4,29.5,24.7,21.3.
1H NMR(400MHz,DMSO)δ10.88(s,1H),8.31(s,1H),8.02(d,J＝13.2Hz,2H),7.71(dd,J＝37.0,8.2Hz,4H),7.57(d,J＝7.7Hz,1H),7.29(d,J＝7.9Hz,1H),7.08(s,1H),6.98(dt,J＝14.6,7.0Hz,2H),4.12(t,J＝7.4Hz,1H),3.59(t,J＝7.4Hz,1H),3.23(dd,J＝14.1,3.9Hz,1H),3.12-3.02(dd,J＝14.1,3.9Hz,1H),3.00-2.79(m,2H),1.22-0.90(m,3H),0.81-0.67(m,1H).13C NMR(100MHz,DMSO)δ167.7,167.5,165.5,136.4,134.2,131.6(2C),129.7(2C),128.2,125.1,124.9,121.2,119.3,118.8,111.5,109.1,55.8,54.1,39.1,31.4,29.5,24.5.
1H NMR(400MHz,DMSO)δ10.86(s,1H),9.07-8.88(m,4H),8.04(d,J＝14.6Hz,2H),7.56(d,J＝7.8Hz,1H),7.27(d,J＝8.0Hz,1H),7.11-6.86(m,3H),4.12(t,J＝7.4Hz,1H),305.60(t,J＝7.4Hz,1H),3.23(dd,J＝14.3,4.0Hz,1H),3.11-2.84(m,3H),1.21-0.92(m,3H),0.79-0.68(m,1H).13C NMR(100MHz,DMSO)δ167.7,167.5,162.3,148.5(2C),137.5,136.3,128.2,127.8(2C),125.0,121.2,121.2,119.3,118.8,111.5,109.1,55.8,54.0,39.6,31.4,29.4,24.2.
1H NMR(400MHz,DMSO)δ10.87(d,J＝1.6Hz,1H),8.22(t,J＝5.5Hz,1H),8.03(dd,J＝10.3,2.1Hz,2H),7.84-7.78(m,2H),7.58(d,J＝7.9Hz,1H),7.54-7.40(m,3H),7.30(d,J＝8.0Hz,1H),7.08(d,J＝2.3Hz,1H),7.06-6.98(m,1H),6.97-6.91(m,1H),4.13(t,J＝7.4Hz,1H),3.60(t,J＝7.4Hz,1H),3.23(dd,J＝14.4,4.6Hz,1H),3.06(dd,J＝14.4,4.5Hz,1H),3.01-2.82(m,2H),1.19-0.94(m,3H),0.80-0.65(m,1H).13C NMR(100MHz,DMSO)δ167.7,167.59,166.5,136.4,135.1,131.4,128.6(2C),128.2,127.5(2C),124.9,121.2,119.3,118.8,111.6,109.1,55.8,54.1,39.0,31.4,29.5,24.6.
1H NMR(400MHz,DMSO)δ10.87(s,1H),8.01(d,J＝18.9Hz,3H),7.80(d,J＝0.8Hz,1H),7.57(d,J＝7.7Hz,1H),7.29(d,J＝8.1Hz,1H),7.05(d,J＝8.2Hz,2H),7.01(t,J＝7.4Hz,1H),6.93(t,J＝7.4Hz,1H),6.60(dd,J＝3.3,1.7Hz,1H),4.12(t,J＝7.4Hz,1H),3.58(t,J＝7.4Hz,1H),3.21(dd,J＝14.4,4.6Hz,1H),3.09-2.97(dd,J＝14.4,4.6Hz,1H),2.94-2.75(m,2H),1.14-0.87(m,3H),0.76-0.57(m,1H).13C NMR(100MHz,DMSO)δ167.6,167.5,158.0,148.5,145.1,136.4,128.2,124.9,121.2,119.3,118.8,113.4,112.2,111.5,109.1,55.8,54.1,38.2,31.2,29.4,24.5.
1H NMR(400MHz,DMSO)δ10.87(d,J＝1.7Hz,1H),8.20(t,J＝5.5Hz,1H),8.02(dd,J＝8.7,2.1Hz,2H),7.57(d,J＝7.9Hz,1H),7.30(d,J＝8.0Hz,1H),7.10-6.88(m,5H),6.63(t,J＝2.3Hz,1H),4.12(t,J＝5.1Hz,1H),3.77(s,6H),3.59(t,J＝5.1Hz,1H),3.25(dd,J＝14.4,4.5Hz,1H),3.06(dd,J＝14.4,4.5Hz,1H),3.00-2.80(m,2H),1.21-0.95(m,3H),0.79-0.60(m,1H).13C NMR(100MHz,DMSO)δ167.7,167.5,166.0,160.7(2C),137.2,136.4,128.2,124.9,121.2,119.3,118.8,111.5,109.1,105.5(2C),103.3,55.8(2C),54.1,49.0,39.1,31.4，29.5，24.6.
1H NMR(400MHz,DMSO)δ11.01(d,J＝1.6Hz,1H),8.07(dd,J＝18.7,2.1Hz,2H),7.60-7.53(m,2H),7.49(t,J＝7.0Hz,1H),7.46-7.36(m,1H),7.24(d,J＝7.9Hz,1H),7.05(d,J＝2.3Hz,1H),6.99-6.85(m,2H),4.11(t,J＝5.1Hz,1H),3.62(s,2H),3.52(t,J＝5.1Hz,1H),3.25(dd,J＝14.4,4.1Hz,1H),3.03(dd,J＝14.4,4.6Hz,1H),2.16-2.00(m,1H),1.12-0.99(m,1H),0.91-0.71(m,2H),0.61-0.47(m,1H).13C NMR(100MHz,DMSO)δ167.5,167.4,137.2,136.3,133.8,132.2,131.5,128.8,128.3,127.5,125.1,121.0,119.4,118.7,111.4,109.0,55.8,54.3,49.5,48.5,31.9,29.4,24.3.
1H NMR(400MHz,DMSO)δ10.93(s,1H),8.21(d,J＝8.3Hz,2H),8.06(d,J＝9.2Hz,2H),7.66-7.51(m,3H),7.24(d,J＝8.0Hz,1H),7.04(d,J＝15.4Hz,1H),6.95(dt,J＝14.7,7.2Hz,2H),4.12(t,J＝7.4Hz,1H),3.76(s,2H),3.53(t,J＝7.4Hz,1H),3.29-3.16(dd,J＝14.4,4.3Hz,1H),3.02(dd,J＝14.4,4.3Hz,1H),2.16-2.00(m,2H),1.14-0.96(m,1H),0.91-0.71(m,2H),0.67-0.42(m,1H).13C NMR(100MHz,DMSO)δ167.5,167.4,147.0,136.3,129.7(2C),128.3,125.1,123.7(2C),121.1,119.4,118.7,111.4,109.0,55.8,54.2,51.7,49.0,48.1,31.7,29.3,23.8.
1H NMR(400MHz,DMSO)δ10.97(d,J＝1.6Hz,1H),8.08(dd,J＝37.7,2.1Hz,2H),7.58(d,J＝7.8Hz,1H),7.55-7.45(m,2H),7.25-7.31(m,3H),7.07(d,J＝2.2Hz,1H),7.03-6.88(m,2H),4.13(t,J＝4.9Hz,1H),4.00-3.87(s,2H),3.56(t,J＝4.9Hz,1H),3.24(dd,J＝14.4,4.2Hz,1H),3.05(dd,J＝14.4,4.6Hz,1H),2.40(t,J＝7.5Hz,2H),1.23-0.83(m,3H),0.65-0.47(m,1H).13C NMR(100MHz,DMSO)δ167.7,167.3,162.7(d,J＝244Hz),136.3,132.6,132.5,129.2,128.2,125.1,121.2,119.4,118.8,116.0,115.8,111.5,109.1,55.8,53.7,49.6,46.3,31.0,29.4,21.5.
