CN111454202A - Heteroaryl formanilide compound containing pentafluorothio and preparation method and application thereof - Google Patents

Heteroaryl formanilide compound containing pentafluorothio and preparation method and application thereof Download PDF

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CN111454202A
CN111454202A CN201910049852.2A CN201910049852A CN111454202A CN 111454202 A CN111454202 A CN 111454202A CN 201910049852 A CN201910049852 A CN 201910049852A CN 111454202 A CN111454202 A CN 111454202A
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phenyl
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membered heteroaryl
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CN111454202B (en
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唐剑峰
迟会伟
吴建挺
韩君
刘莹
张振国
赵士胜
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SHANDONG UNITED PESTICIDE INDUSTRY CO LTD
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    • 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
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    • A01N43/80—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 1,2
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
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Abstract

The invention belongs to the technical field of bactericides, and particularly relates to a heteroaryl formanilide compound containing pentafluorothio and shown in the following formula (I) or pharmaceutically acceptable salt thereof,

Description

Heteroaryl formanilide compound containing pentafluorothio and preparation method and application thereof
Technical Field
The invention belongs to the technical field of bactericides, and particularly relates to a heteroaryl formanilide compound containing pentafluorothio and a preparation method and application thereof.
Background
In the agricultural field, with the problem of disease resistance becoming more serious, farmers need to increase the dosage, so that the drug residue is increased, and the environment is polluted and burdened. There is a need to develop new varieties of pesticides with the aim of reducing the amount of active substance used, while at the same time maintaining effectiveness at least comparable to or better than the known compounds.
Patent WO 2015064764 discloses pentafluorosulfanylbenzenes of the general formula and the specific compounds CK1, CK2 and discloses the use of said compounds as medicaments.
Figure BDA0001950382440000011
The patent US 3117158 discloses pentafluorosulfanylbenzene compounds and a specific compound CK3 shown in the following general formula, but does not report related applications.
Figure BDA0001950382440000012
Disclosure of Invention
In order to further develop bactericides with excellent performance, the invention provides a heteroaryl formanilide compound containing pentafluorothio as shown in the following formula (I) or pharmaceutically acceptable salt thereof,
Figure BDA0001950382440000013
wherein R is1、R2、R3、R4The same or different, each independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, C1-C12Alkyl radical, C1-C12Haloalkyl, C1-C12Alkoxy radical, C1-C12Haloalkoxy, C1-C12Alkoxycarbonyl group, C1-C12Alkylcarbonyl group, C1-C12Alkylsulfonyl radical, C1-C12Alkylsulfinyl radical, C1-C12Alkylthio, phenylcarbonyl, phenyl, -O-phenyl or-O-5-or 6-membered heteroaryl,
the phenylcarbonyl, phenyl, -O-phenyl or-O-5 or 6 membered heteroaryl may be unsubstituted or substituted by one or more Rs1Substituted, said Rs1Selected from the group consisting of: halogen, cyano, nitro, C1-C12Alkyl radical, C1-C12Haloalkyl, C1-C12Alkoxy radicalOr C1-C12A haloalkoxy group;
R5selected from hydrogen or C1-C12An alkyl group;
ar is selected from unsubstituted or substituted by one or more Rs2Substituted 5-20 membered heteroaryl, said Rs2Selected from the group consisting of: halogen, nitro, cyano, hydroxy, C1-C12Alkyl radical, C1-C12Haloalkyl, C1-C12Alkoxy or C1-C12A haloalkoxy group.
According to an embodiment of the present invention, in formula (I),
R1、R2、R3、R4the same or different, each independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkoxycarbonyl group, C1-C6Alkylcarbonyl group, C1-C4Alkylsulfonyl radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylthio, phenylcarbonyl, phenyl, -O-phenyl or-O-5 or 6 membered heteroaryl;
wherein the phenylcarbonyl, phenyl, -O-phenyl, 5 or 6 membered heteroaryl may be unsubstituted or substituted with one or more Rs1Substituted, said Rs1Selected from the group consisting of: halogen, cyano, nitro, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy or C1-C6A haloalkoxy group;
R5independently selected from hydrogen or C1-C6An alkyl group;
ar is selected from the group consisting ofs2Substituted 5-10 membered heteroaryl, said Rs2Selected from the group consisting of: halogen, cyano, nitro, hydroxy, C1-C6Alkyl radical, C1-C6Haloalkyl or C1-C6An alkoxy group.
Preferably, in the formula (I),
R1、R2、R3、R4the same or different, each independently selected from hydrogen, fluorine, chlorine, bromine, cyano, hydroxyl, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkoxycarbonyl group, C1-C6Alkylcarbonyl group, C1-C4Alkylsulfonyl radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylthio, phenylcarbonyl, phenyl, -O-phenyl or-O-5-or 6-membered heteroaryl,
wherein the phenylcarbonyl, phenyl, -O-phenyl or-O-5 or 6 membered heteroaryl may be unsubstituted or substituted with 1 to 3 of the following groups: f, Cl, Br, CN, CH3，OCH3，CF3，OCF3；
R5Selected from hydrogen or C1-C6An alkyl group;
ar is selected from 1-3Rs2Substituted 5-10 membered heteroaryl, said Rs2Selected from the group consisting of: f, Cl, Br, CN, OH, CH3，C2H5，CF3，CHF2，CH2F，CHClF，CClF2，OCH3，OCH2CH3，OCF3，OCH2CF3。
Also preferably, in the formula (I),
R1、R2、R3、R4the same or different, each independently selected from hydrogen, fluorine, chlorine, cyano, hydroxyl, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkoxycarbonyl group, C1-C6Alkylcarbonyl group, C1-C4Alkylsulfonyl radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylthio, phenylcarbonyl, phenyl, -O-phenyl or-O-5-or 6-membered heteroaryl,
wherein the phenylcarbonyl, phenyl, -O-phenyl or-O-5 or 6 membered heteroaryl may be unsubstituted or substituted with 1 to 3 of the following groups: f, Cl, CN, CH3，OCH3，CF3，OCF3；
R5Selected from hydrogen or C1-C6An alkyl group;
ar is selected from 1-3Rs2Substituted 5-10 membered heteroaryl, said Rs2Selected from the group consisting of: f, Cl, Br, CN, OH, CH3，C2H5，CF3，CHF2，CH2F，CHClF，CClF2，OCH3，OCF3。
Wherein the 5-10 membered heteroaryl group may be selected from the following groups:
Figure BDA0001950382440000021
one end of the wavy line is marked as the point where Ar is connected with carbonyl in the formula (I).
For example, in the formula (I),
R1、R2、R3、R4the same or different, each is independently selected from H, F, Cl, CN, OH, CH3，C2H5，CF3，CHF2，OCH3，OC2H5，OCF3，OCH2CF3，COCH3，COOCH3，COOC2H5，SO2CH3，SOCH3，SCH3，
Figure BDA0001950382440000031
Figure BDA0001950382440000032
R5Selected from H, CH3，C2H5，C3H7，C4H9；
Preferably, Ar is selected from the group consisting of:
Figure BDA0001950382440000033
Figure BDA0001950382440000041
by way of example, the compound of formula (I) is selected from the following compounds,
Figure BDA0001950382440000042
Figure BDA0001950382440000043
Figure BDA0001950382440000051
Figure BDA0001950382440000061
Figure BDA0001950382440000071
Figure BDA0001950382440000081
Figure BDA0001950382440000091
Figure BDA0001950382440000101
Figure BDA0001950382440000111
Figure BDA0001950382440000121
Figure BDA0001950382440000131
Figure BDA0001950382440000141
Figure BDA0001950382440000151
Figure BDA0001950382440000161
Figure BDA0001950382440000171
Figure BDA0001950382440000181
Figure BDA0001950382440000191
Figure BDA0001950382440000201
Figure BDA0001950382440000211
Figure BDA0001950382440000221
Figure BDA0001950382440000231
Figure BDA0001950382440000241
Figure BDA0001950382440000251
Figure BDA0001950382440000261
Figure BDA0001950382440000271
Figure BDA0001950382440000281
Figure BDA0001950382440000291
Figure BDA0001950382440000301
for the sake of reducing the space of the specification, exemplary groups and/or compounds of the present invention are described in the form of the above tables.
The invention also provides a preparation method of the compound shown in the formula (I), which comprises the steps of reacting the compound shown in the formula (II) with the compound shown in the formula (III) to obtain the compound shown in the formula (I),
Figure BDA0001950382440000302
wherein R is1、R2、R3、R4、R5Ar has the meaning as defined above, L is selected from a leaving group, for example a halogen atom, such as chlorine, bromine or iodine.
According to an embodiment of the present invention, the reaction may be carried out in the presence of a base; the base can be one, two or more of organic bases such as triethylamine and pyridine, or inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert-butoxide and sodium hydride.
According to an embodiment of the present invention, the reaction may be carried out in a solvent; the solvent may be selected from one, two or more of aromatic hydrocarbon solvents, haloalkane solvents, ether solvents, and the like, for example, one, two or more selected from toluene, dichloromethane, 1, 2-dichloroethane, tetrahydrofuran, t-butyl methyl ether, ethyl acetate, and the like.
According to an embodiment of the present invention, the temperature of the reaction is preferably-10 to 50 ℃.
According to an embodiment of the present invention, the reaction can be carried out by a method described in patent documents CN200680004480 or CN95194436 or other similar methods.
According to an embodiment of the invention, when R5When the compound is not H, the preparation method can further comprise the preparation of a compound shown in the formula (II), and the compound shown in the formula (II) is prepared by carrying out N-alkylation reaction on the compound shown in the formula (IV),
Figure BDA0001950382440000303
wherein R is1、R2、R3、R4、R5Having the definitions as described above L1Selected from leaving groups, for example halogen atoms, such as chlorine, bromine or iodine.
According to an embodiment of the present invention, the N-alkylation reaction may be carried out in the presence of a base; the base can be selected from potassium carbonate, sodium hydroxide, potassium tert-butoxide, sodium hydride, etc.
According to an embodiment of the present invention, the N-alkylation reaction may be carried out in a solvent; the solvent may be selected from, for example, one, two or more of N, N-dimethylformamide, butanone, acetonitrile, methanol, and the like.
According to an embodiment of the present invention, the temperature of the N-alkylation reaction is preferably 25 to 150 ℃.
According to an embodiment of the present invention, the N-alkylation reaction may be carried out by a method described in reference (fine chemical intermediates, 38(2008),8) or other similar methods.
According to an embodiment of the present invention, the compound represented by formula (IV) is commercially available or can be prepared by a known method.
With R1、R2、R3、R4The preparation of the substituents selected from the different classes is illustrated by way of example:
the first scheme is as follows: when R is1C selected from the above definitions1-C6Alkoxy radical, C1-C4Alkylthio, substituted or unsubstituted-O-phenyl or-O-5-or 6-membered heteroaryl, according to exemplary embodiments of the invention, a compound of formula (IV-1) is subjected to an etherification reaction with a compound of formula (VI-a) or (VI-1b) to give a compound of formula (IV-2a) or (IV-2b), respectively,
Figure BDA0001950382440000311
wherein R is2、R3、R4Has the definition as described above; r11、R12Selected from the above definitions R1Alkyl, substituted or unsubstituted phenyl or 5-or 6-membered heteroaryl moiety of (A), L2Selected from leaving groups, for example halogen atoms, such as chlorine, bromine or iodine.
According to an exemplary embodiment of the present invention, the etherification reaction is generally carried out at 0 to 120 ℃, preferably 30 to 80 ℃.
According to exemplary embodiments of the present invention, the solvent used for the etherification reaction may be selected from one, two or more of aromatic hydrocarbon solvents, haloalkane hydrocarbon solvents, ether solvents, alcohol solvents, ketone solvents, amide solvents, and the like, for example, one, two or more selected from toluene, 1, 2-dichloroethane, tetrahydrofuran, t-butyl methyl ether, methanol, ethanol, acetone, butanone, dimethylformamide, dimethylacetamide, and the like.
