CN113200976A - 3-aryl azabicyclo derivatives, preparation thereof and nematicidal application thereof - Google Patents

3-aryl azabicyclo derivatives, preparation thereof and nematicidal application thereof Download PDF

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CN113200976A
CN113200976A CN202110535888.9A CN202110535888A CN113200976A CN 113200976 A CN113200976 A CN 113200976A CN 202110535888 A CN202110535888 A CN 202110535888A CN 113200976 A CN113200976 A CN 113200976A
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cdcl
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CN113200976B (en
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宋恭华
卢奥运
王佳毅
李晖
郑一汀
李涛
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East China University of Science and Technology
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    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A01N43/56—1,2-Diazoles; Hydrogenated 1,2-diazoles
    • 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
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
    • A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
    • 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
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/82—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with three ring hetero 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
    • C07D401/02—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 two hetero rings
    • C07D401/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen 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

Abstract

The invention relates to preparation of a 3-aryl azabicyclo derivative and application thereof in killing nematodes. Specifically, the invention discloses a compound with a structure shown in a formula (I) or a composition thereof, and application of an optical isomer, a cis-trans isomer and an agriculturally and pharmaceutically acceptable salt thereof in the field of nematicidal.

Description

3-aryl azabicyclo derivatives, preparation thereof and nematicidal application thereof
Technical Field
The invention belongs to the field of pesticides. In particular, the invention relates to a 3-aryl azabicyclo derivative, a preparation method thereof and application thereof in killing nematodes.
Technical Field
Plant parasitic nematodes have been developed worldwide as major pathogens of plants in agriculture and forestry, including commercial crops such as potatoes, soybeans, tomatoes, and trees such as olive trees, pine trees, and the like. Crop yield losses of about 12% to 15% per year from plant parasitic nematode infestation, global direct agronomic losses of $ 1570 billion, and the fact that most of their life cycles are completed in the host plant due to the endoparasitic nature of plant parasitic nematodes, protected by the host plant tissue, are difficult to control.
To date, more than 4100 plant parasitic nematodes have been reported, with the most devastating being obligate biotrophic root-knot nematodes (melodogyne spp.). One tenth of the vegetable production worldwide is affected by nematode infestation, wherein 50% of these losses are caused by root-knot nematodes, the damage of which starts with the infestation of 2-instar larvae (J2) on the root elongation region of the plant, J2 releases cell wall lyase through the stylet into the epidermis of the root of the host plant, and then migrates internally through the cortex to the apex region to parasitize selected vascular bundle tissue cells, the complex parasitic relationship between the host cells is regulated by root-knot nematode secretions, and the development and gene expression of the host cells are affected, so that the host cells evolve into larger multinuclear cells, namely Giant cells (giantcel), and thus become the single nutrient donor of the nematodes. As giant cells develop, the adjacent vascular and cortical cells proliferate and become large, and then root nodules are formed.
Pine wood nematodes (Bursaphelenchus xylophilus) originally existed as species of ecological balance in pine trees in North America, have now developed into invasive species in forest ecosystems in Japan, the peninsula Korea and east Asia regions of China, and are further infecting Spanish and Portugal Europe, where more than 100 million hectares of pine trees die each year due to the harm of pine wood nematodes. Pine wood nematode is taken as a parasitic nematode in a migratory plant to cause pine wilt, which seriously damages the forest ecosystem in the far east Asia region, can be carried by a medium insect Monochamus spp to spread from dead pine to healthy pine, has the characteristics of herbivory and phagocytosis unlike other nematodes in the same genus, draws nutrition from parenchyma cells of the xylem of the pine through a resin pipeline to further cause the pine to wither, and starts to feed Botrytis cinerea (Botrytis cinerea) parasitizing on the pine after the pine dies
In 1881, carbon disulfide (CS)2) It is considered as the first product with nematicidal activity, in the middle of the first 20 th century, methyl bromide, Chloropicrin (CP), D-D mixtures (1,3-D and 1,2-D, Shell of 1942), dibromochloropropane (DBCP, Dour of 1955), halogenated hydrocarbon fumigants such as 1, 2-dibromoethylene (EDB, Dow of 1946) were introduced for nematode control, in 1952, dazomet (Mylone) was introduced for nematode control, in 1955, Stauffer developed products including metam (Vapam), and nematicide (Sassen), which can decompose in moist soil, releasing methyl isothiocyanate, hydrogen sulfide, and formaldehyde with fumigating effects, thereby achieving nematicidal purposes. At the beginning of the 20 th century in the 60's, fumigants were gradually replaced by organophosphorus and carbamate nematicides, and highly effective non-fumigant nematicides represented by fenamiphos (Ethoprophos), fosthiazate (1991), Oxamyl (Oxamyl, 1972), aldicarb (Temik, 1962) were usedIt is proposed that the nematocides mainly act on acetylcholinesterase (AChE) of the nervous system of the nematodes, so that nerve conduction of the nematodes is blocked, and physiological activity of the nematodes is disturbed, and then the nematodes die.
Due to environmental pressure, high toxicity, continuous improvement of nematode resistance caused by long-term use, some influences on non-target biological neurotoxicity and the like, some nematicides are gradually eliminated in the market, even some nematicides are forbidden, the variety of currently selected nematicides is few, and the development of novel nematicides is indispensable.
Disclosure of Invention
The invention aims to provide a preparation method and nematicidal application of 3-aryl azabicyclo derivatives, in particular to application in the field of plant parasitic nematodes, thereby playing a role in protecting plants.
The nematicidal compositions described herein comprise an effective amount of a compound or mixture of compounds having any of the formulae described herein, for example the compounds shown below.
In a first aspect of the invention, a compound shown in the general formula I, or an optical isomer, a cis-trans isomer and an agriculturally and pharmaceutically acceptable salt thereof are provided.
Figure BDA0003069814030000021
Wherein the content of the first and second substances,
r is hydrogen, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C15 alkoxy, substituted or unsubstituted 5-or 6-membered heteroaromatic ring, carbonyl-C6-C10 aryl-C1-C15 alkyl, C1-C15 alkoxycarbonyl, C6-C10 aryl-C1-C15 alkoxycarbonyl; said substituted means substituted with one or more substituents selected from the group consisting of: halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, carboxyl and C6-C10 aryl;
X1is CH ═ CH or is absent, X2Is CH ═ CH or is absent, and when X is present1When CH is CH, X is absent2(ii) a When X is present2Is CH ═ CH, in the absence of X1；
A is N, S or CH;
b is N or C;
d is CH, N, O or S;
e is C, N, O or CH;
ar is a benzene ring, a naphthalene ring, a 5-6 membered heteroaromatic ring or an 8-12 membered heteroaromatic bicyclic ring system; r1Is a substituent on Ar, in a number of 0, 1,2, 3 or 4, each R1Each independently selected from: C1-C6 alkyl, C1-C6 alkoxy, halogen, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, cyano, nitro, C6-C10 aryl, 5-or 6-membered heteroaryl, or-OAr1(ii) a Wherein Ar is1Is a C6-C10 aryl, 5-or 6-membered heteroaryl, or 8-12 membered heteroaryl bicyclic ring system; wherein the C6-C10 aryl, 5-or 6-membered heteroaryl is optionally substituted with 1,2, 3 or 4 substituents selected from the group consisting of: halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl and C1-C6 alkoxy.
In another preferred embodiment, R is substituted or unsubstituted C1-C4 alkyl or substituted or unsubstituted C1-C4 alkoxycarbonyl; said substituted means substituted with 1,2 or 3 substituents selected from the group consisting of: halogen, cyano, nitro, hydroxyl, amino, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, carboxyl and phenyl.
In another preferred embodiment, when D is S or O, B is C, A is N, E is N or C (H), X is1And X2Is absent.
In another preferred embodiment, when D is S, B is C, A is N, E is N or C (H), X is1And X2Is absent.
In another preferred embodiment, when D is O, B is C, A is N, E is N, X is1And X2Is absent.
In another preferred embodiment, when D is N, B is C, A is S or N, E is CH or O, X is1And X2Is absent.
In another preferred embodiment, when D is N,b is C, A is S, E is CH, X1And X2Is absent.
In another preferred embodiment, when D is N, B is C, A is N, E is O, X1And X2Is absent.
In another preferred embodiment, when D is CH or N, B is N, A is CH or N, E is C, X is2Is CH ═ CH.
In another preferred embodiment, when D is C, B is N, A is N, E is CH, X is1Is CH ═ CH.
In another preferred embodiment, when D is CH or N, B is N, A is CH or N, E is CH, X is1And X2Is absent.
In another preferred embodiment, when D is N, B is N, A is CH, and E is CH, X is1And X2Is absent.
In another preferred embodiment, when D is N, B is N, a is CH, and E is C, X is CH ═ CH.
In another preferred example, when D is CH and B is N, A is N, E is C, X is CH ═ CH.
In another preferred embodiment, when D is CH, B is N, A is N, E is CH, X is1And X2Is absent.
In another preferred embodiment, the compound has the structure shown below,
Figure BDA0003069814030000031
wherein Ar is as defined in claim 1, optionally having 1,2 or 3 substituents R1；R、R1Is as defined in claim 1.
In another preferred embodiment, Ar is a phenyl ring, a naphthyl ring, a 5-6 membered heteroaromatic ring or an 8-10 membered heteroaromatic bicyclic ring system, optionally with 1,2 or 3 substituents R1；
In the formulae, each R1Each independently selected from: C1-C6 alkyl, C1-C4 alkoxy, fluorine, chlorine, bromine, halogenated C1-C4 alkyl, halogenated C1-C4 alkoxy, cyano, nitro, phenyl, 5-or 6-membered heteroaryl, -O-phenyl, -O-5-or 6-membered heteroaryl; wherein phenyl, 5-or 6-membered heteroaryl is optionally substituted with 1 or 2 substituents selected from the group consisting of: halogen, cyano, nitro, hydroxyl, amino, C1-C4 alkyl, halogenated C1-C4 alkyl and C1-C4 alkoxy.
In another preferred embodiment, the compound has a structure represented by one of 4aa-52 ac.
In a second aspect of the present invention, there is provided a pesticidal composition comprising a compound of the first aspect or an agriculturally pharmaceutically acceptable salt thereof; and an agriculturally acceptable carrier.
In a third aspect of the invention, there is provided the use of a compound of the first aspect or an agriculturally acceptable salt thereof or a pesticidal composition of the second aspect, for the killing or prevention of nematodes; or for the preparation of a medicament for killing or preventing nematodes.
In a fourth aspect of the invention there is provided a method of killing or preventing nematodes including applying a compound of the first aspect or an agriculturally acceptable salt thereof or a pesticidal composition of the second aspect to a plant suffering from or likely to suffer from a pest infestation or to the soil or environment surrounding the plant.
The present invention provides a method of killing or preventing nematodes comprising applying an azabicyclo derivative of the first aspect or an agriculturally acceptable salt thereof or a composition of the second aspect to a plant suffering from or likely to suffer from a pest, or to the soil or environment surrounding it.
In another preferred embodiment, the azabicyclo derivative or an agriculturally pharmaceutically acceptable salt thereof or the pesticidal composition is applied at a concentration of 0.05 to 200 ppm; preferably, 0.1 to 100 ppm; more preferably, it is 0.5 to 50 ppm.
In another preferred embodiment, the nematodes include, but are not limited to, Bursaphelenchus xylophilus, Meloidogyne incognita, cyst nematode, Rhixoma solani, cyst nematode, Meloidogyne pomorum, Meloidogyne incognita, and Meloidogyne incognita.
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 present inventors have made extensive and intensive studies and, as a result, have synthesized a novel class of azabicyclic derivatives having a novel structure for the first time, which have excellent nematicidal activity.
Basic definition
The term "C1-C15 alkyl" refers to a straight or branched chain alkyl group having 1-15 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, 1-butyl, 2-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, or the like. The alkyl group having 1 to 6 carbon atoms is preferable.
The term "C1-C15 alkoxy" refers to a straight or branched chain alkyl group having 1-15 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, 1-butoxy, 2-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy or the like. The alkyl group having 1 to 6 carbon atoms is preferable.
The term "C2-C6 alkenyl" refers to straight or branched chain alkenyl groups having 2-6 carbon atoms, such as ethenyl, n-propenyl, isopropenyl, 1-butenyl, 2-butenyl, pentenyl, hexenyl, or the like. C2 to C4 alkenyl groups may be preferred.
The term "C2-C6 alkynyl" refers to a straight or branched chain alkynyl group having 2-6 carbon atoms, such as ethynyl, n-propynyl, isopropynyl, 1-butynyl, 2-butynyl, pentynyl, hexynyl, or the like. C2 to C4 alkynyl groups may be preferred.
The term "C3-C7 cycloalkyl" refers to a cyclic alkyl group having 3-7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.
The term "ring" or "ring system" refers to a carbocyclic or heterocyclic ring.
The term "heterocycle" means that at least one of the atoms forming the skeleton of said heterocycle is not carbon, is nitrogen, oxygen or sulfur, and the heterocycle is a saturated or partially unsaturated non-aromatic heterocycle, preferably the number of heteroatoms is 1,2, 3 or 4.
The term "5-or 6-membered heteroaromatic ring" refers to a five-or six-membered ring containing one or more heteroatoms selected from carbon, nitrogen, oxygen or sulfur, for example, phenyl, pyridyl, furyl, thienyl, thiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyrimidinyl, oxazolyl, piperazinyl, triazinyl, thiadiazolyl, oxadiazolyl, triazolyl and the like.
The term "8-12 membered heteroaromatic bicyclic ring system" may be selected from: naphthyl, benzofuranyl, quinolinyl, indolyl, benzothiophene, isoquinolinyl, benzothiophene, benzothiazole, benzopyrazolyl, benzimidazole, benzoxazole, benzo- [1,3] -dioxolyl, and the like.
The term "halogen" is fluorine, chlorine, bromine, iodine. The 'halo' is fluoro, chloro, bromo, iodo.
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 compounds of the invention are particularly effective against plant parasitic nematodes.
Nematicide combinations comprising the active substances according to the invention.
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 can be prepared from 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).
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. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.
The invention provides a preparation method of an azabicyclo derivative, which comprises the following steps:
reacting compound A1 with compound A2 in an inert solvent (such as acetonitrile, methanol, isopropanol, ethanol, DMF, etc.) to obtain compound A3
Figure BDA0003069814030000061
Wherein R, Ar is as defined above.
Or the method comprises the steps of:
(1) reacting compound B1 with compound B2 in an inert solvent (e.g., acetonitrile, methanol, isopropanol, ethanol, N-dimethylformamide, N-dimethylacetamide, water, toluene, dimethylsulfoxide, etc.) to give compound B3;
(2) compound B4 and compound B5 were reacted in an inert solvent (e.g., acetonitrile, methanol, isopropanol, ethanol, N-dimethylformamide, N-dimethylacetamide, water, toluene, dimethylsulfoxide, etc.) to give compound B3.
Figure BDA0003069814030000062
Wherein R, Ar is as defined above.
Or the method comprises the steps of: reacting compound C1 with compound C2 in an inert solvent (such as dichloromethane, ethyl acetate, tetrahydrofuran, N-dimethylformamide, dioxane, dichloroethane, chloroform, toluene, xylene, dimethyl sulfoxide, etc.) to obtain compound C3;
Figure BDA0003069814030000063
wherein R, Ar is as defined above.
Or the method comprises the steps of: reacting compound D1 with compound C2 in an inert solvent (such as dichloromethane, ethyl acetate, tetrahydrofuran, N-dimethylformamide, dioxane, dichloroethane, chloroform, toluene, xylene, dimethyl sulfoxide, etc.) to obtain compound D3;
Figure BDA0003069814030000071
wherein R, Ar is as defined above.
Or the method comprises the steps of: reacting compound D1 and compound C2 with lawson's reagent in an inert solvent (e.g., dichloromethane, ethyl acetate, tetrahydrofuran, N-dimethylamide, dioxane, dichloroethane, chloroform, toluene, xylene, dimethyl sulfoxide, etc.) to give compound E3;
Figure BDA0003069814030000072
wherein R, Ar is as defined above.
Or the method comprises the steps of: reacting compound F1 and compound F2 in an inert solvent (such as dichloromethane, ethyl acetate, tetrahydrofuran, N-dimethylformamide, dioxane, dichloroethane, chloroform, toluene, xylene, dimethyl sulfoxide, etc.) under basic conditions (such as triethylamine, potassium carbonate, sodium carbonate, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, etc.) to obtain compound F3
Figure BDA0003069814030000073
Wherein R, Ar is as defined above.