1H NMR(400MHz,DMSO)δ10.97(d,J＝1.7Hz,1H),8.07(dd,J＝36.0,2.1Hz,2H),7.62-7.40(m,5H),7.25(d,J＝8.0Hz,1H),7.11-6.87(m,3H),4.11(t,J＝11.6Hz,1H),3.99-3.83(m,2H),3.56(t,J＝11.6Hz,1H),3.24(dd,J＝14.4,4.2Hz,1H),3.04(dd,J＝14.4,4.5Hz,1H),2.38(t,J＝7.3Hz,2H),1.18-0.85(m,3H),0.63-0.46(m,1H).13C NMR(100MHz,DMSO)δ167.7,167.3,136.3,133.8,132.4,132.0(2C),129.0(2C),128.2,125.1,121.2,119.4,118.8,111.5,109.1,55.8,53.7,49.7,46.5,31.0,29.3,21.5.
1H NMR(400MHz,DMSO)δ10.95(d,J＝1.7Hz,1H),8.12(d,J＝2.1Hz,1H),8.03(d,J＝2.2Hz,1H),7.68-7.62(m,2H),7.57(d,J＝7.8Hz,1H),7.39(d,J＝8.4Hz,2H),7.25(d,J＝8.0Hz,1H),7.06(d,J＝2.2Hz,1H),7.03-6.89(m,2H),4.13(d,J＝1.3Hz,1H),3.96-3.83(m,2H),3.56(s,1H),3.24(dd,J＝14.4,4.2Hz,1H),3.04(dd,J＝14.4,4.6Hz,1H),2.38(t,J＝7.3Hz,2H),1.19-0.86(m,3H),0.64-0.45(m,1H).13C NMR(100MHz,DMSO)δ167.7,167.3,136.3,132.8,132.3(2C),131.9(2C),128.2,125.1,122.5,121.2,119.4,118.8,111.5,109.1,55.8,53.7,49.8,46.5,31.0,29.3,21.5.
1H NMR(400MHz,DMSO)δ10.96(d,J＝1.6Hz,1H),8.12(d,J＝2.1Hz,1H),8.04(d,J＝2.1Hz,1H),7.81(d,J＝8.2Hz,2H),7.66(d,J＝8.1Hz,2H),7.58(d,J＝7.7Hz,1H),7.24(d,J＝7.9Hz,1H),7.07(d,J＝2.2Hz,1H),7.05-6.85(m,2H),4.13(t,J＝7.2Hz,1H),4.06-3.95(m,2H),3.56(t,J＝7.2Hz,1H),3.25(dd,J＝14.4,4.2Hz,1H),3.05(dd,J＝14.4,4.6Hz,1H),2.39(t,J＝7.2Hz,2H),1.22-0.89(m,3H),0.55(dt,J＝12.8,7.3Hz,1H).13C NMR(100MHz,DMSO)δ167.7,167.3,138.7,136.3(2C),130.7,129.4(q,J＝31Hz),128.2,125.8(q,J＝4Hz,2C),125.1,124.6(q,J＝271Hz),121.2,119.4,118.8,111.5,109.1,55.8,53.8,50.1,46.8,31.1,29.3,21.8.
1H NMR(400MHz,DMSO)δ10.95(d,J＝1.7Hz,1H),8.12(d,J＝2.1Hz,1H),8.03(d,J＝2.2Hz,1H),7.57(d,J＝7.8Hz,1H),7.36(d,J＝8.7Hz,2H),7.26(d,J＝8.0Hz,1H),7.10-6.89(m,5H),4.13(d,J＝1.4Hz,1H),3.92-3.81(m,2H),3.78(s,3H),3.56(t,J＝5.0Hz,1H),3.24(dd,J＝14.4,4.3Hz,1H),3.05(dd,J＝14.4,4.6Hz,1H),2.38(t,J＝7.5Hz,2H),1.20-0.84(m,3H),0.63-0.42(m,1H).13C NMR(100MHz,DMSO)δ167.7,167.3,160.1,136.3,131.7(2C),128.2,125.1,124.6,121.2,119.4,118.8,114.4(2C),111.5,109.1,55.8,55.6,53.7,49.9,46.1,31.0,29.4,21.5.
1H NMR(400MHz,DMSO)δ10.96(d,J＝1.6Hz,1H),8.12(d,J＝2.1Hz,1H),8.03(d,J＝2.1Hz,1H),7.57(d,J＝7.9Hz,1H),7.27(d,J＝8.0Hz,1H),7.11-6.87(m,6H),6.09(s,2H),4.13(d,J＝1.3Hz,1H),3.92-3.77(m,2H),3.55(d,J＝4.9Hz,1H),3.24(dd,J＝14.4,4.2Hz,1H),3.05(dd,J＝14.4,4.2Hz,1H),2.36(t,J＝7.5Hz,2H),1.20-0.86(m,3H),0.65-0.39(m,1H).13C NMR(100MHz,DMSO)δ167.7,167.3,148.0,147.8,136.3,128.2,126.5,125.1,124.2,121.2,119.4,118.8,111.5,110.4,109.1,108.7,101.7,55.8,53.7,49.0,46.1,31.0,29.4,21.4.
1H NMR(400MHz,DMSO)δ10.86(s,1H),9.35(s,1H),8.10–7.95(m,2H),7.90(s,2H),7.59(d,J＝7.9Hz,1H),7.34(d,J＝8.1Hz,1H),7.06(dd,J＝15.3,4.7Hz,2H),6.95(t,J＝7.4Hz,1H),4.13(s,1H),3.58(s,1H),3.25(dd,J＝14.4,4.5Hz,1H),3.14–2.97(m,3H),1.15–0.88(m,3H),0.65–0.55(m,1H).13C NMR(100MHz,DMSO)δ180.9,167.2,166.9,145.1(dm,J＝241Hz),141.5(dm,J＝252Hz),140.2(dm,J＝241Hz),136.7(dm,J＝244Hz),135.9,127.7,124.5,124.4–124.1(m),120.7,118.8,118.3,111.1,109.3(dm,J＝20Hz),108.6,55.4,53.6,43.6,31.0,29.0,23.2.
1H NMR(400MHz,DMSO)δ10.88(d,J＝1.7Hz,1H),8.91(s,1H),8.06-7.97(m,2H),7.75(s,1H),7.58(d,J＝7.9Hz,1H),7.40-7.27(m,2H),7.18-6.89(m,5H),4.12(t,J＝5.0Hz,1H),3.56(t,J＝5.0Hz,1H),3.24(dd,J＝14.4,4.6Hz,1H),3.16-3.04(m,3H),1.13-0.92(m,3H),0.70-0.51(m,1H).13C NMR(100MHz,DMSO)δ182.8,167.6,167.5,160.5(d,J＝4Hz),158.0(d,J＝5Hz),136.4,128.8(t,J＝10Hz),128.2,125.0,121.3,119.3,118.8,116.7(t,J＝8Hz),112.3,112.1,111.6,109.1,55.9,54.1,49.0,31.5,29.6,24.0.
1H NMR(400MHz,DMSO)δ10.79(d,J＝54.7Hz,1H),9.23(s,1H),8.01(d,J＝23.6Hz,2H),7.58(d,J＝7.9Hz,1H),7.32(d,J＝8.0Hz,1H),7.27-6.82(m,8H),4.11(d,J＝7.9Hz,1H),3.74(s,3H),3.57(t,J＝7.9Hz,1H),3.23(dd,J＝14.3,4.3Hz,1H),3.15-2.95(m,3H),1.16-0.84(m,3H),0.72-0.61(m,1H).13C NMR(100MHz,DMSO)δ180.9,167.6,167.5,156.9,136.4,132.1,128.2,126.2(2C),125.0,121.2,119.3,118.8,114.3(2C),111.6,109.1,55.9,55.6(2C),54.0,31.3,29.6,24.0.
1H NMR(400MHz,DMSO)δ11.05(s,1H),9.64(s,1H),8.50(t,J＝13.4Hz,1H),8.34-7.91(m,4H),7.58(d,J＝7.8Hz,1H),7.44-6.87(m,5H),4.21-4.14(m,1H),3.57(t,J＝5.7Hz,1H),3.26(dd,J＝13.7,3.0Hz,1H),3.12-2.90(m,3H),1.14-0.54(m,4H).