According to exemplary embodiments of the present invention, the etherification reaction may be carried out in the presence of a base; the base can be one, two or more of organic bases such as triethylamine and pyridine, or inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium tert-butoxide, sodium trifluoroethoxide, sodium hydride and sodium.
According to an exemplary embodiment of the present invention, the reaction can be referred to handbook of organic compound synthesis 2011 edition.
According to an exemplary embodiment of the present invention, the compound represented by formula (VI-1a) or (VI-1b) is commercially available.
Scheme II: when R is1C selected from the above definitions1-C4Alkylsulfonyl radical, C1-C4In the case of alkylsulfinyl, according to an exemplary embodiment of the present invention, it may be prepared from the alkylthio compound represented by the above formula (IV-2b) through an oxidation reaction.
According to exemplary embodiments of the present invention, the oxidation reaction may be performed in an alcohol solvent such as methanol, ethanol, a halogenated hydrocarbon solvent such as dichloromethane, chloroform, etc.; the oxidant adopted in the oxidation reaction can be selected from hydrogen peroxide, peroxybenzoic acid, m-chloroperoxybenzoic acid and the like; the reaction is usually carried out at from 0 to 80 ℃.
According to an exemplary embodiment of the present invention, the oxidation reaction can be carried out by referring to a method described in patent document CN 1269800 or "preparation and synthesis of modern drugs" (first volume) 2007 edition, etc., or other similar methods.
Optionally, when R1Is selected from C1-C4Alkylsulfonyl radical, C1-C4In the case of alkylsulfinyl, the preparation method of the compound of formula (IV) may further include the protection and deprotection reaction of amino group, and the protection and deprotection reaction of amino group may be performed by the protection and deprotection method of amino group commonly used in the art, for example, the protection of amino group with t-butyloxycarbonyl group and the removal of t-butyloxycarbonyl group with hydrogen chloride gas.
The third scheme is as follows: when R is1When selected from the phenyl groups in the above definitions, according to an exemplary embodiment of the present invention, the compound represented by formula (IV-1) is subjected to a Suzuki coupling reaction with the compound represented by formula (VII) to obtain the compound represented by formula (IV-3)Compound (I)
Figure BDA0001950382440000321
Wherein R is2、R3、R4、L2Has the definition as described above; r111Selected from the above definitions R1Phenyl in (1).
According to an exemplary embodiment of the invention, the coupling reaction is generally carried out at 20 to 120 ℃, preferably 50 to 100 ℃.
According to exemplary embodiments of the present invention, the solvent used for the coupling reaction may be selected from one, two or more of aromatic hydrocarbon solvents, haloalkane solvents, ether solvents, ketone solvents, etc., for example, one, two or more selected from toluene, 1, 2-dichloroethane, tetrahydrofuran, t-butyl methyl ether, butanone, etc.
According to exemplary embodiments of the present invention, the coupling reaction may be carried out in the presence of a base; the base may be selected from one, two or more of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and the like.
According to an exemplary embodiment of the present invention, the coupling reaction is facilitated in the presence of a palladium catalyst, such as tetrakistriphenylphosphine palladium, and the like.
According to an exemplary embodiment of the present invention, the coupling reaction can be referred to Metalcalized Cross coupling Reactions, second edition, Organic name reaction and mechanism, 2003 edition, and the like.
According to an exemplary embodiment of the invention, the compounds of formula (VII) are commercially available or can be prepared by known methods, for example, as described in J.org.chem.49(1984),5237 or Tetrahedron L ett.46(2005),4453, etc.
And the scheme is as follows: when R is1C selected from the above definitions1-C6Alkylcarbonyl, phenylcarbonyl, the compounds of formula (IV) are commercially available according to exemplary embodiments of the invention or may be prepared by known methods.
For example, the compound represented by the formula (IV-5) can be produced from the compound represented by the formula (IV-4) through the steps including amino protection, Friedel-crafts acylation reaction, and deprotection reaction.
Figure BDA0001950382440000322
Wherein R is2、R3、R4Has the definition as described above; r1111Selected from the above definitions R1C in (1)1-C6Alkyl, phenyl; PG (Picture experts group)1Is an amino protecting group commonly found in the art, such as t-butyloxycarbonyl.
According to exemplary embodiments of the invention, amino protection and deprotection can be carried out by reference to the methods described in J.org.chem.21(2004),7004 or J.org.chem.63(1998),8424 or Tetrahedron L ett.35(1994),9003, etc.;
according to an exemplary embodiment of the present invention, the friedel-crafts acylation reaction may be carried out in an aromatic hydrocarbon solvent, a haloalkane solvent or the like, for example selected from the group consisting of nitrobenzene, 1, 2-dichloroethane, carbon disulfide or the like; the catalyst used in the reaction can be selected from aluminum trichloride, ferric trichloride, zinc chloride and the like; the reaction temperature can be 20-120 ℃.
According to exemplary embodiments of the present invention, the friedel-crafts acylation reaction can be prepared by referring to the methods described in organic hom reaction and mechanism 2003 edition or Org. L ett.3(2000),1005 or Tetrahedron L ett.44(2003),193, etc.
And a fifth scheme: when R is1Or R2Or R3Or R4C selected from the above definitions1-C6Alkoxycarbonyl, according to an exemplary embodiment of the present invention, the compound of formula (IV-7) can be prepared from the compound of formula (IV-6) by a procedure comprising nitration, carboxylic acid esterification, and amino reduction, with R2For the purpose of illustration, it is to be understood that,
Figure BDA0001950382440000323
wherein R is1、R3、R4Has the definition as described above; r22Selected from the above definitions C1-C6C in alkoxycarbonyl1-C6An alkyl group.
According to an exemplary embodiment of the present invention, the reaction can be carried out by a method described in patent document CN 1878753 or Tetrahedron56(2000)3399, etc., or other similar methods.
According to an embodiment of the present invention, the compound represented by the formula (III) can be obtained by halogenating the compound represented by the formula (VIII),
Figure BDA0001950382440000331
wherein Ar, L have the definitions as described above.
According to an embodiment of the invention, the halogenating agent may be selected from acid halides of inorganic acids, such as phosphorus trichloride, phosphorus pentachloride, thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus tribromide, and the like.
According to an embodiment of the present invention, the halogenation reaction may be carried out in a solvent; the solvent may be selected from one, two or more of aromatic hydrocarbon solvents, halogenated alkane solvents, for example, one, two or more selected from toluene, 1, 2-dichloroethane, petroleum ether, or the like.
According to an embodiment of the present invention, the temperature of the halogenation reaction may be 20 to 120 ℃.
According to an embodiment of the present invention, the halogenation reaction can be carried out by referring to the method described in handbook of organic compound synthesis 2011 edition or other similar methods.
According to an embodiment of the present invention, the compound represented by formula (VII) is commercially available or can be prepared by a known method.
The preparation process of the present invention may, depending on the reaction conditions and the choice of starting materials which are suitable in each case, replace, for example, in a one-step reaction only one substituent with another substituent according to the invention or may replace in the same reaction step a plurality of substituents with further substituents according to the invention.
If the individual compounds are not obtainable via the above-mentioned routes, they can be prepared by derivatizing other compounds of the formula (I) or by routinely varying the synthetic routes described.
The reaction mixture is worked up in a customary manner, such as by mixing with water, phase separation and purification of the crude product by chromatography, for example on alumina or silica gel.
The invention also provides a preparation method of the pharmaceutically acceptable salt of the compound shown in the formula (I), and the pharmaceutically acceptable salt can be prepared by a known method. For example, by treatment with a suitable acid, pharmaceutically acceptable acid addition salts of the compounds of formula (I) are obtained. The preparation method comprises the following steps: the compound shown in the formula (I) and acid (such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, malic acid or citric acid and the like) react in a solvent such as water, ether or toluene and the like, so that the pharmaceutically acceptable salt of the compound shown in the general formula (I) can be conveniently obtained.
The above preparation method can obtain isomer mixture of the compound shown in formula (I), and if pure isomer is required, the isomer can be separated by conventional method such as crystallization or chromatography.
All reactions described above may conveniently be carried out at atmospheric pressure or the autogenous pressure of the particular reaction, unless otherwise indicated.
The invention also provides application of at least one of the compounds shown in the formula (I) or pharmaceutically acceptable salts thereof in preparing bactericides used in agriculture or other fields.
The invention also provides application of at least one of the compounds shown in the formula (I) or pharmaceutically acceptable salts thereof as a bactericide, wherein the bactericide is used in agriculture or other fields.
The present invention also provides a composition comprising at least one of the compounds represented by formula (I) or pharmaceutically acceptable salts thereof as an active ingredient.
The invention also provides the use of said composition, which can be used as a fungicide in agriculture or in other fields.
The present invention also provides a method for controlling pathogenic bacteria, such as phytopathogens, comprising applying an effective amount of at least one of a compound of formula (I) or a pharmaceutically acceptable salt thereof or applying the composition to a growth medium for the phytopathogen.
The examples of diseases mentioned below are intended only to illustrate the invention, but in no way limit it.