Or the method comprises the steps of: reacting compound F1 with compound G2 in an inert solvent (such as dichloromethane, ethyl acetate, tetrahydrofuran, N-dimethylformamide, dioxane, dichloroethane, chloroform, toluene, xylene, dimethyl sulfoxide, etc.) under basic conditions (such as triethylamine, potassium carbonate, sodium carbonate, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, etc.) to obtain compound G3
Figure BDA0003069814030000074
Wherein R, Ar is as defined above.
Or the method comprises the steps of: reacting compound F1 with compound H2 in an inert solvent (such as dichloromethane, ethyl acetate, tetrahydrofuran, N-dimethylformamide, dioxane, dichloroethane, chloroform, toluene, xylene, dimethyl sulfoxide, etc.) under basic conditions (such as triethylamine, potassium carbonate, sodium carbonate, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, etc.) to obtain compounds H3 and H4
Figure BDA0003069814030000081
In the formula, R, R1The definition is the same as before.
Or the method comprises the steps of: reacting compound F1 with compound I2 in an inert solvent (such as dichloromethane, ethyl acetate, tetrahydrofuran, N-dimethylformamide, dioxane, dichloroethane, chloroform, toluene, xylene, dimethyl sulfoxide, etc.) under basic conditions (such as triethylamine, potassium carbonate, sodium carbonate, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium hydride, etc.) to obtain compounds I3 and I4;
Figure BDA0003069814030000082
in the formula, R, R1The definition is the same as before.
The following more specifically describes the preparation of the compounds of the present invention, but these specific methods do not set any limit to the present 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.
Preparation of an intermediate:
Figure BDA0003069814030000083
wherein Ar is as defined above.
Example 1: and (3) preparing an intermediate 2.
Adding 40.0mmol of tropinone 1, 60.0mmol of tert-butyl alcohol and 300mL of tetrahydrofuran into a 500mL round-bottom flask in sequence, placing the reaction liquid into an ice-water bath, stirring and cooling to 0 ℃, then adding 80mmol of potassium tert-butoxide at one time, keeping the temperature at 0 ℃, continuing to stir for 10min, dissolving 60.0mmol of p-toluenesulfonylmethylisocyanogen in 60mL of tetrahydrofuran, slowly dropwise adding the p-toluenesulfonylmethylisocyanogen into the reaction liquid, keeping the reaction liquid at 0 ℃ and stirring for 30min after the dropwise adding is finished, then turning to room temperature to react for 6h, removing the solvent by rotary evaporation after the reaction is finished, adding 125mL of solvent, removing the solvent by addingExtraction with dichloromethane (3X 50mL), combining the organic phases, removing the solvent under reduced pressure to give the crude product, which was subjected to column chromatography to give 5.4g of a colorless oil in 89% yield;1H NMR(400MHz,CDCl3)δ3.20–3.18(m,2H),2.73(tt,J＝12.1,5.6Hz,1H),2.28(s,3H),2.09–2.05(m,2H),2.00(dd,J＝12.7,2.1Hz,2H),1.78(ddd,J＝13.4,5.3,3.3Hz,2H),1.53(dd,J＝14.9,6.5Hz,2H).13C NMR(101MHz,CDCl3)δ122.31,60.07,40.10,34.29,25.62,20.07.MS(GC-MS):C9H14N2[M]+m/z 150.1.
example 2: and (3) preparing an intermediate 3.
And (2) sequentially adding 20.0mmol of compound 2, 150mL of pyridine and 30.0mmol of 20% ammonium sulfide aqueous solution into a 350mL reaction bottle, slowly heating the reaction solution to 55 ℃ for reaction for 48 hours, after the reaction is finished, removing the solvent by rotary evaporation, dissolving the reaction residue into 100mL ice water, adjusting the pH value to 8-9 by using saturated sodium carbonate aqueous solution, filtering, and drying a filter cake to be directly used for the next reaction. 2.1g of light yellow solid, yield 58%;1H NMR(400MHz,DMSO-d6)δ9.28(s,1H),9.11(s,1H),3.13(br,s,2H),2.85(tt,J＝11.4,5.2Hz,1H),2.21(s,3H),1.99–1.92(m,4H),1.57–1.52(m,2H),1.41–1.36(m,2H)ppm.13C NMR(101MHz,DMSO-d6)δ212.23,60.73,49.04,42.15,36.23,26.33ppm.HRMS(EI-TOF)calcd for C9H16N2S[M+]m/z 184.1034,found 184.1035.
example 3: and (4) preparing a target product 4.
And (2) sequentially adding 1mmol of intermediate 3 and 1.1mmol of alpha-bromoarylethanone into a 10mL round-bottom flask, adding 5mL of absolute ethyl alcohol, heating the reaction solution to reflux, reacting for 3h, removing the solvent by rotary evaporation after the reaction is finished, and purifying the crude product by flash chromatography to obtain a target compound 4.
Figure BDA0003069814030000091
Wherein Ar is as defined above.
Example 4: preparation of intermediate 5.
10mmol of the compound 3, 15mmol of sodium acetate, 50mL of acetic acid and 13mmol of 40% chloroacetaldehyde aqueous solution are sequentially added into a 100mL round-bottom flask, the mixture is stirred and slowly heated to 80 ℃ for reaction for 12 hours, the reaction is finished, the solvent is removed under reduced pressure, 30mL of deionized water is added into the reaction residue, the pH is adjusted to 8-9 by saturated sodium carbonate aqueous solution, dichloromethane is used for extraction (3X 30mL), the organic phases are combined, the solvent is removed under reduced pressure to obtain a crude product, and the crude product is subjected to column chromatography to obtain 1.30g of brown oily matter with the yield of 63%.1H NMR(400MHz,CDCl3)δ7.56(d,J＝3.3Hz,1H),7.14(d,J＝3.3Hz,1H),3.48–3.47(m,2H),3.36(tt,J＝12.0,5.5Hz,1H),2.46(s,3H),2.31–2.24(m,2H),2.18–2.14(m,2H),1.93(ddd,J＝14.5,5.1,3.3Hz,2H),1.79(dd,J＝14.7,6.1Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ173.98,141.92,118.21,61.74,39.05,36.64,32.77,25.62ppm.MS(GC-MS):C9H16N2S[M]+m/z 208.1.
Example 5: and (3) preparing a target product 6.
Adding 2mmol of silver carbonate, 0.05mmol of [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride dichloromethane complex, 0.1mmol of triphenylphosphine and 1.2mmol of aryl iodide into a 25mL three-port glass reactor in sequence, then adding 1mmol of compound 5 and 10mL of deionized water, placing the reactor into a microwave synthesizer, inserting an ultrasonic probe, adjusting the height of the probe to be 2-3mm below the liquid level, switching on condensed water, adjusting the microwave power to be 60W and the ultrasonic power to be 75W, reacting for 1.5 hours, cooling the reaction liquid to room temperature after the raw materials are completely reacted, transferring the reaction liquid to a 125mL separating funnel, extracting dichloromethane (3 x 30mL), filtering the extract through diatomite, combining the extracts, removing the solvent through rotary evaporation, and separating by column chromatography to obtain the target compound 6.
Figure BDA0003069814030000092
Wherein Ar is as defined above.
Example 6: and (3) preparing an intermediate 8.
The specific implementation method takes the compound 7 as a reaction raw materialThe same as above for the preparation of intermediate 2.1H NMR(400MHz,CDCl3)δ4.28–4.23(m,2H),2.98(tt,J＝11.9,5.5Hz,1H),2.08–1.92(m,4H),1.88–1.84(m,2H),1.65–1.59(m,2H),1.48(s,9H)ppm.13C NMR(101MHz,CDCl3)δ152.98,121.64,79.92,52.67,52.00,34.19,33.51,28.43,27.85,27.16,20.64ppm.
Example 7: preparation of intermediate 9.
Adding 10mmol of intermediate 8, 15mmol of hydroxylamine hydrochloride, 20.0mmol of sodium bicarbonate, 40mL of ethanol and 8mL of deionized water into a 100mL round-bottom flask in sequence, stirring the reaction solution at room temperature for reaction for 1h, heating and refluxing the reaction solution for further reaction for 8h, removing the solvent by rotary evaporation after the reaction is finished, dissolving the reaction residue in 20mL of deionized water, extracting with ethyl acetate (3X 20mL), combining the extracts, and removing the solvent under reduced pressure to obtain a crude product which can be directly used for the next reaction.
Example 8: preparation of intermediate 10.
Adding 2mmol of a compound 9, 3mmol of aryl formic acid, 10mmol of triethylamine, 5.0mmol of 1-propyl cyclic phosphoric anhydride and 20mL of ethyl acetate into a 50mL round bottom flask in sequence, replacing the reaction liquid with nitrogen for three times, refluxing and reacting for 8 hours under the nitrogen atmosphere, removing the ethyl acetate by rotary evaporation after the reaction is finished, dissolving the reaction residue in 20mL of deionized water, adjusting the pH to 8-9 by using saturated aqueous sodium carbonate solution, extracting with ethyl acetate (20mL multiplied by 3), combining the extracts, and separating the crude product by column chromatography to obtain an intermediate 10.
Example 9: preparation of the target product 11.
Adding 1mmol of compound 10, 10mL of dichloromethane and 2mL of trifluoroacetic acid into a 25mL round bottom flask in sequence, stirring at room temperature for reaction for 5 hours, removing the solvent by rotary evaporation after the reaction is finished, dissolving the reaction residue in 10mL of deionized water, slowly adjusting the pH to 8-9 by using a saturated sodium carbonate aqueous solution, extracting the dichloromethane (20mL multiplied by 3), combining the extract solutions, removing the solvent by rotary evaporation, adding 5mmol of 37% formaldehyde aqueous solution, 10mmol of acetic acid, 5mmol of zinc chips and 10mL of solvent deionized water in sequence, placing the reaction solution in an oil bath at 100 ℃ for reaction for 12 hours, and slowly adding saturated Na after the reaction is finished2CO3The pH value of the reaction liquid is adjusted to 8 by the aqueous solution9, extracting with dichloromethane (20mL multiplied by 4), combining the extracts, removing the solvent by rotary evaporation, and separating by column chromatography to obtain the target product 11
Figure BDA0003069814030000101
Wherein Ar is as defined above.
Example 10: preparation of intermediate 13.
Adding 40mmol of demethyltropinone hydrochloride 12, 45mmol of benzyl bromide and 150mL of acetonitrile into a 250mL round-bottom flask in sequence, stirring at room temperature, adding 100mmol of potassium carbonate, heating the reaction solution to reflux, continuing to react for 8 hours, finishing the reaction, cooling the reaction solution to room temperature, performing suction filtration, washing a filter cake with ethyl acetate (10mL multiplied by 3), removing the solvent from the filtrate through rotary evaporation, and separating a crude product through column chromatography to obtain 7.5g of a colorless oily intermediate 13 with the yield of 87%,1H NMR(400MHz,CDCl3)δ7.40(d,J＝7.4Hz,2H),7.32(t,J＝7.4Hz,2H),7.24(t,J＝7.3Hz,1H),3.72(s,2H),3.45(br,s,2H),2.66(dd,J＝16.0,4.2Hz,2H),2.19–2.15(m,2H),2.10–2.06(m,2H),1.59(dd,J＝14.7,6.7Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ210.09,139.39,128.44,128.38,127.12,58.59,55.13,48.24,27.86ppm.
example 11: preparation of intermediate 14.
The intermediate 13 is used as a reaction raw material, and the specific implementation steps are the same as the preparation of the intermediate 2.1H NMR(400MHz,CDCl3)δ7.35–7.29(m,4H),7.26–7.22(m,1H),3.49(s,2H),3.23(br,s,2H),2.91(t,J＝7.7Hz,1H),2.18–2.07(m,6H),1.84–1.81(m,2H)ppm.13C NMR(101MHz,CDCl3)δ128.55,128.28,126.98,124.83,58.47,57.04,33.50,25.52,19.10ppm.
Example 12: preparation of intermediate 15.
And (3) sequentially adding 20mmol of the intermediate 14, 100mL of deionized water and 20mL of concentrated hydrochloric acid into a 250mL round-bottom flask, heating the reaction solution until reflux reaction is carried out for 48 hours, cooling the reaction solution to room temperature after the reaction is finished, and removing hydrochloric acid and water under reduced pressure to obtain a brown viscous crude product which can be directly used for the next reaction.
Example 13: preparation of intermediate 16.
And (3) transferring all the obtained intermediate 15 into a 250mL round-bottom flask, adding 4mmol of p-toluenesulfonic acid and 100mL of absolute ethanol, heating to reflux for 8h, after the reaction is finished, cooling the reaction liquid to room temperature, removing the ethanol by rotary evaporation, and separating the crude product by column chromatography to obtain 4.8g of oily matter with the yield of 88%.1H NMR(400MHz,CDCl3)δ7.39(d,J＝7.6Hz,2H),7.30(t,J＝7.4Hz,2H),7.22(t,J＝7.2Hz,1H),4.11(q,J＝7.1Hz,2H),3.56(s,2H),3.23(br,s,2H),2.61(tt,J＝11.9,5.6Hz,1H),2.05–2.02(m,2H),1.94(t,J＝12.1Hz,2H),1.65–1.56(m,4H),1.23(t,J＝7.1Hz,3H)ppm.13C NMR(101MHz,CDCl3)δ175.75,139.86,128.53,128.17,126.76,60.25,58.47,56.16,34.85,33.51,26.56,14.28ppm.
Example 14: preparation of intermediate 17.
Adding 30mmol of intermediate 16, 45mmol of 80% hydrazine hydrate and 80mL of absolute ethyl alcohol into a 250mL round-bottom flask in sequence, heating the reaction solution to a reflux state, stirring for 48 hours for reaction, cooling the reaction solution to room temperature after the reaction is finished, removing the ethyl alcohol by rotary evaporation to obtain a white solid crude product, washing the crude product for three times by cold water, filtering to obtain a white solid, and drying the white solid to be directly used for the next reaction. White solid 4.6g, 60% yield.1H NMR(400MHz,DMSO-d6)δ8.88(br,s,1H),7.35(d,J＝7.0Hz,2H),7.31(t,J＝7.4Hz,2H),7.22(t,J＝7.0Hz,1H),4.13(br,s,2H),3.49(s,2H),3.11(br,s,2H),2.44(tt,J＝11.6,5.4Hz,1H),1.98–1.96(m,2H),1.81–1.74(m,2H),1.53(dd,J＝13.6,5.8Hz,2H),1.37–1.32(m,2H)ppm.13C NMR(101MHz,DMSO-d6)δ174.07,140.08,128.24,128.03,126.51,58.19,55.51,33.71,33.44,26.16ppm.
Example 15: preparation of intermediate 18.
Adding 2mmol of a compound 17, 3mmol of aryl formic acid, 5mmol of triethylamine, 5mmol of 1-propyl cyclic phosphoric anhydride and 20mL of ethyl acetate into a 50mL round-bottom flask in sequence, replacing reaction liquid with nitrogen for three times, carrying out reflux reaction for 8 hours under the nitrogen atmosphere, cooling to room temperature after the reaction is finished, removing the ethyl acetate by rotary evaporation, dissolving reaction residues in 20mL deionized water, adjusting the pH to 8-9 by using saturated sodium carbonate aqueous solution, extracting with ethyl acetate (20mL multiplied by 3), combining extract liquor, removing a solvent by rotary evaporation of the extract liquor, and carrying out column chromatography separation to obtain a target product.
Example 16: preparation of intermediate 19.
Adding 18 mmol of compound, 10mL of anhydrous acetonitrile and 2mL of phosphorus oxychloride into a 25mL round-bottom flask in sequence, heating the reaction solution to a reflux state, stirring for reaction for 12h, cooling to room temperature after the reaction is finished, slowly adding 5mL of deionized water, continuing stirring for 10min, slowly dropwise adding a saturated sodium carbonate aqueous solution into the reaction solution to adjust the pH of the reaction solution to 8-9, carrying out rotary evaporation to remove the acetonitrile, dissolving the reaction residue in 10mL of deionized water, extracting with dichloromethane (3X 20mL), combining the extracts, removing the solvent from the extracts through rotary evaporation, and carrying out column chromatography separation to obtain the target product.
Example 17: preparation of target compound 20.
