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CN106543167B - Isothiazole compound and application thereof - Google Patents

Isothiazole compound and application thereof Download PDF

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Publication number
CN106543167B
CN106543167B CN201510592095.5A CN201510592095A CN106543167B CN 106543167 B CN106543167 B CN 106543167B CN 201510592095 A CN201510592095 A CN 201510592095A CN 106543167 B CN106543167 B CN 106543167B
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CN106543167A (en
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杨帆
关爱莹
赵杰
杨吉春
班兰凤
姚忠远
孙芹
刘长令
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Shenyang Sinochem Agrochemicals R&D Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/80—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
    • C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Agronomy & Crop Science (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

The invention belongs to the field of agricultural sterilization and acaricide. In particular to an isothiazole compound and application thereof. The structure of the compound is shown as the following general formula:

Description

Isothiazole compound and application thereof
Technical Field
The invention belongs to the field of agricultural sterilization and acaricide. In particular to an isothiazole compound and application thereof.
Background
Patent JP2000336080 discloses that a compound represented by the following general formula, wherein compound KC1 (numbered 83 in the patent) is mentioned, has a certain bactericidal activity, but no biological activity is reported;
Figure DEST_PATH_GDA0000915652240000011
patent WO9924413 discloses that a compound shown as the following general formula has certain bactericidal activity, wherein the control effect of the compound KC2 (numbered as 5 in the patent) on apple scab is 96% under the condition of 100 g/ha;
Figure DEST_PATH_GDA0000915652240000012
patent CN102942565 discloses that the compound shown in the following general formula has certain bactericidal and insecticidal activity, wherein the compound KC3 (numbered as Mt005-17-1 in the patent) has 40.54% of control effect on cucumber downy mildew under the condition of 50 ppm; the lethality to aphids is 3.67% under the condition of 100ppm, and the lethality to diamondback moth is 42.73% under the condition of 40 ppm;
Figure DEST_PATH_GDA0000915652240000013
WO2013076230 discloses the following specific compounds KC4 and KC5 (the numbers in the patent are respectively 19-24 and 19-66 in Table 19), but no specific activity report is found;
Figure DEST_PATH_GDA0000915652240000014
WO2004046140 discloses the following specific compound KC6 (numbered as II-47 in the patent), but does not report any specific activity;
Figure DEST_PATH_GDA0000915652240000021
in the prior art, the compound with the structure shown as the general formula of the invention is not reported.
Disclosure of Invention
The modern agricultural production needs to continuously develop new pesticides with novel structures and excellent performance. The invention aims to provide an isothiazole compound for controlling various germs and pests and application thereof.
The technical scheme of the invention is as follows:
the invention provides an isothiazole compound, which has a structure shown in the following general formula:
Figure DEST_PATH_GDA0000915652240000022
in the formula:
R1、R2、R3、R4、R5can be the same or different and are respectively selected from hydrogen, halogen, hydroxyl, cyano, carboxyl, amino, nitro and C1-C12Alkyl, halo C1-C12Alkyl radical, C1-C12Alkoxy, halo C1-C12Alkoxy radical, C3-C12Cycloalkyl radical, C2-C12Alkenyl radical, C2-C12Alkynyl, C2-C12Alkenyloxy, halogeno C2-C12Alkenyloxy radical, C2-C12Alkynyloxy, halo C2-C12Alkynyloxy, C1-C12Alkylthio, halo C1-C12Alkylthio radical, C1-C12Alkoxy radical C1-C12Alkyl, halo C1-C12Alkoxy radical C1-C12Alkyl radical, C1-C12Alkylthio group C1-C12Alkyl, halo C1-C12Alkylthio group C1-C12Alkyl radical, C1-C12Alkylsulfinyl, halogeno C1-C12Alkylsulfinyl radical, C1-C12Alkylsulfonyl, halo C1-C12Alkylsulfonyl radical, C1-C12Alkylaminosulfonyl radical, C1-C12Alkylamino, halogeno C1-C12Alkylamino radical, di (C)1-C12Alkyl) amino, C1-C12Alkoxycarbonyl, CONH2、C1-C12Alkylaminocarbonyl, di (C)1-C12Alkyl) aminocarbonyl, cyano C1-C12Alkoxy radical, C1-C12Alkoxycarbonyl radical C1-C12Alkyl radical, C1-C12Alkylaminocarbonyl radical C1-C12Alkyl or di (C)1-C12Alkyl) aminocarbonyl group C1-C12An alkyl group;
x is selected from O or S;
R6、R6'、R7can be the same or different and are respectively selected from hydrogen, halogen, nitro, cyano and C1-C12Alkyl, halo C1-C12Alkyl radical, C3-C12Cycloalkyl of, C1-C12Alkoxy, halo C1-C12Alkoxy radical, C1-C12Alkylthio, halo C1-C12Alkylthio radical, C2-C12Alkenyl, halo C2-C12Alkenyl radical, C2-C12Alkynyl, halo C2-C12Alkynyl, C3-C12Alkenyloxy, halogeno C3-C12Alkenyloxy radical, C3-C12Alkynyloxy, halo C3-C12Alkynyloxy, C1-C12Alkylsulfinyl, halogeno C1-C12Alkylsulfinyl radical, C1-C12Alkylsulfonyl, halo C1-C12Alkylsulfonyl radical, C1-C12Alkylcarbonyl, halo C1-C12Alkylcarbonyl group, C1-C12Alkylcarbonyloxy, C1-C12Alkylcarbonylamino, C1-C12Alkylsulfonyloxy, C1-C12Alkoxycarbonyl group, C1-C12Alkoxycarbonyl radical C1-C12Alkyl radical, C1-C12Alkoxycarbonylamino group, C1-C12Alkoxy radical C1-C12Alkoxy or C1-C12Alkoxycarbonyl radical C1-C12An alkoxy group;
R8selected from hydrogen, halogen, cyano, C1-C8Alkyl, halo C1-C8Alkyl, phenyl which is unsubstituted or further substituted by 1 to 5 of the following groups: halogen, cyano, nitro, hydroxy, amino, mercapto, C1-C8Alkyl, halo C1-C8Alkyl radical, C1-C8Alkoxy or halo C1-C8An alkoxy group;
R9selected from hydrogen, halogen, cyano, C1-C8Alkyl, phenyl which is unsubstituted or further substituted by 1 to 5 of the following groups: halogen, cyano, nitro, hydroxy, amino, mercapto, C1-C8Alkyl, halo C1-C8Alkyl radical, C1-C8Alkoxy or halo C1-C8An alkoxy group;
a is selected from hydrogen, hydroxy, formyl and C1-C12Alkyl, halo C1-C12Alkyl radical, C1-C12Alkoxy, halo C1-C12Alkoxy radical, C3-C12Cycloalkyl radical, C2-C12Alkenyl radical, C2-C12Alkynyl, halo C2-C12Alkenyl, halo C2-C12Alkynyl, C1-C12Alkoxy radical C1-C12Alkyl, halo C1-C12Alkoxy radical C1-C12Alkyl radical, C1-C12Alkylthio group C1-C12Alkyl, halo C1-C12Alkylthio group C1-C12Alkyl radical, C1-C12Alkylsulfinyl, halogeno C1-C12Alkylsulfinyl radical, C1-C12Alkylsulfonyl, halo C1-C12Alkylsulfonyl radical, C1-C12Alkylaminosulfonyl, di (C)1-C12Alkyl) aminosulfonyl, C1-C12Alkylsulfonylaminocarbonyl group, C1-C12Alkylcarbonylaminosulfonyl radical, C3-C12Cycloalkyloxycarbonyl radical, C1-C12Alkylcarbonyl, halo C1-C12Alkylcarbonyl group, C1-C12Alkoxycarbonyl, halo C1-C12Alkoxycarbonyl group, C1-C12Alkyl carbonyl radical C1-C12Alkyl radical, C1-C12Alkoxycarbonyl radical C1-C12Alkyl radical, C1-C12Alkylaminocarbonyl, di (C)1-C12Alkyl) aminocarbonyl, C2-C12Alkenyloxycarbonyl radical, C2-C12Alkynyloxycarbonyl group, C1-C12Alkoxy radical C1-C12Alkoxycarbonyl, unsubstituted or (hetero) arylcarbonyl C which is further substituted by 1 to 51-C6Alkyl, (hetero) arylcarbonyl, (hetero) aryloxycarbonyl, (hetero) aryl C1-C6Alkyloxycarbonyl or (hetero) aryl C1-C6Alkyl groups: halogen, nitro, cyano, C1-C6Alkyl, halo C1-C6Alkyl radical, C1-C6Alkoxy or halo C1-C6An alkoxy group;
b is a substituent directly linked to the carbon atom in position 3,4 or 5 of the six-membered aromatic ring through the amide nitrogen atom, -CRaRb、-CH2CRaRb-or-CH2CRaRbCRaRb-；Ra、RbCan be the same or different and are respectively selected from hydrogen and C1-C12Alkyl radical, C3-C12Cycloalkyl radical, C2-C12Alkenyl radical, C2-C12Alkynyl, halo C2-C12Alkenyl, halo C2-C12Alkynyl, C1-C12Alkoxy radical C1-C12Alkyl, aryl C unsubstituted or further substituted by 1 to 51-C6Alkyl or heteroaryl C1-C6Alkyl groups: halogen, C1-C6Alkyl, halo C1-C6Alkyl radical, C1-C6Alkoxy or halo C1-C6Alkoxy or Ra, RbWith carbon bound to form C3-C8A ring of (a);
w is selected from CH or N.
Preferred compounds of the invention are: in the general formula
R1、R2、R3、R4、R5Can be the same or different and are respectively selected from hydrogen, halogen, hydroxyl, cyano, carboxyl, amino, nitro and C1-C8Alkyl, halo C1-C8Alkyl radical, C1-C8Alkoxy, halo C1-C8Alkoxy radical, C3-C8Cycloalkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, C2-C8Alkenyloxy, halogeno C2-C8Alkenyloxy radical, C2-C8Alkynyloxy, halo C2-C8Alkynyloxy, C1-C8Alkylthio, halo C1-C8Alkylthio radical, C1-C8Alkoxy radical C1-C8Alkyl, halo C1-C8Alkoxy radical C1-C8Alkyl radical, C1-C8Alkylthio group C1-C8Alkyl, halo C1-C8Alkylthio group C1-C8Alkyl radical, C1-C8Alkylsulfinyl, halogeno C1-C8Alkylsulfinyl radical, C1-C8Alkylsulfonyl, halo C1-C8Alkylsulfonyl radical, C1-C8Alkylaminosulfonyl radical, C1-C8Alkylamino, halogeno C1-C8Alkylamino radical, di (C)1-C8Alkyl) amino, C1-C8Alkoxycarbonyl, CONH2、C1-C8Alkylaminocarbonyl, di (C)1-C8Alkyl) aminocarbonyl, cyano C1-C8Alkoxy radical, C1-C8Alkoxycarbonyl radical C1-C8Alkyl radical, C1-C8Alkyl radicalAminocarbonyl group C1-C8Alkyl or di (C)1-C8Alkyl) aminocarbonyl group C1-C8An alkyl group;
x is selected from O or S;
R6、R6'、R7can be the same or different and are respectively selected from hydrogen, halogen, nitro, cyano and C1-C8Alkyl, halo C1-C8Alkyl radical, C3-C6Cycloalkyl of, C1-C8Alkoxy, halo C1-C8Alkoxy radical, C1-C8Alkylthio, halo C1-C8Alkylthio radical, C2-C8Alkenyl, halo C2-C8Alkenyl radical, C2-C8Alkynyl, halo C2-C8Alkynyl, C3-C8Alkenyloxy, halogeno C3-C8Alkenyloxy radical, C3-C8Alkynyloxy, halo C3-C8Alkynyloxy, C1-C8Alkylsulfinyl, halogeno C1-C8Alkylsulfinyl radical, C1-C8Alkylsulfonyl, halo C1-C8Alkylsulfonyl radical, C1-C8Alkylcarbonyl, halo C1-C8Alkylcarbonyl group, C1-C8Alkylcarbonyloxy, C1-C8Alkylcarbonylamino, C1-C8Alkylsulfonyloxy, C1-C8Alkoxycarbonyl group, C1-C8Alkoxycarbonyl radical C1-C8Alkyl radical, C1-C8Alkoxycarbonylamino group, C1-C8Alkoxy radical C1-C8Alkoxy or C1-C8Alkoxycarbonyl radical C1-C8An alkoxy group;
R8selected from hydrogen, halogen, cyano, C1-C6Alkyl, halo C1-C6Alkyl, phenyl which is unsubstituted or further substituted by 1 to 5 of the following groups: halogen, cyano, nitro, hydroxy, amino, mercapto, C1-C6Alkyl, halo C1-C6Alkyl radical, C1-C6Alkoxy or halo C1-C6An alkoxy group;
R9selected from hydrogen, halogen, cyano, C1-C6Alkyl, phenyl which is unsubstituted or further substituted by 1 to 5 of the following groups: halogen, cyano, nitro, hydroxy, amino, mercapto, C1-C6Alkyl, halo C1-C6Alkyl radical, C1-C6Alkoxy or halo C1-C6An alkoxy group;
a is selected from hydrogen, hydroxy, formyl and C1-C8Alkyl, halo C1-C8Alkyl radical, C1-C8Alkoxy, halo C1-C8Alkoxy radical, C3-C8Cycloalkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, halo C2-C8Alkenyl, halo C2-C8Alkynyl, C1-C8Alkoxy radical C1-C8Alkyl, halo C1-C8Alkoxy radical C1-C8Alkyl radical, C1-C8Alkylthio group C1-C8Alkyl, halo C1-C8Alkylthio group C1-C8Alkyl radical, C1-C8Alkylsulfinyl, halogeno C1-C8Alkylsulfinyl radical, C1-C8Alkylsulfonyl, halo C1-C8Alkylsulfonyl radical, C1-C8Alkylaminosulfonyl, di (C)1-C8Alkyl) aminosulfonyl, C1-C8Alkylsulfonylaminocarbonyl group, C1-C8Alkylcarbonylaminosulfonyl radical, C3-C8Cycloalkyloxycarbonyl radical, C1-C8Alkylcarbonyl, halo C1-C8Alkylcarbonyl group, C1-C8Alkoxycarbonyl, halo C1-C8Alkoxycarbonyl group, C1-C8Alkyl carbonyl radical C1-C8Alkyl radical, C1-C8Alkoxycarbonyl radical C1-C8Alkyl radical, C1-C8Alkylaminocarbonyl, di (C)1-C8Alkyl) aminocarbonyl, C2-C8Alkenyloxycarbonyl radical, C2-C8Alkynyloxycarbonyl group, C1-C8Alkoxy radical C1-C8Alkoxycarbonyl, unsubstituted or (hetero) arylcarbonyl C which is further substituted by 1 to 31-C6Alkyl, (hetero) arylcarbonyl, (hetero) aryloxycarbonyl, (hetero) aryl C1-C6Alkyloxycarbonyl or (hetero) aryl C1-C6Alkyl groups: halogen, nitro, cyano, C1-C4Alkyl, halo C1-C4Alkyl radical, C1-C4Alkoxy or halo C1-C4An alkoxy group;
b is a substituent directly linked to the carbon atom in position 3,4 or 5 of the six-membered aromatic ring through the amide nitrogen atom, -CRaRb、-CH2CRaRb-or-CH2CRaRbCRaRb-；Ra、RbCan be the same or different and are respectively selected from hydrogen and C1-C8Alkyl radical, C3-C8Cycloalkyl radical, C2-C8Alkenyl radical, C2-C8Alkynyl, halo C2-C8Alkenyl, halo C2-C8Alkynyl, C1-C8Alkoxy radical C1-C8Alkyl, aryl C unsubstituted or further substituted by 1 to 31-C4Alkyl or heteroaryl C1-C4Alkyl groups: halogen, C1-C4Alkyl, halo C1-C4Alkyl radical, C1-C4Alkoxy or halo C1-C4An alkoxy group; or Ra、RbWith carbon bound to form C3-C8A ring of (a);
w is selected from CH or N.