The compound shown in the formula (I) can be used for preventing and treating the following diseases or corresponding pathogenic bacteria thereof: oomycete diseases such as downy mildew (cucumber downy mildew, rape downy mildew, soybean downy mildew, beet downy mildew, sugarcane downy mildew, tobacco downy mildew, pea downy mildew, loofah downy mildew, wax gourd downy mildew, melon downy mildew, Chinese cabbage downy mildew, spinach downy mildew, radish downy mildew, grape downy mildew, onion downy mildew), white rust (rape white rust, Chinese cabbage white rust), damping-off (rape damping-off, tobacco damping-off, tomato damping-off, pepper damping-off, eggplant damping-off, cucumber damping-off, cotton seedling damping-off), cotton rot (hot pepper rot, loofah sponge rot, wax gourd blight), epidemic diseases (broad bean blight, cucumber blight, pumpkin blight, melon blight, hot pepper, leek blight, garlic blight, cotton blight, tomato blight, etc.; fungi imperfecti diseases such as wilt (sweet potato wilt, cotton wilt, sesame wilt, castor wilt, tomato wilt, bean wilt, cucumber wilt, pumpkin wilt, winter melon wilt, watermelon wilt, sweet melon wilt, hot pepper wilt, broad bean wilt, rape wilt, soybean wilt), root rot (hot pepper root rot, eggplant root rot, bean rot, cucumber root rot, bitter gourd root rot, cotton black root rot, broad bean root rot), damping off (seedling blight of cotton, sesame seedling blight, hot pepper seedling blight, cucumber damping off, cabbage stalk rot), anthracnose (sorghum anthracnose, cotton anthracnose, kenaf anthracnose, jute anthracnose, flax anthracnose, tobacco anthracnose, mulberry leaf, hot pepper, bean disease, cucumber anthracnose, red sesame anthracnose, jute anthracnose, flax anthracnose, tobacco anthracnose, eggplant disease, hot pepper anthracnose, vegetable bean disease, and cucumber blight, Balsam pear anthracnose, pumpkin anthracnose, wax gourd anthracnose, watermelon anthracnose, melon anthracnose, litchi anthracnose), verticillium wilt (cotton verticillium wilt, sunflower verticillium wilt, tomato verticillium wilt, hot pepper verticillium wilt, eggplant verticillium wilt), scab (pumpkin scab, wax gourd scab, melon scab), gray mold (boll gray mold, red ramie gray mold, tomato gray mold, hot pepper gray mold, bean gray mold, celery gray mold, spinach gray mold, kiwi gray mold), brown spot (cotton brown spot, jute brown spot, beet brown spot, peanut brown spot, pepper brown spot, wax gourd brown spot, soybean brown spot, sunflower brown spot, pea brown spot, broad bean brown spot), black spot (flax brown spot, rape black spot, sesame black spot, sunflower black spot, castor black spot, tomato black spot, pepper black spot, eggplant black spot, bean black spot, cucumber black spot, celery black spot, carrot black rot, carrot black spot, apple black spot, peanut black spot), spot blight (tomato spot blight, pepper spot blight, celery spot blight), early blight (tomato early blight, pepper early blight, eggplant early blight, potato early blight, celery early blight), ring spot (soybean ring spot, sesame ring spot, bean ring spot), leaf blight (sesame leaf blight, sunflower leaf blight, watermelon leaf blight, melon leaf blight), stem base rot (tomato stem base rot, bean stem base rot), and others (corn round spot, kenaf waist fold, rice blast, black sheath blight, sugarcane eye spot, cotton boll aspergillosis, peanut crown rot, soybean stem blight, soybean black spot, melon big spot, peanut net spot, tea leaf spot, red leaf spot, black leaf spot, peanut net spot, tea leaf spot, tomato black spot, potato leaf spot, potato black spot, tomato leaf, Pepper white spot disease, white gourd leaf spot disease, celery black rot disease, spinach heart rot disease, kenaf leaf mold disease, kenaf spot disease, jute stem spot disease, soybean purple spot disease, sesame leaf spot disease, castor gray spot disease, tea brown leaf spot disease, eggplant brown orbicular spot disease, kidney bean red spot disease, bitter gourd leukoderma, watermelon spot disease, jute bottom rot disease, sunflower root stem rot disease, kidney bean carbon rot disease, soybean target spot disease, eggplant rod spore leaf spot disease, cucumber target spot disease, tomato leaf mold, eggplant leaf mold, broad bean red spot disease and the like); basidiomycete diseases such as rust (wheat stripe rust, wheat stalk rust, wheat leaf rust, peanut rust, sunflower rust, sugarcane rust, leek rust, onion rust, chestnut rust, soybean rust), smut (maize head smut, maize smut, sorghum head smut, sorghum loose smut, sorghum stalk smut, chestnut kernel smut, sugarcane head smut, kidney bean rust) and others (such as wheat sharp eyespot, rice sheath blight, etc.); ascomycetous diseases, such as powdery mildew (wheat powdery mildew, rape powdery mildew, sesame powdery mildew, sunflower powdery mildew, beet powdery mildew, eggplant powdery mildew, pea powdery mildew, towel gourd powdery mildew, pumpkin powdery mildew, wax gourd powdery mildew, melon powdery mildew, grape powdery mildew, broad bean powdery mildew), sclerotinia rot (flax sclerotinia rot, rape sclerotinia rot, soybean sclerotinia rot, peanut sclerotinia rot, tobacco sclerotinia rot, pepper sclerotinia rot, eggplant sclerotinia rot, kidney bean sclerotinia rot, pea sclerotinia rot, cucumber sclerotinia rot, bitter gourd sclerotinia rot, wax gourd sclerotinia rot, watermelon sclerotinia rot, celery sclerotinia rot), scab (apple scab, pear scab) and the like.
Owing to their positive properties, the abovementioned compounds can be used advantageously for protecting crops, livestock and breeding animals of agricultural and horticultural importance, as well as the environment which is frequently encountered by humans, against harmful bacteria.
The amount of the compound used to achieve the desired effect will vary depending on factors such as the compound used, the crop to be protected, the type of pest, the extent of infection, the climatic conditions, the method of application, and the dosage form employed.
The ingredients of the dosage forms or compositions described herein are selected in accordance with the physical properties of the active ingredient, the mode of application and environmental factors such as soil type, moisture and temperature.
Such dosage forms include liquid formulations such as solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and/or suspensions), and the like, which may optionally be viscous jellies. The dosage forms also include solids such as powders, granules, tablets, pills, films, and the like, which may be water dispersible ("wettable") or water soluble. The effective components can be microencapsulated and made into suspension or solid dosage form; in addition, the whole dosage form of the effective components can be encapsulated. The capsule can control or delay the release of the effective components. Sprayable formulations can be diluted in a suitable medium using spray volumes of about one to several hundred liters per hectare. The compositions in high concentrations are mainly used as intermediates for further processing.
Typical solid diluents are described in Watkins et al, Handbook of Instrument Dust Diluendsand Cariers, 2nd Ed., Dorland Books, Caldwell, N.J.. Typical liquid diluents are described in Marsden, Solventsguide, 2nd Ed., Interscience, New York, 1950. McCutcheon's Detergents and Emulsifiers annular, Allured pub. Corp., Ridgewood, New Jersey, and Sisely and Wood, Encyclopedia of Surface Active Agents, chemical Publ. Co., Inc., New York, 1964, list surfactants and recommended applications. All dosage forms may contain minor amounts of additives to reduce foaming, prevent caking, prevent corrosion, prevent microbial growth, etc., or thickeners to increase viscosity.
Surfactants include, for example, polyethoxylated alcohols, polyethoxylated alkylphenols, polyethoxylated sorbitan fatty acid esters, sulfonated dialkyl succinates, alkyl sulfates, alkyl benzene sulfonates, organosilanes, N, N-dialkyl taurates, lignosulfonates, aldehyde condensates for naphthalenesulfonates, polycarboxylates, and polyoxyethylene/polyoxypropylene block copolymers.
Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, starches, sugars, silica, talc, diatomaceous earth, urea, calcium carbonate, sodium bicarbonate, sodium sulfate; liquid diluents include, for example, water, N-dimethylformamide, dimethylsulfone, N-alkylpyrrolidone, ethylene glycol, polypropylene glycol, paraffin, alkylbenzene, alkylnaphthalene, olive oil, castor oil, linseed oil, tung oil, sesame oil, corn oil, peanut oil, cottonseed oil, soybean oil, rapeseed oil and cocoa butter, fatty acid esters, ketones such as cyclohexanone, 2-heptanone, isophorone and 4-hydroxy-4-methyl-2-pentanone, and alcohols such as methanol, cyclohexanol, dodecanol and tetrahydrofurfuryl alcohol.
Solutions, including emulsifiable concentrates, can be prepared by simply mixing the components. Powders and fines may be prepared by mixing or by grinding, usually in a hammer mill or fluid energy mill. Suspending agents are generally prepared by wet milling, for example as described in US 3060084. Granules and pellets are prepared by spraying the active substance onto the freshly prepared granular carrier or by granulation techniques. See Browning, "agglomerization," Chemical Engineering, Decumber 4, 1967, 147-48; perry's Chemical Engineer's Handbook, 4TH Ed., McGraw-Hill, New York, 1963, 8-57; and WO 9113546. Preparation of pellets as described in US 4172714, water dispersible and water soluble granules as described in US 4144050, US3920442 and DE 3246493 to prepare tablets as described in US 5180587, US 5232701 and US 5208030. Films may be prepared by the methods described in GB2095558 and US 3299566.
More information on processing can be found in US 3235361, column 6, line 16 to column 7, line 19, and examples 10-41; US3309192, column 43 to column 7, column 62 and examples 8, 12, 15, 39, 41, 52, 53, 58, 132, 138, 140, 162, 164, 166, 167 and 169, 182; US 2891855 at column 3, line 66 to column 5, line 17 and examples 1-4; klingman, Weed controls a Science, John Wiley and Sons, inc., New York 1961, 81-96; and Hance et al, WeedControl Handbook, 8th Ed., Blackwell Scientific Publications, Oxford, 1989.
Herein, for certain applications of the composition, for example in agriculture, one, two or more other bactericides, insecticides, acaricides, herbicides, plant growth regulators or fertilizers and the like may be added to the composition of the present invention, thereby giving additional advantages and effects.
Definition and description of terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications, and publications cited herein are incorporated by reference in their entirety unless otherwise indicated. If there are multiple definitions of terms herein, the definition in this section controls.
In the present specification, groups and substituents thereof may be selected by those skilled in the art to mentionMoieties and compounds for stabilization. When a substituent is described by a general formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the formula is written from right to left. For example, CH2O is equivalent to OCH2。
Where a range of numerical values is recited in the specification and claims of this application, and where the range of numerical values can only be "integers," it is to be understood that both endpoints of the range are recited and each integer within the range is also recited. For example, a value of "1 to 5" should be understood to recite each integer of 1,2, 3,4, 5.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "C1-C12Alkyl is understood to mean a straight-chain or branched, saturated monovalent hydrocarbon radical having from 1 to 12 carbon atoms, preferably C1-C6Alkyl, more preferably C1-C4Alkyl groups, such as straight or branched chain saturated monovalent hydrocarbon groups having 1,2, 3 or 4 carbon atoms. The alkyl group is, for example, a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isopentyl group, a 2-methylbutyl group, a 1-ethylpropyl group, a 1, 2-dimethylpropyl group, a neopentyl group, a 1, 1-dimethylpropyl group, a 4-methylpentyl group, a 3-methylpentyl group, a 2-ethylbutyl group, a 1-ethylbutyl group, a 3, 3-dimethylbutyl group, a 2, 2-dimethylbutyl group, a 1, 1-dimethylbutyl group, a 2, 3-dimethylbutyl group, a 1, 3-dimethylbutyl group or a 1, 2-dimethylbutyl group. In particular, the radicals have 1,2, 3,4, 5, 6 carbon atoms ("C)1-C6Alkyl groups) such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, tert-butyl, more particularly groups having 1,2 or 3 carbon atoms ("C)1-C3Alkyl groups) such as methyl, ethyl, n-propyl or isopropyl.
The term "5-20 membered heteroaryl" is understood to include such monovalent monocyclic, bicyclic or tricyclic aromatic ring systems: having 5 to 20 ring atoms and containing 1 to 5 heteroatoms independently selected from N, O and S. The term "5-to 10-membered heteroaryl" is understood to include such monocyclic or bicyclic aromatic ring systems: which has 5, 6, 7, 8, 9, 10 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and which contains 1 to 5, preferably 1 to 3, heteroatoms each independently selected from N, O and S and, in addition, can be benzo-fused in each case. The term "5-or 6-membered heteroaryl" is understood to include such monocyclic aromatic ring systems: having 5 to 6 ring atoms and comprising 1 to 4 heteroatoms independently selected from N, O and S. In particular, the heteroaryl group is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like and their benzo derivatives, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, and benzo derivatives thereof, such as quinolyl, quinazolinyl, isoquinolyl, quinoxalyl, and the like; or isothiazolopyrimidinyl, imidazopyridinyl, azocinyl, indolizinyl, purinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, and the like.
Unless otherwise indicated, heteroaryl includes all possible isomeric forms thereof, e.g., positional isomers thereof. Thus, for some illustrative non-limiting examples, pyridyl includes pyridin-2-yl, pyridin-3-yl, pyridin-4-yl; thienyl includes thien-2-yl, thien-3-yl.
The above for the term "alkyl", e.g. "C1-C6The definition of alkyl "applies equally to compounds containing" C1-C6Other terms for alkyl radicals, e.g. the term "C1-C6Alkoxy group "," C1-C6Haloalkyl "," C1-C6Haloalkoxy "," C1-C6Alkoxycarbonyl group and C1-C6Alkylcarbonyl group and C1-C4Alkylsulfonyl group "," C1-C4Alkylsulfinyl group "," C1-C4Alkylthio ", and the like.
The term "pharmaceutically acceptable salt" as used herein refers to salts that retain the biological potency of the free acid and free base of the specified compound, and that are biologically or otherwise non-adverse. The compounds of the present application also include pharmaceutically acceptable salts, such as nitrates, hydrochlorides, sulfates, phosphates, or the like. Pharmaceutically acceptable salts refer to the form in which the base group in the parent compound is converted to a salt. Pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic groups such as amine (amino) groups. Pharmaceutically acceptable salts of the present application can be synthesized from the parent compound by reacting a basic group in the parent compound with 1-4 equivalents of an acid in a solvent system.
Advantageous effects
The compound shown in the formula (I) shows good activity on various germs in the agricultural or other fields. In addition, the compounds can obtain good control effect at very low dosage, so the compounds can be used for preparing bactericides.