Adding 0.5mmol of intermediate 19, 10mL of anhydrous methanol, 100.0mg of 10% palladium-carbon and 5.0mmol of ammonium formate into a 25mL round-bottom flask in sequence, stirring and reacting overnight at room temperature, after the reaction is finished, carrying out suction filtration on reaction liquid through diatomite, removing a solvent from filtrate through rotary evaporation, dissolving the filtrate in 10mL of deionized water, extracting with dichloromethane (10mL multiplied by 3), combining extract liquor and removing the solvent, adding 2.5mmol of zinc chips, 2.5mmol of 37% formaldehyde aqueous solution, 5mmol of acetic acid and 10mL of deionized water in sequence, placing the reaction liquid at 100 ℃ for reaction for 12 hours, after the reaction is finished, cooling the reaction liquid to room temperature, adjusting the pH of the reaction liquid to 8-9 with saturated sodium carbonate solution, extracting the reaction liquid through dichloromethane (20mL multiplied by 3), combining extract liquor, removing the solvent under reduced pressure, and carrying out column chromatography to obtain the target compound 20.
Example 18: preparation of intermediate 21.
2mmol of intermediate 18, 20mL of anhydrous methanol, 400.0mg of 10% palladium carbon and 5mmol of ammonium formate are sequentially added into a 50mL round-bottom flask, the mixture is stirred at room temperature for reaction overnight, after the reaction is finished, the reaction solution is filtered by suction through diatomite, the filtrate is dissolved in 20mL of deionized water after the solvent is removed by rotary evaporation, the deionized water is extracted by dichloromethane (20mL multiplied by 3), the extract is combined and the solvent is removed, and the crude product can be directly used for the next reaction without column chromatographic separation.
Example 19: preparation of intermediate 22.
Adding 1.5mmol of intermediate 21, 20mL of toluene and 4mmol of Lawson reagent into a 50mL round-bottom flask in sequence, heating the reaction solution to a reflux state for reaction for 12 hours, cooling the reaction solution to room temperature after the raw materials are completely reacted, adding 20mL of deionized water, extracting with ethyl acetate (20mL multiplied by 3), combining the extracts, removing the solvent, and separating the crude product by column chromatography for the next reaction.
Example 20: preparation of target compound 23.
Adding 0.5mmol of intermediate 22, 2.5mmol of zinc dust, 2.5mmol of 37% formaldehyde aqueous solution, 5mmol of acetic acid and 10mL of deionized water into a 25mL round bottom flask in sequence, placing the reaction solution at 100 ℃ for reaction for 12h, after the reaction is finished, cooling the reaction solution to room temperature, adjusting the pH of the reaction solution to 8-9 by using a saturated sodium carbonate solution, extracting the reaction solution by dichloromethane (20mL multiplied by 3), combining the extraction solutions, removing the solvent under reduced pressure, and separating by column chromatography to obtain the target compound.
Figure BDA0003069814030000121
Wherein R is as defined above.
Example 21: preparation of intermediate 25.
Adding 150mL of dichloromethane and 40mmol of compound 24 into a 250mL round-bottom flask in turn, then adding 60mmol of imidazole and 52mmol of triphenylphosphine in turn, stirring and cooling to 0 ℃, then adding 48mmol of iodine elementary substance in one time, continuing stirring at 0 ℃ for reaction for 30min, then turning to room temperature for reaction overnight, after the reaction is finished, removing insoluble substances by suction filtration, washing a filter cake with dichloromethane (20mL multiplied by 3), combining filtrates, removing a solvent under reduced pressure, adding 30mL of deionized water into a reaction residue, adding a saturated sodium carbonate aqueous solution to adjust the pH to 8-9, extracting with dichloromethane (50mL multiplied by 3), removing the solvent from an extract under reduced pressure, and separating a crude product by column chromatography to obtain a target product.
Figure BDA0003069814030000122
Wherein Ar is as defined above.
Example 22: preparation of intermediate 27.
5mmol of the compound 26, 7.5mmol of N, N-dimethylformamide dimethyl acetal and 20mL of absolute ethanol are sequentially added into a 100mL round-bottom flask, the mixture is heated to reflux for reaction for 48 hours, after the reaction is finished, the reaction solution is cooled to room temperature, ethanol is removed under reduced pressure, the reaction residue is dissolved in 50mL of ethyl acetate and washed by saturated saline (20mL multiplied by 3), the solvent is removed from the organic phase under reduced pressure, and the obtained crude product can be directly used for the next reaction.
Example 23: preparation of intermediate 28.
Adding 3mmol of intermediate 27, 4.5mmol of hydrazine hydrochloride, 0.6mmol of p-toluenesulfonic acid and 20mL of absolute ethanol into a 50mL round-bottom flask in sequence, heating to reflux for reaction for 6-8h, cooling the reaction solution to room temperature after the reaction is finished, removing the ethanol under reduced pressure, dissolving the reaction residue in 30mL of deionized water, extracting with ethyl acetate (30mL multiplied by 3), combining the extracts, and separating the crude product by column chromatography to obtain the target product.
Example 24: preparation of intermediate 29.
Adding 2mmol of intermediate 28, 10mL of anhydrous N, N-dimethylformamide and 5mmol of sodium hydride into a 25mL round-bottom flask in sequence, reacting the reaction solution at room temperature for 10min under the atmosphere of nitrogen, then adding 3mmol of intermediate 25, slowly heating the reaction solution to 70 ℃, continuing to react for 12h, after the reaction is finished, cooling the reaction solution to room temperature, slowly dropwise adding 1.0mL of deionized water to quench the residual sodium hydride, transferring the reaction solution to a separating funnel, adding deionized water (20mL), extracting with ethyl acetate (20mL multiplied by 3), combining the extracts, removing the solvent by rotary evaporation, and then carrying out column chromatography to obtain the target product.
Example 25: preparation of target compound 30.
Taking the intermediate 29 as a reaction raw material, and when the R group is benzyl or benzyloxycarbonyl, the specific implementation steps are the same as the preparation method of the target product 20; when the R group is tert-butyloxycarbonyl, the specific implementation steps are the same as the preparation method of the target product 11.
Figure BDA0003069814030000131
Wherein R, Ar is as defined above.
Example 26: preparation of intermediate 32.
Obtained by reacting 4-bromo-1-H-pyrazole 31 with the intermediate 25 under alkaline conditions, and the specific implementation method is the same as the preparation method of the intermediate 29.
Example 27: preparation of intermediate 33.
Adding 2mmol of intermediate 32, 3mmol of arylboronic acid, 4mmol of potassium carbonate and 0.1mmol of tetratriphenylphosphine palladium into a 25mL round-bottom flask in sequence, then adding 10mL of toluene, 1mL of anhydrous ethanol and 1mL of deionized water, placing the reaction solution at 90 ℃ for reflux reaction for 16h, after the reaction is finished, cooling the reaction solution to room temperature, removing the solvent under reduced pressure, dissolving the reaction residue in 20mL of deionized water, extracting with ethyl acetate (20mL multiplied by 3), combining the extraction solutions, and separating the crude product by column chromatography to obtain the target product.
Example 28: preparation of target compound 34.
The intermediate 33 is a reaction raw material, and when the R group is tert-butyloxycarbonyl, the specific implementation steps are the same as the preparation method of the target product 11.
Figure BDA0003069814030000132
Figure BDA0003069814030000141
In the formula, R, R1The definition is the same as before.
Example 29: preparation of intermediate 36.
Adding 20mmol of N-methyl-5-hydroxypyrazole 35 and 6.0mL of anhydrous N, N-dimethylformamide into a 25mL round-bottom flask in sequence, placing the reaction solution in an ice-water bath, stirring and cooling to 0 ℃, and then slowly dropwise adding 6.0mL of phosphorus tribromide into the reaction solutionAfter the dropwise addition, keeping the temperature at 0 ℃ for continuous reaction for 10min, slowly raising the reaction temperature to 80 ℃ for continuous reaction for 8h, after the reaction is finished, cooling the reaction liquid to room temperature, slowly adding 20mL of deionized water into the reaction liquid until the viscous reaction liquid is completely dissolved, slowly adjusting the pH to 8-9 by using a saturated sodium carbonate aqueous solution, extracting the reaction liquid by using ethyl acetate (30mL multiplied by 3), washing an extract (20mL multiplied by 3) by using saturated salt water, removing the solvent from the extract by rotary evaporation, and separating a crude product by using column chromatography to obtain a target product.1H NMR(400MHz,CDCl3)δ9.77(s,1H),7.97(s,1H),3.93(s,3H)ppm.
Example 30: preparation of intermediate 41.
Adding 10.0mmol of 1-methyl-1H-pyrazole-5-formaldehyde 40 and 20mL of reaction solvent N, N-dimethylformamide into a 100mL round-bottom flask in sequence, stirring at room temperature until the raw materials are dissolved, then dissolving 11mmol of N-bromosuccinimide into 10mL of N, N-dimethylformamide, slowly dropwise adding the mixture into the reaction solution, placing the reaction solution at room temperature, continuously stirring for 18H, adding 10mL of 20% sodium hydroxide aqueous solution after the reaction is finished, continuously stirring for 10min, then adding 50mL of deionized water into the reaction solution, extracting with ethyl acetate (30mL multiplied by 3), combining extracts, washing with saturated saline (20mL multiplied by 3), removing the solvent from the extracts through rotary evaporation, and separating the crude product through column chromatography to obtain the target product.1H NMR(400MHz,CDCl3)δ9.87(s,1H),7.50(s,1H),4.14(s,3H)ppm.
Example 31: preparation of intermediate 37 and intermediate 42.
The intermediate 36 or the intermediate 41 is used as a reaction raw material, and the specific implementation steps are the same as the synthesis method of the intermediate 33.
Example 32: preparation of intermediate 38 and intermediate 43.
Adding 0.5mmol of intermediate 37 or intermediate 42, 1.1mmol of p-toluenesulfonylhydrazide and 6mL of n-butanol into a 20mL microwave reaction tube equipped with a magnetic stirrer in sequence, sealing the microwave reaction tube, placing the microwave reaction tube in a microwave synthesizer, reacting at 120 ℃ for 5min, reducing pressure to remove the solvent after the reaction is finished, and separating by column chromatography to obtain intermediate 38 or intermediate 43.
Example 33: preparation of intermediate 39 and intermediate 44.
Adding 1mmol of intermediate 38 or intermediate 43 into a 20mL microwave reaction tube equipped with a magnetic stirrer in sequence, then quickly adding 15.0g of pyridine hydrochloride, quickly covering the microwave tube, placing the microwave tube into a microwave synthesizer, keeping the temperature of 200 ℃ for reaction for 5 hours, dissolving the reactant into 30mL deionized water after the reaction is finished, extracting with ethyl acetate (20mL multiplied by 4), combining the extracts, removing the solvent by rotary evaporation, and separating by column chromatography to obtain intermediate 39 or intermediate 44.
Example 34: preparation of intermediate 45 and intermediate 47.
The intermediate 39 and the intermediate 25 react under alkaline conditions to obtain an intermediate 45 and an intermediate 47, and the specific implementation steps are the same as the preparation method of the intermediate 29.
Example 35: preparation of intermediate 49 and intermediate 51.
The intermediate 44 and the intermediate 25 react under alkaline conditions to obtain an intermediate 49 and an intermediate 51, and the specific implementation steps are the same as the preparation method of the intermediate 29.
Example 36: preparation of the target products 46, 48, 50, 52.
Respectively taking intermediates 45, 47, 49 and 51 as raw materials to react. When the R group is tert-butyloxycarbonyl, the specific procedure is the same as the above-mentioned preparation of intermediate 11.
The following compounds were prepared according to the methods described in examples 1 to 36 using different starting materials, NMR spectra: (NMR)1H NMR), carbon spectrum (13C NMR), High Resolution Mass Spectrometry (HRMS) characterization data as follows:
Figure BDA0003069814030000151
1H NMR(400MHz,CD3OD)δ7.91(d,J＝7.1Hz,2H),7.67(s,1H),7.41(t,J＝7.5Hz,2H),7.36–7.26(m,1H),3.69(s,2H),3.59–3.51(m,1H),2.59(s,3H),2.24(t,J＝12.1Hz,4H),2.17–2.05(m,2H),1.97(d,J＝8.6Hz,2H).13C NMR(101MHz,CD3OD)δ174.75,156.15,135.85,129.90,129.26,127.47,113.90,64.00,39.82,37.96,33.43,25.94.HRMS(EI-TOF)calcd for C17H20N2S[M+]m/z 284.1347；found,284.1346.
Figure BDA0003069814030000152
1H NMR(400MHz,CD3OD)δ7.85(d,J＝7.8Hz,2H),7.47(s,1H),7.29(d,J＝7.9Hz,2H),3.71(s,2H),3.57–3.48(m,1H),2.57(s,3H),2.31(s,3H),2.22–2.03(m,6H),1.94(d,J＝8.7Hz,2H).13C NMR(101MHz,CD3OD)δ173.91,157.23,134.91,131.30,129.46,127.59,114.20,63.80,38.77,38.71,34.50,25.92,21.38.HRMS(EI-TOF)calcd for C18H22N2S[M+]m/z 298.1504；found,298.1502.
Figure BDA0003069814030000153
1H NMR(400MHz,CD3OD)δ7.71(d,J＝8.8Hz,2H),7.39(s,1H),6.85(d,J＝8.8Hz,2H),3.71(s,3H),3.58–3.38(m,3H),2.45(s,3H),2.23–1.97(m,6H),1.87(d,J＝8.5Hz,2H).13C NMR(101MHz,CD3OD)δ175.06,161.20,156.16,128.71,115.11,111.74,63.71,55.81,39.85,38.30,33.62,26.06.HRMS(EI-TOF)calcd for C18H22N2OS[M+]m/z 314.1453；found,314.1455.
Figure BDA0003069814030000161
1H NMR(400MHz,CD3OD)δ7.96–7.88(m,2H),7.63(s,1H),7.13(t,J＝8.7Hz,2H),3.67(s,2H),3.62–3.52(m,1H),2.58(s,3H),2.33–2.08(m,6H),1.99(d,J＝8.1Hz,2H).13C NMR(101MHz,CD3OD)δ175.05,164.06(d,J＝246.0Hz),155.15,132.35,129.34(d,J＝8.2Hz),116.50(d,J＝21.9Hz),113.48,63.85,39.81,38.09,33.52,25.99.HRMS(EI-TOF)calcd for C17H19FN2S[M+]m/z 302.1253；found,302.1252.
Figure BDA0003069814030000162
1H NMR(400MHz,CD3OD)δ7.89(d,J＝8.6Hz,2H),7.71(s,1H),7.39(d,J＝8.6Hz,2H),3.78(s,2H),3.67–3.55(m,1H),2.66(s,3H),2.37–2.14(m,6H),2.05(d,J＝8.1Hz,2H).13C NMR(101MHz,CD3OD)δ174.66,154.95,134.83,134.55,129.90,128.88,114.39,64.18,39.67,37.85,33.29,25.80.HRMS(EI-TOF)calcd for C17H19 35ClN2S[M+]m/z 318.0957；found,318.0959；calcd for C17H19 37ClN2S[M+]m/z 320.0928；found,320.0927.
Figure BDA0003069814030000163
1H NMR(400MHz,CD3OD)δ7.82(d,J＝8.6Hz,2H),7.72(s,1H),7.54(d,J＝8.6Hz,2H),3.73(s,2H),3.67–3.51(m,1H),2.62(s,3H),2.36–2.11(m,6H),2.02(d,J＝8.7Hz,2H).13C NMR(101MHz,CD3OD)δ174.94,154.95,134.95,132.91,129.15,122.90,114.45,64.00,39.76,37.99,33.42,25.91.HRMS(EI-TOF)calcd for C17H19 79BrN2S[M+]m/z 362.0452；found,362.0449；calcd for C17H19 81BrN2S[M+]m/z 364.0432；found,364.0428.
Figure BDA0003069814030000164
1H NMR(400MHz,CD3OD)δ8.27(d,J＝9.0Hz,2H),8.10(d,J＝9.0Hz,2H),7.84(s,1H),3.80(s,2H),3.70–3.55(m,1H),2.68(s,3H),2.43–2.35(m,4H),2.22(d,J＝16.6Hz,2H),2.08(d,J＝8.8Hz,2H).13C NMR(101MHz,CD3OD)δ175.21,153.91,148.52,141.73,128.27,125.39,117.71,64.02,40.21,37.90,33.68,26.31.HRMS(EI-TOF)calcd for C17H19N3O2S[M+]m/z 329.1198；found,329.1197.