Further preferred compounds are: in the general formula
R1、R2、R3、R4、R5Can be the same or different and are respectively selected from hydrogen, halogen, hydroxyl,Cyano, carboxyl, amino, nitro, C1-C4Alkyl, halo C1-C4Alkyl radical, C1-C4Alkoxy, halo C1-C4Alkoxy radical, C3-C4Cycloalkyl radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C2-C4Alkenyloxy, halogeno C2-C4Alkenyloxy radical, C2-C4Alkynyloxy, halo C2-C4Alkynyloxy, C1-C4Alkylthio, halo C1-C4Alkylthio radical, C1-C4Alkoxy radical C1-C4Alkyl, halo C1-C4Alkoxy radical C1-C4Alkyl radical, C1-C4Alkylthio group C1-C4Alkyl, halo C1-C4Alkylthio group C1-C4Alkyl radical, C1-C4Alkylsulfinyl, halogeno C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl, halo C1-C4Alkylsulfonyl radical, C1-C4Alkylaminosulfonyl radical, C1-C4Alkylamino, halogeno C1-C4Alkylamino radical, di (C)1-C4Alkyl) amino, C1-C4Alkoxycarbonyl, CONH2、C1-C4Alkylaminocarbonyl, di (C)1-C4Alkyl) aminocarbonyl, cyano C1-C12Alkoxy radical, C1-C4Alkoxycarbonyl radical C1-C4Alkyl radical, C1-C4Alkylaminocarbonyl radical C1-C4Alkyl or di (C)1-C4Alkyl) aminocarbonyl group C1-C4An alkyl group;
x is selected from O or S;
R6、R6'、R7can be the same or different and are respectively selected from hydrogen, halogen, nitro, cyano and C1-C4Alkyl, halo C1-C4Alkyl radical, C3-C6Cycloalkyl of, C1-C4Alkoxy, halo C1-C4Alkoxy radical, C1-C4Alkylthio, halo C1-C4Alkylthio radical, C2-C4Alkenyl radical, C2-C4Alkynyl, C1-C4Alkylsulfinyl radical, C1-C4Alkylsulfonyl radical, C1-C4Alkylcarbonyl or C1-C4Alkoxy radical C1-C4An alkoxy group;
R8selected from hydrogen, halogen, cyano, C1-C4Alkyl, halo C1-C4Alkyl, phenyl which is unsubstituted or further substituted by 1 to 5 of the following groups: halogen, cyano, nitro, hydroxy, amino, mercapto, C1-C4Alkyl, halo C1-C4Alkyl radical, C1-C4Alkoxy or halo C1-C6An alkoxy group;
R9selected from hydrogen, halogen, cyano, C1-C4Alkyl, phenyl which is unsubstituted or further substituted by 1 to 5 of the following groups: halogen, cyano, nitro, hydroxy, amino, mercapto, C1-C4Alkyl, halo C1-C4Alkyl radical, C1-C4Alkoxy or halo C1-C4An alkoxy group;
a is selected from hydrogen and C1-C4Alkyl radical, C1-C4Alkoxycarbonyl group, C1-C4Alkoxycarbonyl radical C1-C4Alkyl radical, C1-C4Alkoxycarbonyl group, C1-C4Alkyl carbonyl radical C1-C4An alkyl group;
b is a substituent directly linked to the carbon atom in position 3,4 or 5 of the six-membered aromatic ring through the amide nitrogen atom, -CRaRb、-CH2CRaRb-or-CH2CRaRbCRaRb-；Ra、RbCan be the same or different and is respectively selected from hydrogen, methyl or ethyl;
w is selected from CH or N.
Further preferred compounds are:
the structure of the compound is shown as I-A, I-B, I-C, I-D, I-E, II-A, III-A and III-B:
Figure DEST_PATH_GDA0000915652240000051
R1、R2、R3、R4、R5can be the same or different and are respectively selected from hydrogen, halogen, cyano, nitro and C1-C4Alkyl, halo C1-C4Alkyl radical, C1-C4Alkoxy or halo C1-C4An alkoxy group;
R6、R6'、R7can be the same or different and are respectively selected from hydrogen, halogen, nitro, cyano and C1-C4Alkyl, halo C1-C4Alkyl radical, C1-C4Alkoxy, halo C1-C4Alkoxy radical, C1-C4An alkylcarbonyl group;
R8selected from hydrogen, halogen, cyano, C1-C4Alkyl, halo C1-C4An alkyl group;
R9selected from hydrogen, halogen, cyano, C1-C4An alkyl group;
a is selected from hydrogen;
Ra、Rbcan be the same or different and are respectively selected from hydrogen, methyl or ethyl.
Still further preferred compounds are:
in the general formula I-A, I-B, I-C, I-D, I-E, II-A, III-A or III-B
R1、R2、R3、R4、R5Can be the same or different and are respectively selected from hydrogen, halogen, cyano, nitro and C1-C4Alkyl, halo C1-C4Alkyl radical, C1-C4Alkoxy or halo C1-C4An alkoxy group;
R6、R6'、R7can be the same or different and are respectively selected from hydrogen, halogen, nitro, cyano and C1-C4An alkyl group;
R8selected from hydrogen, halogen, cyano, C1-C4Alkyl, halo C1-C4An alkyl group;
R9selected from hydrogen, halogen, cyano, C1-C4An alkyl group;
a is selected from hydrogen;
Ra、Rbselected from hydrogen.
Further preferred compounds of the invention are:
in the general formula I-A, I-B, I-C, I-D, I-E, II-A, III-A or III-B
R1、R2、R3、R4、R5Can be the same or different and are respectively selected from hydrogen, halogen, cyano, nitro and C1-C4Alkyl, halo C1-C2Alkyl radical, C1-C4Alkoxy or halo C1-C2An alkoxy group;
R6、R6'、R7can be the same or different and are respectively selected from hydrogen, halogen and C1-C4An alkyl group;
R8selected from hydrogen, halogen, cyano, C1-C2Alkyl, halo C1-C2An alkyl group;
R9selected from hydrogen, halogen, cyano, C1-C2An alkyl group;
a is selected from hydrogen;
Ra、Rbselected from hydrogen.
Preferred specific compounds of the invention are:
in the general formula I-A, I-B, I-C, I-D, I-E, II-A, III-A or III-B
R1、R2、R3、R4、R5Can be the same or different and are respectively selected from hydrogen, halogen, cyano, nitro and C1-C4Alkyl, halo C1-C2Alkyl radical, C1-C4An alkoxy group;
R6、R6'、R7selected from hydrogen;
R8selected from halogens;
R9selected from halogens;
a is selected from hydrogen;
Ra、Rbselected from hydrogen.
In the definitions of the compounds of the general formula given above, the terms used in the collection generally represent the following substituents:
halogen: refers to fluorine, chlorine, bromine or iodine. Alkyl groups: straight-chain or branched alkyl groups, such as methyl, ethyl, propyl, isopropyl or tert-butyl. Cycloalkyl groups: substituted or unsubstituted cyclic alkyl groups, such as cyclopropyl, cyclopentyl or cyclohexyl. Substituents such as methyl, halogen, and the like. Halogenated alkyl groups: straight-chain or branched alkyl groups in which the hydrogen atoms may be partially or completely substituted with halogen atoms, for example, chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl and the like. Alkoxy groups: straight or branched chain alkyl groups attached to the structure via oxygen atom linkages. Haloalkoxy groups: straight-chain or branched alkoxy groups in which the hydrogen atoms may be partially or completely replaced by halogen atoms. For example, chloromethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, trifluoroethoxy and the like. Alkylthio group: straight or branched chain alkyl groups attached to the structure via a sulfur atom. Haloalkylthio: straight-chain or branched alkylthio groups in which the hydrogen atoms in these alkyl groups may be partially or wholly replaced by halogen atoms, such as chloromethylthio, dichloromethylthio, trichloromethylthio, fluoromethylthio, difluoromethylthio, trifluoromethylthio, chlorofluoromethylthio and the like. Alkenyl: straight-chain or branched alkenes, for example ethenyl, 1-propenyl, 2-propenyl and the different butenyl, pentenyl and hexenyl isomers. Alkenyl also includes polyenes such as 1, 2-allenyl and 2, 4-hexadienyl. Halogenated alkenyl groups: straight-chain or branched alkenes in which the hydrogen atoms may be partially or completely replaced by halogen atoms. Alkynyl: straight-chain or branched alkynes, for example ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl and hexynyl isomers. Alkynyl also includes groups consisting of multiple triple bonds, such as 2, 5-hexadiynyl. Halogenated alkynyl group: straight-chain or branched alkynes, in which the hydrogen atoms may be partially or completely replaced by halogen atoms. Alkenyloxy: linear or branched alkenes linked to the structure via an oxygen atom bond. Haloalkenyloxy: straight-chain or branched alkenyloxy groups in which the hydrogen atoms may be partially or completely replaced by halogen atoms. Alkynyloxy: straight or branched alkynes, linked to the structure via oxygen atom bonds. Haloalkynyloxy: straight-chain or branched alkynyloxy, in which the hydrogen atoms may be partially or completely substituted by halogen atoms. Alkenyloxycarbonyl radical: such as CH2 ═ CHCH2OCO-, etc. Alkynyloxycarbonyl group: such as CH ≡ CCH2OCO-, etc. Alkylamino group: straight or branched chain alkyl, linked to the structure via a nitrogen atom.