In addition, the compound has simple preparation steps and high yield, thereby having good application prospect.
Detailed Description
The technical solution of the present invention will be further described in detail with reference to specific embodiments. The following examples are merely illustrative and explanatory of the present invention and should not be construed as limiting the scope of the invention. All the technologies realized based on the above-mentioned contents of the present invention are covered in the protection scope of the present invention.
Unless otherwise indicated, the raw materials and reagents used in the following examples are all commercially available products or can be prepared by known methods.
The following method was used for L C-MS analysis:
chromatography column, Agilent ZORBAX SB-C18150 mm × 4.6.6 mm, 5 μm (inner diameter);
detection wavelength: 254 nm;
the flow rate is 0.8m L/min;
column temperature: 30 ℃;
gradient elution conditions:
time (min) Acetonitrile (%) 0.1% aqueous formic acid (%)
0.00 50 50
5.00 50 50
15.00 90 10
20.00 90 10
Synthetic examples
Example 1: 3- (difluoromethyl) -1-methyl-N- (3- (pentafluorothio) phenyl) -1 h-pyrazole-4-carboxamide (Compound 25)
Figure BDA0001950382440000371
1.1g (5mmol) of 3- (pentafluorothio) aniline and 0.76g (7.5mmol) of triethylamine are dissolved in 15m L dichloromethane in sequence, the mixture is cooled to 5 ℃ in a low-temperature bath, 1.01g (5.2mol) of 3- (difluoromethyl) -1-methyl-1-hydro-pyrazole-4-carbonyl chloride is added to the mixture in portions, the temperature is maintained below 20 ℃, after the addition, the reaction is carried out for 5h at room temperature, 10m L saturated sodium bicarbonate aqueous solution is added to the reaction system, dichloromethane (3 × 15m L) is used for extraction, organic layers are combined, 10m L saturated common salt water is washed, anhydrous magnesium sulfate is dried, decompression and desolvation are carried out, and column chromatography (eluent: mixed solution of ethyl acetate and petroleum ether (1:5)) is carried out to obtain 1.63g of a product, wherein the yield is 86%.
LC/MS[M+H]+＝378.05、[M+Na]+＝400.03、[M+K]+＝416。
1H-NMR (400MHz, solvent CDCl)3)(ppm):3.98(3H,s),6.88(1H,t),7.24(1H,s),7.68(1H,s),7.72(1H,s),7.76(1H,s),8.06(1H,s),8.30(1H,s)。
Example 2: 3, 4-dichloro-N- (3- (pentafluorothio) phenyl) isothiazole-5-carboxamide (Compound 33)
Figure BDA0001950382440000372
1.1g (5mmol) of 3- (pentafluorothio) aniline and 0.76g (7.5mmol) of triethylamine are sequentially dissolved in 15m L dichloromethane, the mixture is cooled to 5 ℃ by low-temperature bath, 1.01g (5.2mol) of 3, 4-dichloroisothiazole-5-acyl chloride is added to the mixture in batches, the temperature is maintained below 20 ℃, after the addition is finished, the reaction is carried out for 5h at room temperature, 10m L saturated sodium bicarbonate aqueous solution is added to the reaction system, dichloromethane (3 × 15m L) is extracted, organic layers are combined, 10m L saturated common salt water is washed, anhydrous magnesium sulfate is dried, decompression and desolvation is carried out, and column chromatography (eluent: mixed solution of ethyl acetate and petroleum ether (1:5)) is carried out to obtain 1.6g of a product with the yield of 80%.
LC/MS[M+H]+＝398.92、[M+Na]+＝420.9、[M+K]+＝436.87。
1H-NMR (400MHz, solvent CDCl)3)(ppm):7.26(1H,d),7.37(1H,d),7.73(1H,d),7.80(1H,d),8.64(1H,s)。
Example 3: n- (3-fluoro-5- (pentafluorothio) phenyl) -3- (trifluoromethyl) pyrazine 2-amide (Compound 71)
Figure BDA0001950382440000373
1.18g (5mmol) of 3-fluoro-5- (pentafluorothio) aniline and 0.76g (7.5mmol) of triethylamine are sequentially dissolved in 15m L dichloromethane, the mixture is cooled to 5 ℃ in a low-temperature bath, 1.09g (5.2mol) of 3- (trifluoromethyl) pyrazine-2-acyl chloride is added to the mixture in portions, the temperature is maintained below 20 ℃, the mixture is reacted for 5 hours at room temperature, 10m L saturated sodium bicarbonate aqueous solution is added to the reaction system, dichloromethane (3 × 10m L) is used for extraction, organic layers are combined, 15m L saturated common salt water is washed, anhydrous magnesium sulfate is dried, decompression and desolvation is carried out, and column chromatography (eluent: mixed solution of ethyl acetate and petroleum ether (1:5)) is carried out, so that 1.76g of the product is obtained, and the yield is 86%.
LC/MS[M+H]+＝412.02、[M+Na]+＝434、[M+K]+＝449.97。
1H-NMR (400MHz, solvent CDCl)3)(ppm):7.32(1H,d),7.68(1H,s),7.78(1H,d),8.26(1H,d),8.42(1H,d),8.70(1H,s)。
Example 4: 8-chloro-N- (3-fluoro-5- (pentafluorothio) phenyl) -6- (trifluoromethyl) imidazo [1,2-a ] pyridine-2-amide (compound 86)
Figure BDA0001950382440000381
1.18g (5mmol) of 3-fluoro-5- (pentafluorothio) aniline and 0.76g (7.5mmol) of triethylamine are sequentially dissolved in 15m L dichloromethane, the mixture is cooled to 5 ℃ in a low-temperature bath, 1.48g (5.2mol) of 8-chloro-6- (trifluoromethyl) imidazo [1,2-a ] pyridine-2-carbonyl chloride is added to the mixture in portions, the temperature is maintained below 20 ℃, the mixture is reacted for 5 hours at room temperature, 10m L saturated aqueous sodium bicarbonate solution is added to the reaction system, dichloromethane (3 × 10m L) is extracted, organic layers are combined, 15m L saturated common salt is washed with water, anhydrous magnesium sulfate is dried, the solvent is removed under reduced pressure, and column chromatography (eluent: mixed solution of ethyl acetate and petroleum ether (1:4)) is performed to obtain 1.81g of a product with a yield of 75%.
LC/MS[M+H]+＝484、[M+Na]+＝505.98、[M+K]+＝521.95。
1H-NMR (400MHz, solvent CDCl)3)(ppm):7.45(1H,d),7.63(1H,s),7.68(1H,s),7.76(1H,d),8.26(1H,d),8.62(1H,s),8.76(1H,s)。
Example 5: n- (3-fluoro-5- (pentafluorothio) phenyl) -2-methyl-4- (trifluoromethyl) thiazole-5-carboxamide (Compound 99)
Figure BDA0001950382440000382
1.18g (5mmol) of 3-fluoro-5- (pentafluorothio) aniline and 0.76g (7.5mmol) of triethylamine are sequentially dissolved in 15m L dichloromethane, the mixture is cooled to 5 ℃ in a low-temperature bath, 1.19g (5.2mol) of 2-methyl-4- (trifluoromethyl) thiazole-5-acyl chloride is added to the mixture in batches, the temperature is maintained below 20 ℃, after the addition, the reaction is carried out for 5h at room temperature, 10m L saturated sodium bicarbonate aqueous solution is added to the reaction system, dichloromethane (3 × 10m L) is used for extraction, the organic layers are combined, 15m L saturated common salt water is washed, anhydrous magnesium sulfate is used for drying, decompression and desolventization are carried out, and 1.82g of a product is obtained (eluent: a mixed solution of ethyl acetate and petroleum ether (1:4)) with the yield of 85%.
LC/MS[M+H]+＝431、[M+Na]+＝452.98、[M+K]+＝468.95。
1H-NMR (400MHz, solvent CDCl)3)(ppm):2.84(3H,s),7.30(1H,d),7.63(1H,s),7.72(1H,d),8.62(1H,s)。
Example 6: 3, 4-dichloro-N- (3-fluoro-5- (pentafluorothio) phenyl) isothiazole-5-carboxamide (Compound 103)
Figure BDA0001950382440000383
1.18g (5mmol) of 3-fluoro-5- (pentafluorothio) aniline and 0.76g (7.5mmol) of triethylamine are sequentially dissolved in 15m L dichloromethane, the mixture is cooled to 5 ℃ in a low-temperature bath, 1.01g (5.2mol) of 3, 4-dichloroisothiazole-5-acyl chloride is added to the mixture in batches, the temperature is maintained below 20 ℃, after the addition, the reaction is carried out for 5h at room temperature, 10m L saturated sodium bicarbonate aqueous solution is added to the reaction system, dichloromethane (3 × 15m L) is extracted, organic layers are combined, 10m L saturated common salt water is washed, anhydrous magnesium sulfate is dried, decompression and desolventization are carried out, and column chromatography (eluent: mixed solution of ethyl acetate and petroleum ether (1:5)) is carried out to obtain 1.58g of a product with the yield of 76%.
LC/MS[M+H]+＝416.91、[M+Na]+＝438.89、[M+K]+＝454.86。
1H-NMR (400MHz, solvent CDCl)3)(ppm):7.37(1H,d),7.73(1H,s),7.82(1H,d),8.66(1H,s)。
Example 7: 5, 7-dichloro-N- (3-fluoro-5- (pentafluorothio) phenyl) benzo [ d ] thiazole-2-amide (Compound 140)
Figure BDA0001950382440000391
1.18g (5mmol) of 3-fluoro-5- (pentafluorothio) aniline and 0.76g (7.5mmol) of triethylamine are sequentially dissolved in 15m L dichloromethane, the mixture is cooled to 5 ℃ in a low-temperature bath, 1.39g (5.2mol) of 5, 7-dichlorobenzo [ d ] thiazole-2-carbonyl chloride is added to the mixture in portions, the temperature is maintained below 20 ℃, after the addition, the reaction is carried out for 5h at room temperature, 10m L saturated sodium bicarbonate aqueous solution is added to the reaction system, dichloromethane (3 × 15m L) is used for extraction, the organic layers are combined, 10m L saturated common salt water is washed, anhydrous magnesium sulfate is used for drying, decompression and desolventization are carried out, and 1.93g of the product is obtained with the yield of 83 percent.
LC/MS[M+H]+＝466.93、[M+Na]+＝488.91、[M+K]+＝504.88。
1H-NMR (400MHz, solvent CDCl)3)(ppm):7.36(1H,d),7.42(1H,s),7.72(1H,s),7.72(1H,d),7.81(1H,d),8.65(1H,s)。
Example 8: 3, 4-dichloro-N- (3-methoxy-5- (pentafluorothio) phenyl) isothiazole-5-carboxamide (Compound 148)
Figure BDA0001950382440000392
The first step of reaction: 3-methoxy-5- (pentafluorothio) aniline
3.02g (10mmol) of 3-bromo-5- (pentafluorothio) aniline and 3.60g (20mmol) of 30% sodium methoxide solution are sequentially dissolved in 25m L of methanol, the mixture is gradually heated to reflux, the temperature is kept for 5h, the reaction is kept for 5h, atmospheric distillation is carried out, the solvent is removed, 25m L of water is added into the residue, the pH value is adjusted to be 7-8 by dilute hydrochloric acid, ethyl acetate (3 × 20m L) is extracted, organic layers are combined, 10m L of saturated common salt water is washed, anhydrous magnesium sulfate is dried, and decompression and desolventization are carried out to obtain 1.98g of light yellow solid, and the yield is 80%.