Figure BDA0003069814030000165
1H NMR(400MHz,CD3OD)δ8.11(d,J＝8.2Hz,2H),7.92(s,1H),7.69(d,J＝8.4Hz,2H),3.91(s,2H),3.71–3.63(m,1H),2.76(s,3H),2.44–2.35(m,4H),2.23(d,J＝10.1,2H),2.12(d,J＝8.8Hz,2H).13C NMR(101MHz,CD3OD)δ174.38,154.42,139.32,130.62(q,J＝32.3Hz),127.86,126.76(q,J＝3.8Hz),125.78(q,J＝271.3Hz),116.45,64.52,39.66,37.49,33.09,25.68.HRMS(EI-TOF)calcd for C18H19F3N2S[M+]m/z 352.1221；found,352.1224.
Figure BDA0003069814030000171
1H NMR(400MHz,CD3OD)δ7.94(s,1H),7.73–7.54(m,2H),7.39(d,J＝8.4Hz,1H),3.71(s,2H),3.54–3.47(m,1H),2.58(s,3H),2.34–2.06(m,6H),1.98(d,J＝8.5Hz,2H).13C NMR(101MHz,CD3OD)δ174.64,153.74,135.93,133.93,132.89,131.94,129.37,126.83,115.43,64.18,39.83,37.78,33.37,25.97.HRMS(EI-TOF)calcd for C17H18 35Cl2N2S[M+]m/z 352.0568；found,352.0562；calcd for C17H18 35Cl37ClN2S[M+]m/z 354.0538；found,354.0543；calcd for C17H18 37Cl2N2S[M+]m/z 356.0509；found,356.0518.
Figure BDA0003069814030000172
1H NMR(400MHz,CD3OD)δ7.78–7.74(m,3H),7.23(t,J＝1.9Hz,1H),3.74(s,2H),3.58–3.48(m,1H),2.60(s,3H),2.27–2.16(m,4H),2.14–2.07(m,2H),1.99(d,J＝8.8Hz,2H).13C NMR(101MHz,CD3OD)δ174.77,153.05,138.85,136.53,128.53,125.73,116.48,64.30,39.64,37.73,33.19,25.72.HRMS(EI-TOF)calcd for C17H18 35Cl2N2S[M+]m/z 352.0568；found,352.0563；calcd for C17H18 35Cl37ClN2S[M+]m/z 354.0538；found,354.0542；calcd for C17H18 37Cl2N2S[M+]m/z 356.0509；found,356.0523.
Figure BDA0003069814030000173
1H NMR(400MHz,CD3OD)δ7.60(s,1H),7.52(s,1H),6.63(d,J＝3.0Hz,1H),6.40(d,J＝3.3Hz,1H),3.71(s,2H),3.57–3.48(m,1H),2.55(s,3H),2.30–2.14(m,6H),2.07(d,J＝9.2Hz,2H).13C NMR(101MHz,CD3OD)δ172.35,149.26,142.01,140.04,114.35,110.86,105.92,64.30,39.13,37.54,33.24,25.74.HRMS(EI-TOF)calcd for C15H18N2OS[M+]m/z 274.1140；found,274.1141.
Figure BDA0003069814030000174
1H NMR(400MHz,CD3OD)δ8.68(d,J＝6.3Hz,2H),7.89(d,J＝6.3Hz,2H),7.73(s,1H),3.72(s,2H),3.67–3.50(m,1H),2.62(s,3H),2.30–2.17(m,4H),2.13–2.06(m,2H),1.98(d,J＝8.4Hz,2H).13C NMR(101MHz,CD3OD)δ174.83,151.21,146.35,142.18,122.62,116.27,64.86,39.57,37.31,32.89,26.20.HRMS(EI-TOF)calcd for C16H19N3S[M+]m/z 285.1300；found,285.1299.
Figure BDA0003069814030000175
1H NMR(400MHz,CD3OD)δ7.73(s,1H),7.45(d,J＝8.7Hz,2H),6.92(d,J＝8.8Hz,2H),3.78(s,3H),3.36–3.27(m,3H),2.30(s,3H),2.14–2.11(m,2H),2.00–1.93(m,2H),1.89(ddd,J＝13.3,5.3,2.9Hz,2H),1.73(dd,J＝14.1,6.0Hz,2H)ppm.13C NMR(101MHz,CD3OD)δ175.40,161.35,139.81,137.08,128.91,125.04,115.68,62.48,55.92,40.26,38.74,34.48,26.81ppm.HRMS(EI-TOF)calcd for C18H22N2OS[M+]m/z 314.1453,found 314.1457.
Figure BDA0003069814030000181
1H NMR(400MHz,CD3OD)δ7.58(s,1H),7.32(d,J＝7.4Hz,1H),7.28–7.27(m,2H),7.25–7.20(m,1H),3.50–3.45(m,3H),2.43(s,3H),2.35(s,3H),2.22–2.19(m,2H),2.12–2.00(m,4H),1.86(dd,J＝14.3,5.8Hz,2H)ppm.13C NMR(101MHz,CD3OD)δ176.40,140.99,138.28,137.46,132.01,131.61,129.87,127.36,62.97,40.10,38.49,34.10,26.52,21.28ppm.HRMS(EI-TOF)calcd for C18H22N2S[M+]m/z 298.1504,found 298.1505.
Figure BDA0003069814030000182
1H NMR(400MHz,CD3OD)δ7.74(s,1H),7.42(d,J＝7.3Hz,2H),7.25(t,J＝7.5Hz,2H),7.18(t,J＝7.3Hz,1H),3.27–3.18(m,3H),2.20(s,3H),2.02–1.99(m,2H),1.91–1.85(m,2H),1.80(ddd,J＝13.3,5.1,2.8Hz,2H),1.63(dd,J＝14.2,6.1Hz,2H)ppm.13C NMR(101MHz,CD3OD)δ176.21,139.85,138.31,132.58,130.34,129.46,127.60,62.60,40.25,38.66,34.46,26.74ppm.HRMS(EI-TOF)calcd for C17H20N2S[M+]m/z 284.1347,found 284.1348.
Figure BDA0003069814030000183
1H NMR(400MHz,CD3OD)δ7.87(s,1H),7.53–7.50(m,2H),7.38–7.34(m,2H),3.29–3.28(m,3H),2.32(s,3H),2.15–2.13(m,2H),2.02–1.90(m,4H),1.75(dd,J＝14.3,5.9Hz,2H)ppm.13C NMR(101MHz,CD3OD)δ176.93,138.83,138.46,135.07,131.33,130.38,128.96,62.45,40.32,38.77,34.61,26.82ppm.HRMS(EI-TOF)calcd for C17H19 35ClN2S[M+]m/z 318.0957,found 318.0956.calcd for C17H19 37ClN2S[M+]m/z 320..0928,found 320..0928.
Figure BDA0003069814030000184
1H NMR(400MHz,CDCl3)δ7.78(s,1H),7.63(s,1H),7.41–7.38(m,2H),7.21(t,J＝7.9Hz,1H),3.40–3.34(m,3H),2.39(s,3H),2.14–2.09(m,4H),1.96–1.93(m,2H),1.74(dd,J＝13.8,5.4Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ175.44,138.02,136.36,133.51,130.72,130.38,129.16,125.06,122.92,61.06,39.70,37.53,33.81,26.02ppm.HRMS(EI-TOF)calcd for C17H19 79BrN2S[M+]m/z 362.0452,found 362.0454.calcd for C17H19 81BrN2S[M+]m/z 364.0432,found 364.0436.
Figure BDA0003069814030000191
1H NMR(400MHz,CDCl3)δ8.18–8.15(m,2H),7.89(s,1H),7.62–7.58(m,2H),3.50(br,s,2H),3.39(tt,J＝11.9,5.4Hz,1H),2.48(s,3H),2.35(t,J＝12.4Hz,2H),2.20–2.17(m,2H),2.00–1.97(m,2H),1.82(dd,J＝14.9,6.1Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ175.07,146.05,138.80,136.88,135.20,125.93,123.46,60.79,38.37,35.88,32.55,24.68ppm.HRMS(EI-TOF)calcd for C17H19N3O2S[M+]m/z 329.1198,found 329.1197.
Figure BDA0003069814030000192
1H NMR(400MHz,CDCl3)δ7.78(s,1H),7.51(br,s,4H),3.50(br,s,2H),3.35(tt,J＝11.9,5.4Hz,1H),2.47(s,3H),2.33(t,J＝12.2Hz,2H),2.18–2.14(m,2H),1.98–1.92(m,2H),1.79(dd,J＝14.6,6.0Hz,2H)ppm.13C NMR(100MHz,CDCl3)δ173.71,137.72,135.95,133.97,128.75(q,J＝32.7Hz),125.70,124.98(q,J＝3.7Hz),122.97(q,J＝272.1Hz),60.86,38.30,35.76,32.37,24.65ppm.HRMS(EI-TOF)calcd for C18H19F3N2S[M+]m/z 352.1221,found 352.1222.
Figure BDA0003069814030000193
1H NMR(400MHz,CD3OD)δ7.65(s,1H),7.42–7.38(m,2H),7.03–6.97(m,2H),3.50(br,s,2H),3.35(tt,J＝11.6,5.3Hz,1H),2.48(s,3H),2.33(t,J＝12.3Hz,2H),2.19–2.14(m,2H),1.98–1.94(m,2H),1.82(dd,J＝14.4,6.1Hz,2H)ppm.13C NMR(101MHz,CD3OD)δ172.24(s),161.76(d,J＝248.4Hz),136.94,136.16,127.49(d,J＝8.2Hz),126.43(d,J＝3.4Hz),115.15(d,J＝22.0Hz),61.15,37.92,35.51,31.80,24.40ppm.HRMS(EI-TOF)calcd for C17H19FN2S[M+]m/z 302.1253,found 302.1252.
Figure BDA0003069814030000194
1H NMR(400MHz,CD3OD)δ8.28(s,1H),8.09(dd,J＝8.2,2.0Hz,1H),7.85(s,1H),7.76(d,J＝7.8Hz,1H),7.51(t,J＝8.0Hz,1H),3.68(br,s,2H),3.44(tt,J＝12.0,5.5Hz,1H),2.61(s,3H),2.61–2.54(m,2H),2.28–2.25(m,2H),2.07–2.02(m,2H),1.93(dd,J＝14.6,5.8Hz,2H)ppm.13C NMR(100MHz,CD3OD)δ175.00,150.05,140.35,137.96,134.20,133.79,131.76,124.16,122.36,64.27,39.81,37.31,33.57,26.07ppm.HRMS(EI-TOF)calcd for C17H19N3O2S[M+]m/z 329.1198,found 329.1197.
Figure BDA0003069814030000195
1H NMR(400MHz,CD3OD)δ7.75(s,1H),7.43–7.37(m,2H),7.26–7.22(m,2H),3.79(br,s,2H),3.48(tt,J＝12.0,5.5Hz,1H),2.66(s,3H),2.44–2.37(m,2H),2.32–2.28(m,2H),2.15–2.10(m,2H),2.01(dd,J＝14.8,5.8Hz,2H)ppm.13C NMR(101MHz,CD3OD)δ174.63,142.50,136.26,133.82,132.76,131.86,131.16,130.98,128.65,64.21,39.78,37.11,33.34,26.21ppm.HRMS(EI-TOF)calcd for C17H19 35ClN2S[M+]m/z 318.0957,found 318.0956.calcd for C17H19 37ClN2S[M+]m/z 320.0928,found 320.0930.
Figure BDA0003069814030000201
1H NMR(400MHz,CDCl3)δ7.87(d,J＝1.3Hz,1H),7.32(t,J＝8.1Hz,1H),7.28–7.22(m,2H),3.35–3.28(m,3H),2.32(s,3H),2.09–2.01(m,4H),1.91–1.86(m,2H),1.68(dd,J＝14.4,6.2Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ175.08,157.49(d,J＝254.7Hz),139.57(d,J＝7.4Hz),129.03(d,J＝4.5Hz),128.90(d,J＝4.0Hz),126.93(d,J＝3.5Hz),120.52(d,J＝9.6Hz),118.89(d,J＝25.5Hz),117.87(d,J＝13.8Hz),60.13,38.77,36.67,32.80,25.10ppm.HRMS(EI-TOF)calcd for C17H18 79BrFN2S[M+]m/z 380.0358,found 380.0359.calcd for C17H18 81BrFN2S[M+]m/z 382.0338,found 382.0338.
Figure BDA0003069814030000202
1H NMR(400MHz,CDCl3)δ7.75(s,1H),7.40(d,J＝8.1Hz,2H),7.18(d,J＝7.9Hz,2H),3.40–3.32(m,3H),2.39(s,3H),2.36(s,3H),2.15–2.08(m,4H),1.95(ddd,J＝13.5,5.2,3.3Hz,2H),1.75(dd,J＝14.4,6.2Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ174.34,138.35,137.96,136.85,129.65,128.75,126.50,61.20,39.75,37.70,33.87,26.13,21.18ppm.HRMS(EI-TOF)calcd for C18H22N2S[M+]m/z 298.1504,found 298.1505.
Figure BDA0003069814030000203
1H NMR(400MHz,CDCl3)δ7.69(s,1H),7.06(s,2H),6.87(s,1H),3.33–3.25(m,3H),2.31(s,3H),2.26(s,3H),2.08–1.98(m,4H),1.87(ddd,J＝13.0,4.6,2.6Hz,2H),1.67(dd,J＝14.4,6.3Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ173.59,137.56,137.44,136.12,130.37,128.73,123.47,60.06,38.67,36.65,32.87,25.15,20.23ppm.HRMS(EI-TOF)calcd for C19H24N2S[M+]m/z 312.1660,found 312.1663.
Figure BDA0003069814030000204
1H NMR(400MHz,CDCl3)δ7.72(s,1H),7.45–7.42(m,2H),7.33–7.30(m,2H),3.73(br,s,2H),3.42(tt,J＝10.0,5.4Hz,1H),2.68–2.62(m,5H),2.30–2.27(m,2H),2.07–2.02(m,2H),1.96(dd,J＝14.8,5.9Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ174.29,136.71,136.03,131.11,129.56,127.01,120.89,60.17,38.76,36.69,32.91,25.08ppm.HRMS(EI-TOF)calcd for C17H19 79BrN2S[M+]m/z 362.0452,found 362.0451.calcd for C17H19 81BrN2S[M+]m/z 364.0432,found 364.0434.
Figure BDA0003069814030000211
1H NMR(400MHz,CDCl3)δ7.83(s,1H),7.59(d,J＝8.4Hz,2H),7.53(d,J＝8.4Hz,2H),3.36–3.30(m,3H),2.33(s,3H),2.10–2.04(m,4H),1.92–1.87(m,2H),1.69(dd,J＝14.0,5.8Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ175.89,138.28,135.18,135.08,131.79,125.81,117.51,110.23,60.20,38.92,36.81,33.02,25.04ppm.HRMS(EI-TOF)calcd for C18H19N3S[M+]m/z 309.1300,found 309.1299.
Figure BDA0003069814030000212
1H NMR(400MHz,CDCl3)δ7.77(s,1H),7.54–7.51(m,2H),7.23(d,J＝8.1Hz,2H),3.40–3.33(m,1H),3.31–3.29(m,2H),2.36(s,3H),2.14–2.11(m,2H),2.05(td,J＝13.1,2.3Hz,2H),1.94(ddd,J＝13.3,5.1,3.0Hz,2H),1.72(dd,J＝14.4,6.3Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ175.82,148.72,137.83,136.52,130.43,127.87,121.45,120.38(q,J＝257.6Hz).61.04,39.94,37.98,34.02,26.13ppm.HRMS(EI-TOF)calcd for C18H19F3N2OS[M+]m/z 368.1170,found 368.1173.
Figure BDA0003069814030000213
1H NMR(400MHz,CDCl3)δ7.71(s,1H),7.26–7.22(m,2H),7.18(t,J＝7.4Hz,1H),7.04(d,J＝7.1Hz,1H),3.54(br,s,2H),3.37(tt,J＝11.4,5.0Hz,1H),2.53(s,3H),2.40(t,J＝12.8Hz,2H),2.30(s,3H),2.21–2.18(m,2H),1.99–1.96(m,2H),1.87–1.82(m,2H)ppm.13C NMR(101MHz,CDCl3)δ171.73,137.99,137.74,136.25,130.25,127.96,127.90,126.39,122.77,60.90,37.87,35.35,32.15,24.63,20.35ppm.HRMS(EI-TOF)calcd for C18H22N2S[M+]m/z 298.1504,found 298.1503.