Haloalkylamino group: straight-chain or branched alkylamino, the hydrogen atoms on these alkyl groups may be partially or fully substituted by halogen atoms. Dialkylamino group: such as (CH3)2NH-, (C2H5)2 NH-. Alkylsulfinyl group: straight or branched chain alkyl groups are attached to the structure via a sulfinyl (-SO-) group, such as methylsulfinyl. Cyanoalkoxy group: CN-alkoxy, for example CNCH3O, CNC2H 5O. Alkylsulfinyl group: straight or branched chain alkyl groups are attached to the structure via a sulfinyl (-SO-) group, such as methylsulfinyl. Haloalkylsulfinyl group: straight-chain or branched alkylsulfinyl groups in which the hydrogen atoms of the alkyl group may be partially or fully substituted by halogen atoms. An alkylsulfonyl group: the linear or branched alkyl group is attached to the structure via a sulfonyl group (-SO2-), such as a methylsulfonyl group. Haloalkylsulfonyl group: straight-chain or branched alkylsulfonyl wherein the hydrogen atoms of the alkyl group may be partially or wholly substituted by halogen atoms. An alkylcarbonyl group: the alkyl group is attached to the structure via a carbonyl group, such as CH3CO-, CH3CH2 CO-. Halogenated alkylcarbonyl group: the hydrogen atoms on the alkyl group of the alkylcarbonyl group may be partially or fully substituted with halogen atoms, such as CF3 CO-. Alkylcarbonyloxy group: for example CH3COO-, CH3CH2 NHCOO-. Alkylsulfonyloxy group: alkyl-S (O) 2-O-. Alkoxycarbonyl group: alkyl-O-CO-, such as CH3OCO-, C2H5 OCO-. Halogenated alkoxycarbonyl group: the hydrogen atoms of the alkyl group of the alkoxycarbonyl group may be partially or wholly replaced by halogen atoms, e.g. ClCH2CH2OCO-, CF3CH2OCO-, etc. Alkoxycarbonylalkyl groups: alkoxycarbonyl-alkyl-, such as CH3OCOCH 2-. Alkoxycarbonylalkoxy group: alkyl-O-CO-alkyl-O-. Alkoxycarbonylamino group: alkyl-O-CO-NH-. Alkoxyalkyl groups: alkyl-O-alkyl-, for example CH3OCH 2-. Haloalkoxyalkyl groups: the hydrogen atoms on the alkyl group of the alkoxyalkyl group may be partially or fully substituted with halogen atoms. Such as ClCH2CH2OCH 2-. Alkylthioalkyl: alkyl-S-alkyl-, such as CH3SCH 2-. Haloalkylthioalkyl: the hydrogen atoms on the alkyl group of the alkylthioalkyl group may be partially or fully substituted with halogen atoms, such as ClCH2CH2SCH2-, CF3CH2SCH2-, or the like. Alkoxyalkoxy group: alkyl-O-, such as CH3OCH 2O-. Alkylaminosulfonyl: alkyl-NH-SO 2-. Dialkylaminosulfonyl: (alkyl) 2-N-SO 2-. Alkylsulfonylaminocarbonyl group: alkyl-SO 2-NH-CO-. Alkylcarbonylaminosulfonyl: alkyl-CO-NH-SO 2-. Cycloalkyloxycarbonyl group: such as cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, and the like. Alkylcarbonylalkyl group: alkyl-CO-alkyl-. Alkyl amino carbonyl: alkyl-NH-CO-, for example CH3NHCO-, (CH3)2 NCO-. Dialkylaminocarbonyl group: (alkyl) 2-NH-CO-, for example (CH3)2-N-CO-, (C2H5) 2-N-CO-. Alkoxy alkoxycarbonyl group: such as CH3O CH2CH2OCO-, etc. Alkylaminocarbonylalkyl: such as CH3NH2COCH 2-. Dialkylaminocarbonylalkyl: such as (CH3)2NH2COCH 2-. Aryl: including phenyl or naphthyl and the like. Heteroaryl group: refers to a five or six membered ring containing 1 or more heteroatoms of N, O, S. For example, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyridazinonyl, indolyl, benzofuranyl, benzoxazolyl, benzothienyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzopyrazolyl, quinoxalinyl, and the like. (hetero) arylcarbonyl group: such as benzoyl, 4-chlorobenzoyl, picolinoyl, pyrimidoyl, pyrazinoyl and the like. (hetero) aryloxycarbonyl group: such as phenoxycarbonyl, 4-chlorophenoxycarbonyl, 4-nitrophenoxycarbonyl, naphthyloxycarbonyl, pyridyloxycarbonyl, pyrimidyloxycarbonyl and the like. (hetero) arylcarbonylalkyl: such as PhCOCH 2-. (hetero) arylalkyloxycarbonyl: such as benzyloxycarbonylA group such as a 4-chlorobenzyloxycarbonyl group, a 4-trifluoromethylbenzyloxycarbonyl group, and a pyridylmethyloxycarbonyl group. (hetero) arylalkyl: such as benzyl, phenethyl, p-chlorobenzyl,
Figure DEST_PATH_GDA0000915652240000071
And the like.
Tables 1-3 list R in generic formula I, II or III, respectively8、R9、Ra、RbAlthough some of these substituents are not limited to these substituents, other substituents in formula I, II or iii are as described above.
TABLE 1R8Substituent group
R8 R8 R8
H F Cl
Br I CN
CH3 C2H5 CHF2
CFH2 CF3 CH2CHF2
TABLE 2R9Substituent group
R9 R9 R9
H F Cl
Br I CN
CH3 C2H5
TABLE 3Ra(Rb) Substituent group
Figure DEST_PATH_GDA0000915652240000081
Some of the compounds of the present invention can be illustrated by the specific compounds listed in tables 4-146, but are not intended to limit the present invention. In the general formula compounds I-A, I-B, I-C, I-D, I-E, II-A, III-A or III-B, R in the formula compounds6＝R6'＝H。
In the general formula I-A
Figure DEST_PATH_GDA0000915652240000082
When A ═ H, R8＝R9＝Cl，R7When H, R1、R2、R3、R4、R5The substituents, as shown in Table 4, represent compounds numbered 4-1 to 4-180.
TABLE 4
Figure DEST_PATH_GDA0000915652240000091
Figure DEST_PATH_GDA0000915652240000101
Figure DEST_PATH_GDA0000915652240000111
Figure DEST_PATH_GDA0000915652240000121
Figure DEST_PATH_GDA0000915652240000131
Table 5: when A ═ H, R8＝Cl，R9＝CH3，R7When H, the substituent R1、R2、R3、R4、R5Corresponding to Table 4, the numbers of the representative compounds are 5-1 to 5-180, which correspond to 1-180 in Table 4.
Table 6: when A ═ H, R8＝CH3，R9＝H，R7When H, the substituent R1、R2、R3、R4、R5Corresponding to Table 4, the numbers of the representative compounds are 6-1 to 6-180, which correspond to 1-180 in Table 4.
Table 7: when A ═ H, R8＝H，R9＝CH3，R7When H, the substituent R1、R2、R3、R4、R5In agreement with Table 4, the representative compounds are numbered from 7-1 to 7-180, corresponding in sequence to 1-180 of Table 4.
Table 8: when A ═ H, R8＝H，R9＝CN，R7When H, the substituent R1、R2、R3、R4、R5Corresponding to Table 4, the numbers of the representative compounds are from 8-1 to 8-180, which in turn correspond to 1-180 of Table 4.
Table 9: when A ═ H, R8＝H，R9＝CH2Cl，R7When H, the substituent R1、R2、R3、R4、R5In agreement with Table 4, the representative compounds are numbered from 9-1 to 9-180, corresponding in sequence to 1-180 of Table 4.
Table 10: a ═ H, R8＝R9＝Cl，R7When Cl, the substituent R1、R2、R3、R4、R5Corresponding to Table 4, the numbers of the representative compounds are from 10-1 to 10-180, which in turn correspond to 1-180 of Table 4.
Table 11: when A ═ H, R8＝Cl，R9＝CH3，R7When Cl, the substituent R1、R2、R3、R4、R5In agreement with Table 4, the representative compounds are numbered from 11-1 to 11-180, corresponding in sequence to 1-180 of Table 4.
Table 12: when A ═ H, R8＝CH3，R9＝H，R7When Cl, the substituent R1、R2、R3、R4、R5Corresponding to Table 4, the numbers of the representative compounds are 12-1 to 12-180, which correspond to 1-180 in Table 4.
Table 13: when A ═ H, R8＝H，R9＝CH3，R7When Cl, the substituent R1、R2、R3、R4、R5Corresponding to Table 4, the representative compounds are numbered from 13-1 to 13-180, which in turn correspond to 1-180 of Table 4.
Table 14: when A ═ H, R8＝H，R9＝CN，R7When Cl, the substituent R1、R2、R3、R4、R5In agreement with Table 4, the representative compounds are numbered 14-1 to 14-180, corresponding in sequence to 1-180 of Table 4.
Table 15: when A ═ H, R8＝H，R9＝CH2Cl，R7When Cl, the substituent R1、R2、R3、R4、R5Corresponding to Table 4, the representative compounds are numbered from 15-1 to 15-180, which in turn correspond to 1-180 of Table 4.
In the general formula I-B,
Figure DEST_PATH_GDA0000915652240000132
table 16: when A ═ H, R8＝R9＝Cl，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5Corresponding to Table 4, the numbers of the representative compounds are 16-1 to 16-180, which correspond to 1-180 in Table 4.
Table 17: when A ═ H, R8＝Cl，R9＝CH3，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5Corresponding to Table 4, the numbers of the representative compounds are 17-1 to 17-180, which correspond to 1-180 in Table 4.
Table 18: when A ═ H, R8＝CH3，R9＝H，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5In agreement with Table 4, the representative compounds are numbered from 18-1 to 18-180, corresponding in sequence to 1-180 of Table 4.
Table 19: when A ═ H, R8＝H，R9＝CH3，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5In agreement with Table 4, the representative compounds are numbered from 19-1 to 19-180, corresponding in sequence to 1-180 of Table 4.
Table 20: when A ═ H, R8＝H，R9＝CN，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5Corresponding to Table 4, the numbers of the representative compounds are from 20-1 to 20-180, which in turn correspond to 1-180 of Table 4.
Table 21: when A ═ H, R8＝H，R9＝CH2Cl，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5Corresponding to Table 4, the numbers of the representative compounds are 21-1 to 21-180, which correspond to 1-180 in Table 4.
Table 22: when A ═ H, R8＝R9＝Cl，Ra＝Rb＝H，R7When Cl, the substituent R1、R2、R3、R4、R5In agreement with Table 4, the representative compounds are numbered from 22-1 to 22-180, corresponding in turn to 1-180 of Table 4.
Table 23: when A ═ H, R8＝Cl，R9＝CH3，Ra＝Rb＝H，R7When Cl, the substituent R1、R2、R3、R4、R5Corresponding to Table 4, the numbers of the representative compounds are 23-1 to 23-180, which correspond to 1-180 in Table 4.
Table 24: when A ═ H, R8＝CH3，R9＝H，Ra＝Rb＝H，R7When Cl, the substituent R1、R2、R3、R4、R5Corresponding to Table 4, the numbers of the representative compounds are 24-1 to 24-180, which correspond to 1-180 in Table 4.
Table 25: when A ═ H, R8＝H，R9＝CH3，Ra＝Rb＝H，R7When Cl, the substituent R1、R2、R3、R4、R5Corresponding to Table 4, the representative compounds are numbered from 25-1 to 25-180, which in turn correspond to 1-180 of Table 4.
Table 26: when A ═ H, R8＝H，R9＝CN，Ra＝Rb＝H，R7When Cl, the substituent R1、R2、R3、R4、R5Corresponding to Table 4, the representative compounds are numbered from 26-1 to 26-180, which in turn correspond to 1-180 of Table 4.
Table 27: when A ═ H, R8＝H，R9＝CH2Cl，Ra＝Rb＝H，R7When Cl, the substituent R1、R2、R3、R4、R5Corresponding to Table 4, the representative compounds are numbered from 27-1 to 27-180, which in turn correspond to 1-180 of Table 4.
Table 28: when A ═ H, R8＝R9＝Cl，Rb＝R7＝H，Ra＝CH3When the substituent R is1、R2、R3、R4、R5Corresponding to Table 4, the representative compounds are numbered from 28-1 to 28-180, which in turn correspond to tables 4 from 1 to 180.
Table 29: when A ═ H, R8＝Cl，R9＝CH3，Rb＝R7＝H，Ra＝CH3When the substituent R is1、R2、R3、R4、R5Corresponding to Table 4, the representative compounds are numbered from 29-1 to 29-180, which in turn correspond to 1-180 of Table 4.
Table 30: when A ═ H, R8＝CH3，R9＝H，Rb＝R7＝H，Ra＝CH3When the substituent R is1、R2、R3、R4、R5Corresponding to Table 4, the numbers of the representative compounds are from 30-1 to 30-180, which in turn correspond to 1-180 of Table 4.
Table 31: when A ═ H, R8＝H，R9＝CH3，Rb＝R7＝H，Ra＝CH3When the substituent R is1、R2、R3、R4、R5Corresponding to Table 4, the numbers of the representative compounds are 31-1 to 31-180, which correspond to 1-180 in Table 4.
Table 32: when A ═ H, R8＝H，R9＝CN，Rb＝R7＝H，Ra＝CH3When the substituent R is1、R2、R3、R4、R5Corresponding to Table 4, the representative compounds are numbered from 32-1 to 32-180, which in turn correspond to 1-180 of Table 4.
Table 33: when A ═ H, R8＝H，R9＝CH2Cl，Rb＝R7＝H，Ra＝CH3When the substituent R is1、R2、R3、R4、R5Corresponding to Table 4, the representative compounds are numbered 33-1 to 33-180, which in turn correspond to 1-180 of Table 4.
Table 34: when A ═ H, R8＝R9＝Cl，R7＝H，Ra＝Rb＝CH3When the substituent R is1、R2、R3、R4、R5In agreement with Table 4, the representative compounds are numbered 34-1 to 34-180, corresponding in sequence to 1-180 of Table 4.
Table 35: when A ═ H, R8＝Cl，R9＝CH3，R7＝H，Ra＝Rb＝CH3When the substituent R is1、R2、R3、R4、R5Corresponding to Table 4, the numbers of the representative compounds are 35-1 to 35-180, which correspond to 1-180 in Table 4.
Table 36: when A ═ H, R8＝CH3，R9＝H，R7＝H，Ra＝Rb＝CH3When the substituent R is1、R2、R3、R4、R5Corresponding to Table 4, the numbers of the representative compounds are 36-1 to 36-180, which correspond to 1-180 in Table 4.
Table 37: when A ═ H, R8＝H，R9＝CH3，R7＝H，Ra＝Rb＝CH3When it is takenSubstituent R1、R2、R3、R4、R5Corresponding to Table 4, the representative compounds are numbered from 37-1 to 37-180, which in turn correspond to 1-180 of Table 4.
Table 38: when A ═ H, R8＝H，R9＝CN，Rb＝R7＝H，Ra＝CH3When the substituent R is1、R2、R3、R4、R5In agreement with Table 4, the representative compounds are numbered from 38-1 to 38-180, corresponding in turn to 1-180 of Table 4.
Table 39: when A ═ H, R8＝H，R9＝CH2Cl，Rb＝R7＝H，Ra＝CH3When the substituent R is1、R2、R3、R4、R5Corresponding to Table 4, the representative compounds are numbered from 39-1 to 39-180, which in turn correspond to 1-180 of Table 4.
Table 40: when A ═ H, R8＝R9＝Cl，Rb＝H，Ra＝CH3，R7When Cl, the substituent R1、R2、R3、R4、R5Corresponding to Table 4, the numbers of the representative compounds are 40-1 to 40-180, which correspond to 1-180 in Table 4.