LC/MS[M+H]+＝250.03、[M+Na]+＝272.01、[M+K]+＝287.98。
The second step of reaction: 3, 4-dichloro-N- (3-methoxy-5- (pentafluorothio) phenyl) isothiazole-5-carboxamide
1.39g (5mmol) of 3-methoxy-5- (pentafluorothio) aniline and 0.76g (7.5mmol) of triethylamine are sequentially dissolved in 15m L dichloromethane, the mixture is cooled to 5 ℃ in a low-temperature bath, 1.01g (5.2mol) of 3, 4-dichloroisothiazole-5-acyl chloride is added to the mixture in batches, the temperature is maintained below 20 ℃, after the addition, the reaction is carried out for 5h at room temperature, 10m L saturated sodium bicarbonate aqueous solution is added to the reaction system, dichloromethane (3 × 15m L) is extracted, organic layers are combined, 10m L saturated common salt water is washed, anhydrous magnesium sulfate is dried, decompression and desolvation are carried out, and column chromatography (eluent: mixed solution of ethyl acetate and petroleum ether (1:4)) is carried out, so that 1.67g of the product is obtained, and the yield is 78%.
LC/MS[M+H]+＝428.93、[M+Na]+＝450.91、[M+K]+＝466.88。
1H-NMR (400MHz, solvent CDCl)3)(ppm):3.86(3H,s),7.13(1H,d),7.50(1H,d),7.68(1H,d),8.65(1H,s)。
Example 9: methyl 3- (3, 4-dichloroisothiazole-5-amide) -5- (pentafluorothio) benzoate (Compound 153)
Figure BDA0001950382440000393
The first step is as follows: 3-nitro-5- (pentafluorothio) -benzoic acid
At room temperature, 5.02g (20mmol) of 3- (pentafluorothio) benzoic acid is dissolved in 50m L fuming nitric acid, 12m L concentrated sulfuric acid is added into the solution under ice bath, the solution is naturally heated to the room temperature, the reaction solution is poured into 150g of crushed ice after being stirred for 18h, the product is obtained after stirring for 1h and suction filtration, and the light yellow solid is obtained after 5.2g and the yield is 90 percent after drying.
LC/MS[M+H]+＝293.99、[M+Na]+＝315.97、[M+K]+＝331.94。
The second step is that: 3-Nitro-5- (pentafluorothio) benzoic acid methyl ester
5.0g (17mmol) of 3-nitro-5- (pentafluorothio) -benzoic acid are dissolved in 100m L of methanol at room temperature, 4.16g (35mmol) of thionyl chloride is added dropwise at room temperature, the mixture is heated to reflux, the mixture is stirred for 6h, the volatile constituents are distilled off under reduced pressure, the residue is coevaporated with 50m L of toluene once, and column chromatography of the residue (eluent: mixed liquor of ethyl acetate and petroleum ether (1:7)) is carried out to give 4.58g of product with a yield of 86%.
LC/MS[M+H]+＝308、[M+Na]+＝329.98、[M+K]+＝345.95。
The third step: 3-amino-5- (pentafluorothio) benzoic acid methyl ester
4.8g (15mmol) of methyl 3-nitro-5- (pentafluorothio) benzoate were dissolved in 60m L methanol, 6m L acetic acid and 0.32g Pd/C (10%). mixture was hydrogenated at 6 Pa atmospheric pressure for 48h, the catalyst was filtered off and the solvent was distilled off under reduced pressure to give 3.6g of product in 86% yield.
LC/MS[M+H]+＝278.03、[M+Na]+＝300.01、[M+K]+＝315.98。
The fourth step: methyl 3- (3, 4-dichloroisothiazole-5-amide) -5- (pentafluorothio) benzoate
1.39g (5mmol) of 3-amino-5- (pentafluorothio) benzoic acid methyl ester and 0.76g (7.5mmol) of triethylamine were sequentially dissolved in 15m L dichloromethane, the mixture was cooled to 5 ℃ in a low temperature bath, 1.01g (5.2mol) of 3, 4-dichloroisothiazole-5-acid chloride was added to the above mixture in portions, the temperature was maintained at 20 ℃ or lower after the addition, reaction was carried out at room temperature for 5 hours, 10m L saturated sodium bicarbonate aqueous solution was added to the reaction system, dichloromethane (3 × 15m L) was extracted, the organic layers were combined, 10m L saturated common salt water was washed, anhydrous magnesium sulfate was dried, desolvation was carried out under reduced pressure, and 1.96g of a product was obtained (eluent: a mixed solution of ethyl acetate and petroleum ether (1:6)) with a yield of 86%.
LC/MS[M+H]+＝456.93、[M+Na]+＝478.91、[M+K]+＝494.88。
1H-NMR (400MHz, solvent CDCl)3)(ppm):3.92(3H,s),7.42(1H,d),7.78(1H,d),7.96(1H,d),8.69(1H,s)。
Example 10: 3, 4-dichloro-N- (4' -chloro-5- (pentafluorothio) biphenyl-3-yl) isothiazole-5-amide (compound 162)
Figure BDA0001950382440000401
The first step of reaction: 4' -chloro-5- (pentafluorothio) biphenyl-3-aniline
At room temperature, 3.02g (10mmol) of 3-bromo-5- (pentafluorothio) aniline, 1.72g (11mmol) of p-chlorobenzeneboronic acid, 2.07g (15mmol) of potassium carbonate and 0.05g of palladium (tetratriphenylphosphine) are sequentially dissolved in 25m L toluene, the temperature is gradually increased to 85 ℃ under the protection of nitrogen, the reaction is kept warm for 6 hours, the reaction liquid is cooled to room temperature, 30m L water is added into the reaction liquid, layers are separated, L is taken, a water layer is extracted by toluene (3 × 20m 25), organic layers are combined, 15m L saturated common salt water is washed, anhydrous magnesium sulfate is dried, and decompression and desolventization are carried out, so that 2.48g of gray solid is obtained, and the yield is 75%.
LC/MS[M+H]+＝330.02、[M+Na]+＝352、[M+K]+＝367.97。
The second step of reaction: 3, 4-dichloro-N- (4' -chloro-5- (pentafluorothio) biphenyl-3-yl) isothiazol-5-carboxamide
1.65g (5mmol) of 3-methoxy-5- (pentafluorothio) aniline and 0.76g (7.5mmol) of triethylamine are sequentially dissolved in 15m L dichloromethane, the mixture is cooled to 5 ℃ by low-temperature bath, 1.01g (5.2mol) of 3, 4-dichloroisothiazole-5-acyl chloride is added to the mixture in batches, the temperature is maintained below 20 ℃, after the addition, the reaction is carried out for 5h at room temperature, 10m L saturated sodium bicarbonate aqueous solution is added to the reaction system, dichloromethane (3 × 15m L) is extracted, organic layers are combined, 10m L saturated common salt water is washed, anhydrous magnesium sulfate is dried, decompression and desolventization are carried out, and column chromatography (eluent: mixed solution of ethyl acetate and petroleum ether (1:4)) is carried out to obtain 1.73g of a product, and the yield is 68%.
LC/MS[M+H]+＝508.92、[M+Na]+＝530.9、[M+K]+＝546.87。
1H-NMR (400MHz, solvent CDCl)3)(ppm):7.30(1H,d),7.42(2H,d),7.76(1H,d),7.81(2H,d),7.93(1H,d),8.72(1H,s)。
Example 11: 3, 4-dichloro-N- (2- (methylsulfonyl) -5- (pentafluorothio) phenyl) isothiazole-5-amide (Compound 238)3, 4-dichloro-N- (2- (methylsulfonyl) -5- (pentafluorothio) phenyl) isothiazole-5-amide (Compound 239)
Figure BDA0001950382440000411
The first step of reaction: tert-butyl 2- (methylthio) -5- (pentafluorothio) phenylcarbamate
5.58g (20mmol) of 2- (methylthio) -5- (pentafluorothio) aniline and 9.12g (50mmol) of tetramethylammonium hydroxide hydrate were dissolved in 80m L acetonitrile, 6.55g (30mmol) of di-tert-butyl dicarbonate was added to the above solution in portions, the obtained solution was stirred at room temperature for 15 hours, the solvent was distilled off under reduced pressure from the reaction solution, 50m L of water was added to the reaction solution, ether (3 × 25m L) was extracted, the organic layers were combined, 20m L of saturated brine was washed, anhydrous sodium sulfate was dried, desolvation under reduced pressure was carried out, and column chromatography (eluent: mixed solution of ethyl acetate and petroleum ether (1:5)) was carried out to obtain 6.25g of a product with a yield of 85%.
LC/MS[M+H]+＝366.06、[M+Na]+＝388.04、[M+K]+＝404.01。
The second step of reaction: tert-butyl 2- (methylsulfonyl) -5- (pentafluorothio) phenyl carbamate
6.15g (16mmol) of tert-butyl 2- (methylthio) -5- (pentafluorothio) phenylcarbamate and 4.06g (20mmol) of 85% m-chloroperoxybenzoic acid (MCPBA) were dissolved in 50m L chloroform at 0 ℃ in this order, the mixture was gradually warmed to room temperature, and the reaction mixture was stirred for 10 hours, washed with 5m L of a saturated aqueous sodium sulfite solution, 15m L of a saturated aqueous sodium bicarbonate solution and 20m L of water in this order, and subjected to column chromatography (eluent: a mixture (1:5) of ethyl acetate and petroleum ether) to give 2.68g of tert-butyl 2- (methylsulfonyl) -5- (pentafluorothio) phenylcarbamate in a yield of 46% and 1.92g of tert-butyl 2- (methylsulfonyl) -5- (pentafluorothio) phenylcarbamate in a yield of 30%.
LC/MS[M+H]+＝382.06、[M+Na]+＝404.04、[M+K]+＝420.01。
LC/MS[M+H]+＝398.05、[M+Na]+＝420.03、[M+K]+＝436。
The third step of reaction: 2- (Methylsulfidenyl) -5- (pentafluorothio) aniline
At room temperature, 5g of hydrogen chloride gas is introduced into 25m L of methanol, the mixture is cooled to below 5 ℃ in an ice bath, 2.5g (6mmol) of 5m L methanol solution of tert-butyl 2- (methyl sulfoxide) -5- (pentafluorothio) phenyl carbamate is dropwise added into the hydrogen chloride methanol solution, the solution is stirred for 8h at the room temperature after 15min, the reaction solution is decompressed and distilled to remove the methanol, and the residue is washed by ether (2 × 10m L), so that 1.48g of the product is obtained, and the yield is 86%.
LC/MS[M+H]+＝282.01、[M+Na]+＝303.99、[M+K]+＝319.96。
2- (methylsulfonyl) -5- (pentafluorothio) aniline
At room temperature, 4.5g of hydrogen chloride gas is introduced into 20m L of methanol, the mixture is cooled to below 5 ℃ in an ice bath, 1.9g (4.8mmol) of tert-butyl 2- (methylsulfonyl) -5- (pentafluorothio) phenyl carbamate in 5m L of methanol solution is dropwise added into the hydrogen chloride methanol solution, the solution is stirred for 8h at room temperature after 15min, the methanol is evaporated from the reaction solution under reduced pressure, and the residue is washed by ether (2 × 10m L) to obtain 1.16g of the product with the yield of 82%.
LC/MS[M+H]+＝298、[M+Na]+＝319.98、[M+K]+＝335.95。
And a fourth step of reaction: 3, 4-dichloro-N- (2- (methylsulfinylidene) -5- (pentafluorothio) phenyl) isothiazole-5-amide
1.46g (5mmol) of 2- (methylsulfonyl) -5- (pentafluorothio) aniline and 0.76g (7.5mmol) of triethylamine are sequentially dissolved in 15m L dichloromethane, the solution is cooled to 5 ℃ in a low-temperature bath, 1.01g (5.2mol) of 3, 4-dichloroisothiazole-5-acyl chloride is added to the mixture in batches, the temperature is maintained below 20 ℃, the reaction is carried out for 5h at room temperature after the addition, 10m L saturated sodium bicarbonate aqueous solution is added to the reaction system, dichloromethane (3 × 15m L) is extracted, the organic layers are combined, 10m L saturated common salt water is washed, anhydrous magnesium sulfate is dried, decompression and desolventization are carried out, and column chromatography (eluent: mixed solution of ethyl acetate and petroleum ether (1:4)) is carried out, so that 1.75g of the product is obtained, and the yield is 76%.