Figure BDA0003069814030000214
1H NMR(400MHz,CDCl3)δ7.72(s,1H),7.21(t,J＝7.9Hz,1H),7.03(d,J＝7.5Hz,1H),6.97(s,1H),6.78(d,J＝8.2Hz,1H),3.76(s,3H),3.50(br,s,2H),3.35(tt,J＝11.5,5.3Hz,1H),2.49(s,3H),2.33(t,J＝12.6Hz,2H),2.19–2.16(m,2H),1.98–1.95(m,2H),1.84–1.79(m,2H)ppm.13C NMR(101MHz,CDCl3)δ172.29,158.94,137.54,136.56,131.65,129.05,118.19,112.61,111.29,60.67,54.34,37.94,35.52,32.26,24.72ppm.HRMS(EI-TOF)calcd for C18H22N2OS[M+]m/z 314.1453,found 314.1456.
Figure BDA0003069814030000221
1H NMR(400MHz,CDCl3)δ7.75(s,1H),7.33(s,1H),7.32(s,1H),7.22(t,J＝1.8Hz,1H),3.49(br,s,2H),3.41–3.32(m,1H),2.48(s,3H),2.34(t,J＝12.8Hz,2H),2.20–2.17(m,2H),1.99–1.94(m,2H),1.82(dd,J＝14.3,5.8Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ176.11,138.80,135.55,135.43,134.44,127.77,124.83,61.27,39.72,37.51,33.91,26.03ppm.HRMS(EI-TOF)calcd for C17H18 35Cl2N2S[M+]m/z 352.0568,found 352.0567.calcd for C17H18 35Cl37ClN2S[M+]m/z 354.0538,found 354.0544.calcd for C17H18 37Cl2N2S[M+]m/z 356.0509,found 356.0518.
Figure BDA0003069814030000222
1H NMR(400MHz,CDCl3)δ7.73(s,1H),7.30–7.20(m,2H),7.14(dt,J＝9.8,2.2Hz,1H),6.95–6.90(m,1H),3.58(br,s,2H),3.38(tt,J＝12.0,5.5Hz,1H),2.55(s,3H),2.44(t,J＝12.4Hz,2H),2.24–2.20(m,2H),2.02–1.97(m,2H),1.87(dd,J＝14.6,5.9Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ172.46,161.96(d,J＝246.7Hz),137.07,136.53(d,J＝2.7Hz),132.41(d,J＝8.3Hz),129.61(d,J＝8.6Hz),121.42(d,J＝2.9Hz),113.96(d,J＝21.2Hz),112.44(d,J＝23.0Hz),60.98,37.93,35.32,32.14,24.57ppm.HRMS(EI-TOF)calcd for C17H19FN2S[M+]m/z 302.1253,found 302.1254.
Figure BDA0003069814030000223
1H NMR(400MHz,CDCl3)δ7.73(s,1H),7.42(t,J＝1.6Hz,1H),7.31(dt,J＝7.3,1.6Hz,1H),7.23(t,J＝7.7Hz,1H),7.19(dt,J＝7.9,1.7Hz,1H),3.53(br,s,2H),3.36(tt,J＝12.0,5.4Hz,1H),2.51(s,3H),2.38(t,J＝12.3Hz,2H),2.21–2.17(m,2H),1.99–1.94(m,2H),1.83(dd,J＝14.6,6.0Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ172.86,137.09,136.19,133.87,132.13,129.25,127.06,125.48,123.81,60.86,38.08,35.53,32.27,24.65ppm.HRMS(EI-TOF)calcd for C17H19 35ClN2S[M+]m/z 318.0957,found 318.0961.calcd for C17H19 37ClN2S[M+]m/z 320.0928,found 320.0932.
Figure BDA0003069814030000224
1H NMR(400MHz,CDCl3)δ7.78(s,1H),7.66(s,1H),7.61(d,J＝7.6Hz,1H),7.49–7.41(m,2H),3.67(br,s,2H),3.42(tt,J＝11.8,5.3Hz,1H),2.61–2.52(m,5H),2.27–2.24(m,2H),2.05–2.00(m,2H),1.91(dd,J＝14.5,5.9Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ172.37,137.39,136.35,131.20,130.44(q,J＝32.5Hz),128.91,128.62,123.71(q,J＝3.6Hz),122.78(q,J＝272.5Hz),122.22(q,J＝3.7Hz),61.22,37.78,35.01,31.98,24.42ppm.HRMS(EI-TOF)calcd for C18H19F3N2S[M+]m/z 352.1221,found 352.1223.
Figure BDA0003069814030000231
1H NMR(400MHz,CDCl3)δ7.69(s,1H),7.59(dd,J＝8.0,1.1Hz,1H),7.36(dd,J＝7.7,1.7Hz,1H),7.26(td,J＝7.6,1.2Hz,1H),7.13(td,J＝7.7,1.7Hz,1H),3.58(br,s,2H),3.40(tt,J＝12.0,5.5Hz,1H),2.55(s,3H),2.44(t,J＝12.3Hz,2H),2.24–2.21(m,2H),2.05–1.99(m,2H),1.87(dd,J＝14.7,6.0Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ173.06,140.40,134.89,132.65,131.14,130.98,128.70,126.57,122.02,60.86,37.73,35.13,31.94,24.64ppm.HRMS(EI-TOF)calcd for C17H19 79BrN2S[M+]m/z 362.0452,found 362.0453.calcd for C17H19 81BrN2S[M+]m/z 364.0432,found 364.0432.
Figure BDA0003069814030000232
1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.48(d,J＝7.4Hz,1H),7.21(t,J＝7.6Hz,1H),6.91(t,J＝8.9Hz,2H),3.84(s,3H),3.54(br,s,2H),3.38(tt,J＝11.2,5.1Hz,1H),2.53(s,3H),2.39(t,J＝11.8Hz,2H),2.22–2.20(m,2H),2.01–1.96(m,2H),1.87–1.82(m,2H)ppm.13C NMR(101MHz,CDCl3)δ173.17,155.35,139.61,133.57,129.12,128.57,120.98,120.41,111.42,61.76,55.54,38.65,36.19,32.89,25.71ppm.HRMS(EI-TOF)calcd for C18H22N2OS[M+]m/z 314.1453,found 314.1452.
Figure BDA0003069814030000233
1H NMR(400MHz,CDCl3)δ8.02–8.00(m,1H),7.81–7.77(m,2H),7.65(s,1H),7.44–7.37(m,4H),3.46(br,s,2H),3.43–3.35(m,1H),2.45(s,3H),2.36–2.29(m,2H),2.17–2.13(m,2H),1.99(ddd,J＝13.4,4.6,2.7Hz,2H),1.79(dd,J＝14.5,6.0Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ173.50,139.85,134.49,132.70,130.80,128.06,127.68,127.63,127.40,125.74,125.18,124.20,124.19,60.61,38.11,35.78,32.29,24.81ppm.HRMS(EI-TOF)calcd for C21H22N2S[M+]m/z 334.1504,found 334.1506.
Figure BDA0003069814030000234
1H NMR(400MHz,CDCl3)δ8.54(d,J＝2.2Hz,1H),7.84(s,1H),7.77(dd,J＝8.3,2.5Hz,1H),7.36(d,J＝8.3Hz,1H),3.44–3.36(m,3H),2.40(s,3H),2.17–2.10(m,4H),2.00–1.94(m,2H),1.77(dd,J＝14.0,5.9Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ176.51,150.60,147.02,138.84,136.31,132.99,126.87,124.45,61.20,39.86,37.75,33.96,26.04ppm.HRMS(EI-TOF)calcd for C16H18 35ClN3S[M+]m/z 319.0910,found 319.0912.calcd for C16H18 37ClN3S[M+]m/z 321.0880,found 321.0881.
Figure BDA0003069814030000241
1H NMR(400MHz,CDCl3)δ7.77(s,1H),7.38(s,1H),7.34(d,J＝8.3Hz,1H),7.30–7.27(m,1H),3.99(br,s,2H),3.57(tt,J＝12.1,5.3Hz,1H),2.96–2.89(m,2H),2.85(s,3H),2.45–2.42(m,2H),2.40(s,3H),2.21–2.11(m,4H)ppm.13C NMR(101MHz,CDCl3)δ170.76,138.55,137.62,136.87,134.42,129.64,129.59,129.12,125.26,63.02,34.52,32.38,29.68,25.11,20.02ppm.HRMS(EI-TOF)calcd for C18H21 35ClN2S[M+]m/z 332.1114,found 332.1112.calcd for C18H21 37ClN2S[M+]m/z 334.1084,found 334.1092.
Figure BDA0003069814030000242
1H NMR(400MHz,CDCl3)δ7.70(s,1H),7.33–7.26(m,2H),7.00(t,J＝8.9Hz,1H),3.40–3.31(m,3H),2.37(s,3H),2.30(s,3H),2.15–2.04(m,4H),1.94(ddd,J＝13.4,5.1,3.2Hz,2H),1.74(dd,J＝14.4,6.3Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ174.9,161.1(d,J＝246.8Hz),137.3,137.1(d,J＝0.9Hz),129.7(d,J＝5.3Hz),127.5(d,J＝3.8Hz),125.6(d,J＝8.1Hz),125.5(d,J＝17.8Hz)115.6(d,J＝22.9Hz),61.1,39.9,37.9,33.9,26.1,14.5(d,J＝3.4Hz)ppm.HRMS(EI-TOF)calcd for C18H21FN2S[M+]m/z 316.1409,found 316.1408.
Figure BDA0003069814030000243
1H NMR(400MHz,CDCl3)δ7.77(s,1H),7.50(d,J＝8.3Hz,1H),7.36(d,J＝1.9Hz,1H),7.18(dd,J＝8.2,2.1Hz,1H),3.40–3.32(m,3H),2.41(s,3H),2.38(s,3H),2.15–2.06(m,4H),1.94(ddd,J＝12.9,4.6,2.7Hz,2H),1.74(dd,J＝14.4,6.3Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ175.20,138.55,137.57,137.11,132.84,130.78,128.70,125.32,124.39,61.15,39.85,37.78,33.95,26.12,22.91ppm.HRMS(EI-TOF)calcd for C18H21 79BrN2S[M+]m/z 376.0609,found 376.0611.calcd for C18H21 81BrN2S[M+]m/z 378.0588,found 378.0590.
Figure BDA0003069814030000244
1H NMR(400MHz,CDCl3)δ7.72(s,1H),7.28–7.27(m,1H),7.22–7.20(m,2H),7.08(d,J＝7.4Hz,1H),3.54(br,s,2H),3.37(tt,J＝12.0,5.4Hz,1H),2.60(q,J＝7.6Hz,2H),2.52(s,3H),2.38(t,J＝13.4Hz,2H),2.21–2.18(m,2H),2.01–1.96(m,2H),1.85(dd,J＝14.6,5.9Hz,2H),1.19(t,J＝7.6Hz,3H)ppm.13C NMR(101MHz,CDCl3)δ171.81,144.12,138.05,136.23,130.29,127.98,126.78,125.29,123.03,60.81,37.89,35.45,32.19,27.77,24.65,14.55ppm.HRMS(EI-TOF)calcd for C19H24N2S[M+]m/z 312.1660,found 312.1661.
Figure BDA0003069814030000251
1H NMR(400MHz,CDCl3)δ7.72(s,1H),7.29–7.28(m,1H),7.26–7.25(m,1H),7.20(s,1H),7.13–7.10(m,1H),3.49(br,s,2H),3.36(tt,J＝11.9,5.3Hz,1H),2.86(hept,J＝6.9Hz,1H),2.48(s,3H),2.33–2.27(m,2H),2.19–2.15(m,2H),1.99–1.93(m,2H),1.81(dd,J＝14.6,6.0Hz,2H),1.20(d,J＝6.9Hz,6H)ppm.13C NMR(101MHz,CDCl3)δ172.15,148.75,138.01,136.23,130.31,127.99,125.28,123.95,123.21,60.66,38.07,35.68,33.08,32.30,24.74,22.90ppm.HRMS(EI-TOF)calcd for C20H26N2S[M+]m/z 326.1817,found 326.1819.
Figure BDA0003069814030000252
1H NMR(400MHz,CDCl3)δ7.75(s,1H),7.45(d,J＝8.4Hz,2H),7.39(d,J＝8.4Hz,2H),3.39–3.28(m,3H),2.36(s,3H),2.13–2.08(m,2H),2.06–2.02(m,2H),1.93(ddd,J＝13.2,4.9,2.9Hz,2H),1.72(dd,J＝14.3,6.2Hz,2H),1.33(s,9H)ppm.13C NMR(101MHz,CDCl3)δ174.8,151.2,138.1,137.0,128.8,126.4,125.9,61.1,39.9,37.9,34.6,34.0,31.2,26.2ppm.HRMS(EI-TOF)calcd for C21H28N2S[M+]m/z 340.1973,found 340.1974.
Figure BDA0003069814030000253
1H NMR(400MHz,CDCl3)δ7.79(s,1H),7.70(dt,J＝8.9,1.8Hz,2H),7.25(dt,J＝8.7,2.1Hz,2H),3.40–3.33(m,3H),2.38(s,3H),2.16–2.06(m,4H),1.94(ddd,J＝12.9,4.7,2.9Hz,2H),1.75(dd,J＝14.2,6.4Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ175.5,138.1,137.8,137.1,131.2,128.2,93.3,61.1,39.8,37.7,34.0,26.1ppm.HRMS(EI-TOF)calcd for C17H19IN2S[M+]m/z 410.0314,found 410.0316.
Figure BDA0003069814030000254
1H NMR(400MHz,CDCl3)δ7.74(s,1H),7.56(d,J＝1.6Hz,1H),7.46(d,J＝8.6Hz,1H),7.21(dd,J＝8.6,1.1Hz,1H),3.39(tt,J＝11.9,5.7Hz,1H),3.31(br,s,2H),2.36(s,3H),2.15–2.10(m,2H),2.08–2.04(m,2H),1.97(ddd,J＝13.1,5.0,3.0Hz,2H),1.73(dd,J＝14.4,6.1Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ177.0,148.8(q,J＝2.0Hz),141.7,133.9,132.6,131.4,126.0,123.4,120.3(q,J＝258.9Hz),119.9,61.1,40.0,38.0,33.9,26.2ppm.HRMS(EI-TOF)calcd for C18H18 79BrF3N2OS[M+]m/z 446.0275,found 446.0276.calcd for C18H18 81BrF3N2OS[M+]m/z 448.0255,found 448.0254.
Figure BDA0003069814030000261
1H NMR(400MHz,CDCl3)δ7.79(s,1H),7.78(s,1H),7.46(dd,J＝8.5,2.0Hz,1H),7.31(d,J＝8.4Hz,1H),3.41–3.32(m,3H),2.37(s,3H),2.16–2.04(m,4H),1.97–1.92(m,2H),1.73(dd,J＝14.1,6.2Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ176.5,145.9(q,J＝1.5Hz),138.6,135.1,132.0,131.7,126.7,122.6,120.4(q,J＝259.6Hz),116.7,61.1,39.9,37.9,34.1,26.1ppm.HRMS(EI-TOF)calcd for C18H18 79BrF3N2OS[M+]m/z 446.0275,found 446.0273.calcd for C18H18 81BrF3N2OS[M+]m/z 448.0255,found 448.0258.
Figure BDA0003069814030000262
1H NMR(400MHz,CDCl3)δ7.76(s,1H),7.20(s,2H),3.38–3.31(m,1H),3.29–3.27(m,2H),2.42(s,6H),2.34(s,3H),2.13–2.09(m,2H),2.03(td,J＝12.9,2.4Hz,1H),1.92(ddd,J＝13.2,5.3,3.2Hz,2H),1.71(dd,J＝14.3,6.2Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ175.3,138.9,137.4,137.1,130.0,126.1,61.0,39.9,37.9,34.0,26.2,23.8ppm.HRMS(EI-TOF)calcd for C19H23 79BrN2S[M+]m/z 390.0765,found 390.0764.calcd for C19H23 81BrN2S[M+]m/z 392.0745,found 392.0747.