Table 41: when A ═ H, R8＝Cl，R9＝CH3，Rb＝H，Ra＝CH3，R7When Cl, the substituent R1、R2、R3、R4、R5Corresponding to Table 4, the representative compounds are numbered from 41-1 to 41-180, which in turn correspond to 1-180 of Table 4.
Table 42: when A ═ H, R8＝CH3，R9＝H，Rb＝H，Ra＝CH3，R7When Cl, the substituent R1、R2、R3、R4、R5Corresponding to Table 4, the representative compounds are numbered from 42-1 to 42-180, which in turn correspond to 1-180 of Table 4.
Table 43: when A ═ H, R8＝H，R9＝CH3，Rb＝H，Ra＝CH3，R7When Cl, the substituent R1、R2、R3、R4、R5Corresponding to Table 4, the representative compounds are numbered 43-1 through 43-180, which in turn correspond to 1-180 of Table 4.
Table 44: when A ═ H, R8＝H，R9＝CN，Rb＝H，Ra＝CH3，R7When Cl, the substituent R1、R2、R3、R4、R5Corresponding to Table 4, the numbers of the representative compounds are 44-1 to 44-180, which correspond to 1-180 in Table 4.
Table 45: when A ═ H, R8＝H，R9＝CH2Cl，Rb＝H，Ra＝CH3，R7When Cl, the substituent R1、R2、R3、R4、R5Corresponding to Table 4, the representative compounds are numbered from 45-1 to 45-180, which in turn correspond to 1-180 of Table 4.
In the general formula I-C, the compound,
Figure DEST_PATH_GDA0000915652240000151
when A ═ H, R8＝R9＝Cl，Ra＝Rb＝R7When H, R1、R2、R3、R4、R5For the various substituents, see Table 46, for compounds numbered 46-1 through 46-16.
TABLE 46
Numbering R1 R2 R3 R4 R5
1 H H H H H
2 H H H Cl H
3 H H H CF3 H
4 H H H OCH3 H
5 H H H CH3 H
6 H H H NO2 H
7 H H H F H
8 CF3 H H H H
9 Cl H H H H
10 H H H H Cl
11 H Cl H Cl H
12 H Cl H CF3 H
13 H F H CN H
14 H H Cl H Cl
15 H CH3 H H H
16 F H H F H
Table 47: when A ═ H, R8＝Cl，R9＝CH3，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 47-1 through 47-16, which in turn correspond to tables 46 1-16.
Table 48: when A ═ H, R8＝CH3，R9＝H，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 48-1 through 48-16, which in turn correspond to tables 46 at 1-16.
Table 49: when A ═ H, R8＝H，R9＝CH3，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 49-1 through 49-16, which in turn correspond to tables 46 1-16.
Table 50: when A ═ H, R8＝H，R9＝CN，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 50-1 to 50-16, which in turn correspond to tables 46 at 1-16.
Table 51: when A ═ H, R8＝H，R9＝CH2Cl，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 51-1 through 51-16, which in turn correspond to tables 46 at 1-16.
Table 52: when A ═ H, R8＝R9＝Cl，Ra＝Rb＝H，R7When Cl, the substituent R1、R2、R3、R4、R5Consistent with Table 46, representative compounds are numbered 52-1 through 52-16, which in turn correspond to tables 46 at 1-16.
Table 53: when A ═ H, R8＝Cl，R9＝CH3，Ra＝Rb＝H，R7When Cl, the substituent R1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 53-1 to 53-16, corresponding in sequence to tables 1-16 of Table 46.
Table 54: when A ═ H, R8＝CH3，R9＝H，Ra＝Rb＝H，R7When Cl, the substituent R1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 55-1 to 54-16, which in turn correspond to tables 46 1-16.
Table 55: when A ═ H, R8＝H，R9＝CH3，Ra＝Rb＝H，R7When Cl, the substituent R1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 55-1 to 55-16, which in turn correspond to tables 46 1-16.
Table 56: when A ═ H, R8＝H，R9＝CN，Ra＝Rb＝H，R7When Cl, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 56-1 through 56-16, which in turn correspond to tables 46 at 1-16.
Table 57: when A ═ H, R8＝H，R9＝CH2Cl，Ra＝Rb＝H，R7When Cl, the substituent R1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 57-1 through 57-16, which in turn correspond to tables 46 at 1-16.
Table 58: when A ═ H, R8＝R9＝Cl，Rb＝R7＝H，Ra＝CH3When the substituent R is1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 58-1 through 58-16, which in turn correspond to tables 46 at 1-16.
Table 59: when A ═ H, R8＝Cl，R9＝CH3，Rb＝R7＝H，Ra＝CH3When the substituent R is1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 59-1 to 59-16, which in turn correspond to tables 46 1-16.
Table 60: when A ═ H, R8＝CH3，R9＝H，Rb＝R7＝H，Ra＝CH3When the substituent R is1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 60-1 through 60-16, which in turn correspond to tables 46 at 1-16.
Table 61: when A ═ H, R8＝H，R9＝CH3，Rb＝R7＝H，Ra＝CH3When the substituent R is1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 61-1 to 61-16, which in turn correspond to tables 46 1-16.
Table 62: when A ═ H, R8＝H，R9＝CN，Rb＝R7＝H，Ra＝CH3When the substituent R is1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 62-1 through 62-16, which in turn correspond to tables 46 at 1-16.
Table 63: when A ═ H, R8＝H，R9＝CH2Cl，Rb＝R7＝H，Ra＝CH3When the substituent R is1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 63-1 through 63-16, which in turn correspond to tables 46 at 1-16.
Table 64: when A ═ H, R8＝R9＝Cl，R7＝H，Ra＝Rb＝CH3When the substituent R is1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 64-1 through 64-16, which in turn correspond to tables 46 at 1-16.
Table 65: when A ═ H, R8＝Cl，R9＝CH3，R7＝H，Ra＝Rb＝CH3When the substituent R is1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 65-1 to 65-16, corresponding in sequence to tables 46 1-16.
Table 66: when A ═ H, R8＝CH3，R9＝H，R7＝H，Ra＝Rb＝CH3When the substituent R is1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 66-1 through 66-16, which in turn correspond to tables 46 at 1-16.
Table 67: when A ═ H, R8＝H，R9＝CH3，R7＝H，Ra＝Rb＝CH3When the substituent R is1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 67-1 through 67-16, which in turn correspond to tables 46 at 1-16.
Table 68: when A ═ H, R8＝H，R9＝CN，R7＝H，Ra＝Rb＝CH3When the substituent R is1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 68-1 through 68-16, which in turn correspond to tables 46 at 1-16.
Table 69: when A ═ H, R8＝H，R9＝CH2Cl，R7＝H，Ra＝Rb＝CH3When the substituent R is1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 69-1 to 69-16, which in turn correspond to tables 46 1-16.
Table 70: when A ═ H, R8＝R9＝Cl，Rb＝H，Ra＝CH3，R7When Cl, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 70-1 through 70-16, which in turn correspond to tables 46 at 1-16.
Table 71: when A ═ H, R8＝Cl，R9＝CH3，Rb＝H，Ra＝CH3，R7When Cl, the substituent R1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 71-1 to 71-16, corresponding in sequence to tables 46 1-16.
Table 72: when A ═ H, R8＝CH3，R9＝H，Rb＝H，Ra＝CH3，R7When Cl, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 72-1 through 72-16, which in turn correspond to tables 46 at 1-16.
Table 73: when A ═ H, R8＝H，R9＝CH3，Rb＝H，Ra＝CH3，R7When Cl, the substituent R1、R2、R3、R4、R5Consistent with Table 46, representative compounds are numbered 73-1 through 73-16, which in turn correspond to tables 46 at 1-16.
Table 74: when A ═ H, R8＝H，R9＝CN，Rb＝H，Ra＝CH3，R7When Cl, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 74-1 through 74-16, which in turn correspond to tables 46 at 1-16.
Table 75: when A ═ H, R8＝H，R9＝CH2Cl，Rb＝H，Ra＝CH3，R7When Cl, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 75-1 through 75-16, which in turn correspond to tables 46 at 1-16.
In the general formula I-D,
Figure DEST_PATH_GDA0000915652240000171
table 76: when A ═ H, R8＝R9＝Cl，R7When H, the substituent R1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 76-1 through 76-16, which in turn correspond to tables 46 at 1-16.
Table 77: when A ═ H, R8＝Cl，R9＝CH3，R7When H, the substituent R1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 77-1 to 77-16, which in turn correspond to tables 46 1-16.
Table 78: when A ═ H, R8＝CH3，R9＝H，R7When H, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 78-1 through 78-16, which in turn correspond to tables 46 at 1-16.
Table 79: when A ═ H, R8＝H，R9＝CH3，R7When H, the substituent R1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 79-1 to 79-16, which in turn correspond to tables 46 1-16.
Table 80: when A ═ H, R8＝H，R9＝CN，R7When H, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 80-1 through 80-16, which in turn correspond to tables 46 at 1-16.
Table 81: when A ═ H, R8＝H，R9＝CH2Cl，R7When H, the substituent R1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered from 81-1 to 81-16, corresponding in sequence to tables 46 from 1 to 16.
Table 82: when A ═ H, R8＝R9＝Cl，R7When Cl, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 82-1 through 82-16, which in turn correspond to tables 46 at 1-16.
Table 83: when A ═ H, R8＝Cl，R9＝CH3，R7When Cl, the substituent R1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 83-1 to 83-16, which in turn correspond to tables 46 1-16.
Table 84: when A ═ H, R8＝CH3，R9＝H，R7When Cl, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 84-1 through 84-16, which in turn correspond to tables 46 at 1-16.
Table 85: when A ═ H, R8＝H，R9＝CH3，R7When Cl, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 85-1 through 85-16, which in turn correspond to tables 1-16 of Table 46.
Table 86: when A ═ H, R8＝H，R9＝CN，R7When Cl, the substituent R1、R2、R3、R4、R5Consistent with Table 46, representative compounds are numbered 86-1 through 86-16, which in turn correspond to tables 46 at 1-16.
Table 87: when A ═ H, R8＝H，R9＝CH2Cl，R7When Cl, the substituent R1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 87-1 to 87-16, corresponding in sequence to tables 46 1-16.
In the general formula I-E, the compound is shown in the specification,
Figure DEST_PATH_GDA0000915652240000181
table 88: when A ═ H, R8＝R9＝Cl，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 88-1 through 88-16, which in turn correspond to tables 46 at 1-16.
Table 89: when A ═ H, R8＝Cl，R9＝CH3，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 89-1 to 89-16, corresponding in sequence to 1-16 of Table 46.
Table 90: when A ═ H, R8＝CH3，R9＝H，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 90-1 through 90-16, which in turn correspond to tables 46 at 1-16.
Table 91: when A ═ H, R8＝H，R9＝CH3，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 91-1 through 91-16, which in turn correspond to tables 46 1-16.
Table 92: when A ═ H, R8＝H，R9＝CN，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 92-1 through 92-16, which in turn correspond to tables 46 at 1-16.
Table 93: when A ═ H, R8＝H，R9＝CH2Cl，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5Consistent with Table 46, representative compounds are numbered 93-1 through 93-16, which in turn correspond to tables 46 at 1-16.
Table 94: when A ═ H, R8＝R9＝Cl，Ra＝Rb＝H，R7When Cl, the substituent R1、R2、R3、R4、R5Corresponding to Table 46, the numbers of the representative compounds are 94-1 to 94-16, which are shown in the following table46 from 1 to 16.
Table 95: when A ═ H, R8＝R9＝Cl，Rb＝R7＝H，Ra＝CH3When the substituent R is1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 95-1 to 95-16, which in turn correspond to tables 46 1-16.
Table 96: when A ═ H, R8＝Cl，R9＝CH3，Rb＝R7＝H，Ra＝CH3When the substituent R is1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 96-1 to 96-16, which in turn correspond to tables 46 1-16.
Table 97: when A ═ H, R8＝CH3，R9＝H，Rb＝R7＝H，Ra＝CH3When the substituent R is1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 97-1 through 97-16, which in turn correspond to tables 46 at 1-16.
Table 98: when A ═ H, R8＝H，R9＝CH3，Rb＝R7＝H，Ra＝CH3When the substituent R is1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 98-1 to 98-16, which in turn correspond to tables 46 1-16.
Table 99: when A ═ H, R8＝H，R9＝CN，Rb＝R7＝H，Ra＝CH3When the substituent R is1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 99-1 through 99-16, which in turn correspond to tables 46 at 1-16.
Table 100: when A ═ H, R8＝H，R9＝CH2Cl，Rb＝R7＝H，Ra＝CH3When the substituent R is1、R2、R3、R4、R5In agreement with Table 46, the representative compound is numbered 100-1-100-16, which in turn correspond to 1-16 of table 46.
Table 101: when A ═ H, R8＝R9＝Cl，R7＝H，Ra＝Rb＝CH3When the substituent R is1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 101-1 through 101-16, which in turn correspond to tables 46 at 1-16.
Table 102: when A ═ H, R8＝R9＝Cl，Rb＝H，Ra＝CH3，R7When Cl, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 102-1 through 102-16, which in turn correspond to tables 46 at 1-16.
In the general formula II-A,
Figure DEST_PATH_GDA0000915652240000182
table 103: when A ═ H, R8＝R9＝Cl，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 103-1 through 103-16, which in turn correspond to tables 46 at 1-16.
Table 104: when A ═ H, R8＝Cl，R9＝CH3，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 104-1 through 104-16, which in turn correspond to tables 46 at 1-16.
Table 105: when A ═ H, R8＝CH3，R9＝H，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 105-1 through 105-16, which in turn correspond to tables 1-16 of Table 46.
Table 106: when A ═ H, R8＝H，R9＝CH3，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 106-1 through 106-16, which in turn correspond to tables 46 at 1-16.
Table 107: when A ═ H, R8＝H，R9＝CN，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 107-1 to 107-16, corresponding in sequence to 1-16 of Table 46.