13C NMR(100MHz,DMSO)δ181.7,167.5,167.3,155.0,141.7,137.3,136.3,134.5,128.2,124.9,123.7,123.0,121.2,119.3,118.8,111.5,109.0,55.9,54.1,45.8,31.3,29.4,24.5.
1H NMR(400MHz,DMSO)δ10.87(d,J＝1.5Hz,1H),9.41(s,1H),8.09-7.95(m,2H),7.58(d,J＝7.9Hz,1H),7.46-7.28(m,4H),7.19-6.86(m,5H),4.12(d,J＝1.3Hz,1H),3.58(t,J＝5.7Hz,1H),3.24(dd,J＝14.4,4.5Hz,1H),3.12-3.01(m,3H),1.15-0.84(m,3H),0.7-0.54(m,1H).13C NMR(100MHz,DMSO)δ181.0,167.6,167.4,159.3(d,J＝240Hz),136.4,128.2,125.9(d,J＝5Hz,2C),125.0,121.2,119.4,118.8,115.7,115.5(d,J＝23Hz,2C),111.6,109.1,55.9,54.0,43.6,31.4,29.5,23.9.
1H NMR(400MHz,DMSO)δ10.91(d,J＝1.9Hz,1H),9.76(s,1H),8.03(dd,J＝28.4,1.8Hz,2H),7.80(t,J＝5.3Hz,1H),7.58(d,J＝7.9Hz,1H),7.49-7.41(m,4H),7.33(d,J＝8.1Hz,1H),7.07(d,J＝2.3Hz,1H),7.05-6.98(m,1H),6.98-6.89(m,1H),4.13(d,J＝1.5Hz,1H),3.57(t,J＝4.8Hz,2H),3.25(dd,J＝14.4,4.4Hz,1H),3.15-3.04(m,3H),1.12-0.87(m,3H),0.61(m,1H).13C NMR(100MHz,DMSO)δ180.7,167.7,167.4,139.5,136.4,131.6,128.6,128.2,125.0,124.5,121.3,119.3,119.0,118.8,116.0,111.6,109.1,55.9,54.1,43.6,31.4,29.5,23.8.
1H NMR(400MHz,DMSO)δ10.86(d,J＝1.7Hz,1H),9.34(s,1H),8.01(dd,J＝24.6,2.0Hz,2H),7.58(d,J＝7.9Hz,1H),7.39-7.19(m,4H),7.16-6.85(m,5H),4.11(d,J＝1.4Hz,1H),3.57(t,J＝4.8Hz,1H),3.24(dd,J＝14.4,4.5Hz,1H),3.10-3.01(m,3H),2.16(s,3H),1.18-0.80(m,3H),0.68-0.54(m,1H).13C NMR(100MHz,DMSO)δ180.6,167.6,167.4,136.9,136.4,133.9,129.5(2C),128.2,125.0,123.9(2C),121.2,119.3,118.8,111.6,109.1,55.9,54.0,43.6,31.4,29.5,24.0,20.9.
1H NMR(400MHz,DMSO)δ10.83(t,J＝22.4Hz,1H),9.01(s,1H),8.05-7.95(m,2H),7.57(d,J＝7.9Hz,1H),7.43-6.87(m,10H),4.10(d,J＝1.7Hz,1H),3.56(t,J＝4.8Hz,1H),3.23(dd,J＝14.4,4.6Hz,1H),3.10-3.01(m,3H),2.16(s,3H),1.11-0.88(m,3H),0.65-0.49(m,1H).13C NMR(100MHz,DMSO)δ181.3,167.6,167.5,137.5,136.4,130.9,128.5,128.2,126.8,126.7,125.0,124.5,121.2,119.3,118.8,111.6,109.1,55.9,54.0,31.4,29.6,24.2,21.2,18.1.
1H NMR(400MHz,DMSO)δ10.87(d,J＝1.5Hz,1H),9.41(s,1H),8.09-7.95(m,2H),7.58(d,J＝7.9Hz,1H),7.46-7.28(m,4H),7.19-6.86(m,5H),4.12(d,J＝1.3Hz,1H),3.58(t,J＝5.7Hz,1H),3.24(dd,J＝14.4,4.5Hz,1H),3.12-3.01(m,3H),1.15-0.84(m,3H),0.7-0.54(m,1H).13C NMR(100MHz,DMSO)δ181.0,167.6,167.4,152.0(d,J＝239Hz),136.4,128.8(d,J＝10Hz),128.2,125.0,124.7(d,J＝4Hz),121.7(d,J＝8Hz),121.2,120.6,119.4,118.8,115.1(d,J＝9Hz),111.6,109.1,55.9,54.0,43.6,31.4,29.5,23.9.
1H NMR(400MHz,DMSO)δ10.92(d,J＝1.8Hz,1H),9.81(s,1H),8.10-7.97(m,2H),7.84(t,J＝5.0Hz,1H),7.63-7.45(m,3H),7.36-7.29(m,3H),7.11-6.86(m,3H),4.12(d,J＝1.4Hz,1H),3.58(t,J＝5.7Hz,1H),3.25(dd,J＝14.4,4.4Hz,1H),3.16-2.96(m,3H),1.11-0.82(m,3H),0.65-0.53(m,1H).13C NMR(101MHz,DMSO)δ180.8,167.7,167.4,139.1,136.4,128.6,128.3,127.9,125.0,124.7,121.2,119.3,119.0,118.8,116.0,111.62,109.0,55.9,54.1,43.5,31.4,29.5,23.8.
1H NMR(400MHz,DMSO)δ10.87(d,J＝1.6Hz,1H),9.08(s,1H),8.10-7.97(m,2H),7.59(d,J＝7.9Hz,3H),7.41-7.21(m,2H),7.12-6.88(m,4H),4.13(d,J＝1.5Hz,1H),3.57(t,J＝4.8Hz,1H),3.25(dd,J＝14.4,4.5Hz,1H),3.16-2.96(m,3H),1.11-0.82(m,3H),0.71-0.53(m,1H).13C NMR(100MHz,DMSO)δ182.0,167.6,167.5,159.3(dd,J＝233,11Hz),156.7(dd,J＝222,10Hz),136.4,130.0(dd,J＝10,3Hz),128.2,125.0,123.9(t,J＝20Hz),121.3,119.4,118.8,111.6,111.4(dd,J＝19,3Hz),109.1,104.6(t,J＝239,11Hz),55.92,54.1,44.0,31.4,29.5,23.9.
1H NMR(400MHz,DMSO)δ10.88(d,J＝1.6Hz,1H),9.46(s,1H),8.08–7.95(m,2H),7.58(d,J＝7.9Hz,1H),7.49–7.26(m,5H),7.14–6.88(m,4H),4.12(d,J＝1.3Hz,1H),3.58(d,J＝7.9Hz,1H),3.25(dd,J＝14.4,4.5Hz,1H),3.16–2.98(m,3H),1.13–0.85(m,3H),0.72–0.53(m,1H).13C NMR(100MHz,DMSO)δ180.73,167.70,167.49,158.8,139.54,136.41,131.60,128.60,128.24,125.04,124.50,121.30,119.38,119.01,118.86,116.05,111.63,109.11,55.93,54.10,43.61,31.46,29.55,23.86.
1H NMR(400MHz,DMSO)δ10.91(d,J＝1.8Hz,1H),8.40-8.32(m,2H),8.13(d,J＝2.3Hz,1H),7.99(d,J＝2.4Hz,1H),7.76(d,J＝1.7Hz,1H),7.59(d,J＝7.6Hz,2H),7.33(d,J＝8.1Hz,1H),7.11-6.91(m,4H),4.14(d,J＝2.3Hz,1H),3.54(t,J＝3.9Hz,1H),3.27(dd,J＝14.4,4.2Hz,1H),3.04(dd,J＝14.4,4.2Hz,1H),2.78-2.53(m,2H),1.08-1.00(m,1H),0.51-0.42(m,1H).13C NMR(100MHz,DMSO)δ167.7,167.4,154.9,140.9,136.4,128.2,126.6(q,J＝4Hz),125.1(q,J＝4Hz),125.0,125.2(q,J＝270Hz),122.6(q,J＝32Hz),121.3,121.2,120.4,119.4,118.9,111.6,109.0,56.0,52.0,35.1,34.9,29.7.