Figure BDA0003069814030000263
1H NMR(400MHz,CDCl3)δ7.80(s,1H),7.50(d,J＝8.6Hz,1H),7.37(d,J＝1.7Hz,2H),7.17(ddd,J＝8.6,2.3,1.0Hz,1H),3.39(tt,J＝11.9,5.7Hz,1H),3.32–3.30(m,2H),2.37(s,3H),2.15–2.11(m,2H),2.06(dd,J＝12.5,2.0Hz,2H),1.96(ddd,J＝13.3,5.4,3.3Hz,2H),1.74(dd,J＝14.5,6.2Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ177.1,148.8(d,J＝1.8Hz),141.7,133.5,132.4,132.2,129.4,122.9,120.3(q,J＝258.8Hz),119.5,61.1,39.9,37.9,33.9,26.2ppm.HRMS(EI-TOF)calcd for C18H18 35ClF3N2OS[M+]m/z 402.0780,found 402.0782.calcd for C18H18 37ClF3N2OS[M+]m/z 404.0751,found 404.0751.
Figure BDA0003069814030000264
1H NMR(400MHz,CDCl3)δ7.84(s,1H),7.62–7.57(m,6H),7.45(t,J＝7.6Hz,2H),7.36(t,J＝7.3Hz,1H),3.42–3.34(m,1H),3.31–3.30(m,2H),2.37(s,3H),2.14–2.11(m,2H),2.07–2.04(m,2H),1.95(ddd,J＝13.3,5.1,3.1Hz,2H),1.73(dd,J＝14.3,6.3Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ175.30,140.78,140.28,137.82,137.38,130.62,128.86,127.64,127.56,126.95,126.92,61.09,39.98,38.01,34.08,26.23ppm.HRMS(EI-TOF)calcd for C23H24N2S[M+]m/z 360.1660,found 360.1663.
Figure BDA0003069814030000271
1H NMR(400MHz,CDCl3)δ7.87(s,1H),7.73(s,1H),7.62(d,J＝7.4Hz,2H),7.54–7.46(m,5H),7.39(t,J＝7.3Hz,1H),3.39(tt,J＝12.0,5.7Hz,1H),3.31(br,s,2H),2.38(s,3H),2.16–2.11(m,2H),2.08–2.05(m,2H),1.97(ddd,J＝13.1,4.7,2.8Hz,2H),1.74(dd,J＝14.4,6.2Hz,3H)ppm.13C NMR(101MHz,CDCl3)δ175.35,142.12,140.57,138.06,137.57,132.14,129.43,128.86,127.65,127.18,126.87,125.50,125.46,61.11,39.94,37.93,34.06,26.23ppm.HRMS(EI-TOF)calcd for C23H24N2S[M+]m/z 360.1660,found 360.1662.
Figure BDA0003069814030000272
1H NMR(400MHz,CDCl3)δ7.86(s,1H),7.73–7.67(m,1H),7.63–7.61(m,1H),7.55–7.37(m,6H),3.43–3.36(m,1H),3.32(br,s,2H),2.39(s,3H),2.16–2.13(m,2H),2.09–2.06(m,2H),2.00–1.94(m,2H),1.75(dd,J＝14.2,6.1Hz,2H)ppm.HRMS(EI-TOF)calcd for C23H23 35ClN2S[M+]m/z 394.1270,found 394.1272.calcd for C23H23 37ClN2S[M+]m/z 396.1241,found 396.1249.
Figure BDA0003069814030000273
1H NMR(400MHz,CDCl3)δ7.72(s,1H),7.49–7.45(m,2H),7.38–7.32(m,2H),7.15–7.11(m,1H),7.05–7.04(m,1H),7.03–7.01(m,2H),7.00–6.99(m,1H),3.39–3.32(m,1H),3.29–3.27(m,2H),2.35(s,3H),2.13–2.10(m,2H),2.04(td,J＝12.9,2.3Hz,2H),1.93(ddd,J＝13.3,5.3,3.2Hz,2H),1.72(dd,J＝14.4,6.3Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ174.95,157.31,156.73,138.76,137.56,136.92,129.84,128.06,123.65,119.13,119.09,61.07,40.03,38.08,34.05,26.23ppm.HRMS(EI-TOF)calcd for C23H24N2OS[M+]m/z 376.1609,found 376.1612.
Figure BDA0003069814030000274
1H NMR(400MHz,CDCl3)δ7.86(d,J＝3.7Hz,1H),7.62(d,J＝5.0Hz,1H),7.18(t,J＝4.4Hz,1H),4.39–4.30(m,2H),3.39(tt,J＝11.9,5.3Hz,1H),2.11–2.05(m,4H),1.93–1.87(m,2H),1.78(dd,J＝14.1,6.5Hz,2H),1.49(s,9H)ppm.13C NMR(101MHz,CDCl3)δ173.51,171.07,153.35,131.77,131.65,128.43,125.92,79.40,53.46,52.72,35.08,34.60,28.52,28.29,27.71,27.62ppm.HRMS(EI-TOF)calcd for C18H23N3O3S[M+]m/z 361.1460,found 361.1462.
Figure BDA0003069814030000281
1H NMR(400MHz,CDCl3)δ8.17–8.14(m,2H),7.35(d,J＝8.2Hz,2H),4.39–4.32(m,2H),3.47–3.38(m,1H),2.16–2.07(m,4H),1.92–1.88(m,2H),1.83–1.78(m,2H),1.50(s,9H)ppm.13C NMR(101MHz,CDCl3)δ174.20,173.76,153.35,152.23(q,J＝1.6 Hz),129.90,122.77,121.05,120.26(q,J＝258.9Hz),79.37,53.45,52.75,35.01,34.66,28.48,28.27,27.67,27.58ppm.HRMS(EI-TOF)calcd for C21H24F3N3O4[M+]m/z 439.1719,found 439.1723.
Figure BDA0003069814030000282
1H NMR(400MHz,CDCl3)δ8.18(d,J＝8.0Hz,2H),7.74(d,J＝8.1Hz,2H),4.37–4.28(m,2H),3.41(tt,J＝11.8,5.2Hz,1H),2.10–2.04(m,4H),1.90–1.85(m,2H),1.80–1.74(m,2H),1.46(s,9H)ppm.13C NMR(101MHz,CDCl3)δ174.10,173.90,153.36,134.13(q,J＝32.9Hz),128.39,127.44(q,J＝1.1Hz),126.07(q,J＝3.7Hz),123.45(q,J＝272.7Hz),79.41,53.43,52.75,34.96,34.63,28.49,28.31,27.70,27.65ppm.HRMS(EI-TOF)calcd for C21H24F3N3O3[M+]m/z 423.1770,found 423.1767.
Figure BDA0003069814030000283
1H NMR(400MHz,CDCl3)δ7.80–7.79(m,1H),7.57–7.56(m,1H),7.13–7.10(m,1H),3.62(br,s,2H),3.23–3.14(m,1H),2.60(s,3H),2.48–2.39(m,2H),2.29–2.26(m,2H),1.97–1.85(m,4H)ppm.13C NMR(101MHz,CDCl3)δ172.48,171.25,131.99,131.85,128.48,125.62,61.27,38.27,32.81,26.32,25.60ppm.HRMS(EI-TOF)calcd for C14H17N3OS[M+]m/z 275.1092,found 275.1093.
Figure BDA0003069814030000284
1H NMR(400MHz,CDCl3)δ7.93(s,1H),7.91–7.89(m,1H),7.41–7.36(m,2H),3.31–3.29(m,2H),3.19(tt,J＝12.0,5.5Hz,1H),2.42(s,3H),2.37(s,3H),2.19–2.12(m,4H),1.82(ddd,J＝13.6,5.2,3.3Hz,2H),1.75–1.69(m,2H)ppm.13C NMR(101MHz,CDCl3)δ175.45,173.97,138.86,133.30,128.88,128.51,125.13,124.26,60.61,39.71,34.63,27.16,26.21,21.24ppm.HRMS(EI-TOF)calcd for C17H21N3O[M+]m/z 283.1685,found 283.1683.
Figure BDA0003069814030000291
1H NMR(400MHz,CDCl3)δ8.17(d,J＝8.8Hz,2H),7.36(d,J＝8.2Hz,2H),3.41(br,s,2H),3.23(tt,J＝11.8,5.4Hz,1H),2.45(s,3H),2.28–2.18(m,4H),1.90–1.84(m,2H),1.79(dd,J＝14.5,6.1Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ174.21,173.83,152.23(q,J＝1.7Hz),129.95,122.78,121.07,120.27(q,J＝259.0Hz),60.84,39.49,34.31,26.88,26.01ppm.HRMS(EI-TOF)calcd for C17H18F3N3O2[M+]m/z 353.1351,found 353.1352.
Figure BDA0003069814030000292
1H NMR(400MHz,CDCl3)δ8.21(d,J＝8.3Hz,2H),7.75(d,J＝8.4Hz,2H),3.33–3.30(m,2H),3.20(tt,J＝12.0,5.5Hz,1H),2.36(s,3H),2.19–2.12(m,4H),1.81(ddd,J＝13.5,5.0,3.1Hz,2H),1.72(dd,J＝14.6,6.3Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ174.24,173.95,134.00(q,J＝32.9Hz),128.37,127.47,126.02(q,J＝3.7Hz),123.45(q,J＝272.7Hz),60.66,39.78,34.69,27.04,26.08ppm.HRMS(EI-TOF)calcd for C17H18F3N3O[M+]m/z 337.1402,found 337.1400.
Figure BDA0003069814030000293
1H NMR(400MHz,CDCl3)δ8.01(d,J＝8.5Hz,2H),7.46(d,J＝8.5Hz,2H),3.33(br,s,2H),3.18(tt,J＝11.9,5.5Hz,1H),2.38(s,3H),2.20–2.12(m,4H),1.84–1.78(m,2H),1.72(dd,J＝14.3,6.1Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ204.82,174.39,173.95,138.93,129.39,129.28,122.78,60.70,39.66,34.52,26.98,26.08ppm.HRMS(EI-TOF)calcd for C16H18 35ClN3O[M+]m/z 303.1138,found 303.1139.calcd for C16H18 37ClN3O[M+]m/z 305.1109,found 305.1116.
Figure BDA0003069814030000294
1H NMR(400MHz,CDCl3)δ8.09(dt,J＝9.5,2.7Hz,2H),7.42(d,J＝7.1Hz,2H),7.35–7.31(m,4H),7.27–7.25(m,1H),3.62(s,2H),3.41–3.33(m,3H),2.21–2.14(m,4H),1.87(ddd,J＝13.3,5.1,3.4Hz,2H),1.74(dd,J＝14.6,6.4Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ169.87,163.55,151.38,139.49,128.83,128.57,128.53,128.36,128.26,126.93,122.68,121.25,121.20,120.33(q,J＝258.6Hz),58.57,56.51,35.09,27.43,26.42ppm.HRMS(EI-TOF)calcd for C23H22F3N3O2[M+]m/z 429.1664,found 429.1666.
Figure BDA0003069814030000301
1H NMR(400MHz,CDCl3)δ8.20(d,J＝8.1Hz,2H),7.87(dd,J＝6.4,2.7Hz,2H),7.74(d,J＝8.3Hz,2H),7.46–7.40(m,3H),4.20(d,J＝6.4Hz,2H),3.93(s,2H),3.66–3.58(m,1H),3.28(t,J＝12.9Hz,2H),2.47–2.45(m,2H),2.18–2.10(m,4H)ppm.13C NMR(101MHz,CDCl3)δ167.16,164.14,133.27(q,J＝32.9Hz),131.03,130.11,129.40,128.77,127.40,126.29(q,J＝272.9Hz),126.73,126.05(q,J＝3.7Hz),60.25,55.28,32.60,26.27,24.84ppm.HRMS(EI-TOF)calcd for C23H22F3N3O[M+]m/z 413.1715,found 413.1714.
Figure BDA0003069814030000302
1H NMR(400MHz,CDCl3)δ8.07(d,J＝8.8Hz,2H),7.34(d,J＝8.3Hz,2H),3.43–3.34(m,3H),2.40(s,3H),2.29–2.17(m,4H),1.90(ddd,J＝13.0,4.4,2.7Hz,4H),1.75(dd,J＝14.6,6.3Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ169.27,163.67,151.42(q,J＝2.0Hz),128.56,122.54,121.19,120.29(q,J＝258.8Hz),60.77,40.05,34.59,26.79,25.86ppm.HRMS(EI-TOF)calcd for C17H18F3N3O2[M+]m/z 353.1351,found 353.1349.
Figure BDA0003069814030000303
1H NMR(400MHz,CDCl3)δ7.85(s,1H),7.81(d,J＝7.6Hz,1H),7.37(t,J＝7.6Hz,1H),7.32(d,J＝7.7Hz,1H),3.41–3.32(m,3H),2.42(s,3H),2.37(s,3H),2.23–2.14(m,4H),1.87(ddd,J＝13.5,5.1,3.3Hz,2H),1.72(dd,J＝14.5,6.2Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ169.05,164.85,138.83,132.30,128.87,127.30,123.88,60.70,40.21,34.83,26.90,25.95,21.28ppm.HRMS(EI-TOF)calcd for C17H21N3O[M+]m/z 283.1685,found 283.1684.
Figure BDA0003069814030000304
1H NMR(400MHz,CDCl3)δ7.90(d,J＝8.9Hz,2H),6.94(d,J＝8.9Hz,2H),3.82(s,3H),3.34–3.26(m,3H),2.31(s,3H),2.15–2.08(m,4H),1.84–1.79(m,2H),1.66(dd,J＝14.2,6.1Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ168.63,164.62,162.14,128.49,116.59,114.39,60.69,55.42,40.14,34.77,26.86,25.97ppm.HRMS(EI-TOF)calcd for C17H21N3O2[M+]m/z 299.1634,found 299.1630.
Figure BDA0003069814030000311
1H NMR(400MHz,CDCl3)δ8.01(d,J＝6.6Hz,2H),7.49(d,J＝6.4Hz,2H),3.40–3.33(m,3H),2.37(s,3H),2.23–2.14(m,4H),1.90–1.85(m,2H),1.75–1.70(m,2H)ppm.13C NMR(101MHz,CDCl3)δ169.12,164.67,131.49,128.95,126.73,124.01,60.67,40.10,34.68,26.86,25.95ppm.HRMS(EI-TOF)calcd for C16H18ClN3O[M+]m/z,found.
Figure BDA0003069814030000312
1H NMR(400MHz,CDCl3)δ8.15(d,J＝8.2Hz,2H),7.76(d,J＝8.3Hz,2H),3.43–3.34(m,3H),2.38(s,3H),2.24–2.16(m,4H),1.90(ddd,J＝12.8,4.6,2.8Hz,2H),1.73(dd,J＝14.6,6.3Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ169.79,163.57,133.15(q,J＝32.7Hz),127.25,127.08,126.04(q,J＝3.8Hz),123.55(d,J＝272.7Hz),60.71,40.22,34.80,26.92,25.92ppm.HRMS(EI-TOF)calcd for C17H18F3N3O[M+]m/z 337.1402,found 337.1403.
Figure BDA0003069814030000313
1H NMR(400MHz,DMSO-d6)δ8.22(d,J＝8.1Hz,2H),7.99(d,J＝8.1Hz,2H),4.07(br,s,2H),3.80(tt,J＝12.1,6.5Hz,1H),3.24(s,3H),3.11(s,3H),2.53–2.50(m,2H),2.43–2.40(m,2H),2.27–2.19(m,4H)ppm.13C NMR(101MHz,DMSO-d6)δ168.13,162.98,131.47(q,J＝32.4Hz),127.31,127.10,126.41(q,J＝3.6Hz),123.67(q,J＝272.4Hz),67.54,50.32,43.54,28.69,24.53,22.58ppm.HRMS(ESI-TOF)calcd for C18H21F3N3O[M+]m/z 352.1637,found 352.1638.
Figure BDA0003069814030000314
1H NMR(400MHz,CDCl3)δ7.97(d,J＝8.7Hz,2H),7.31(d,J＝8.6Hz,2H),3.58(tt,J＝11.8,5.6Hz,1H),3.36(br,s,2H),2.39(s,3H),2.19–2.12(m,4H),2.04–1.97(m,2H),1.79(dd,J＝14.4,6.0Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ175.39,166.65,150.93,129.37,128.88,128.54,121.29,121.20,120.32(q,J＝258.3Hz),61.30,40.12,38.51,31.39,25.94ppm.HRMS(EI-TOF)calcd for C17H18F3N3OS[M+]m/z 369.1123,found 369.1122.