Table 108: when A ═ H, R8＝H，R9＝CH2Cl，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 108-1 through 108-16, which in turn correspond to tables 46 at 1-16.
Table 109: when A ═ H, R8＝R9＝Cl，Ra＝Rb＝H，R7When Cl, the substituent R1、R2、R3、R4、R5Consistent with Table 46, representative compounds are numbered 109-1 through 109-16, which in turn correspond to tables 46 at 1-16.
Table 110: when A ═ H, R8＝R9＝Cl，Rb＝R7＝H，Ra＝CH3When the substituent R is1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 110-1 through 110-16, which in turn correspond to tables 46 at 1-16.
Table 111: when A ═ H, R8＝R9＝Cl，R7＝H，Ra＝Rb＝CH3When the substituent R is1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered from 111-1 to 111-16, which in turn correspond to tables 46 from 1-16.
Table 112: when A ═ H, R8＝R9＝Cl，Rb＝H，Ra＝CH3，R7When Cl, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 112-1 through 112-16, which in turn correspond to tables 46 at 1-16.
In the general formula III-A, the compound,
Figure DEST_PATH_GDA0000915652240000191
table 113: when A ═ H, R8＝R9＝Cl，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 113-1 to 113-16, which in turn correspond to tables 46 1-16.
Table 114: when A ═ H, R8＝Cl，R9＝CH3，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 114-1 through 114-16, which in turn correspond to tables 46 at 1-16.
Table 115: when A ═ H, R8＝CH3，R9＝H，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 115-1 to 115-16, which in turn correspond to tables 46 1-16.
Table 116: when A ═ H, R8＝H，R9＝CH3，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 116-1 through 116-16, which in turn correspond to tables 46 at 1-16.
Table 117: when A ═ H, R8＝H，R9＝CN，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 117-1 to 117-16, corresponding in sequence to tables 1-16 of Table 46.
Table 118: when a is equal to H, the compound is,R8＝H，R9＝CH2Cl，Ra＝Rb＝R7when H, the substituent R1、R2、R3、R4、R5Consistent with Table 46, representative compounds are numbered 118-1 through 118-16, which in turn correspond to tables 46 at 1-16.
Table 119: when A ═ H, R8＝R9＝Cl，Ra＝Rb＝H，R7When Cl, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 119-1 through 119-16, which in turn correspond to tables 46 at 1-16.
Table 120: when A ═ H, R8＝R9＝Cl，Rb＝R7＝H，Ra＝CH3When the substituent R is1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 120-1 through 120-16, which in turn correspond to tables 46 at 1-16.
Table 121: when A ═ H, R8＝R9＝Cl，R7＝H，Ra＝Rb＝CH3When the substituent R is1、R2、R3、R4、R5Consistent with Table 47, the representative compounds are numbered 121-1 through 121-16, which in turn correspond to tables 1-16 of Table 46.
Table 122: when A ═ H, R8＝R9＝Cl，Rb＝H，Ra＝CH3，R7When Cl, the substituent R1、R2、R3、R4、R5Consistent with Table 47, representative compounds are numbered 122-1 through 122-16, which in turn correspond to tables 1-16 of Table 46.
In the general formula III-B, the compound,
Figure DEST_PATH_GDA0000915652240000201
table 123: when A ═ H, R8＝R9＝Cl，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 123-1 through 123-16, which in turn correspond to tables 46 at 1-16.
Table 124: when A ═ H, R8＝Cl，R9＝CH3，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5Consistent with Table 46, representative compounds are numbered 124-1 through 124-16, which in turn correspond to tables 46 at 1-16.
Table 125: when A ═ H, R8＝CH3，R9＝H，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 125-1 to 125-16, which in turn correspond to tables 46 1-16.
Table 126: when A ═ H, R8＝H，R9＝CH3，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 126-1 through 126-16, which in turn correspond to tables 46 at 1-16.
Table 127: when A ═ H, R8＝H，R9＝CN，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 127-1 to 127-16, which in turn correspond to tables 46 1-16.
Table 128: when A ═ H, R8＝H，R9＝CH2Cl，Ra＝Rb＝R7When H, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 128-1 through 128-16, which in turn correspond to tables 46 at 1-16.
Table 129: when A ═ H, R8＝R9＝Cl，Ra＝Rb＝H，R7When Cl, the substituent R1、R2、R3、R4、R5In agreement with Table 47, the representative compounds are numbered 129-1 to 129-16, in that order1-16 of Table 46.
Table 130: when A ═ H, R8＝R9＝Cl，Rb＝R7＝H，Ra＝CH3When the substituent R is1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 130-1 through 130-16, which in turn correspond to tables 46 at 1-16.
Table 131: when A ═ H, R8＝R9＝Cl，R7＝H，Ra＝Rb＝CH3When the substituent R is1、R2、R3、R4、R5In agreement with Table 46, the representative compounds are numbered 131-1 to 131-16, which in turn correspond to tables 46 1-16.
Table 132: when A ═ H, R8＝R9＝Cl，Rb＝H，Ra＝CH3，R7When Cl, the substituent R1、R2、R3、R4、R5Consistent with Table 46, the representative compounds are numbered 132-1 through 132-16, which in turn correspond to tables 46 at 1-16.
Table 133: in the general formula I-A, when R is8＝Cl，R9＝Cl，R7＝R1＝R2＝R3＝R5When H, R4The substituent A is shown in Table 133, and represents the compound number 133-1- - -133-140.
Table 133
Figure DEST_PATH_GDA0000915652240000202
Figure DEST_PATH_GDA0000915652240000211
Figure DEST_PATH_GDA0000915652240000221
Table 134: in the general formula I-A, when R is8＝Cl，R9＝Cl，R7＝R1＝R2＝R3＝R5＝H，R4When H, substituent a is in accordance with table 133, representing compound numbers 134-1 to 134-140, which in turn correspond to tables 133 from 1 to 140.
Table 135: in the general formula I-A, when R is8＝Cl，R9＝Cl，R7＝R1＝R3＝R5＝H，R2＝Cl，R4＝CF3When the substituent A is in accordance with Table 133, it represents the compound number 135-1 to 135-140, which in turn corresponds to 1-140 of Table 133.
Table 136: in the general formula I-A, when R is8＝Cl，R9＝Cl，R7＝R1＝R2＝R3＝R5＝H，R4＝CF3When the substituent A is in accordance with Table 133, it represents the compound number 136-1- - -136-140, which in turn corresponds to 1-140 of Table 133.
Table 137: in the general formula I-B, when R is8＝Cl，R9＝Cl，Ra＝Rb＝R7＝R1＝R2＝R3＝R5When H, R4The substituent A is shown in Table 133, and represents the compound number 137-1- - -137-140, which in turn corresponds to 1-140 of Table 133.
Table 138: in the general formula I-B, when R is8＝Cl，R9＝Cl，Ra＝Rb＝R7＝R1＝R2＝R3＝R5＝H，R4When H, substituent A is in accordance with Table 133, representing compounds numbered 138-1-138-140, which in turn correspond to tables 133 from 1-140.
Table 139: in the general formula I-B, when R is8＝Cl，R9＝Cl，Ra＝Rb＝R7＝R1＝R3＝R5＝H，R2＝Cl，R4＝CF3When the substituent A is in accordance with Table 133, it represents the compound numbers 139-1 to 139-140, which correspond to 1 to 140 of Table 133 in this order.
Table 140: in the general formula I-B, when R is8＝Cl，R9＝Cl，Ra＝Rb＝R7＝R1＝R2＝R3＝R5＝H，R4＝CF3When the substituent A is in accordance with Table 133, it represents the compound numbers 140-1-140, which correspond to 1-140 of Table 133 in turn.
Table 141: in the general formula I-B, when R is8＝Cl，R9＝Cl，Ra＝Rb＝R7＝R1＝R2＝R3＝R5＝H，R4When F, substituent a is in accordance with table 133, representing compound numbers 141-1 to 141-140, which in turn correspond to 1-140 of table 133.
Table 142: in the general formula I-B, when R is8＝Cl，R9＝Cl，Ra＝Rb＝R7＝R1＝R3＝R5＝H，R2＝R4When Cl, substituent A is in accordance with Table 133, representing compounds numbered 142-1-142-140, which in turn correspond to tables 133 from 1-140.
Table 143: in the general formula I-B, when R is8＝Cl，R9＝Cl，Ra＝Rb＝R7＝R2＝R3＝R4＝R5＝H，R1＝CF3When the substituent A is in accordance with Table 133, it represents the compound number 143-1- - -143-140, which in turn corresponds to 1-140 of Table 133.
Table 144: in the general formula I-B, when R is8＝Cl，R9＝Cl，Ra＝Rb＝R7＝R2＝R3＝R4＝R5＝H，R1When Cl, substituent A is in accordance with Table 133, representing compound numbers 144-1-144-140, which in turn correspond to 1-140 of Table 133.
Table 145: in the general formula I-B, when R is8＝Cl，R9＝Cl，Ra＝Rb＝R7＝R1＝R2＝R3＝R4＝H，R5＝CH3When the substituent A is in accordance with Table 133, it represents the compound number 145-1 to 145-140, which in turn corresponds to 1-140 of Table 133.
Table 146: in the general formula I-B, when R is8＝Cl，R9＝Cl，Ra＝Rb＝R7＝R1＝R2＝R5＝H，R3＝R4When F, substituent a is in accordance with table 133, representing compound numbers 146-1 to 146-140, which in turn correspond to tables 1-140 of table 133.
The preparation method of the compound of the general formula I of the invention is shown as follows, and the preparation of the compounds of the general formulae II and III can be carried out by referring to the compound of the general formula I, except that the starting material substituted 6-chloronicotinic acid (M-1) is replaced by substituted 2-chloroisonicotinic acid and substituted 2-chloronicotinic acid.
The compounds of the general formula I according to the invention are prepared according to the following process, the reaction scheme being as follows, where the radicals are as defined above unless otherwise stated:
Figure DEST_PATH_GDA0000915652240000231
and reacting the intermediate H and the intermediate L under alkaline conditions to obtain the compound shown in the general formula I.
Suitable bases may be selected from, for example, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, pyridine, sodium methoxide, sodium ethoxide, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, etc.
The reaction is carried out in a suitable solvent, which may be selected from, for example, tetrahydrofuran, 1, 4-dioxane, acetonitrile, toluene, xylene, benzene, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, acetone, or butanone.
The reaction temperature may be between room temperature and the boiling temperature of the solvent, and is generally from 20 to 100 ℃.
The reaction time is from 30 minutes to 20 hours, usually from 1 to 10 hours.
The intermediate L moiety is commercially available or may be prepared according to known methods, for example as described in reference to DE102005031348 or CN 102942565.
Intermediate H differs according to the definition of A, B and X and was prepared in three cases:
in the first case:
when a is equal to H, the compound is,
1) the nitrogen atom of B ═ amide is directly bonded to the carbon atom at the 5-position of the six-membered aromatic ring, see patents WO9948871, WO2108649 Journal of organometallic chemistry,677(1-2), 57-72; 2003. CN101028598 or tetrahedron Letters,53(35), 4665-4668; 2012 or prepared as follows.
Figure DEST_PATH_GDA0000915652240000232
Reacting the intermediate H-A1 with H-A2 in a suitable solvent in the presence of a suitable base at a suitable temperature for 30 minutes to 20 hours, usually 1 to 10 hours, to obtain an intermediate H-A3; the intermediate H-A is prepared by reducing H-A3 with zinc powder, and the operation method of the step is shown in patents WO9948871 and WO 2108649.
The intermediates were derived from: intermediates H-A1 and H-A2 are either commercially available or prepared according to conventional methods.
Suitable bases may be selected from, for example, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, pyridine, sodium methoxide, sodium ethoxide, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, etc.
The reaction is carried out in a suitable solvent, which may be selected from, for example, tetrahydrofuran, 1, 4-dioxane, acetonitrile, toluene, xylene, benzene, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, acetone, or butanone.
The reaction temperature may be between room temperature and the boiling temperature of the solvent, and is generally from 20 to 100 ℃.
The reaction time is from 30 minutes to 20 hours, usually from 1 to 10 hours.
2)B＝CRaRbReference is made to the preparation described in patents WO 2013111864, WO 2013089212 or WO 2013042139, as shown below:
Figure DEST_PATH_GDA0000915652240000241
wherein U is a leaving group, and is halogen, hydroxyl, or the like.
Reacting the intermediate H-B1 with H-B2 in a suitable solvent in the presence of a suitable base at a suitable temperature for 30 minutes to 20 hours, usually 1 to 10 hours, to obtain an intermediate H-B3; H-B3 is subjected to hydrogenation reduction in the presence of a suitable catalyst such as ammonia water to obtain an intermediate H-B4; specific preparations can be found in documents j.am.chem.soc,70,3788 (1948); 82,681 (1960); 82,2386 (1960); chem, 49,2990 (1971); chem,37,335 (1972); organic Syntheses, Coll.Vol.3, p.229, p.720(1955), Vol.23, p.71(1943) or Vol.27, p.18 (1947). Suitable catalysts may be selected from raney nickel, palladium on carbon or platinum oxide and the like.
The intermediates were derived from: intermediates H-B1 and H-B2 are either commercially available or prepared according to conventional methods.
Suitable bases may be selected from, for example, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, pyridine, sodium methoxide, sodium ethoxide, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, etc.
The reaction is carried out in a suitable solvent, which may be selected from, for example, tetrahydrofuran, 1, 4-dioxane, acetonitrile, toluene, xylene, benzene, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, acetone, or butanone.
The reaction temperature may be between room temperature and the boiling temperature of the solvent, and is generally from 20 to 100 ℃.
The reaction time is from 30 minutes to 20 hours, usually from 1 to 10 hours.