LC/MS[M+H]+＝460.91、[M+Na]+＝482.89、[M+K]+＝498.86。
1H-NMR (400MHz, solvent CDCl)3)(ppm):2.66(3H,s),7.32(1H,d),7.72(1H,d),7.92(1H,d),8.75(1H,s)。
3, 4-dichloro-N- (2- (methylsulfonyl) -5- (pentafluorothio) phenyl) isothiazole-5-carboxamide
1.10g (3.7mmol) of 2- (methylsulfonyl) -5- (pentafluorothio) aniline and 0.51g (5mmol) of triethylamine are sequentially dissolved in 15m L dichloromethane, the mixture is cooled to 5 ℃ in a low-temperature bath, 0.86g (4.0mol) of 3, 4-dichloroisothiazole-5-acyl chloride is added to the mixture in batches, the temperature is maintained below 20 ℃, after the addition, the reaction is carried out for 5h at room temperature, 10m L saturated sodium bicarbonate aqueous solution is added to the reaction system, dichloromethane (3 × 15m L) is used for extraction, organic layers are combined, 10m L saturated common salt water is washed, anhydrous magnesium sulfate is used for drying, decompression and desolventization are carried out, and the product is obtained by 1.27g and the yield is 72 percent (eluent: the mixed solution of ethyl acetate and petroleum ether (1: 4)).
LC/MS[M+H]+＝476.9、[M+Na]+＝498.88、[M+K]+＝514.85。
1H-NMR (400MHz, solvent CDCl)3)(ppm):3.36(3H,s),7.38(1H,d),7.78(1H,d),7.98(1H,d),8.78(1H,s)。
Example 12: 3, 4-dichloro-N- (2- (2-fluorobenzoyl) -5- (pentafluorothio) phenyl) isothiazole-5-amide (compound 241)
Figure BDA0001950382440000421
The first step of reaction: tert-butyl 3- (pentafluorothio) phenyl carbamate
6.04g (20mmol) of 3- (pentafluorothio) aniline and 9.12g (50mmol) of tetramethylammonium hydroxide hydrate were dissolved in 80m L acetonitrile, 6.55g (30mmol) of di-tert-butyl dicarbonate was added to the above solution in portions, the obtained solution was stirred at room temperature for 15 hours, the reaction solution was evaporated under reduced pressure to remove the solvent, 50m L water was added to the reaction solution, ether (3 × 25m L) was extracted, the organic layers were combined, 20m L of saturated saline was washed with water, anhydrous sodium sulfate was dried, desolvation under reduced pressure was performed, and column chromatography (eluent: a mixed solution of ethyl acetate and petroleum ether (1:5)) was performed to obtain 4.86g of a white solid with a yield of 75%.
LC/MS[M+H]+＝320.08、[M+Na]+＝342.06、[M+K]+＝358.03。
The second step of reaction: tert-butyl 2- (2-fluorobenzoyl) -5- (pentafluorosulfanyl) phenylcarbamate
At room temperature, 2.62g (15mmol) of 2-fluorobenzoyl chloride, 4.80g (15mmol) of tert-butyl 3- (pentafluorothio) phenyl carbamate and 2.66g (20mmol) of aluminum trichloride are sequentially dissolved in 25m L dichloroethane, heating is carried out until reflux, the reaction is kept warm for 5h, the reaction liquid is cooled to room temperature, filtering is carried out, 10m L saturated sodium bicarbonate aqueous solution is added into the filtrate, layering is carried out, an organic layer is taken, dichloroethane (3 × 15m L) is extracted, the organic layer is combined, 10m L saturated common salt is washed with water, anhydrous magnesium sulfate is dried, decompression and desolventization are carried out, and column chromatography (eluent: mixed solution (1:4) of ethyl acetate and petroleum ether) is carried out to obtain 3.96g with the yield of 60%.
LC/MS[M+H]+＝442.09、[M+Na]+＝464.07、[M+K]+＝480.04。
The third step of reaction: (2-amino-4- (pentafluorothio) phenyl) (2-fluorophenyl) methanone
At room temperature, 7g of hydrogen chloride gas is introduced into 30m L of methanol, the mixture is cooled to below 5 ℃ in an ice bath, 3.6g (8mmol) of 5m L methanol solution of tert-butyl 2- (2-fluorobenzoyl) -5- (pentafluorothio) phenyl carbamate is dropwise added into the hydrogen chloride methanol solution, the solution is stirred for 8 hours at room temperature after 15min, the reaction solution is decompressed and distilled to remove the methanol, and the residue is washed by ether (2 × 10m L), so that 2.39g of the product is obtained, and the yield is 85%.
LC/MS[M+H]+＝342.04、[M+Na]+＝364.02、[M+K]+＝379.99。
And a fourth step of reaction: 3, 4-dichloro-N- (2- (2-fluorobenzoyl) -5- (pentafluorothio) phenyl) isothiazole-5-amide
1.70g (5mmol) of (2-amino-4- (pentafluorothio) phenyl) (2-fluorophenyl) ketone and 0.76g (7.5mmol) of triethylamine were sequentially dissolved in 15m L dichloromethane, the mixture was cooled to 5 ℃ in a low-temperature bath, 1.01g (5.2mol) of 3, 4-dichloroisothiazole-5-acid chloride was added to the above mixture in portions, the temperature was maintained at 20 ℃ or lower, after the addition, the reaction was carried out at room temperature for 5 hours, 10m L saturated aqueous sodium bicarbonate solution was added to the reaction system, dichloromethane (3 × 15m L) was extracted, the organic layers were combined, 10m L saturated brine was washed, anhydrous magnesium sulfate was dried, the precipitation was carried out under reduced pressure, and column chromatography (eluent: a mixed solution of ethyl acetate and petroleum ether (1:4)) was carried out to obtain 1.68g, with a yield of 65%.
LC/MS[M+H]+＝520.94、[M+Na]+＝542.92、[M+K]+＝558.89。
1H-NMR (400MHz, solvent CDCl)3)(ppm):7.35(1H,d),7.45(1H,m),7.48(1H,d),7.64(1H,m),7.73(1H,d),7.82(1H,m),7.92(1H,d),8.72(1H,s)。
Example 13: N-methyl-N- (3- (pentafluorothio) phenyl) -4- (trifluoromethyl) nicotinamide (compound 281)
Figure BDA0001950382440000431
The first step of reaction: n-methyl-3- (pentafluorothio) aniline
At room temperature, 0.8g (20mmol) of 60% sodium hydride and 2.19g (10mmol) of 3- (pentafluorothio) aniline are sequentially dissolved in 25m L acetonitrile, the temperature is gradually increased to 50 ℃, the temperature is kept for 1h, 2.13g (15mmol) of methyl iodide is added into the solution, the temperature is gradually increased to reflux, the reaction solution is stirred for 5h, the reaction solution is cooled to room temperature, the acetonitrile is evaporated under normal pressure, 10g of crushed ice is added into the residue, ethyl acetate (3 × 20m L) is used for extraction, organic layers are combined, 15m L saturated common salt water is used for washing, anhydrous magnesium sulfate is used for drying, the pressure is reduced for desolventization, and column chromatography (eluent: mixed solution of ethyl acetate and petroleum ether (1:4)) is carried out to obtain 1.51g of gray solid with the yield of 60%.
LC/MS[M+H]+＝234.04、[M+Na]+＝256.02、[M+K]+＝271.99。
The second step of reaction: N-methyl-N- (3- (pentafluorothio) phenyl) -4- (trifluoromethyl) nicotinamide
1.19g (5mmol) of N-methyl-3- (pentafluorothio) aniline and 0.76g (7.5mmol) of triethylamine are sequentially dissolved in 15m L dichloromethane, the mixture is cooled to 5 ℃ in a low-temperature bath, 1.01g (5.2mol) of 3, 4-dichloroisothiazole-5-acyl chloride is added to the mixture in batches, the temperature is maintained below 20 ℃, after the addition, the reaction is carried out for 5h at room temperature, 10m L saturated sodium bicarbonate aqueous solution is added to the reaction system, dichloromethane (3 × 15m L) is extracted, organic layers are combined, 10m L saturated common salt water is washed, anhydrous magnesium sulfate is dried, decompression and desolventization are carried out, and column chromatography (eluent: mixed solution of ethyl acetate and petroleum ether (1:4)) is carried out to obtain 1.39g of a product with the yield of 68%.
LC/MS[M+H]+＝407.05、[M+Na]+＝429.03、[M+K]+＝445。
Other compounds of the invention were synthesized according to the methods described above.
Further characterization data for the compounds of the formula (I) are as follows:
Figure BDA0001950382440000432
Figure BDA0001950382440000441
Figure BDA0001950382440000451
Figure BDA0001950382440000461
Figure BDA0001950382440000471
Figure BDA0001950382440000481
formulation examples
In the following examples, all percentages are by weight and all dosage forms are prepared by conventional methods.
Example 14:
in this example, the compound obtained in the above example is used to prepare a wettable powder, which is specifically prepared by using the following raw material compositions in proportion:
2560.0% of compound, 4.0% of dodecylphenol polyethoxy glycol ether, 5.0% of sodium lignosulfonate, 6.0% of sodium aluminosilicate and 25.0% of montmorillonite (calcined)
Example 15:
in this example, granules were prepared using the compounds obtained in the above examples, specifically using the following raw material compositions:
3310.0% of compound, 2% of sodium dodecyl sulfate as other components, 6% of calcium lignosulfonate, 10% of potassium chloride, 1% of polydimethylsiloxane and 100% of soluble starch.
Example 16:
in this example, the compound obtained in the above example is used to prepare an extruded pellet, specifically using the following raw material composition:
7125.0% of compound, 10.0% of anhydrous calcium sulfate, 5.0% of crude calcium lignosulfonate, 1.0% of sodium alkyl naphthalene sulfonate and 59.0% of calcium/magnesium bentonite.
Example 17:
in this example, the compound obtained in the above example is used to prepare emulsifiable concentrate, and specifically, the emulsifiable concentrate is prepared by using the following raw material compositions:
10325.0% of compound, 15060% of solvent, PEG 4005% of Rhodacal 70/B3% of RhodameenRAM/77%.
Example 18:
in this example, the compound obtained in the above example is used to prepare an aqueous suspension, specifically, the following raw material composition is used to prepare the aqueous suspension:
14030.0% of compound, 5.0% of POE polystyrene phenyl ether sulfate, 0.5% of xanthan gum, 5% of polyethylene glycol, 1% of triethanolamine, 0.5% of sorbitol and water to make up to 100.0%.
Biological activity assay
The compound of the invention has good activity on various germs in the agricultural field.
Example 19:
1. measurement of fungicidal Activity
The compound of the invention performs in vitro bacteriostatic activity or in vivo protection effect tests on various fungal diseases of plants. The results of the bactericidal activity measurement are shown in the following examples.
1.1 in vitro bactericidal Activity assay
The test method is as follows: dissolving a compound sample to be detected with a suitable solvent (the kind of the solvent is acetone, methanol, DMSO, etc., and is selected according to the dissolving capacity of the solvent on the sample), and preparing the solution to be detected with the required concentration. Under an ultraclean working environment, adding a solution to be detected into micropores of a 96-hole culture plate, adding a pathogen propagule suspension into the micropore, and placing the treated culture plate in a constant-temperature incubator for culture. And (4) after 24 hours, carrying out investigation, visually observing the germination or growth condition of the pathogen propagules during the investigation, and evaluating the bacteriostatic activity of the compound according to the germination or growth condition of the control treatment.