1H NMR(400MHz,DMSO)δ10.91(d,J＝1.9Hz,1H),8.35(s,1H),8.11(d,J＝2.4Hz,1H),7.97(d,J＝2.5Hz,1H),7.59(d,J＝7.9Hz,1H),7.34(d,J＝8.0Hz,1H),7.10-6.92(m,5H),6.52(s,1H),5.89(t,J＝6.0Hz,1H),4.15-4.10(m,1H),3.50-3.43(m,1H),3.28(dd,J＝14.4,4.1Hz,1H),3.04(dd,J＝14.4,4.6Hz,1H),2.68-2.45(m,2H),2.18(s,6H),1.14-1.04(m,1H),0.26-0.18(m,1H).13C NMR(100MHz,DMSO)δ167.6,167.5,156.0,140.6,137.9(2C),136.4,128.2,125.1,123.2,121.4,119.4,118.9,116.1(2C),111.6,109.0,56.0,51.9,35.4,34.8,29.8,21.6(2C).
1H NMR(400MHz,DMSO)δ10.89(t,J＝7.8Hz,1H),8.87(s,1H),8.12(d,J＝2.3Hz,1H),7.94(d,J＝2.5Hz,1H),7.78(d,J＝2.5Hz,1H),7.58(d,J＝7.9Hz,1H),7.48-7.40(m,1H),7.33(d,J＝7.2Hz,1H),7.20(dd,J＝8.8,2.5Hz,1H),7.09-6.91(m,3H),6.04(t,J＝6.0Hz,1H),4.12(d,J＝2.5Hz,1H),3.53-3.43(m,1H),3.26(dd,J＝14.4,4.2Hz,1H),3.03(dd,J＝14.4,4.6Hz,1H),2.67-2.52(m,2H),1.14-0.97(m,1H),0.38-0.22(m,1H).13C NMR(100MHz,DMSO)δ167.6,167.5,155.4,141.1,136.4,131.3,130.8,128.2,125.0,122.6,121.3,119.4,119.2,118.8,118.2,111.6,109.0,55.9,51.9,35.0(2C),29.7.
1H NMR(400MHz,DMSO)δ10.91(d,J＝1.9Hz,1H),9.08(s,1H),8.14(d,J＝2.3Hz,1H),7.97(d,J＝2.5Hz,1H),7.69-7.49(m,5H),7.33(d,J＝8.0Hz,1H),7.14-6.93(m,3H),6.12(t,J＝5.9Hz,1H),4.13(dd,J＝6.4,4.0Hz,1H),3.53-3.47(m,1H),3.28(dd,J＝14.4,4.1Hz,1H),3.04(dd,J＝14.4,4.6Hz,1H),2.66-2.53(m,2H),1.13-0.98(m,1H),0.37-0.21(m,1H).13C NMR(100MHz,DMSO)δ167.6,167.4,155.1,145.3,136.3,133.5(2C),128.1,125.0,121.3,119.9,119.4,118.9,117.9(2C),111.6,109.0,102.8,56.0,51.9,35.0,34.9,29.7.
1H NMR(400MHz,DMSO)δ10.90(d,J＝1.8Hz,1H),8.44(dd,J＝8.2,1.6Hz,1H),8.20-8.06(m,2H),7.97-7.95(m,2H),7.58(d,J＝7.9Hz,1H),7.35-7.28(m,2H),7.10-6.84(m,4H),4.19-4.08(m,1H),3.60-3.47(m,1H),3.27(dd,J＝14.4,4.2Hz,1H),3.04(dd,J＝14.4,4.7Hz,1H),2.75-2.52(m,2H),1.13-0.98(m,1H),0.50-0.35(m,1H).13C NMR(100MHz,DMSO)δ167.6,167.4,155.2,142.0,138.9,136.6,134.2,128.7,128.1,125.0,123.8,121.3,119.4,118.8,111.6,109.0,55.9,51.9,35.0,35.0,29.6.
1H NMR(400MHz,DMSO)δ10.92(d,J＝1.8Hz,1H),8.14(t,J＝4.6Hz,1H),8.00(d,J＝2.4Hz,1H),7.91-7.82(m,1H),7.60(d,J＝7.2Hz,3H),7.39-7.29(m,2H),7.23-7.17(m,1H),7.09-6.90(m,3H),6.54(t,J＝5.7Hz,1H),4.20-4.07(m,1H),3.51(d,J＝5.7Hz,1H),3.28(dd,J＝14.4,4.1Hz,1H),3.05(dd,J＝14.4,4.6Hz,1H),2.73-2.55(m,2H),1.17-1.00(m,1H),0.50-0.35(m,1H).13C NMR(100MHz,DMSO)δ167.6,167.3,160.3,154.3,136.4,136.3,131.8,128.1,126.2,125.1,123.1,123.0,121.7,121.3,119.4,118.9,111.6,109.0,56.0,51.9,35.4,34.7,29.7.
1H NMR(400MHz,DMSO)δ10.96(d,J＝1.8Hz,1H),8.97(d,J＝6.5Hz,1H),8.15(d,J＝2.3Hz,1H),7.98(d,J＝2.5Hz,1H),7.58(d,J＝7.9Hz,1H),7.33(d,J＝8.0Hz,1H),7.11-6.87(m,4H),6.67(t,J＝5.9Hz,1H),4.12(d,J＝2.4Hz,1H),3.49(t,J＝3.1Hz,1H),3.26(dd,J＝14.4,4.0Hz,1H),3.05(dd,J＝14.4,4.6Hz,1H),2.70-2.54(m,2H),1.13-0.98(m,1H),0.50-0.35(m,1H).13C NMR(100MHz,DMSO)δ167.6,167.3,160.8,154.0,147.9,136.3,128.1,125.0,121.3,119.4,118.8,111.6,109.0,56.0,51.9,35.5,34.7,29.6.
1H NMR(400MHz,DMSO)δ10.91(d,J＝1.5Hz,1H),8.92(s,1H),8.13(d,J＝2.1Hz,1H),7.97(d,J＝2.3Hz,1H),7.91(s,1H),7.60(d,J＝7.9Hz,1H),7.51-7.32(m,3H),7.20(d,J＝7.5Hz,1H),7.10-6.93(m,3H),6.04(t,J＝5.9Hz,1H),4.13(d,J＝2.4Hz,1H),3.55-3.46(m,1H),3.28(dd,J＝14.4,4.1Hz,1H),3.05(dd,J＝14.4,4.5Hz,1H),2.70-2.52(m,2H),1.18-1.01(m,1H),0.39-0.24(m,1H).13C NMR(100MHz,DMSO)δ167.6,167.5,155.6,141.7,136.3,130.1,129.8(q,J＝29Hz),128.2,125.1,124.7(q,J＝271Hz),121.6,121.3,119.4,118.9,117.7(q,J＝4Hz),114.1(q,J＝4Hz),111.6,109.0,56.0,51.9,35.1,35.2,29.7.
1H NMR(400MHz,DMSO)δ10.92(s,1H),8.33(s,1H),8.10(d,J＝2.1Hz,1H),7.97(d,J＝2.3Hz,1H),7.59(d,J＝7.8Hz,1H),7.34(dd,J＝8.4,5.2Hz,1H),7.23(d,J＝8.9Hz,2H),7.10-6.74(m,5H),5.83(t,J＝6.0Hz,1H),4.11(d,J＝2.4Hz,1H),3.68(s,4H),3.49-3.41(m,1H),3.27(dd,J＝14.3,4.1Hz,1H),3.03(dd,J＝14.4,4.5Hz,1H),2.69-2.43(m,3H),1.09(td,J＝13.7,6.5Hz,1H),0.19(qd,J＝9.8,4.9Hz,1H).13C NMR(100MHz,DMSO)δ167.6,156.2,154.4,136.3,133.9,128.2,125.0,121.3,120.3,120.1,119.4,118.9,114.4,114.3,111.6,109.0,56.0,55.6,55.6,51.9,35.4,34.9,29.8.