3)B＝-CH2CRaRbReference is made to the preparation of the process described in patents WO9404527, US20110054173 or WO2011022, as follows:
Figure DEST_PATH_GDA0000915652240000242
wherein U is a leaving group, and is halogen, hydroxyl, or the like.
Reacting the intermediate H-C1 with H-C2 in a suitable solvent in the presence of a suitable base at a suitable temperature for 30 minutes to 20 hours, usually 1 to 10 hours, to obtain an intermediate H-C3; H-C3 is reduced with red aluminum to obtain H-C4, which is disclosed in EP 1840128; H-C4 reacts with thionyl chloride to prepare H-C5, which is a conventional experimental method; H-C5 is reacted with sodium cyanide to obtain H-C6, the operation method of the step is shown in patents WO2007045989 and WO 2009115257; according to Journal of Organic Chemistry 71(21), 8023-8027; 2006. synthesis, (24), 4242-; finally, H-C7 is reduced by hydrogenation in the presence of a suitable catalyst, such as ammonia, to give the intermediate H-C, which can be prepared in accordance with the references j.am.chem.soc,70,3788 (1948); 82,681 (1960); 82,2386 (1960); chem, 49,2990 (1971); chem,37,335 (1972); organic Syntheses, Coll.Vol.3, p.229, p.720(1955), Vol.23, p.71(1943) or Vol.27, p.18 (1947). Suitable catalysts may be selected from raney nickel, palladium on carbon or platinum oxide and the like.
The intermediates were derived from: intermediates H-C1 and H-C2 are either commercially available or prepared according to conventional methods.
Suitable bases may be selected from, for example, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, pyridine, sodium methoxide, sodium ethoxide, sodium hydride, potassium tert-butoxide, sodium tert-butoxide, etc.
The reaction is carried out in a suitable solvent, which may be selected from, for example, tetrahydrofuran, 1, 4-dioxane, acetonitrile, toluene, xylene, benzene, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, acetone, or butanone.
The reaction temperature may be between room temperature and the boiling temperature of the solvent, and is generally from 20 to 100 ℃.
The reaction time is from 30 minutes to 20 hours, usually from 1 to 10 hours.
4)B＝-CH2CRaRbCRaRbThe preparation method comprises the following steps:
Figure DEST_PATH_GDA0000915652240000251
preparation of H-D1 reference Synthesis from H-C7, (9), 727-9; 1983 or Tetrahedron Letters,39(51), 9455-9456; 1998; the procedure for the preparation of H-D2 from H-D1 corresponds to B ═ CH 2-.
In the second case: when a ≠ H, it is prepared starting from the intermediate of a ≠ H, and the specific procedure is carried out as described in WO 2004093800A.
In the third case: when a ═ O or S, the preparation process is as described in patent WO 2012075917.
Although compounds of formula I, II or iii of the present invention are isothiazoles, as well as some of the compounds disclosed in the prior art, there are still significant differences in structural characteristics. And due to the structural difference, the compound has better bactericidal and/or insecticidal and acaricidal activity, and can be used for killing bacteria and/or insects and acaricidal activity at a small dosage.
The compounds of the general formula I, II or III show excellent activity to various germs in agriculture or other fields, and also show better activity to pest and acarid. Therefore, the technical scheme of the invention also comprises the application of the compounds of the general formula I, II or III in preparing bactericides, insecticides and acaricides in agriculture or other fields.
The examples of diseases mentioned below are intended only to illustrate the invention, but in no way limit it.
Compounds of formula I, II or III can be used to control the following diseases: 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, tomato black spot, tomato black spot, tomato black spot, tomato black spot, tomato, 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 spot, etc, 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. Particularly, the composition has good control effect on corn rust, rice blast, cucumber gray mold and cucumber downy mildew under lower dosage.
Compounds of formula I, II or III can be used to control the following pests: diamondback moth, armyworm, aphid and tetranychus cinnabarinus still have good control effect under lower dosage.
Owing to their positive properties, the abovementioned compounds can be used advantageously for protecting crops, domestic animals and breeding animals of agricultural and horticultural importance, as well as the environment in which humans are often exposed, against harmful germs, pests and mites.
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.
A dose of 10 g to 5 kg of compound per hectare provides adequate control.
The invention also comprises a bactericidal, insecticidal and acaricidal composition which takes the compound of the general formula I, II or III as an active component. The weight percentage of the active components in the composition for killing bacteria, insects and mites is between 0.5 and 99 percent. The composition also comprises a carrier acceptable in agriculture, forestry and sanitation.
The compositions of the present invention may be administered in the form of a formulation. The compounds of formula I, II or III as active ingredients are dissolved or dispersed in a carrier or formulated so as to be more easily dispersed for bactericidal, insecticidal use. For example: the chemical preparations can be prepared into wettable powder, oil suspension, water suspension, aqueous emulsion, aqueous solution or missible oil and the like. In these compositions, at least one liquid or solid carrier is added, and when necessary, a suitable surfactant may be added.
The technical scheme of the invention also comprises a method for preventing and controlling germs, pests and mites, which comprises the following steps: the sterilizing, insecticidal and acaricidal composition is applied to the pathogenic bacteria or the growth medium thereof. Preferably, an effective amount of 10 to 1000 grams per hectare is generally selected, with an effective amount of 20 to 500 grams per hectare being preferred.
For certain applications, for example in agriculture, one or more further fungicides, insecticides, herbicides, plant growth regulators or fertilizers and the like can be added to the fungicidal, insecticidal and acaricidal compositions according to the invention, whereby additional advantages and effects can be achieved.
It should be understood that various changes and modifications may be made within the scope of the present invention as defined by the claims.
Detailed Description
The following specific examples are intended to further illustrate the invention, but the invention is by no means limited to these examples. (all materials are commercially available unless otherwise noted)
Synthetic examples
Example 1: preparation of intermediate 6- (4-chlorophenoxy) -3-aminopyridine
1) Preparation of 6- (4-chlorophenoxy) -3-nitropyridine
Figure DEST_PATH_GDA0000915652240000271
10.0g (7.8mmol) of p-chlorophenol was added to a 250mL three-necked flask, and 50mL of DMF was added to dissolve it, followed by stirring at room temperature for 10min, then 2.3g (9.5mmol) of NaH was added, and stirring at room temperature was continued for 3 h. After stirring, adding 12.3g (7.8mmol) of 2-chloro-5-nitropyridine, slowly heating to 80 ℃, after TLC reaction is completed (about 3h), cooling to room temperature, adding 1000mL of water to precipitate a large amount of solid, performing suction filtration, and drying to obtain 16.8g of an off-white solid product, wherein the yield is as follows: 94 percent.1H-NMR (300MHz, internal standard TMS, solvent CDCl3)δ(ppm):7.02(d,1H),7.20(d,2H),7.60(d,2H),.8.41(dd,1H),8.90(d,1H).
2) Preparation of 6- (4-chlorophenoxy) -3-aminopyridine
Figure DEST_PATH_GDA0000915652240000272
Adding 2.0g (8.0mmol) of 6- (4-chlorophenoxy) -3-nitropyridine into a 150mL three-necked flask, adding 20mLAcOH, adding 1.37g (2.1mmol) of zinc powder in batches, reacting at room temperature for 3h, after the reaction is completed by TLC, suspending and distilling to remove the solvent, adding NaOH (5%) aqueous solution to adjust the pH to be neutral, extracting with 3X 20mL of ethyl acetate, and carrying out organic phase extractionWith anhydrous MgSO4Drying, rotary steaming, and performing column chromatography to obtain light red oily product 1.3g with yield of 81%.
Example 2: preparation of Compounds 4-7
Figure DEST_PATH_GDA0000915652240000273
Adding 0.5g (2.0mmol) of 6- (4-chlorophenoxy) -3-aminopyridine into a 100mL three-necked flask, adding 20mL of acetonitrile and 0.2g (2.4mmol) of triethylamine, then adding 0.5g (2.3mmol) of 3, 4-dichloroisothiazole acyl chloride in batches, heating for reflux reaction, after TLC finishes the reaction, removing the solvent by rotary evaporation, and carrying out column chromatography to obtain 0.7g of a light yellow solid product, namely a compound 4-7. The yield thereof was found to be 86%.1H-NMR (300MHz, internal standard TMS, solvent CDCl3)δ(ppm):7.01(d,1H), 7.09(d,2H),7.37(d,2H),8.16(dd,1H),8.31(s,1H),8.47(bs,1H).
Example 3: preparation of intermediate (6- (4-trifluoromethylphenoxy) pyridin-3-yl) methylamine
1) Preparation of 6- (4-trifluoromethylphenoxy) nicotinonitrile
Figure DEST_PATH_GDA0000915652240000281
103g (3.0mol) of 70% sodium hydride is added in portions to 350ml of N, N-dimethylformamide solution of 32.4g (0.2mol) of p-trifluoromethylphenol, the mixture is stirred and reacted for 4h at room temperature, then 27.7g (0.2mol) of 6-chloronicotinonitrile is added in portions, after the addition is finished, the reaction mixture is heated to 100 ℃ for reaction for 10h, after the TLC monitoring reaction is finished, the reaction solution is poured into water, extracted by ethyl acetate, washed by organic phase and saturated saline, dried, filtered, desolventized, and after the residue is cooled and solidified, filtered, washed by petroleum ether, and dried to obtain 42.0g of light brown solid, namely 6- (4-trifluoromethylphenoxy) nicotinonitrile.
2) Preparation of (6- (4-trifluoromethylphenoxy) pyridin-3-yl) methylamine
Figure DEST_PATH_GDA0000915652240000282
A mixture consisting of 2.64g (0.01mol) of 6- (4-trifluoromethylphenoxy) nicotinonitrile, Raney nickel (1.0g), 10ml of 25% ammonia water and 50ml of ethanol is stirred and reacted for 3 to 15 hours at room temperature in a hydrogen atmosphere, after the reaction is monitored by TLC, the Raney nickel is filtered, and the solvent is evaporated under reduced pressure to obtain 2.6g of light green viscous liquid, wherein the yield is 95.0 percent. A colorless oil.
Example 4: preparation of Compounds 16-22
Figure DEST_PATH_GDA0000915652240000283
Adding 0.5g (2.0mmol) of (6- (4-trifluoromethylphenoxy) pyridine-3-yl) methylamine into a 100mL three-necked bottle, adding 20mL of acetonitrile and 0.2g (2.4mmol) of triethylamine, then adding 0.5g (2.3mmol) of 3, 4-dichloroisothiazole acyl chloride in batches, heating for reflux reaction, removing the solvent by rotary evaporation after TLC reaction is finished, and performing column chromatography to obtain 0.7g of a light yellow solid product, namely a compound 16-22, a yellow solid with a melting point of 123.8 ℃. The yield thereof was found to be 86%.1H-NMR (300MHz, internal standard TMS, solvent CDCl3)δ(ppm):4.63(d,2H),7.00(d,1H),7.26(d,3H),7.66(d,2H),87.79(dd,1H),18(d,1H).
Example 5: preparation of Compound 46-2
Figure DEST_PATH_GDA0000915652240000284
Adding 0.2g (1.5mmol) of triethylamine into 10ml of acetonitrile solution of 0.3g (1.0mmol) of 2- (6- (4-chlorophenoxy) pyridin-3-yl) ethylamine (the specific synthesis method is shown in WO2014063642A1), adding 0.3g (1.2mmol) of 3, 4-dichloroisothiazole acyl chloride while stirring, heating to 80 ℃ after the addition is finished for reaction for 2h, performing desolventization after the TLC monitoring reaction is finished, and performing column chromatography on the residue (the eluent is ethyl acetate and petroleum ether (the boiling range is 60-90 ℃) and the volume ratio is 1: 2) to obtain 0.4g of a product, namely the compound 46-2, which is yellow oily liquid. Yield 91.0% as colorless oil.1H-NMR (300MHz, internal standard TMS,solvent CDCl3)δ(ppm):3.10(t,2H),3.85(q,2H),6.91(bs,1H),6.99(t,1H),7.05(dd,2H),7.33(d,2H),7.57(d,1H),8.08(d,1H).
Example 6: preparation of intermediate 4- (4-aminophenoxy) -3-fluorobenzonitrile
1) Preparation of 3-fluoro-4- (4-nitrophenoxy) benzonitrile
Figure DEST_PATH_GDA0000915652240000291
10.8g (78mmol) of p-nitrophenol are introduced into a 250mL three-necked flask, 50mL of DMF are added and dissolved, the mixture is stirred at room temperature for 10min, then 2.3g (95mmol) of NaH are added and stirring is continued at room temperature for 3 h. After stirring, adding 10.8g (78mmol) of 3, 4-difluorobenzonitrile, slowly heating to 80 ℃, after TLC reaction is completed (about 3h), cooling to room temperature, adding 1000mL of water, precipitating a large amount of solid, performing suction filtration, and drying to obtain 18.5g of a gray solid product, wherein the yield is as follows: 92 percent.1H-NMR (300MHz, internal standard TMS, solvent CDCl3)δ(ppm):3.71(bs,1H),6.72(d,2H),6.89(m,3H),.7.30(dd,1H),7.44(d,1H).
2) Preparation of intermediate 4- (4-aminophenoxy) -3-fluorobenzonitrile
Figure DEST_PATH_GDA0000915652240000292
Adding 2.1g (8.0mmol) of 3-fluoro-4- (4-nitrophenoxy) benzonitrile into a 150mL three-necked flask, adding 20mL of LAcOH, then adding 1.37g (2.1mmol) of zinc powder in portions, reacting at room temperature for 3h, after TLC reaction is completed, suspending to remove the solvent, adding NaOH (5%) aqueous solution to adjust pH to neutrality, extracting with 3X 20mL of ethyl acetate, and using anhydrous MgSO4Drying, rotary steaming and column chromatography to obtain light red oily product 1.5g, yield 83%.