(1) The in vitro inhibitory activity (expressed as inhibition rate) of some compounds on Pyricularia oryzae was tested as follows:
the compounds with the inhibition rate of more than 80 percent on rice blast germs at the dosage of 50ppm comprise: 5. 14, 25, 31, 33, 40, 56, 62, 71, 77, 86, 95, 99, 101, 103, 110, 113, 126, 132, 140, 141, 148, 153, 161, 162, 163, 170, 186, 201, 206, 207, 220, 229, 238, 239, 241, 250, 257, 264, 271, 281, 286, 291, 298, 300, 305, 313, 320, 323, 331, 335, 347, 350, and the like. At this dose, the inhibition rates of control drugs CK1 and CK2 on Pyricularia oryzae were 10% and 30%, respectively; the control CK3 showed an inhibition rate of 0 against Pyricularia oryzae.
At a dose of 10ppm, the compounds with the inhibition rate of more than 80 percent on rice blast germs comprise: 5. 25, 31, 33, 40, 56, 62, 86, 95, 99, 101, 103, 110, 113, 126, 132, 140, 141, 148, 153, 161, 162, 163, 170, 186, 201, 206, 207, 220, 229, 238, 239, 241, 250, 257, 264, 271, 281, 286, 291, 298, 305, 313, 320, 323, 331, 335, 347, 350, etc. At this dose, the inhibition rate of control drugs CK1 and CK2 against Pyricularia oryzae was 0.
Examples of the compounds having an inhibitory rate against Pyricularia oryzae of 80% or more at a dose of 2.5ppm include 5, 31, 33, 40, 56, 62, 86, 95, 101, 103, 110, 113, 126, 132, 140, 141, 148, 153, 161, 163, 186, 229, 241, 250, 257, 264, 298, 305, 313, 320, 323, 335, 350 and the like.
(2) The in vitro bacteriostatic activity (expressed as inhibition rate) of part of compounds on rice sheath blight bacteria is as follows:
the compounds with the inhibition rate of more than 80 percent on the rhizoctonia solani under the dosage of 50ppm comprise: 5. 25, 31, 33, 40, 56, 62, 86, 95, 101, 103, 110, 113, 126, 132, 140, 141, 148, 153, 161, 162, 163, 170, 186, 201, 206, 207, 229, 238, 239, 241, 250, 257, 264, 271, 286, 298, 305, 313, 320, 323, 331, 347, 350, etc.
The compounds with the inhibition rate of more than 80 percent on the rhizoctonia solani under the dosage of 10ppm comprise: 25. 31, 33, 56, 62, 86, 95, 101, 103, 113, 126, 132, 140, 141, 148, 153, 161, 163, 170, 186, 201, 206, 250, 264, 271, 286, 305, 313, 320, 350, etc. At this dose, the inhibition rate of control drugs CK1, CK2 and CK3 against Rhizoctonia solani was 0.
Examples of the compounds having an inhibitory rate against Rhizoctonia solani of 80% or more at a dose of 2.5ppm include 31, 86, 95, 103, 113, 126, 132, 140, 148, 153, 163, 170, 186, 201, 271, 286, 305, 313, 320 and the like.
(3) The in vitro bacteriostatic activity (expressed as inhibition rate) of part of compounds on ustilaginoidea virens is tested as follows:
the compounds with the inhibition rate of more than 80 percent on ustilaginoidea virens at the dosage of 50ppm comprise: 5. 25, 31, 33, 40, 62, 86, 95, 99, 101, 103, 110, 113, 126, 132, 140, 141, 148, 153, 161, 162, 163, 170, 186, 201, 206, 207, 220, 229, 238, 239, 241, 250, 257, 264, 271, 281, 286, 291, 298, 300, 305, 313, 320, 323, 331, 335, 347, 350, etc. At this dose, the inhibition rates of the control medicaments CK1 and CK2 on ustilaginoidea virens are respectively 10% and 20%; the control CK3 showed an inhibition rate of 0 against Ustilaginoidea virens.
The compounds with the inhibition rate of more than 80 percent on ustilaginoidea virens at the dose of 10ppm comprise: 5. 31, 33, 40, 62, 86, 95, 101, 103, 110, 113, 126, 140, 141, 148, 153, 161, 162, 163, 186, 206, 207, 229, 239, 241, 250, 257, 264, 271, 291, 298, 305, 313, 323, 331, 335, 347, 350, and the like. At this dose, the inhibition rate of control drugs CK1 and CK2 against ustilaginoidea virens was 0.
(4) The in vitro bacteriostatic activity (expressed as inhibition rate) of part of the compounds on botrytis cinerea is as follows:
at a dose of 50ppm, the compounds with the inhibition rate of more than 80 percent on botrytis cinerea comprise: 5. 14, 25, 31, 33, 40, 56, 62, 71, 77, 86, 95, 99, 101, 103, 110, 113, 126, 132, 140, 141, 148, 153, 161, 162, 163, 170, 186, 201, 206, 207, 220, 229, 238, 239, 241, 250, 264, 271, 281, 286, 291, 298, 300, 305, 313, 320, 323, 347, 350, and the like. The inhibition rates of the control medicaments CK1, CK2 and CK3 on botrytis cinerea are respectively 30%, 10% and 5%.
At a dose of 10ppm, the compounds with the inhibition rate of more than 80 percent on botrytis cinerea comprise: 5. 25, 31, 56, 62, 86, 95, 103, 113, 126, 132, 140, 141, 148, 153, 161, 163, 170, 186, 201, 206, 250, 264, 271, 281, 286, 291, 305, 313, 320, 347, 350, etc. The inhibition ratio of the control drugs CK1, CK2 and CK3 on Botrytis cinerea is 0.
(5) The in vitro inhibitory activity (expressed as inhibition) of some compounds against Colletotrichum capsici was tested as follows:
the compounds with the inhibition rate of more than 80 percent on the colletotrichum capsici at the dosage of 50ppm comprise: 5. 14, 25, 31, 33, 40, 56, 62, 71, 77, 86, 95, 99, 101, 103, 110, 113, 126, 132, 140, 141, 148, 153, 161, 162, 163, 170, 186, 201, 206, 207, 220, 229, 238, 239, 241, 250, 257, 264, 271, 281, 286, 291, 298, 300, 305, 313, 320, 323, 331, 335, 347, 350, etc.; the inhibition rates of the control medicaments CK1 and CK2 on colletotrichum capsici are respectively 30% and 20%; the control CK3 showed an inhibition rate of 0 against Colletotrichum capsici.
The compounds with the inhibition rate of more than 80 percent on the colletotrichum capsici at the dosage of 10ppm comprise: 5. 31, 33, 40, 56, 62, 86, 95, 101, 103, 110, 113, 126, 132, 140, 141, 148, 153, 161, 163, 186, 229, 241, 250, 257, 264, 281, 298, 305, 313, 320, 323, 350, and the like. At this dose, the inhibition rate of control drugs CK1 and CK2 against colletotrichum capsici was 0.
(6) The in vitro bacteriostatic activity (expressed as inhibition rate) of part of compounds on wheat scab germ is tested as follows:
the compounds with the inhibition rate of more than 80 percent on the wheat scab germ at the dosage of 50ppm comprise: 5. 31, 33, 40, 56, 62, 86, 95, 101, 103, 110, 113, 126, 132, 140, 141, 148, 153, 161, 162, 163, 170, 186, 201, 206, 207, 229, 238, 239, 241, 250, 257, 264, 271, 281, 286, 291, 298, 305, 313, 320, 323, 347, and the like. At this dose, the inhibition rate of control drugs CK1, CK2, and CK3 against fusarium graminearum is 0.
The compounds with the inhibition rate of more than 80 percent on the wheat scab germ at the dosage of 10ppm comprise: 31. 95, 103, 110, 113, 126, 132, 140, 141, 148, 153, 161, 162, 163, 170, 186, 201, 206, 207, 250, 257, 264, 271, 281, 305, 313, 320, 323, 347, and the like.
(7) The results of in vitro bacteriostatic activity (expressed as inhibition rate) of some compounds against phytophthora capsici are as follows:
at a dose of 50ppm, the compounds with the inhibition rate of more than 80 percent on phytophthora capsici have the following characteristics: 5. 14, 31, 33, 40, 71, 95, 103, 113, 132, 140, 141, 161, 163, 170, 186, 201, 206, 207, 220, 229, 241, 250, 257, 281, 291, 298, 305, 313, 320, 323, 331, 335, 347, 350, etc. The inhibition rates of the control drugs CK1, CK2 and CK3 on phytophthora capsici were 30%, 40% and 20%, respectively.
At a dose of 10ppm, the compounds with the inhibition rate of more than 80 percent on phytophthora capsici have the following characteristics: 5. 31, 33, 40, 71, 95, 103, 140, 141, 161, 163, 170, 186, 206, 229, 241, 250, 281, 291, 298, 305, 313, 323, 347, etc. The inhibition rates of the control drugs CK1, CK2 and CK3 on Phytophthora capsici were 0, 10% and 0, respectively.
(8) The results of the in vitro bacteriostatic activity (expressed as inhibition rate) of part of the compounds on the early blight of tomato are as follows:
the compounds with the inhibition rate of more than 80 percent on the tomato early blight bacteria under the dosage of 50ppm comprise: 5. 14, 25, 31, 33, 40, 62, 71, 77, 86, 95, 99, 101, 103, 110, 113, 126, 132, 140, 141, 148, 153, 161, 162, 163, 170, 186, 201, 206, 207, 220, 229, 238, 239, 241, 250, 257, 264, 271, 281, 286, 291, 298, 300, 305, 313, 320, 323, 331, 335, 347, 350, and the like. The inhibition rates of the control medicaments CK1, CK2 and CK3 on the early blight of tomato are 40%, 25% and 15% respectively.
At a dose of 10ppm, the compounds with the inhibition rate of more than 80 percent on the tomato early blight bacteria comprise: 5. 31, 33, 40, 95, 101, 103, 110, 113, 126, 140, 141, 148, 153, 161, 162, 163, 170, 186, 201, 206, 207, 220, 229, 238, 239, 241, 250, 257, 264, 271, 286, 291, 298, 305, 313, 320, 323, 331, 335, 347, 350, and the like. The control drugs CK1, CK2 and CK3 all had an inhibitory rate of 0 against early blight of tomato.
(9) The in vitro bacteriostatic activity (expressed as inhibition rate) of part of compounds on the potato black nevus bacteria is as follows:
at a dose of 50ppm, the compounds with the inhibition rate of more than 80 percent on the potato black nevus germ comprise: 5. 25, 31, 33, 40, 56, 62, 86, 95, 101, 103, 110, 113, 126, 140, 141, 148, 153, 161, 162, 163, 170, 201, 206, 207, 229, 238, 239, 241, 250, 257, 264, 271, 298, 313, 320, 323, 331, 350, and the like.
At a dose of 10ppm, the compounds with the inhibition rate of more than 80 percent on the potato black nevus germ comprise: 31. 33, 40, 95, 101, 103, 113, 126, 140, 141, 148, 153, 161, 163, 170, 201, 250, 264, 271, 313, 331, 350, etc. At this dose, the inhibition ratio of the control drugs CK1, CK2, and CK3 against potato black mole germ was 0.
(10) The results of the in vitro bacteriostatic activity (expressed as inhibition rate) of some compounds against sclerotinia sclerotiorum were as follows:
the compounds with the inhibition rate of more than 80 percent on sclerotinia sclerotiorum under the dosage of 50ppm comprise: 5. 25, 31, 33, 40, 56, 71, 86, 95, 99, 101, 103, 110, 113, 126, 132, 140, 141, 148, 153, 161, 162, 163, 170, 186, 201, 206, 207, 220, 229, 238, 239, 241, 250, 264, 271, 286, 291, 298, 300, 305, 313, 320, 323, 347, 350, etc. The inhibition rates of the control drugs CK1, CK2 and CK3 on Sclerotinia sclerotiorum are 10%, 20% and 0, respectively.