1H NMR(400MHz,DMSO)δ10.91(s,1H),9.50(s,1H),8.15(s,1H),8.09(s,1H),7.94(dd,J＝14.7,5.2Hz,2H),7.67(d,J＝8.7Hz,1H),7.59(d,J＝7.9Hz,1H),7.32(t,J＝7.0Hz,1H),7.13-6.99(m,2H),6.95(t,J＝7.4Hz,1H),6.28(t,J＝5.8Hz,1H),4.14(d,J＝1.9Hz,1H),3.51(s,1H),3.28(dd,J＝14.4,4.0Hz,1H),3.04(dd,J＝14.4,4.5Hz,1H),2.70-2.52(m,2H),1.10-1.02(m,1H),0.39-0.33(m,1H).13C NMR(100MHz,DMSO)δ167.7,167.5,154.9,145.7,136.6,136.3,132.1(q,J＝30Hz),129.6,128.2,125.1,123.0(q,J＝272Hz),121.3,120.6,119.4,118.9,116.6,115.2(q,J＝6Hz),111.6,109.0,99.3,56.0,51.9,35.2,34.8,29.7.
1H NMR(400MHz,DMSO)δ10.90(s,1H),8.73(s,1H),8.14(s,1H),8.00(d,J＝15.0Hz,2H),7.59(d,J＝7.8Hz,1H),7.33(d,J＝8.0Hz,1H),7.14-6.90(m,3H),6.47(t,J＝5.5Hz,1H),4.13(s,1H),3.50(s,1H),3.27(dd,J＝14.3,3.8Hz,1H),3.04(dd,J＝14.2,4.2Hz,1H),2.69-2.54(m,2H),1.02-0.98(m,1H),0.43-0.38(m,1H).13C NMR(101MHz,DMSO)δ167.67,167.36,166.5(d,J＝214Hz),155.02,136.37,128.18,127.0(d,J＝206Hz),125.5(d,J＝106Hz),125.06,121.34,120.3(d,J＝206Hz),119.43,118.87,111.60,110.3(d,J＝288Hz),109.04,102.1(d,J＝25Hz),56.01,51.95,35.07,34.96,29.69.
1H NMR(400MHz,DMSO)δ10.91(s,1H),8.98(s,1H),8.13(d,J＝1.8Hz,1H),7.97(d,J＝2.0Hz,1H),7.62-7.53(m,5H),7.34(d,J＝8.1Hz,1H),7.10-6.91(m,3H),6.07(t,J＝5.9Hz,1H),4.13(d,J＝2.3Hz,1H),3.49(s,1H),3.28(dd,J＝14.3,4.0Hz,1H),3.04(dd,J＝14.4,4.5Hz,1H),2.69-2.53(m,2H),1.10-1.02(m,1H),0.35-0.33(m,1H).13C NMR(100MHz,DMSO)δ167.6,167.4,155.4,144.5,136.3,128.2,126.3(q,J＝3Hz，2C),125.1,125.0(q,J＝267Hz)，121.5(q,J＝31Hz)，121.3,119.4,118.8,117.7(2C),111.6,109.0,56.0,51.9,35.1,35.0,29.7.
1H NMR(400MHz,DMSO)δ10.91(s,1H),8.53(s,1H),8.42(d,J＝8.8Hz,1H),8.08(d,J＝20.8Hz,2H),7.77(s,1H),7.57(dd,J＝20.1,8.4Hz,2H),7.34(d,J＝8.1Hz,1H),7.24(t,J＝5.9Hz,1H),7.13(d,J＝1.8Hz,1H),7.05(t,J＝7.4Hz,1H),6.95(t,J＝7.4Hz,1H),4.15(s,1H),3.77(s,1H),3.29-3.08(m,2H),2.92-2.78(m,1H),2.67-2.55(m,1H).13C NMR(100MHz,DMSO)δ167.7,166.4,154.7,140.9,136.4,128.0,126.5(q,J＝4Hz),125.1(q,J＝3Hz),124.7,124.1(q,J＝270Hz),122.5(q,J＝33Hz),121.3,121.1,120.3,119.1,118.9,111.7,109.2,55.7,54.8,42.9,29.9.
1H NMR(400MHz,DMSO)δ10.91(s,1H),8.48(s,1H),8.07(d,J＝25.8Hz,2H),7.56(d,J＝7.8Hz,1H),7.34(d,J＝8.1Hz,1H),7.14-6.93(m,6H),6.52(s,1H),6.00(s,1H),4.14(s,1H),3.69(s,1H),3.29-3.08(m,2H),2.75-2.54(m,2H),2.18(s,6H).13C NMR(100MHz,DMSO)δ167.7,166.9,155.3,140.6,137.9(2C),136.3,128.0,124.8,123.2,121.3,119.2,118.9,115.9(2C),111.7,109.2,55.6,54.9,42.7,29.6,21.6(2C).
1H NMR(400MHz,DMSO)δ10.91(s,1H),8.12(s,2H),8.01(d,J＝1.5Hz,1H),7.58(d,J＝7.9Hz,1H),7.34(d,J＝8.1Hz,1H),7.23(dd,J＝11.4,5.2Hz,1H),7.12-7.04(m,4H),6.97(t,J＝7.4Hz,1H),6.25(t,J＝5.9Hz,1H),4.15(s,1H),3.69(t,J＝5.7Hz,1H),3.29-3.08(m,2H),2.92-2.78(m,1H),2.66-2.52(m,1H).13C NMR(100MHz,DMSO)δ167.7,167.0,159.5(d,J＝5Hz),156.9(d,J＝5Hz),155.1,136.3,128.0,126.7(t,J＝10Hz),124.8,121.3,119.2,118.8,116.4(t,J＝8Hz),112.1,111.9,111.7,109.1,55.5,54.9,43.0,29.4.
1H NMR(400MHz,DMSO)δ10.92(s,1H),9.23(s,1H),8.18(d,J＝1.4Hz,1H),8.06(d,J＝1.7Hz,1H),7.71-7.49(m,5H),7.33(d,J＝8.0Hz,1H),7.10(d,J＝2.1Hz,1H),7.05(t,J＝7.2Hz,1H),6.95(d,J＝7.5Hz,1H),6.24-6.15(m,1H),4.16(s,1H),3.70(t,J＝5.6Hz,1H),3.21(dd,J＝14.5,4.4Hz,1H),3.11(dd,J＝14.5,4.4Hz,1H),2.72-2.64(m,1H),2.54-2.41(m,1H).13C NMR(100MHz,DMSO)δ167.6,166.8,154.6,145.2,136.3,133.6(2C),128.0,124.8,121.4,119.9,119.2,118.9,117.8(2C),111.7,109.1,102.9,55.6,54.4,42.7,29.6.
1H NMR(400MHz,DMSO)δ10.91(s,1H),8.49(d,J＝7.7Hz,1H),8.35(s,1H),8.06(d,J＝22.1Hz,2H),7.96(dd,J＝4.5,1.5Hz,1H),7.55(d,J＝7.9Hz,1H),7.39-7.27(m,2H),7.12(s,2H),7.05(t,J＝7.5Hz,1H),6.95(t,J＝7.4Hz,1H),4.15(s,1H),3.76(s,1H),3.24-3.09(m,2H),2.88-2.74(m,1H),2.70-2.54(m,1H).13C NMR(100MHz,DMSO)δ167.7,166.4,155.0,141.9,138.8,136.3,134.3,128.5,128.0,124.7,123.8,121.4,119.1,118.9,111.7,109.2,55.7,54.8,42.9,29.9.