Figure BDA0003069814030000315
1H NMR(400MHz,CDCl3)δ7.75(s,1H),7.69(d,J＝7.6Hz,1H),7.34(t,J＝7.6Hz,1H),7.27(d,J＝8.2Hz,1H),3.57(tt,J＝11.9,5.6Hz,1H),3.35(br,s,2H),2.41(s,3H),2.39(s,3H),2.17–2.10(m,4H),2.02–1.96(m,2H),1.78(dd,J＝14.4,6.3Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ174.80,168.42,138.90,131.67,130.16,128.94,128.29,125.06,61.27,40.07,38.46,31.36,25.97,21.29ppm.HRMS(EI-TOF)calcd for C17H21N3S[M+]m/z 299.1456,found 299.1457.
Figure BDA0003069814030000321
1H NMR(400MHz,CDCl3)δ8.16(d,J＝8.2Hz,2H),7.76(d,J＝8.3Hz,2H),3.50(s,2H),3.48–3.38(m,1H),2.49(s,3H),2.42(t,J＝12.3Hz,2H),2.28–2.20(m,2H),2.01–1.93(m,2H),1.83(dd,J＝14.6,6.2Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ169.15,163.69,133.19(q,J＝32.9Hz),128.12,127.14,126.05(q,J＝3.7Hz),123.53(q,J＝272.9Hz),61.06,39.74,34.11,26.58,25.66ppm.HRMS(EI-TOF)calcd for C17H18F3N3S[M+]m/z 353.1174,found 353.1175.
Figure BDA0003069814030000322
1H NMR(400MHz,CDCl3)δ7.83(dt,J＝9.6,2.8Hz,2H),7.54(d,J＝2.4Hz,1H),7.41–7.30(m,5H),7.23(d,J＝8.1Hz,2H),6.56(d,J＝2.4Hz,1H),5.18(s,2H),4.41–4.37(m,3H),2.62–2.43(m,4H),1.90–1.86(m,2H),1.75–1.73(m,2H)ppm.13C NMR(101MHz,CDCl3)δ153.60,149.06,148.57(q,J＝1.7Hz),136.89,132.56,129.46,128.53,128.04,127.92,126.77,121.16,120.52(q,J＝256.7Hz),102.91,66.82,52.80,51.99,34.63,33.98,28.46,27.77ppm.HRMS(EI-TOF)calcd for C25H24F3N3O3[M+]m/z 471.1770,found 471.1772.
Figure BDA0003069814030000323
1H NMR(400MHz,CDCl3)δ7.92(d,J＝8.1Hz,2H),7.63(d,J＝8.2Hz,2H),7.56(d,J＝2.4Hz,1H),7.41–7.30(m,5H),6.63(d,J＝2.4Hz,1H),5.18(s,2H),4.43–4.38(m,3H),2.62–2.43(m,4H),1.91–1.87(m,2H),1.76–1.71(m,2H)ppm.13C NMR(101MHz,CDCl3)δ153.60,148.89,137.12(q,J＝2.7Hz),136.87,129.58,129.27(q,J＝32.4Hz),128.54,128.05,127.92,125.55(q,J＝3.9Hz),125.54,124.27(q,J＝271.8Hz),103.38,66.83,52.93,51.97,34.64,34.01,28.48,27.78ppm.HRMS(EI-TOF)calcd for C25H24F3N3O2[M+]m/z 455.1821,found 455.1823.
Figure BDA0003069814030000331
1H NMR(400MHz,CDCl3)δ7.84(d,J＝8.7Hz,2H),7.56(d,J＝2.2Hz,1H),7.23(d,J＝8.2Hz,2H),6.54(d,J＝2.2Hz,1H),4.41(tt,J＝6.5,2.6Hz,1H),3.21(br,s,2H),2.56–2.44(m,4H),2.30(s,3H),1.94–1.91(m,2H),1.63(dd,J＝14.2,6.3Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ148.87,148.44(q,J＝1.5Hz),132.82,129.29,126.72,121.11,120.52(q,J＝256.9Hz),102.54,59.53,52.13,40.19,35.16,25.62ppm.HRMS(EI-TOF)calcd for C18H20F3N3O[M+]m/z 351.1558,found 351.1559.
Figure BDA0003069814030000332
1H NMR(400MHz,CDCl3)δ7.65(s,1H),7.61(d,J＝7.7Hz,1H),7.54(d,J＝2.3Hz,1H),7.27(t,J＝7.6Hz,1H),7.09(d,J＝7.5Hz,1H),6.54(d,J＝2.3Hz,1H),4.40(tt,J＝7.0,2.7Hz,1H),3.20–3.17(m,2H),2.58–2.54(m,2H),2.47–2.42(m,2H),2.39(s,3H),2.28(s,3H),1.93–1.89(m,2H),1.65–1.59(m,2H)ppm.13C NMR(101MHz,CDCl3)δ150.27,138.06,133.88,128.89,128.45,128.10,126.10,122.64,102.43,59.54,52.05,40.23,35.13,25.64,21.52ppm.HRMS(EI-TOF)calcd for C18H23N3[M+]m/z 281.1892,found 281.1894.
Figure BDA0003069814030000333
1H NMR(400MHz,CDCl3)δ7.75(d,J＝8.7Hz,2H),7.53(d,J＝1.9Hz,1H),6.92(d,J＝8.6Hz,2H),6.48(d,J＝2.1Hz,1H),4.41–4.36(m,1H),3.83(s,3H),3.19(br,s,2H),2.57–2.53(m,2H),2.48–2.41(m,2H),2.29(s,3H),1.93–1.90(m,2H),1.65(dd,J＝14.0,6.3Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ159.08,150.00,128.90,126.90,126.67,113.95,101.86,59.56,55.30,51.89,40.20,35.10,25.61ppm.HRMS(EI-TOF)calcd for C18H23N3O[M+]m/z 297.1841,found 297.1842.
Figure BDA0003069814030000334
1H NMR(400MHz,CDCl3)δ7.83(d,J＝7.7Hz,2H),7.55(d,J＝1.7Hz,1H),7.38(t,J＝7.6Hz,2H),6.56(d,J＝2.1Hz,1H),4.42–4.39(m,1H),3.21(br,s,2H),2.58–2.54(m,2H),2.50–2.43(m,2H),2.30(s,3H),1.93–1.90(m,2H),1.66(dd,J＝14.1,6.3Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ150.13,133.97,129.02,128.54,127.32,125.44,102.46,59.57,51.98,40.16,35.07,25.57ppm.HRMS(EI-TOF)calcd for C17H20 35ClN3[M+]m/z 301.1346,found 301.1343.calcd for C17H20 37ClN3[M+]m/z 303.1316,found 303.1317.
Figure BDA0003069814030000335
1H NMR(400MHz,CDCl3)δ7.93(d,J＝8.2Hz,2H),7.63(d,J＝8.2Hz,2H),7.59(d,J＝2.1Hz,1H),6.62(d,J＝2.2Hz,1H),4.45–4.40(m,1H),3.22(br,s,2H),2.57–2.45(m,4H),2.30(s,3H),1.95–1.92(m,2H),1.63(dd,J＝14.2,6.4Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ148.71,137.37,129.42,129.08(q,J＝32.3Hz),125.49,125.48(q,J＝4.2Hz),124.35(q,J＝271.8Hz),103.02,59.51,52.27,40.20,35.19,25.62ppm.HRMS(EI-TOF)calcd for C18H20F3N3[M+]m/z 335.1609,found 335.1612.
Figure BDA0003069814030000341
1H NMR(400MHz,CDCl3)δ7.81–7.79(m,2H),7.55(d,J＝2.2Hz,1H),7.28–7.25(m,2H),7.02(d,J＝8.6Hz,2H),6.96–6.92(m,2H),6.52(d,J＝2.2Hz,1H),4.42–4.37(m,1H),3.20(br,s,2H),2.57–2.53(m,2H),2.49–2.42(m,2H),2.29(s,3H),1.94–1.90(m,2H),1.66–1.61(m,2H)ppm.13C NMR(101MHz,CDCl3)δ156.19,156.03,149.50,129.88,129.67,129.15,128.01,127.00,119.76,119.29,102.23,59.56,52.05,40.27,35.17,25.64ppm.HRMS(EI-TOF)calcd for C23H24 35ClN3O[M+]m/z 393.1608,found 393.1610.calcd for C23H24 37ClN3O[M+]m/z 395.1578,found 395.1581.
Figure BDA0003069814030000342
1H NMR(400MHz,CDCl3)δ7.52(d,J＝2.2Hz,1H),7.35(d,J＝1.5Hz,1H),7.28(dd,J＝8.1,1.6Hz,1H),6.83(d,J＝8.1Hz,1H),6.45(d,J＝2.3Hz,1H),5.96(s,2H),4.37(tt,J＝6.9,2.6Hz,1H),3.18(br,s,2H),2.55–2.51(m,2H),2.46–2.39(m,2H),2.28(s,3H),1.93–1.90(m,2H),1.62(dd,J＝14.2,6.2Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ149.88,147.86,146.92,128.99,128.45,119.00,108.37,106.17,101.98,100.93,59.50,52.02,40.30,35.20,25.65ppm.HRMS(EI-TOF)calcd for C18H21N3O2[M+]m/z 311.1634,found 311.1632.
Figure BDA0003069814030000343
1H NMR(400MHz,CDCl3)δ7.81–7.78(m,2H),7.55(d,J＝2.3Hz,1H),7.35–7.31(m,2H),7.11–7.07(m,1H),7.07–7.01(m,4H),6.51(d,J＝2.3Hz,1H),4.40(tt,J＝6.9,2.7Hz,1H),3.20(br,s,2H),2.57–2.52(m,2H),2.48–2.42(m,2H),2.29(s,3H),1.94–1.91(m,2H),1.65(dd,J＝14.3,6.3Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ157.47,156.44,149.66,129.70,129.47,129.08,126.90,123.06,119.25,118.61,102.18,59.54,52.03,40.26,35.17,26.92,25.63ppm.HRMS(EI-TOF)calcd for C23H25N3O[M+]m/z 359.1998,found 359.1999.
Figure BDA0003069814030000351
1H NMR(400MHz,CDCl3)δ7.87(d,J＝8.7Hz,2H),7.56(d,J＝2.2Hz,1H),7.30(d,J＝8.7Hz,2H),7.25(d,J＝3.8Hz,1H),6.81(d,J＝3.8Hz,1H),6.54(d,J＝2.3Hz,1H),4.40(tt,J＝6.8,2.8Hz,1H),3.19(br,s,2H),2.56–2.52(m,2H),2.48–2.41(m,2H),2.29(s,3H),1.94–1.91(m,2H),1.63(dd,J＝14.2,6.3Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ174.14,154.73,149.16,137.67,132.00,129.20,126.98,120.35,112.87,102.44,59.49,52.16,40.32,35.26,25.65ppm.HRMS(EI-TOF)calcd for C20H22N4OS[M+]m/z 366.1514,found 366.1510.
Figure BDA0003069814030000352
1H NMR(400MHz,CDCl3)δ8.03(d,J＝4.8Hz,1H),7.87(d,J＝8.6Hz,2H),7.76(d,J＝7.7Hz,1H),7.55(d,J＝2.0Hz,1H),7.18(d,J＝8.6Hz,2H),6.96(dd,J＝7.5,4.9Hz,1H),6.55(d,J＝2.2Hz,1H),4.44–4.39(m,1H),3.23(br,s,2H),2.60–2.56(m,2H),2.51–2.45(m,2H),2.31(s,3H),1.94–1.91(m,2H),1.67(dd,J＝14.0,6.3Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ159.16,152.84,149.53,145.19,139.24,131.13,129.06,126.67,121.57,119.18,119.06,102.45,59.61,51.90,40.13,34.99,25.45ppm.HRMS(EI-TOF)calcd for C22H23 35ClN4O[M+]m/z 394.1560,found 394.1558.calcd for C22H23 37ClN4O[M+]m/z 396.1531,found 396.1530.
Figure BDA0003069814030000353
1H NMR(400MHz,CDCl3)δ7.86(s,1H),7.83(s,1H),7.62–7.57(m,4H),4.42–4.27(m,3H),2.57–2.45(s,4H),1.91–1.84(m,2H),1.69–1.61(m,2H),1.51(s,9H)ppm.13C NMR(101MHz,CDCl3)δ153.53,136.23(q,J＝1.3Hz),136.15,128.27(q,J＝32.4Hz),125.84(q,J＝3.7Hz),125.47,125.44,124.25(q,J＝271.9Hz),79.62,53.21,51.88,51.12,34.53,34.13,28.76,28.51,28.27ppm.HRMS(EI-TOF)calcd for C22H26F3N3O2[M+]m/z 421.1977,found 421.1976.
Figure BDA0003069814030000354
1H NMR(400MHz,CDCl3)δ7.79(s,1H),7.76(s,1H),7.49(d,J＝8.8Hz,2H),7.21(d,J＝8.0Hz,2H),4.41–4.24(m,3H),2.59–2.44(m,4H),1.90–1.87(m,2H),1.67–1.62(m,2H),1.50(s,9H)ppm.13C NMR(101MHz,CDCl3)δ153.52,147.64(q,J＝1.6Hz),135.92,131.55,126.67,125.03,121.77,121.50,120.53(q,J＝258.7Hz)79.56,53.10,51.97,51.11,34.52,34.07,28.69,28.51,28.15ppm.HRMS(EI-TOF)calcd for C22H26F3N3O3[M+]m/z 437.1926,found 437.1928.
Figure BDA0003069814030000361
1H NMR(400MHz,CDCl3)δ7.72(s,2H),7.41(d,J＝8.8Hz,2H),6.91(d,J＝8.7Hz,2H),4.39(tt,J＝6.8,3.9Hz,1H),3.82(s,3H),3.21(br,s,2H),2.49–2.36(m,4H),2.28(s,3H),1.96–1.92(m,2H),1.58(dd,J＝14.3,6.3Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ158.25,135.49,126.63,125.51,124.31,122.45,114.27,59.44,55.33,52.17,40.31,35.36,25.92ppm.HRMS(EI-TOF)calcd for C18H23N3O[M+]m/z 297.1841,found 297.1845.
Figure BDA0003069814030000362
1H NMR(400MHz,CDCl3)δ7.78(s,1H),7.77(s,1H),7.29(d,J＝9.8Hz,2H),7.24(t,J＝7.5Hz,1H),7.03(d,J＝7.2Hz,1H),4.39(tt,J＝6.8,3.6Hz,1H),3.20(br,s,2H),2.53–2.41(m,4H),2.37(s,3H),2.28(s,3H),1.95–1.91(m,2H),1.56(dd,J＝14.3,6.4Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ138.38,135.80,132.71,128.73,127.06,126.19,124.81,122.75,122.55,59.42,52.25,40.31,35.34,25.92,21.48ppm.HRMS(EI-TOF)calcd for C18H23N3[M+]m/z 281.1892,found 281.1895.
Figure BDA0003069814030000363
1H NMR(400MHz,CDCl3)δ7.77(s,1H),7.75(s,1H),7.40(d,J＝8.4Hz,2H),7.31(d,J＝8.3Hz,2H),4.40(tt,J＝6.8,3.7Hz,1H),3.20(br,s,2H),2.49–2.43(m,4H),2.27(s,3H),1.96–1.93(m,2H),1.55(dd,J＝14.1,6.0Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ135.71,131.80,131.35,128.92,126.63,124.90,121.59,59.36,52.42,40.35,35.50,26.03ppm.HRMS(EI-TOF)calcd for C17H20 35ClN3[M+]m/z 301.1346,found 301.1348.calcd for C17H20 37ClN3[M+]m/z 303.1316,found 303.1321.
Figure BDA0003069814030000364
1H NMR(400MHz,CDCl3)δ7.85(s,1H),7.82(s,1H),7.61–7.56(m,4H),4.43(p,J＝5.2Hz,1H),3.23–3.21(m,2H),2.49–2.47(m,4H),2.28(s,3H),1.98–1.94(m,2H),1.56(dd,J＝14.9,6.0Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ136.43,135.97,128.07(q,J＝32.5Hz),125.76(q,J＝3.7Hz),125.41,125.36,124.28(q,J＝271.7Hz),121.36,59.34,52.54,40.31,35.50,26.02ppm.HRMS(EI-TOF)calcd for C18H20F3N3[M+]m/z 335.1609,found 335.1612.