Example 7: preparation of Compounds 76-13
Figure DEST_PATH_GDA0000915652240000293
Adding 0.2g (1.5mmol) of triethylamine into a solution of 0.2g (1.0mmol) of 4- (4-aminophenoxy) -3-fluorobenzonitrile in 10ml of acetonitrile, adding 0.3g (1.2mmol) of 3, 4-dichloroisothiazole acyl chloride with stirring, raising the temperature to 80 ℃ after the addition is finished, reacting for 2 hours, monitoring by TLC, performing desolventization, and purifying by using a residue column chromatography (an eluent is ethyl acetate and petroleum ether (the boiling range is 60-90 ℃) with the volume ratio of 1: 2) to obtain 0.3g of a product, namely a compound 76-13 which is a yellow solid and 122.6 ℃. Yield 91.0% as colorless oil.1H-NMR (300MHz, internal standard TMS, solvent CDCl3)δ(ppm):7.01(t,1H),7.11(d,2H),7.41(d,2H),7.69(d,2H),8.55(bs,1H).
Example 8: preparation of 1- (4- (2-chloro-4- (trifluoromethyl) phenoxy) phenyl) ethylamine
1) Preparation of 1- (4- (2-chloro-4- (trifluoromethyl) phenoxy) phenyl) ethanone
Figure DEST_PATH_GDA0000915652240000294
Adding 103g (3.0mol) of 70% sodium hydride into a solution of 19.6g (0.1mol) of 2-chloro-4-trifluoromethylphenol in 250ml of N, N-dimethylformamide, stirring at room temperature for reaction for 4h, then adding 30.8g (0.2mol) of 4-chloroacetophenone in batches, heating the reaction mixture to 100 ℃ after the addition is finished, reacting for 10h, after TLC monitoring reaction is finished, pouring the reaction solution into water, extracting with ethyl acetate, washing the organic phase with water, washing with saturated saline, drying, filtering, desolventizing, cooling and solidifying the residue, filtering, washing with petroleum ether, and airing to obtain 41.0g of light brown solid, namely 1- (4- (2-chloro-4- (trifluoromethyl) phenoxy) phenyl) ethanone.1H-NMR (300MHz, internal standard TMS, solvent CDCl3)δ(ppm):2.48(s,3H),6.75(d,1H),7.01(d,2H),7.38(d,1H),7.48(d,2H),7.95(d,2H).
2) Preparation of 1- (4- (2-chloro-4- (trifluoromethyl) phenoxy) phenyl) ethylamine
Figure DEST_PATH_GDA0000915652240000301
To a solution of 0.3g (1.0mmol) of 1- (4- (2-chloro-4- (trifluoromethyl) phenoxy) phenyl) ethanone in 10ml of methanol was added 0.4g (5mmol) of ammonium acetate, and NaBH was added under stirring in ice bath3CN 0.3g (5mmol), reacting at room temperature for 8h after the addition is finished, performing desolventizing after the TLC monitoring reaction is finished, and purifying the residue by column chromatography (eluent is ethyl acetate and petroleum ether (boiling range is 60-90 ℃) with the volume ratio of 1: 1) to obtain 0.2g of a colorless oily substance.1H-NMR (300MHz, internal standard TMS, solvent CDCl3)δ(ppm):,1.36(s,3H),3.98(q,1H),6.71(d,1H),6.78(d,2H),7.26(d,2H),7.29(d,1H),7.39(d,1H).
Example 9: preparation of Compounds 95-12
Figure DEST_PATH_GDA0000915652240000302
Adding 0.2g (1.5mmol) of triethylamine into a 10ml acetonitrile solution of 0.3g (1.0mmol) of 1- (4- (2-chloro-4- (trifluoromethyl) phenoxy) phenyl) ethylamine, adding 0.3g (1.2mmol) of 3, 4-dichloroisothiazole acyl chloride with stirring, heating to 80 ℃ after the addition is finished, reacting for 2h, monitoring by TLC, performing desolventization, and purifying by using residue column chromatography (eluent is ethyl acetate and petroleum ether (boiling range is 60-90 ℃) with the volume ratio of 1: 2) to obtain 0.4g of a product, namely 95-12 of a compound, a white solid, 98.6 ℃. Yield 91.0% as colorless oil.1H-NMR (300MHz, internal standard TMS, solvent CDCl3)δ(ppm):1.60(s,3H),5.29(q,1H),6.93(d,1H),7.03(d,2H),7.09(d,3H),7.72(d,1H),8.21(bs,1H).
Example 10: preparation of intermediate (2- (3-trifluoromethylphenoxy) pyridin-3-yl) methylamine
1) Preparation of 2- (3-trifluoromethylphenoxy) nicotinonitrile
Figure DEST_PATH_GDA0000915652240000303
103g (3.0mol) of 70% sodium hydride is added in portions to 350ml of N, N-dimethylformamide solution of 32.4g (0.2mol) of m-trifluoromethylphenol, the mixture is stirred and reacted for 4h at room temperature, then 27.7g (0.2mol) of 2-chloronicotinonitrile is added in portions, after the addition is finished, the reaction mixture is heated to 100 ℃ for reaction for 10h, after the TLC monitoring reaction is finished, the reaction solution is poured into water, extracted by ethyl acetate, washed by organic phase and saturated saline, dried, filtered, desolventized, and after the residue is cooled and solidified, filtered, washed by petroleum ether, and dried to obtain 42.0g of light brown solid, namely the 2- (3-trifluoromethylphenoxy) nicotinonitrile.
2) Preparation of (2- (3-trifluoromethylphenoxy) pyridin-3-yl) methylamine
Figure DEST_PATH_GDA0000915652240000311
A mixture consisting of 2.64g (0.01mol) of 2- (3-trifluoromethylphenoxy) nicotinonitrile, Raney nickel (1.0g), 10ml of 25% ammonia water and 50ml of ethanol is stirred and reacted for 3 to 15 hours at room temperature in a hydrogen atmosphere, after TLC monitoring reaction is finished, Raney nickel is filtered, and a solvent is evaporated under reduced pressure to obtain 2.6g of light green viscous liquid, wherein the yield is 95.0 percent. A colorless oil.
Example 11: preparation of Compound 113-8
Figure DEST_PATH_GDA0000915652240000312
Adding 0.5g (2.0mmol) (2- (3-trifluoromethylphenoxy) pyridine-3-yl) methylamine into a 100mL three-necked flask, adding 20mL acetonitrile and 0.2g (2.4mmol) triethylamine, then adding 0.5g (2.3mmol)3, 4-dichloroisothiazole acyl chloride in batches, heating for reflux reaction, after TLC is completed, removing the solvent by rotary evaporation, and performing column chromatography to obtain 0.7g of a light yellow solid product, namely a compound 113-8, a white solid, 105.7 ℃. The yield thereof was found to be 86%.1H-NMR (300MHz, internal standard TMS, solvent CDCl3)δ(ppm):4.60(d,2H),7.02(d,1H),7.27(d,3H),7.68(d,2H),7.80(dd,1H),8.17(d,1H).
Example 12: preparation of intermediate 2- (6- (4-chlorophenoxy) pyridin-2-yl) ethylamine
1) Preparation of methyl 2- (4-chlorophenoxy) nicotinate
Figure DEST_PATH_GDA0000915652240000313
103g (3.0mol) of 70% sodium hydride is added in batches to a solution of 25.6g (0.2mol) of p-chlorophenol in 350ml of N, N-dimethylformamide, the mixture is stirred and reacted for 4h at room temperature, then 34.2g (0.2mol) of methyl 2-chloronicotinate is added in batches, after the addition is finished, the reaction mixture is heated to 100 ℃ for reaction for 10h, after the TLC monitoring reaction is finished, the reaction solution is poured into water, extracted by ethyl acetate, washed by organic phase and saturated saline, dried, filtered, desolventized, and after the residue is cooled and solidified, filtered, washed by petroleum ether, and dried to obtain 42.0g of light brown solid, namely methyl 2- (4-chlorophenoxy) nicotinate. A white solid. Melting point: 125.8 ℃.1H-NMR (300MHz, internal standard TMS, solvent CDCl3)δ(ppm):3.95(3H,s),7.10(2H,d),7.37(2H,d),8.26(2H,d).
2) Preparation of (2- (4-chlorophenoxy) pyridin-3-yl) methanol
Figure DEST_PATH_GDA0000915652240000314
Adding 74.5g (0.24mol) of 65% red aluminum toluene solution into 500ml of anhydrous ether solution of 52.6g (0.2mol) of 2- (4-chlorophenoxy) methyl nicotinate at 0 ℃, stirring for reaction at room temperature for 4h after adding, then adding 10% sodium hydroxide solution prepared in advance dropwise at 0 ℃ until the reaction mixture becomes clear, then heating to 35 ℃ for reaction for 2h, pouring the reaction solution into water after monitoring the reaction by TLC, extracting with toluene, washing with water, washing with saturated salt water, drying, filtering, desolventizing, and purifying by residue column chromatography (eluent is ethyl acetate and petroleum ether (boiling range is 60-90 ℃) at a volume ratio of 1:3) to obtain 42.2g of (2- (4-chlorophenoxy) pyridin-3-yl) methanol. A brown solid. Melting point: 95.1 ℃.1H-NMR (300MHz, internal standard TMS, solvent CDCl3)δ(ppm):2.21(1H,bs),4.83(2H,s),7.04(1H,d),7.08(2H,d),7.37(2H,d),7.79(1H,t),8.07(1H,d).
3) Preparation of 3-chloromethyl-2- (4-chlorophenoxy) pyridine
Figure DEST_PATH_GDA0000915652240000321
Adding 17.9g (0.2mol) of thionyl chloride dropwise into a solution of 23.5g (0.1mol) of (6- (4-chlorophenoxy) pyridin-2-yl) methanol in 350ml of dichloromethane at 0 ℃, stirring the mixture at room temperature for 4 hours after the addition is finished, distilling off excessive thionyl chloride under reduced pressure after TLC monitoring reaction is finished, adding water into the residue, extracting the residue with ethyl acetate, washing the organic phase with water, washing with saturated sodium bicarbonate, washing with saturated saline, drying, filtering and desolventizing to obtain 22.8g of a product, namely 3-chloromethyl-2- (4-chlorophenoxy) pyridine. A pale yellow solid. Melting point: 51.1 ℃.1H-NMR (300MHz, internal standard TMS, solvent CDCl3)δ(ppm):4.74(2H,s),7.04(2H,dd),7.10(1H,d),7.37(2H,d),7.80(1H,d),8.10(1H,d).
4) Preparation of 2- (2- (4-chlorophenoxy) pyridin-3-yl) acetonitrile
Figure DEST_PATH_GDA0000915652240000322
Dissolving 2.7g (55mmol) of sodium cyanide in 300ml of dimethyl sulfoxide at 40 ℃, adding 13.9g (50mmol) of 6-chloromethyl-2- (4-chlorophenoxy) pyridine, adding a catalytic amount of 18-crown-6, heating the reaction mixture to 80 ℃ for reaction for 2 hours, after the TLC monitoring reaction is finished, pouring the reaction liquid into water, extracting with toluene, washing the organic phase with water, washing with saturated salt water, drying, filtering, desolventizing, and carrying out column chromatography on the residue (the eluent is ethyl acetate and petroleum ether (the boiling range is 60-90 ℃) at a volume ratio of 1:3) to purify to obtain 11.2g of the product, namely 2- (2- (4-chlorophenoxy) pyridin-3-yl) acetonitrile. A white solid.1H-NMR (300MHz, internal standard TMS, solvent CDCl3)δ(ppm):3.86(2H,s),7.05(1H,d),7.08(2H,d),7.38(2H,d),7.82(1H,d),8.11(1H,d).
5) Preparation of 2- (2- (4-chlorophenoxy) pyridin-3-yl) ethylamine
Figure DEST_PATH_GDA0000915652240000323
A mixture consisting of 2.4g (0.01mol) of 2- (2- (4-chlorophenoxy) pyridine-3-yl) acetonitrile, Raney nickel (1.0g), 10ml of 25% ammonia water and 50ml of ethanol is stirred and reacted for 3 to 15 hours at room temperature under hydrogen atmosphere, after TLC monitoring reaction is finished, Raney nickel is filtered, and the solvent is evaporated under reduced pressure to obtain 2.3g of light green viscous liquid, wherein the yield is 95.0%. A pale green oil.1H-NMR (300MHz, internal standard TMS, solvent CDCl3)δ(ppm):1.46(2H,bs),2.94(2H,t),3.08(2H,t),6.53(1H,d),7.35(1H,d),7.40(1H,dd),7.48(2H,dd),7.61(2H,dd).
Example 13: preparation of Compound 123-2
Figure DEST_PATH_GDA0000915652240000331
Adding 0.2g (1.5mmol) of triethylamine into a 10ml acetonitrile solution of 0.3g (1.0mmol) of 2- (2- (4-chlorophenoxy) pyridin-3-yl) ethylamine, adding 0.3g (1.2mmol) of 3, 4-dichloroisothiazole acyl chloride under stirring, heating to 80 ℃ after the addition is finished, reacting for 2 hours, monitoring the reaction by TLC, desolventizing, and purifying by residue column chromatography (eluent is ethyl acetate and petroleum ether (boiling range is 60-90 ℃) with the volume ratio of 1: 2) to obtain 0.4g of a product, namely the compound 123-2, a white solid, 113.6 ℃. Yield 91.0% as colorless oil.1H-NMR (300MHz, internal standard TMS, solvent CDCl3)δ(ppm):3.08(t,2H),3.86(q,2H),6.91(bs,1H),6.99(t,1H),7.04(d,2H),7.35(d,2H),7.59(d,1H),8.06(d,1H).