1H NMR(400MHz,DMSO)δ10.92(s,1H),8.22-8.05(m,2H),7.86(d,J＝7.8Hz,1H),7.70-7.49(m,2H),7.42-6.88(m,7H),6.70(s,1H),4.21-4.09(m,1H),3.85-3.73(m,1H),3.25-3.10(m,2H),3.07-2.55(m,2H).13C NMR(100MHz,DMSO)δ167.6,167.3,160.3,154.3,136.4,136.3,131.8,128.1,126.2,125.1,123.1,123.0,121.7,121.3,119.4,118.9,111.6,109.0,55.6,54.4,42.7,29.6.
1H NMR(400MHz,DMSO)δ10.92(s,1H),9.64(s,1H),8.21(s,1H),8.12(d,J＝1.6Hz,1H),8.07(s,1H),7.95(d,J＝8.6Hz,1H),7.63(dt,J＝10.3,5.1Hz,1H),7.56(d,J＝7.9Hz,1H),7.32(d,J＝8.1Hz,1H),7.14-6.86(m,3H),6.34-6.16(m,1H),4.14(t,J＝5.4Hz,1H),3.72(t,J＝5.4Hz,1H),3.28-3.05(m,2H),2.77-2.61(m,1H),2.51-2.39(m,1H).13C NMR(100MHz,DMSO)δ167.6,166.8,154.4,145.7,136.7,136.3,132.2(q,J＝32Hz),128.0,124.8,123.0(q,J＝271Hz),121.3,120.5,119.2,118.9,116.6,115.9(q,J＝5Hz),111.6,109.0,99.3,55.7,54.2,42.8,29.6.
1H NMR(400MHz,DMSO)δ10.92(s,1H),9.03(d,J＝23.5Hz,1H),8.17(d,J＝1.4Hz,1H),8.07(d,J＝1.7Hz,1H),7.94(s,1H),7.57(d,J＝7.9Hz,1H),7.50-7.39(m,2H),7.34(d,J＝8.0Hz,1H),7.21(d,J＝6.7Hz,1H),7.11(d,J＝2.1Hz,1H),7.05(t,J＝7.5Hz,1H),6.96(t,J＝7.4Hz,1H),6.09(t,J＝5.9Hz,1H),4.16(t,J＝5.4Hz,1H),3.72(t,J＝5.4Hz,1H),3.28-3.05(m,2H),2.77-2.61(m,1H),2.51-2.39(m,1H).13C NMR(100MHz,DMSO)δ167.6,166.9,155.1,129.9(q,J＝31Hz),141.7,136.3,130.1,128.0,124.8,124.7(q,J＝271Hz),121.5,121.3,119.2,118.9,117.7(q,J＝4Hz),113.93(q,J＝4Hz),111.7,109.1,55.6,54.6,42.8,29.6.
1H NMR(400MHz,DMSO)δ10.92(s,1H),8.48(s,1H),8.07(d,J＝30.1Hz,2H),7.57(d,J＝7.9Hz,1H),7.34(d,J＝8.1Hz,1H),7.25(d,J＝8.9Hz,2H),7.11(s,1H),7.05(t,J＝7.5Hz,1H),6.96(t,J＝7.4Hz,1H),6.80(d,J＝9.0Hz,2H),5.92(s,1H),4.14(s,1H),3.68(s,4H),3.28-3.05(m,2H),2.73-2.54(m,2H).13C NMR(100MHz,DMSO)δ167.7,166.9,155.5,154.4,136.3,133.9,128.0,124.8,121.3,119.8(2C),119.2,118.9,114.3(2C),111.7,109.1,55.6,55.8,54.9,42.8,29.6.
1H NMR(400MHz,DMSO)δ10.91(s,1H),8.90(s,1H),8.19-8.04(m,3H),7.55(d,J＝7.7Hz,1H),7.34(d,J＝8.0Hz,1H),7.11(d,J＝7.4Hz,1H),7.05(t,J＝7.5Hz,1H),6.95(t,J＝7.4Hz,1H),6.65(d,J＝5.8Hz,1H),4.15(s,1H),3.72(s,1H),3.29-3.08(m,2H),2.75-2.54(m,2H).13C NMR(100MHz,DMSO)δ167.7,166.6,166.4(d,J＝214Hz),154.6,136.3,128.0,126.9(d,J＝206Hz),125.4(d,J＝106Hz),124.7,121.3,120.2(d,J＝206Hz),119.1,118.8,111.7,110.3(d,J＝288Hz),109.1,102.1(d,J＝25Hz),55.7,54.5,42.7,29.7.
1H NMR(400MHz,DMSO)δ10.92(s,1H),9.11(s,1H),8.17(s,1H),8.07(s,1H),7.57(d,J＝7.9Hz,5H),7.34(d,J＝8.1Hz,1H),7.13-6.87(m,3H),6.13(t,J＝5.8Hz,1H),4.16(t,J＝5.8Hz,1H),3.70(t,J＝5.8Hz,1H),3.27-2.96(m,2H),2.72-2.47(m,2H).13C NMR(100MHz,DMSO)δ167.6,166.9,154.9,144.5,136.3,128.0,126.4,126.3,125.0(q,J＝267Hz),124.8,121.5(q,J＝31Hz),121.3,119.2,118.9,117.6(2C),111.7,109.1,55.6,54.5,42.7,29.6.
Example 8: nematicidal activity of the compounds of the invention.
The southern root-knot nematode (Meloidogyne incognita) selected by the invention is cultivated by the Huzhou modern agriculture center of the Chinese academy of sciences for a long time. The nematicidal activity of the compounds of the invention was determined by assay in a test tube.
The specific test operation process comprises the following steps: southern root-knot nematode (Meloidogyne incognita) is used as a test target, cucumber seedlings are used as test hosts, and a test tube planting method is adopted. And (4) preparing the sample to be tested according to the required concentration, and preparing sufficient root-knot nematode second-instar larvae. After planting cucumber seedlings of one week old in test tubes, adding a proper amount of prepared liquid medicine into the test tubes, and inoculating about 2000 larvae into each test tube. The test tube is placed at 20-25 ℃ and cultivated under 10h of light, and the result is investigated after 20 d. Counting the root knots on the root system of each plant, and grading and counting the inhibition rate according to the root knot number. Distilled water is used as a blank control, distilled water and meloidogyne incognita are used as negative controls, and fenamiphos and abamectin solution are used as positive controls (respectively used as positive controls).
Inhibition (%) - (control score-treatment score)/control score × 100%
The results show that: the compound has good inhibition effect on root-knot nematodes.
The inhibitory activity of some of the compounds tested at various concentrations on nematodes is shown in table 1:
nematicidal Activity of the Compounds of Table 1
Compound (I) Nematode inhibition (%) Compound (I) Nematode inhibition (%) Compound (I) Nematode inhibition (%)
10a-1 18.0a 14a-3 80.1c 11a-11 68.9c
10a-2 51.1a 14a-4 83.6c 11a-12 76.4c
10a-3 48.4a 14a-5 65.4c 11a-13 86.7
10a-4 51.1a 14a-6 78.2c 10b-1 43.2c
10a-5 29.9a 14a-7 100.0c 10b-2 57.7c
10a-6 73.1b 14a-8 84.1c 10b-3 68.2c
10a-7 89.3b 14a-9 89.0c 10b-4 65.7c
10a-8 84.9b 14a-10 68.6c 10b-5 46.5c
10a-9 72.2b 14a-11 81.8c 10b-6 43.7c
10a-10 28.2b 15a-1 97.7c 10b-7 79.5c
10a-11 58.3b 15a-2 84.7c 10b-8 69.7c
10a-12 60.8b 15a-3 100.0c 10b-9 81.8c
10a-13 65.1b 15a-4 82.6c 10b-10 72.3c
10a-14 55.8b 15a-5 89.4c 10b-11 70.3c
10a-15 39.2b 15a-6 74.6c 10b-12 68.8c
10a-16 44.4b 15a-7 90.9c 10c-1 57.9c
10a-17 72.5b 15a-8 84.8c 10c-2 58.0c
10a-18 49.2b 15a-9 86.4c 10c-3 61.6c
10a-19 77.9b 11a-1 90.9c 10c-4 60.7c
10a-20 24.9b 11a-2 64.5c 10c-5 65.1c
10a-21 75.8b 11a-3 81.8c 10c-6 65.1c
10a-22 67.2b 11a-4 75.0c 10c-7 61.7c
10a-23 50.6b 11a-5 73.9c 10c-8 67.3c
10a-24 49.2b 11a-6 62.9c 10c-9 53.7c
10a-25 82.2b 11a-7 65.1c 10c-10 47.3c
10a-26 76.1b 11a-8 44.9c 10c-11 56.9c
14a-1 61.7c 11a-9 70.5c 14b-1 80.1c
14a-2 67.0c 11a-10 45.8c 15b-1 77.6c
a: inhibition at 40 ppm; b: inhibition at 10 ppm; c: inhibition at 25ppm
Example 9: the compound of the invention is tested by re-screening for nematicidal activity.