Figure BDA0003069814030000365
1H NMR(400MHz,CDCl3)δ7.78(s,1H),7.75(s,1H),7.48(d,J＝8.5Hz,2H),7.20(d,J＝8.1Hz,2H),4.41(p,J＝5.0Hz,1H),3.21(br,s,2H),2.49–2.47(m,4H),2.28(s,3H),1.97–1.93(m,2H),1.57(dd,J＝14.5,6.2Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ147.55(q,J＝1.7Hz),135.76,131.73,126.61,124.99,121.46,120.50(d,J＝256.9Hz),59.40,52.36,40.26,35.38,25.92ppm.HRMS(EI-TOF)calcd for C18H20F3N3O[M+]m/z 351.1558,found 351.1561.
Figure BDA0003069814030000371
1H NMR(400MHz,CDCl3)δ8.66(d,J＝8.4Hz,1H),8.05(s,1H),7.99(s,1H),7.74(d,J＝8.4Hz,1H),7.54(d,J＝8.9Hz,1H),7.33(d,J＝8.9Hz,1H),4.64(p,J＝5.1Hz,1H),4.37–4.29(m,2H),2.70–2.55(m,4H),1.83–1.81(m,2H),1.68–1.62(m,2H),1.52(s,9H)ppm.13C NMR(101MHz,CDCl3)δ153.52,144.43,131.59,128.03(q,J＝32.2Hz),127.87,125.45(q,J＝3.9Hz),124.62(q,J＝272.1Hz),123.11,123.06,122.81,122.25(q,J＝3.2Hz),120.04,119.36,79.52,54.27,52.12,51.32,34.81,34.34,28.57,28.46,27.99ppm.HRMS(EI-TOF)calcd for C24H26F3N3O2[M+]m/z 445.1977,found 445.1973.
Figure BDA0003069814030000372
1H NMR(400MHz,CDCl3)δ8.43(s,1H),8.32(d,J＝8.5Hz,1H),8.20(s,1H),7.81–7.76(m,2H),7.53(d,J＝9.1Hz,1H),4.79(tt,J＝7.7,5.9Hz,1H),4.48–4.32(m,2H),2.74–2.63(m,2H),2.36–2.20(m,2H),2.04–1.93(m,4H),1.55(s,9H)ppm.13C NMR(101MHz,CDCl3)δ153.99,137.77,131.55,129.36,128.34,127.75,126.40(q,J＝32.4Hz),126.15(q,J＝4.4Hz),124.49(q,J＝271.6Hz),123.68,123.19(q,J＝4.2,3.7Hz),119.47,111.58,79.57,51.78,50.97,49.78,35.68,35.32,29.79,29.31,28.55ppm.HRMS(EI-TOF)calcd for C24H26F3N3O2[M+]m/z 445.1977,found 445.1976.
Figure BDA0003069814030000373
1H NMR(400MHz,CDCl3)δ8.48(s,1H),8.15(d,J＝8.3Hz,1H),8.10(s,1H),7.76–7.71(m,2H),7.62(d,J＝9.2Hz,1H),4.68(p,J＝5.6Hz,1H),4.42–4.33(m,2H),2.75–2.59(m,4H),1.92–1.89(m,2H),1.70–1.63(m,2H),1.52(s,9H)ppm.13C NMR(101MHz,CDCl3)δ153.59,147.12,129.81,129.58,127.56,126.84(q,J＝32.2Hz),126.07(q,J＝4.1Hz),124.50(q,J＝271.9Hz),123.80,122.64(q,J＝3.5Hz),122.09,119.31,117.77,79.67,54.50,51.95,51.13,35.16,34.77,29.07,28.52,28.45ppm.HRMS(EI-TOF)calcd for C24H26F3N3O2[M+]m/z 445.1977,found 445.1971.
Figure BDA0003069814030000381
1H NMR(400MHz,CDCl3)δ8.69(d,J＝8.4Hz,1H),8.07(s,1H),8.06(s,1H),7.75(dd,J＝8.3,1.2Hz,1H),7.59(d,J＝8.9Hz,1H),7.37(d,J＝8.9Hz,1H),4.71(tt,J＝6.6,3.1Hz,1H),3.25(s,2H),2.69–2.57(m,4H),2.30(s,3H),1.94–1.91(m,2H),1.64–1.59(m,2H)ppm.13C NMR(101MHz,CDCl3)δ144.46,131.54,127.96(q,J＝32.2Hz),127.90,125.47(q,J＝4.1Hz),124.62(q,J＝272.1Hz),123.06,122.99,122.73,122.24(q,J＝3.3Hz),120.10,119.23,59.49,53.54,40.15,35.73,25.82.HRMS(EI-TOF)calcd for C20H20F3N3[M+]m/z 359.1609,found 359.1611.
Figure BDA0003069814030000382
1H NMR(400MHz,CDCl3)δ8.38(s,1H),8.22(d,J＝8.1Hz,1H),7.89(d,J＝8.0Hz,1H),7.68(d,J＝9.1Hz,1H),7.61–7.57(m,1H),7.50(d,J＝9.1Hz,1H),7.47–7.43(m,1H),4.95(tt,J＝8.0,5.7Hz,1H),3.30–3.27(m,2H),2.65(dt,J＝14.6,7.6Hz,2H),2.31(s,3H),2.22(ddd,J＝14.3,5.6,1.1Hz,2H),2.11–2.04(m,2H),1.93–1.88(m,2H)ppm.13C NMR(101MHz,CDCl3)δ137.21,130.92,129.30,128.65,127.50,127.39,127.19,124.36,122.85,119.78,110.58,59.49,48.82,40.61,36.96,27.07ppm.HRMS(EI-TOF)calcd for C19H21N3[M+]m/z 291.1735,found 291.1738.
Figure BDA0003069814030000383
1H NMR(400MHz,CDCl3)δ8.34(s,1H),8.14(d,J＝8.6Hz,1H),7.86(d,J＝2.1Hz,1H),7.59(d,J＝9.1Hz,1H),7.53(dd,J＝8.6,2.0Hz,2H),4.94(tt,J＝8.0,5.8Hz,1H),3.30–3.27(m,2H),2.64(dt,J＝14.6,7.6Hz,2H),2.31(s,3H),2.19(ddd,J＝14.4,5.8,1.2Hz,2H),2.10–2.07(m,2H),1.88(dd,J＝13.9,6.3Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ137.15,130.85,130.19,129.79,127.67,127.57,126.32,125.76,124.36,119.46,111.73,59.43,48.98,40.65,37.04,27.13ppm.2D NOESY NMR(600MHz,CDCl3)showed a cross peak fromδ2.22,2.65,4.96 toδ7.56.HRMS(EI-TOF)calcd for C19H20 35ClN3[M+]m/z 325.1346,found 325.1345.calcd for C19H20 37ClN3[M+]m/z 327.1316,found 327.1322.
Figure BDA0003069814030000384
1H NMR(400MHz,CDCl3)δ8.42(s,1H),8.31(d,J＝8.5Hz,1H),8.19(s,1H),7.80–7.75(m,2H),7.60(d,J＝9.1Hz,1H),5.01(tt,J＝8.1,5.0Hz,1H),3.40–3.37(m,2H),2.80(dt,J＝14.5,7.5Hz,2H),2.40(s,3H),2.29–2.24(m,2H),2.13–2.05(m,2H),2.03–1.98(m,2H)ppm.13C NMR(101MHz,CDCl3)δ137.80,131.37,129.34,128.32,127.63,126.31(q,J＝32.3Hz),126.12(q,J＝3.8Hz),124.49(q,J＝272.1Hz),123.65,123.11(q,J＝3.3Hz),119.42,111.87,59.80,48.70,40.30,36.51,26.60ppm.HRMS(EI-TOF)calcd for C20H20F3N3[M+]m/z 359.1609,found 359.1604.
Figure BDA0003069814030000391
1H NMR(400MHz,CDCl3)δ8.40(s,1H),8.05(d,J＝7.9Hz,1H),7.80(d,J＝7.9Hz,1H),7.66(d,J＝9.2Hz,1H),7.55(d,J＝9.2Hz,1H),7.51(t,J＝7.5Hz,1H),7.42(t,J＝7.5Hz,1H),4.69(tt,J＝7.0,3.8Hz,1H),3.25(br,s,2H),2.67–2.54(m,4H),2.28(s,3H),1.94–1.91(m,2H),1.57(dd,J＝14.5,6.5Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ146.75,130.20,128.83,127.69,127.59,126.55,124.85,123.16,121.27,118.17,117.88,59.46,53.51,40.32,35.91,26.15ppm.HRMS(EI-TOF)calcd for C19H21N3[M+]m/z 291.1735,found 291.1737.
Figure BDA0003069814030000392
1H NMR(400MHz,CDCl3)δ8.37(s,1H),7.97(d,J＝8.5Hz,1H),7.77(d,J＝2.1Hz,1H),7.68(d,J＝9.2Hz,1H),7.47–7.44(m,2H),4.70(p,J＝5.6Hz,1H),3.38–3.24(m,2H),2.62–2.59(m,4H),2.29(s,3H),1.97–1.94(m,2H),1.58(dd,J＝14.5,6.3Hz,2H)ppm.13C NMR(101MHz,CDCl3)δ146.59,131.29,130.24,127.89,126.83,126.57,125.90,124.57,121.33,119.16,117.75,59.44,53.67,40.33,36.05,26.25ppm.2D NOESY NMR(600MHz,CDCl3)showed a cross peak fromδ1.59,2.63,4.71toδ8.39.HRMS(EI-TOF)calcd for C19H20 35ClN3[M+]m/z 325.1346,found 325.1342.calcd for C19H20 37ClN3[M+]m/z 327.1316,found 327.1325.
Figure BDA0003069814030000393
1H NMR(400MHz,CDCl3)δ8.48(s,1H),8.15(d,J＝8.4Hz,1H),8.09(s,1H),7.75(d,J＝9.2Hz,1H),7.72(dd,J＝8.4,1.3Hz,1H),7.60(d,J＝9.2Hz,1H),4.75(p,J＝5.6Hz,1H),3.29(p,J＝3.7Hz,2H),2.63(dd,J＝5.5,4.0Hz,4H),2.31(s,3H),1.99–1.96(m,2H),1.62–1.56(m,2H)ppm.13C NMR(101MHz,CDCl3)δ147.08,129.87(q,J＝0.6Hz),129.51,127.37,126.69(q,J＝32.2Hz),126.04(q,J＝4.2Hz),124.53(q,J＝271.8Hz),123.78,122.55(q,J＝3.4Hz),122.03,119.37,117.61,59.45,53.82,40.33,36.09,26.26ppm.HRMS(EI-TOF)calcd for C20H20F3N3[M+]m/z 359.1609,found 359.1611.
example 37: nematicidal testing of the compounds of the invention.
Pine wood nematodes (Bursaphelenchus xylophilus) and Meloidogyne incognita (Meloidogyne incognita) selected by the present invention were purchased from the Huzhou modern agriculture center, a Chinese academy, and tested to determine the nematicidal activity of the compounds of the present invention.
The specific test operation process comprises the following steps:
and (3) accurately weighing the positive control medicament and the target compound by an electronic analytical balance, dissolving the positive control medicament and the target compound by using dimethyl sulfoxide, and diluting the positive control medicament and the target compound by using an aqueous solution containing 0.2% triton to obtain a mother solution with a certain concentration, wherein the content of the organic solvent in the water is less than 1%, and the concentration of the mother solution is 2 times of the highest concentration required by the test. In actual test, a proper amount of mother liquor and an aqueous solution containing 0.2% of triton are respectively taken and diluted to the required concentration for standby. The prepared drug solution was added to a 96-well plate at 50 μ L per well, and each drug was repeated twice. A continuous applicator was used to add 50. mu.L of nematode suspension (about 50 nematodes) to the drug, which was covered and placed in a 22. + -. 1 ℃ observation chamber. Assuming that 0.2% triton aqueous solution per ml contains 4uL dimethyl sulfoxide as a CK control group, abamectin (5ppm) and fluensulfone (5ppm) as a positive control group, the number of nematode deaths at 24 hours, 48 hours and 72 hours is checked, and the average mortality of the nematodes in two repeated tests is calculated.
Corrected mortality-control mortality)/(1-control mortality) x 100%
TABLE 140 ppm mortality of the Compounds of the invention to two nematodes (%)
Figure BDA0003069814030000401
Figure BDA0003069814030000411
As can be seen from Table 1, some of the compounds had excellent nematicidal activity at a concentration of 40 ppm.
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 shown in a general formula I, or an optical isomer, a cis-trans isomer and an agriculturally and pharmaceutically acceptable salt thereof,
Figure FDA0003069814020000011
in the formula (I), the compound is shown in the specification,
r is hydrogen, substituted or unsubstituted C1-C15 alkyl, substituted or unsubstituted C3-C7 cycloalkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C15 alkoxy, substituted or unsubstituted 5-or 6-membered heteroaromatic ring, carbonyl-C6-C10 aryl-C1-C15 alkyl, C1-C15 alkoxycarbonyl, C6-C10 aryl-C1-C15 alkoxycarbonyl; said substituted means substituted with one or more substituents selected from the group consisting of: halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, carboxyl and C6-C10 aryl;
X1is CH ═ CH or is absent, X2Is CH ═ CH or is absent, and when X is present1When CH is CH, X is absent2(ii) a When X is present2Is CH ═ CH, in the absence of X1；
A is N, S or CH;
b is N or C;
d is CH, N, O or S;
e is C, N, O or CH;
ar is a benzene ring, a naphthalene ring, a 5-6 membered heteroaromatic ring or an 8-12 membered heteroaromatic bicyclic ring system; r1Is a substituent on Ar, in a number of 0, 1,2, 3 or 4, each R1Each independently selected from: C1-C6 alkyl, C1-C6 alkoxy, halogen, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy, cyano, nitro, C6-C10 aryl, 5-or 6-membered heteroaryl, or-OAr1(ii) a Wherein Ar is1Is a C6-C10 aryl, 5-or 6-membered heteroaryl, or 8-12 membered heteroaryl bicyclic ring system; wherein the C6-C10 aryl, 5-or 6-membered heteroaryl is optionally substituted with 1,2, 3 or 4 substituents selected from the group consisting of: halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, halogenated C1-C6 alkyl and C1-C6 alkoxy.
2. The compound of claim 1, wherein when D is S or O, B is C, A is N, E is N or C (H), X is1And X2Is absent.
3. The compound of claim 1, wherein X is X when D is N, B is C, A is S or N, E is CH or O1And X2Is absent.
4. The compound of claim 1, wherein X is when D is CH or N, B is N, A is CH or N, E is C2Is CH ═ CH;
when D is C, B is N, A is N, E is CH, X1Is CH ═ CH; or
When D is CH or N, B is N, A is CH or N, E is CH, X1And X2Is absent.
5. The compound of claim 1, wherein the compound has a structure selected from the group consisting of:
Figure FDA0003069814020000021
wherein Ar is as defined in claim 1, optionally having 1,2 or 3 substituents R1；
R、R1Is as defined in claim 1.
6. A compound according to claim 1 or 5 wherein Ar is a phenyl ring, a naphthyl ring, a 5-6 membered heteroaromatic ring or an 8-10 membered heteroaromatic bicyclic ring system, optionally having 1,2 or 3 substituents R1；
In the formulae, each R1Each independently selected from: C1-C6 alkyl, C1-C4 alkoxy, fluorine, chlorine, bromine, halogenated C1-C4 alkyl, halogenated C1-C4 alkoxy, cyano, nitro, phenyl, 5-or 6-membered heteroaryl, -O-phenyl, -O-5-or 6-membered heteroaryl; wherein phenyl, 5-or 6-membered heteroaryl is optionally substituted with 1 or 2 substituents selected from the group consisting of: halogen, cyano, nitro, hydroxyl, amino, C1-C4 alkyl, halogenated C1-C4 alkyl and C1-C4 alkoxy.
7. The compound of claim 1, wherein the compound is selected from the group consisting of:
Figure FDA0003069814020000031
Figure FDA0003069814020000041
Figure FDA0003069814020000051
Figure FDA0003069814020000061
8. a pesticidal composition comprising a compound according to any one of claims 1 to 7 or an agriculturally pharmaceutically acceptable salt thereof; and an agriculturally acceptable carrier.
9. Use of a compound according to any one of claims 1 to 7 or an agriculturally pharmaceutically acceptable salt thereof or a pesticidal composition according to claim 8 for nematicidal or nematicidal purposes; or for the preparation of a medicament for killing or preventing nematodes.
10. A method of killing or preventing nematodes including applying a compound according to any one of claims 1 to 7 or an agriculturally acceptable salt thereof or a pesticidal composition according to claim 8 to a plant suffering from or susceptible to a pest, or to the soil or environment surrounding the plant.
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