At a dose of 10ppm, the compounds with the inhibition rate of more than 80 percent on sclerotinia sclerotiorum have the following components: 5. 31, 56, 95, 103, 113, 126, 140, 141, 148, 153, 161, 162, 163, 170, 201, 206, 250, 264, 271, 291, 298, 313, 320, 347, 350, etc. The inhibition rates of the control medicaments CK1 and CK2 on Sclerotinia sclerotiorum are both 0.
1.2 Activity assay for Living body protection
The measurement method is as follows: the living potted plant determination method is adopted, i.e. a sample of the compound to be tested is dissolved by a small amount of solvent (the type of the solvent is acetone, methanol, DMF, etc., and is selected according to the dissolving capacity of the solvent to the sample, and the volume ratio of the solvent amount to the liquid spraying amount is equal to or less than 0.05), and diluted by water containing 0.1 percent of Tween 80 to prepare the liquid to be tested with the required concentration. The solution to be tested is sprayed on diseased host plants (the host plants are standard potted seedlings cultured in a greenhouse) on a crop sprayer, and disease inoculation is carried out after 24 hours. According to the characteristics of diseases, inoculating the disease plants needing temperature and moisture control culture, then culturing in an artificial climate chamber, transferring into a greenhouse for culture after the diseases are infected, and directly inoculating and culturing the disease plants without moisture control culture in the greenhouse. The compound disease control effect evaluation is carried out after the control is sufficiently ill (usually, one week).
(1) The results of the test on the control effect of partial compounds on rice blast are as follows:
the compounds with the rice blast preventing effect of more than 80 percent comprise 31, 33, 62, 86, 95, 99, 103, 110, 113, 126, 132, 140, 141, 148, 161, 162, 170, 186, 201, 206, 207, 220, 229, 238, 239, 241, 250, 257, 264, 271, 281, 286, 291, 298, 305, 313, 320, 323, 331, 335, 347, 350 and the like under the dosage of 100 ppm. At the dosage, the control medicaments CK1 and CK2 have the control effect of 20 percent and 10 percent on rice blast; the control CK3 had a rice blast controlling effect of 0.
At a dose of 10ppm, the compounds with the rice blast control effect of more than 80 percent comprise: 31. 62, 86, 95, 103, 110, 113, 126, 132, 140, 141, 148, 161, 186, 229, 241, 250, 257, 264, 298, 313, 323, 335, 350, and the like. At this dose, the control agents CK1 and CK2 had a rice blast controlling effect of 0.
(2) The results of the test on the prevention effect of part of compounds on wheat powdery mildew are as follows:
at a dose of 100ppm, the compounds with the control effect on wheat powdery mildew of more than 80 percent comprise: 5. 31, 33, 40, 56, 62, 86, 95, 101, 103, 110, 113, 126, 132, 140, 141, 148, 153, 161, 163, 186, 229, 241, 250, 257, 264, 298, 305, 313, 320, 323, 350, and the like. At this dose, the control drugs CK1, CK2, and CK3 had 20%, 40%, and 10% of the control effect on wheat powdery mildew, respectively.
At a dose of 10ppm, more than 80% of compounds with the prevention effect on wheat powdery mildew comprise: 31. 86, 95, 101, 103, 110, 113, 126, 140, 141, 153, 161, 229, 241, 250, 257, 298, 305, 313, 320, 323, 350, and the like. At this dose, the control drugs CK1, CK2, and CK3 had control effects on wheat powdery mildew of 0, 10%, and 0, respectively.
(3) The results of the control effect test of part of compounds on cucumber downy mildew are as follows:
at a dose of 100ppm, the compounds with the control effect on cucumber downy mildew of more than 80 percent comprise: 5. 31, 33, 40, 71, 95, 103, 113, 132, 140, 141, 161, 163, 170, 186, 201, 206, 207, 229, 281, 291, 305, 313, 320, 323, etc. At this dose, the control drugs CK1, CK2 and CK3 had control effects on cucumber downy mildew of 20%, 30% and 0, respectively.
At a dose of 10ppm, the compounds with the control effect on cucumber downy mildew of more than 80 percent comprise: 5. 31, 33, 71, 95, 103, 113, 132, 140, 141, 161, 163, 170, 186, 206, 291, 305, 313, 323, etc. At this dose, the control agents CK1 and CK2 had control effects on cucumber downy mildew of 0% and 10%, respectively.
(4) The results of the test on the control effect of part of compounds on cucumber gray mold are as follows:
at a dose of 100ppm, the compounds with more than 80 percent of control effect on cucumber gray mold comprise: 5. 31, 33, 40, 95, 99, 101, 103, 110, 113, 126, 140, 141, 148, 153, 161, 162, 163, 170, 186, 201, 206, 207, 220, 229, 238, 239, 241, 250, 264, 271, 286, 291, 298, 305, 313, 323, 347, 350, and the like. The control medicaments CK1, CK2 and CK3 have 0 control effect on cucumber gray mold.
At the dose of 10ppm, the compounds with the control effect on cucumber gray mold being more than 80 percent comprise: 5. 31, 33, 95, 103, 113, 126, 140, 141, 148, 153, 161, 163, 170, 250, 264, 271, 291, 305, 313, 347, 350, etc.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (10)

1. A heteroaryl formanilide compound containing pentafluorothio and shown as a formula (I) or a pharmaceutically acceptable salt thereof,
Figure FDA0001950382430000011
wherein R is1、R2、R3、R4The same or different, each independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, C1-C12Alkyl radical, C1-C12Alkyl halidesBase, C1-C12Alkoxy radical, C1-C12Haloalkoxy, C1-C12Alkoxycarbonyl group, C1-C12Alkylcarbonyl group, C1-C12Alkylsulfonyl radical, C1-C12Alkylsulfinyl radical, C1-C12Alkylthio, phenylcarbonyl, phenyl, -O-phenyl or-O-5-or 6-membered heteroaryl,
the phenylcarbonyl, phenyl, -O-phenyl or-O-5 or 6 membered heteroaryl may be unsubstituted or substituted by one or more Rs1Substituted, said Rs1Selected from the group consisting of: halogen, cyano, nitro, C1-C12Alkyl radical, C1-C12Haloalkyl, C1-C12Alkoxy or C1-C12A haloalkoxy group;
R5selected from hydrogen or C1-C12An alkyl group;
ar is selected from unsubstituted or substituted by one or more Rs2Substituted 5-20 membered heteroaryl, said Rs2Selected from the group consisting of: halogen, nitro, cyano, hydroxy, C1-C12Alkyl radical, C1-C12Haloalkyl, C1-C12Alkoxy or C1-C12A haloalkoxy group.
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein in formula (I),
R1、R2、R3、R4the same or different, each independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkoxycarbonyl group, C1-C6Alkylcarbonyl group, C1-C4Alkylsulfonyl radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylthio, phenylcarbonyl, phenyl, -O-phenyl or-O-5 or 6 membered heteroaryl;
wherein the phenylcarbonyl, phenyl, -O-phenyl, 5 or 6 membered heteroaryl may be unsubstituted or substituted with one or more Rs1Substituted, said Rs1Selected from the group consisting of: halogen, cyano, nitro, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy or C1-C6A haloalkoxy group;
R5independently selected from hydrogen or C1-C6An alkyl group;
ar is selected from the group consisting ofs2Substituted 5-10 membered heteroaryl, said Rs2Selected from the group consisting of: halogen, cyano, nitro, hydroxy, C1-C6Alkyl radical, C1-C6Haloalkyl or C1-C6An alkoxy group;
preferably, in the formula (I), R1、R2、R3、R4The same or different, each independently selected from hydrogen, fluorine, chlorine, bromine, cyano, hydroxyl, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkoxycarbonyl group, C1-C6Alkylcarbonyl group, C1-C4Alkylsulfonyl radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylthio, phenylcarbonyl, phenyl, -O-phenyl or-O-5-or 6-membered heteroaryl,
wherein the phenylcarbonyl, phenyl, -O-phenyl or-O-5 or 6 membered heteroaryl may be unsubstituted or substituted with 1 to 3 of the following groups: f, Cl, Br, CN, CH3，OCH3，CF3，OCF3；
R5Selected from hydrogen or C1-C6An alkyl group;
ar is selected from 1-3Rs2Substituted 5-10 membered heteroaryl, said Rs2Selected from the group consisting of: f, Cl, Br, CN, OH, CH3，C2H5，CF3，CHF2，CH2F，CHClF，CClF2，OCH3，OCH2CH3，OCF3，OCH2CF3。
3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein in formula (I),
R1、R2、R3、R4the same or different, each independently selected from hydrogen, fluorine, chlorine, cyano, hydroxyl, C1-C6Alkyl radical, C1-C6Haloalkyl, C1-C6Alkoxy radical, C1-C6Haloalkoxy, C1-C6Alkoxycarbonyl group, C1-C6Alkylcarbonyl group, C1-C4Alkylsulfonyl radical, C1-C4Alkylsulfinyl radical, C1-C4Alkylthio, phenylcarbonyl, phenyl, -O-phenyl or-O-5-or 6-membered heteroaryl,
wherein the phenylcarbonyl, phenyl, -O-phenyl or-O-5 or 6 membered heteroaryl may be unsubstituted or substituted with 1 to 3 of the following groups: f, Cl, CN, CH3，OCH3，CF3，OCF3；
R5Selected from hydrogen or C1-C6An alkyl group;
ar is selected from 1-3Rs2Substituted 5-10 membered heteroaryl, said Rs2Selected from the group consisting of: f, Cl, Br, CN, OH, CH3，C2H5，CF3，CHF2，CH2F，CHClF，CClF2，OCH3，OCF3。
Wherein the 5-10 membered heteroaryl group may be selected from the following groups:
Figure FDA0001950382430000021
one end of the wavy line is marked as the point where Ar is connected with carbonyl in the formula (I).
4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein in formula (I),
R1、R2、R3、R4the same or different, each is independently selected from H, F, Cl, CN, OH, CH3，C2H5，CF3，CHF2，OCH3，OC2H5，OCF3，OCH2CF3，COCH3，COOCH3，COOC2H5，SO2CH3，SOCH3，SCH3，
Figure FDA0001950382430000022
Figure FDA0001950382430000023
R5Selected from H, CH3，C2H5，C3H7，C4H9；
Preferably, Ar is selected from the group consisting of:
Figure FDA0001950382430000031
5. the compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein formula (I) is selected from the group consisting of:
Figure FDA0001950382430000041
Figure FDA0001950382430000042
Figure FDA0001950382430000051
Figure FDA0001950382430000061
Figure FDA0001950382430000071
Figure FDA0001950382430000081
Figure FDA0001950382430000091
Figure FDA0001950382430000101
Figure FDA0001950382430000111
Figure FDA0001950382430000121
Figure FDA0001950382430000131
Figure FDA0001950382430000141
Figure FDA0001950382430000151
Figure FDA0001950382430000161
Figure FDA0001950382430000171
Figure FDA0001950382430000181
Figure FDA0001950382430000191
Figure FDA0001950382430000201
Figure FDA0001950382430000211
Figure FDA0001950382430000221
Figure FDA0001950382430000231
Figure FDA0001950382430000241
Figure FDA0001950382430000251
Figure FDA0001950382430000261
Figure FDA0001950382430000271
Figure FDA0001950382430000281
Figure FDA0001950382430000291
6. a process for the preparation of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, which comprises reacting a compound of formula (II) with a compound of formula (III) to give a compound of formula (I),
Figure FDA0001950382430000292
wherein R is1、R2、R3、R4、R5L is selected from a leaving group, for example a halogen atom, such as chlorine, bromine or iodine.
7. Use of a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, for the manufacture of a fungicide for use in agriculture or in other fields.
8. A composition comprising as an active ingredient at least one compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.
9. Use of the composition of claim 8 as a fungicide for use in agriculture or other fields.
10. A method for controlling pathogens, such as phytopathogens, comprising applying to the growth medium of the phytopathogen an effective amount of at least one compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.
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