A part of the compounds with high primary screening activity were selected for re-screening test as in example 8, and the results of re-screening test for nematode inhibitory activity of the part of the test compounds at different concentrations are shown in Table 2.
Table 2 Compound Re-screening test for nematode inhibition
Note: "-" indicates a low inhibition ratio
The results show that: the compound has a good inhibition effect on root-knot nematodes, a part of the compound can achieve 100% inhibition rate at a low concentration, especially the compound 15a-3 still has 100% inhibition effect at a concentration of 20ppm, the inhibition rate can still achieve 75% at a concentration of 1ppm, and the compound shows excellent nematode inhibition effect.
Example 10: the compounds of the invention were tested for their pesticidal activity.
The armyworm (pseudoaltia separatate Walker) selected by the invention belongs to lepidoptera, has tiny and soft body and is a common chewing crop pest, and is used as a test object to test and determine the insecticidal activity of a tested compound by adopting an immersion method.
The specific test operation process comprises the following steps: accurately weighing various samples, respectively adding 2ml of dimethyl sulfoxide (DMSO) and 18ml of clear water, adding 3 drops of emulsifier triton to prepare a liquid medicine, and adding 2ml of DMSO and 18ml of clear water to prepare a blank, and adding 3 drops of emulsifier triton to prepare the liquid medicine. Soaking young corn seedlings of 2-3 leaf stage in the prepared liquid medicine, taking out and drying after the leaves are completely soaked, and cutting off the leaves (the length is 5cm) for later use. 10 armyworms of 2 years old are inoculated into the insect breeding tube (after weighing the weight of the insect body), the soaked leaves are placed into the insect breeding tube, and the mouth is covered by gauze (three groups are repeated for each compound). And (3) checking the weight change of the test insects after 96 hours, keeping the temperature at 22-27 ℃ and the humidity at 70-80% in the experimental process, and weighing the weight of each insect-raising tube insect body after 96 hours.
The growth inhibition ratio (%) - (96-hour control worm weight-control worm weight) - (96-hour administration worm weight-pre-administration worm weight) ]/(96-hour control worm weight-control worm weight) × 100%.
The results show that: the compound of the invention has obvious inhibition effect on the growth of armyworm, and observation shows that the armyworm body of an administration group is obviously leaner than that of a control group, and the food intake is also obviously smaller than that of the control group. And the growth and development of the armyworm in the administration group are obviously lagged behind those in the control group.
The results of the growth inhibitory activity of some of the tested compounds against armyworm at 500ppm are shown in Table 3.
Table 3 armyworm growth inhibition test for Compounds
Compound (I) Armyworm growth inhibition (%) Compound (I) Armyworm growth inhibition (%) Compound (I) Armyworm growth inhibition (%)
10a-2 91.5 14a-7 95 11a-12 93.9
10a-4 88.5 14a-8 70.2 10b-1 96.6
10a-7 67.8 14a-9 65.4 10b-2 96.9
10a-8 69.4 14a-10 84.3 10b-3 97.9
10a-9 60.9 14a-11 85.7 10b-4 90.5
10a-10 56 15a-1 69.6 10b-5 91.9
10a-11 59.9 15a-2 86.9 10b-6 93.2
10a-12 80.5 15a-3 74.7 10b-7 75.8
10a-14 9.1 15a-4 74.4 10b-8 93.8
10a-15 24 15a-5 86.6 10b-9 97.7
10a-16 67.5 15a-6 64.4 10b-10 96.9
10a-17 89.5 15a-7 88.4 10b-11 95
10a-18 89.7 15a-8 86.2 10b-12 96.5
10a-20 95.5 15a-9 71.4 10c-1 86.6
10a-22 89.9 11a-1 92.5 10c-2 94.1
10a-23 92.9 11a-2 95 10c-3 94.8
10a-24 89.8 11a-3 84.8 10c-4 85.5
10a-25 90 11a-4 93.4 10c-5 99.3
10a-26 92.1 11a-6 88.9 10c-6 91.9
14a-1 89.1 11a-7 88 10c-7 92.4
14a-2 90.7 11a-8 88.7 10c-8 92.1
14a-3 85.1 11a-9 85.6 10c-9 92
14a-4 95.9 11a-10 83.8 10c-10 95.2
14a-5 72.7 11a-11 99.6 10c-11 87.8
14a-6 86.8
Example 11: human 5-HT2a receptor activity assay for compounds of the invention.
The screening method comprises the following steps: luciferase reporter gene detection method
1. Test materials and reagents
Transfection of plasmids: 5-HT2a (from University of Missouri-Rolla Resource Center, Missouri), pCRE-luc (available from Shanghai Industrial Biotechnology, Inc.), pRL-SV40 (available from Beijing Bian orange blue Biotech, Inc.);
cell culture medium: DMEM, 10% FBS; host cell: CHO-K1 cells, (Chinese hamster ovary cells, purchased from Shanghai Med. cell); target: the 5-HT2a receptor;
test compounds: compounds prepared in the examples of the present invention;
positive control: natural ligand-Serotonin (Serotonin, 5-HT, available from Bailingwei science, Ltd.)
2. Test method
When 5-HT2a, pCRE-luc and pRL-SV40 plasmids are co-transfected into CHO-K1 cells and Gq-coupled 5-HT2a is activated, calcium channels can be opened, transcription factor CREB is activated through calcium flow and is combined with CRE to cause the expression of luciferase reporter gene.
If the compound to be detected can excite the receptor, the compound to be detected can activate the expression of the luciferase after being co-cultured with the cells, otherwise, the expression of the luciferase is inhibited, the luciferase substrate is added to emit fluorescence, and the excitation level of the compound to the receptor can be judged by detecting the fluorescence intensity.
The agonistic activity of the test compound is equal to the fluorescence intensity of the test compound/the fluorescence intensity of the DMSO group, wherein the agonistic activity of the DMSO group is represented as 1.
The pRL-SV40 plasmid contains an SV40 replication origin, so that the downstream renilla luciferase can be expressed and used as an internal reference in a detection experiment, and factors of experiment change are reduced, so that the test is not interfered by the change of experiment conditions.
The results show that: the compounds of the present invention have agonist activity against 5-HT2 a. The results of some of the tests are shown in table 4. 5-HT as agonist control; DMSO is blank control. Among them, 10a-10 in particular, showed significant agonistic activity, EC, in human 5-HT2a50The value was 51.6 nM.
TABLE 4 Activity assay of human 5-HT2a receptor (5-HT2aR)
Note: the agonistic activity of the compounds of the invention was determined at 50 μ M; the agonistic activity of 5-HT was determined at 1. mu.M.
Example 12: oily suspensions
Preparing the following components in proportion: 25% by weight of any of the compounds prepared in the examples of the present invention; 5% polyoxyethylene sorbitol hexaoleate; 70% of higher aliphatic hydrocarbon oil. The components were ground together in a sand mill until the solid particles fell below about 5 microns. The resulting viscous suspension can be used as such, but it can also be emulsified in water.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. A compound having a structure represented by formula (I) or a pharmaceutically acceptable salt or an agriculturally pharmaceutically acceptable salt thereof,
wherein,
R1is substituted or unsubstituted C1～C10Alkyl, substituted or unsubstituted C1～C10Alkoxy radicalRadical, substituted or unsubstituted C2～C10Alkenyl, substituted or unsubstituted C2～C10Alkenyloxy, substituted or unsubstituted C2～C10Alkynyl, substituted or unsubstituted C2～C10Alkynyloxy, substituted or unsubstituted C1～C10Ester group, substituted or unsubstituted C1～C10Alkylcarbonyl, substituted or unsubstituted C1～C10Alkoxycarbonyl, substituted or unsubstituted C5～C10Aryl, substituted or unsubstituted C2～C8Heteroaryl, substituted or unsubstituted C3～C8Heterocycloalkyl, substituted or unsubstituted-C1～C6alkylene-C5～C10Aryl, or substituted or unsubstituted-C1～C6alkylene-C2～C8A heteroaryl group; wherein substituted means substituted with one or more substituents selected from the group consisting of: nitro, halogen, cyano, amino, hydrazino, C1～C6Acylamino, hydroxy, C1～C6Alkyl, hydroxy C1～C6Alkyl radical, C1～C6Alkoxy, halo C1～C6Alkyl, halo C1～C6Alkoxy radical, C2～C6Alkenyl radical, C2～C6Alkenyloxy radical, C1～C6Alkoxy radical, C2～C6Alkenyl radical, C2～C6Alkynyl, C1～C6Ester group, C1～C6Alkylcarbonyl group, C1～C6Alkoxycarbonyl group, C5～C10Aryl, halo C5～C10Aryl and C3～C8A heterocycloalkyl group;
n is an integer of 1 to 3; x is carbonyl (C ═ O), thiocarbonyl (C ═ S) or CH2(ii) a Y is absent, or NH;
R2is substituted or unsubstituted C1～C10Alkyl, substituted or unsubstituted C1～C10Ester radicals, substituted orUnsubstituted C1～C10Alkylcarbonyl, substituted or unsubstituted C1～C10Alkoxycarbonyl, substituted or unsubstituted C5～C10Aryl, substituted or unsubstituted C3～C8Heterocycloalkyl, substituted or unsubstituted C5～C10Aryl, or substituted or unsubstituted C2～C8A heteroaryl group; wherein substituted means substituted with one or more substituents selected from the group consisting of: nitro, halogen, cyano, amino, hydrazino, C1～C6Acylamino, hydroxy, C1～C6Alkyl, hydroxy C1～C6Alkyl, -O-C1～C6alkylene-O-, C1～C6Alkoxy, halo C1～C6Alkyl, halo C1～C6Alkoxy radical, C2～C6Alkenyl radical, C2～C6Alkenyloxy radical, C1～C6Alkoxy radical, C2～C6Alkenyl radical, C2～C6Alkynyl, C1～C6Ester group, C1～C6Alkylcarbonyl group, C1～C6Alkoxycarbonyl group, C5～C10Aryl, halo C5～C10Aryl and C3～C8A heterocycloalkyl group.
2. The compound of claim 1, or a pharmaceutically or agriculturally acceptable salt thereof, having a structure according to formula 10, formula 11, formula 14, or formula 15,
in the formula, n and R1、R2The definition is the same as claim 1.
3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereofOr an agriculturally pharmaceutically acceptable salt, characterized in that R1Is substituted or unsubstituted C1～C10Alkyl, substituted or unsubstituted C1～C10Alkoxy, substituted or unsubstituted-CH2-indolyl, substituted or unsubstituted-CH2-phenyl, substituted or unsubstituted-CH2-pyridyl, substituted or unsubstituted-CH2-benzopyridyl, substituted or unsubstituted-CH2-pyrrolyl, substituted or unsubstituted-CH2-thienyl, substituted or unsubstituted-CH2-benzothienyl, substituted or unsubstituted-CH2-furyl, substituted or unsubstituted-CH2-a benzofuranyl group; wherein substituted means substituted with one or more substituents selected from the group consisting of: nitro, halogen, cyano, amino, hydrazino, C1～C6Acylamino, hydroxy, C1～C6Alkyl, hydroxy C1～C6Alkyl radical, C1～C6Alkoxy, halo C1～C6Alkyl, halo C1～C6Alkoxy radical, C2～C6Alkenyl radical, C2～C6Alkenyloxy radical, C1～C6Alkoxy radical, C2～C6Alkenyl radical, C2～C6Alkynyl, C1～C6Ester group, C1～C6Alkylcarbonyl group, C1～C6Alkoxycarbonyl group, C5～C10Aryl, halo C5～C10Aryl and C3～C8A heterocycloalkyl group.
4. The compound of claim 1 or 2, or a pharmaceutically or agriculturally acceptable salt thereof, wherein R is2Is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted 1, 3, 4-thiadiazole, substituted or unsubstituted benzothiazolyl, substituted or unsubstituted thienyl, substituted or unsubstituted benzothienyl, substituted or unsubstituted phenyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted, orSubstituted or unsubstituted furyl, substituted or unsubstituted benzofuryl; wherein substituted means substituted with one or more substituents selected from the group consisting of: nitro, halogen, cyano, amino, hydrazino, C1～C6Acylamino, hydroxy, C1～C6Alkyl, hydroxy C1～C6Alkyl, -O-C1～C6alkylene-O-, C1～C6Alkoxy, halo C1～C6Alkyl, halo C1～C6Alkoxy radical, C2～C6Alkenyl radical, C2～C6Alkenyloxy radical, C1～C6Alkoxy radical, C2～C6Alkenyl radical, C2～C6Alkynyl, C1～C6Ester group, C1～C6Alkylcarbonyl group, C1～C6Alkoxycarbonyl group, C5～C10Aryl, halo C5～C10Aryl and C3～C8A heterocycloalkyl group.
5. A composition comprising (a) a compound according to any one of claims 1 to 4, or a pharmaceutically or agriculturally acceptable salt thereof, (b) a pharmaceutically or agriculturally acceptable carrier.
6. Use of a compound according to any one of claims 1 to 4 or a pharmaceutically or agriculturally acceptable salt thereof or a composition according to claim 5 for killing or preventing an agricultural pest; or for preparing pesticides for killing or preventing agricultural pests.
7. Use according to claim 6, for the preparation of an insecticide for killing or preventing lepidopteran insects, for the preparation of an insecticide for inhibiting feeding, growth or nematode feeding by lepidopteran insects.
8. Use of a compound according to any one of claims 1 to 4, or a pharmaceutically or agriculturally acceptable salt thereof, or a composition according to claim 5, for the preparation of a human 5-HT2a receptor ligand or a human 5-HT2a receptor agonist.
9. A process for the preparation of a compound according to claim 2 or a pharmaceutically or agriculturally acceptable salt thereof,
(a) the method comprises the following steps: reacting compound 7 and compound 5 in an inert solvent in the presence of a base to give compound 10;
(b) the method comprises the following steps: reacting compound 9 and compound 5 in an inert solvent in the presence of a base to give compound 10;
(c) the method comprises the following steps: reacting compound 12 and compound 5 in an inert solvent in the presence of a condensing agent to obtain compound 10;
(d) the method comprises the following steps: reacting compound 13 and compound 5 in an inert solvent in the presence of a reducing agent to give compound 10;
10. a method of combating and/or controlling insects, which comprises applying a compound as claimed in any one of claims 1 to 4 or a pharmaceutically or agriculturally acceptable salt thereof or a composition as claimed in claim 5 to a plant suffering or likely to suffer from insect pests or to the soil or environment surrounding the plant.
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CN109196012A (en) * 2016-03-31 2019-01-11 路博润先进材料公司 Biodegradable and/or biological absorbable thermoplastic polyurethane
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