Example 14: preparation of intermediate 2- (4- (4-chlorophenoxy) pyridin-4-yl) ethylamine
1) Preparation of methyl 2- (4-chlorophenoxy) isonicotinate
Figure DEST_PATH_GDA0000915652240000332
To a solution of 25.6g (0.2mol) of p-chlorophenol in 350ml of N, N-dimethylformamide were added 103g (3.0mol) of 70% sodium hydride in portions, and the reaction was stirred at room temperatureAnd 4h, adding 34.2g (0.2mol) of 2-chloroisonicotinic acid methyl ester in batches, heating the reaction mixture to 100 ℃ for reaction for 10h, after the TLC monitoring reaction is finished, pouring the reaction liquid into water, extracting with ethyl acetate, washing the organic phase with water, washing with saturated saline water, drying, filtering, desolventizing, cooling and solidifying the residue, filtering, washing with petroleum ether, and drying to obtain a light brown solid 42.0g, namely 2- (4-chlorophenoxy) isonicotinic acid methyl ester. Melting point: and (4) 64-66 ℃.1H-NMR (300MHz, internal standard TMS, solvent CDCl3)δ(ppm):1.41(3H,t),4.43(2H,q),7.08(2H,d),7.15(2H,d),7.37(1H,d),7.56(1H,d),8.29(1H,d).
2) Preparation of (2- (4-chlorophenoxy) pyridin-4-yl) methanol
Figure DEST_PATH_GDA0000915652240000333
Adding 74.5g (0.24mol) of 65% red aluminum toluene solution into 500ml of anhydrous ether solution of 52.6g (0.2mol) of methyl 2- (4-chlorophenoxy) isonicotinate at 0 ℃, stirring for reaction at room temperature for 4h after adding, then adding 10% sodium hydroxide solution prepared in advance dropwise at 0 ℃ until the reaction mixture becomes clear, then heating to 35 ℃ for reaction for 2h, pouring the reaction solution into water after monitoring the reaction by TLC, extracting with toluene, washing with water, washing with saturated salt water, drying, filtering, desolventizing, and purifying by residue column chromatography (eluent is ethyl acetate and petroleum ether (boiling range is 60-90 ℃) at volume ratio of 1:3) to obtain 42.2g of (2- (4-chlorophenoxy) pyridin-4-yl) methanol. A yellow liquid.1H-NMR (300MHz, internal standard TMS, solvent CDCl3)δ(ppm):3.95(bs,1H),4.70(s,2H),6.87(d,1H),6.98(d,1H),7.14(d,2H),7.34(d,2H),8.11(d,1H).
3) Preparation of 4-chloromethyl-2- (4-chlorophenoxy) pyridine
Figure DEST_PATH_GDA0000915652240000334
23.5g (0.1mol) of (2- (4-chlorophenoxy) pyridin-4-yl)Adding 17.9g (0.15mol) of thionyl chloride dropwise into 350ml of methanol solution in dichloromethane, stirring at room temperature for reaction for 4 hours after the addition is finished, distilling off excessive thionyl chloride under reduced pressure after TLC monitoring reaction is finished, adding water into residue, extracting with ethyl acetate, washing organic phase with water, saturated sodium bicarbonate, saturated saline, drying, filtering, and desolventizing to obtain 22.8g of product, namely 4-chloromethyl-2- (4-chlorophenoxy) pyridine. A white solid. Melting point: 78-80 ℃.1H-NMR (300MHz, internal standard TMS, solvent CDCl3)δ(ppm):4.59(2H,s),6.96(1H,d),7.17(2H,d),7.33(1H,d),7.46(2H,d),8.40(1H,s).
4) Preparation of 2- (2- (4-chlorophenoxy) pyridin-4-yl) acetonitrile
Figure DEST_PATH_GDA0000915652240000341
Dissolving 2.7g (55mmol) of sodium cyanide in 300ml of dimethyl sulfoxide at 40 ℃, adding 13.9g (50mmol) of 4-chloromethyl-2- (4-chlorophenoxy) pyridine, adding a catalytic amount of 18-crown-6, heating the reaction mixture to 80 ℃ for reaction for 2 hours, after the TLC monitoring reaction is finished, pouring the reaction liquid into water, extracting with toluene, washing the organic phase with water, washing with saturated salt water, drying, filtering, desolventizing, and carrying out column chromatography on the residue (the eluent is ethyl acetate and petroleum ether (the boiling range is 60-90 ℃) at a volume ratio of 1:3) to obtain 11.2g of a product, namely 2- (2- (4-chlorophenoxy) pyridin-4-yl) acetonitrile. A white solid.1H-NMR (300MHz, internal standard TMS, solvent CDCl3)δ(ppm):3.77(2H,s),6.94(1H,d),7.01(1H,d),7.09(2H,d),7.38(2H,d),8.17(1H,s).
5) Preparation of 2- (2- (4-chlorophenoxypyridin-4-yl) ethylamine
Figure DEST_PATH_GDA0000915652240000342
A mixture of 2.4g (0.01mol) of 2- (2- (4-chlorophenoxy) pyridin-4-yl) acetonitrile, Raney nickel (1.0g), 10ml of 25% ammonia water and 50ml of ethanol was stirred under hydrogen at room temperature for 3-15 hours, and after completion of the TLC monitoring reaction, the mixture was filteredRaney nickel is removed, and the solvent is distilled off under reduced pressure to obtain 2.3g of reddish brown viscous liquid, with the yield of 95.0%. Brown oil.1H-NMR (300MHz, internal standard TMS, solvent CDCl3)δ(ppm):1.46(2H,bs),2.70(2H,t),2.94(2H,t),6.87(1H,d),7.07(2H,dd),7.34(2H,dd),7.55(1H,dd),8.02(1H,d).
Example 15: preparation of Compound 103-2
Figure DEST_PATH_GDA0000915652240000343
Adding 0.2g (1.5mmol) of triethylamine into a 10ml acetonitrile solution of 0.3g (1.0mmol) of 2- (2- (4-chlorophenoxy) pyridin-4-yl) ethylamine, adding 0.3g (1.2mmol) of 3, 4-dichloroisothiazole acyl chloride with stirring, heating to 80 ℃ after the addition is finished, reacting for 2h, monitoring the reaction by TLC, performing desolventization, and purifying by residue column chromatography (eluent is ethyl acetate and petroleum ether (the boiling range is 60-90 ℃) at the volume ratio of 1: 2) to obtain 0.4g of a product, namely the compound 103-2, which is a yellow oily liquid. Yield 91.0% as colorless oil.1H-NMR (300MHz, internal standard TMS, solvent CDCl3)δ(ppm):3.07(t,2H),3.85(q,2H),6.90(bs,1H),6.96(t,1H),7.04(d,2H),7.34(d,2H),7.61(d,1H),8.07(d,1H).
Other compounds of the invention may be prepared by reference to the above examples.
Physical property data and nuclear magnetic data of some of the compounds (1HNMR, 300MHz, internal standard TMS, ppm) as follows:
4-7 (pink solid, 124.0 ℃): δ 7.01(d,1H),7.09(d,2H),7.37(d,2H),8.16(dd,1H),8.31(s,1H),8.47(bs,1H).
16-1 (yellow solid, 102.7 ℃): δ 4.63(d,2H),7.13(t,1H),7.22(t,1H),7.41(d,2H),7.73(dd,1H),8.19(d,1H).
16-6 (yellow oily liquid): δ 4.62(d,2H),6.94(d,1H),7.06(d,1H),7.35(d,2H),7.40(d,2H),7.74(d,1H),8.16(d,1H).
16-22 (white solid, 118.9 ℃): δ 4.63(d,2H),6.95(d,1H),7.08(d,1H),7.36(d,2H),7.41(d,2H),7.75(d,1H),8.16(d,1H).
16-22 (yellow solid, 123.8 ℃): δ 4.63(d,2H),8.18(d,1H),7.00(d,1H),7.26(d,3H),7.66(d,2H), 7.79(dd,1H).
16-82 (white solid, 116.4 ℃): δ 4.63(d,2H),7.03(d,1H),7.15(d,2H),7.30(q,1H),7.48(d,1H),7.78(dd,1H),8.10(d,1H).
16-121 (yellow oily liquid): δ 4.62(d,2H),8.15(d,1H),7.01(d,1H),7.25(d,3H),7.67(d,2H),7.81(dd,1H).
28-4 (yellow solid, 108.4 ℃): δ 1.65(d,3H),5.29(q,1H),6.93(d,1H),7.03(d,1H),7.15(t,4H),7.71(dd,1H),8.20(s,1H).
46-2 (yellow oily liquid): δ 3.10(t,2H),3.85(q,2H),6.91(bs,1H),6.99(t,1H),7.05(dd,2H),7.33(d,2H),7.57(d,1H),8.08(d,1H).
46-8 (white solid, 146.8 ℃): δ 3.08(t,2H),3.82(q,2H),6.92(bs,1H),6.95(t,1H),7.06(d,2H),7.36(d,2H),7.63(dd,1H),8.06(d,1H).
46-14 (yellow oily liquid): δ 3.08(t,2H),3.87(q,2H),5.33(bs,1H),6.95(d,1H),7.08(t,1H),7.10(d,1H),7.41(m,2H),7.60(d,1H),8.09(t,1H).
76-13 (yellow solid, 122.6 ℃): δ 7.01(t,1H),7.11(d,2H),7.41(d,2H),7.69(d,2H),8.55(bs,1H).
95-12 (white solid, 98.6 ℃): δ 1.60(s,3H),5.29(q,1H),6.93(d,1H),7.03(d,2H),7.09(d,3H),7.72(d,1H),8.21(bs,1H).
103-2：δ3.07(t,2H),3.85(q,2H),6.90(bs,1H),6.96(t,1H),7.04(d,2H),7.34(d,2H),7.61(d,1H),8.07(d,1H).
113-8 (white solid, 105.7 ℃): δ 4.60(d,2H),8.17(d,1H),7.02(d,1H),7.27(d,3H),7.68(d,2H),7.80(dd,1H).
113-15 (white solid, 129.1 ℃): δ 4.65(d,2H),7.01(d,1H),7.25(d,3H),7.64(d,2H),7.77(dd,1H),8.17(d,1H).
113-16 (yellow solid, 119.7 ℃): δ 4.81(d,2H),7.06(d,1H),7.25(d,2H),7.64(s,1H),7.80(d,1H),8.08(d,1H).
123-1 (yellow oily liquid): δ 3.10(t,2H),3.87(q,2H),5.30(bs,1H),6.97(d,1H),7.09(q,2H),7.12(d,1H),7.42(m,2H),7.60(dd,1H),8.08(t,1H).
123-2 (white solid, 113.6 ℃): δ 3.08(t,2H),3.86(q,2H),6.91(bs,1H),6.99(t,1H),7.04(d,2H),7.35(d,2H),7.59(d,1H),8.06(d,1H).
Examples of measurement of biological Activity
The compound of the invention has good activity on various germs in the agricultural field and also has good insecticidal and acaricidal activity.
Example 16: measurement of fungicidal Activity
The compound sample of the invention is used for carrying out in vitro bacteriostatic activity or in vivo protection effect tests on various fungal diseases of plants. The results of the bactericidal activity measurements are given in the examples below.
(1) In vitro determination of bacteriostatic activity
The measurement method is as follows: the high-throughput screening method is adopted, i.e. a compound sample to be detected is dissolved by using a proper solvent (the type of the solvent is acetone, methanol, DMF, and the like, and is selected according to the dissolving capacity of the solvent on the sample), and a liquid to be detected with the required concentration is prepared. 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.
The results of the in vitro bacteriostatic activity (expressed as inhibition) test of some compounds are as follows:
inhibition rate of Pyricularia oryzae:
when the concentration of the liquid medicine is 25mg/L, the inhibition rate of the compounds 4-7, 16-1, 16-22, 28-4, 46-2, 103-2 and the like is 100 percent; when the concentration of the liquid medicine is 8.3mg/L, the inhibition rate of the compounds 4-7 and the like is 100 percent; the inhibition rate of the compounds 4-7, etc. was 100% at a drug solution concentration of 2.8 mg/L.
(2) Living body protecting Activity assay
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).
The results of the in vivo protective activity test of some compounds are as follows:
the in vivo control effect on cucumber downy mildew is as follows:
when the concentration of the liquid medicine is 400mg/L, the control effects of the compounds 4-7, 16-22, 16-121, 46-14, 123-2 and the like are all 100 percent, and the control effect of the compounds 113-16 and the like is 98 percent;
when the concentration of the liquid medicine is 100mg/L, the control effect of the compounds 4-7 and the like reaches 100 percent.
In-vivo control of corn rust:
when the concentration of the liquid medicine is 400mg/L, the control effect of the compounds 4-7 and the like is 100 percent, and the control effect of the compounds 16-1 and the like is more than 80 percent.
The in vivo control effect on cucumber anthracnose is as follows:
when the concentration of the liquid medicine is 400mg/L, the control effect of the compounds 16-1, 16-7, 16-22, 16-82, 16-121, 46-2, 46-8, 46-14, 103-2, 113-8, 113-15, 123-1 and the like is 100 percent, and the control effect of the compounds 16-6, 28-4, 95-12 and the like is 98 percent;
when the concentration of the liquid medicine is 100mg/L, the control effect of the compounds 16-1, 16-7, 16-22, 103-2 and the like is 100 percent, the control effect of the compounds 46-2 and the like is 95 percent, and the control effect of the compounds 16-6 and the like is 85 percent;
when the concentration of the liquid medicine is 25mg/L, the control effect of the compound 16-7 and the like is 98 percent, the control effect of the compound 16-22 and the like is 95 percent, and the control effect of the compound 16-1 and the like is 90 percent;
when the concentration of the liquid medicine is 6.25mg/L, the control effect of the compound 16-7 and the like is 90 percent, the control effect of the compound 16-1 and the like is 85 percent, and the control effect of the compound 16-22 and the like is 80 percent;
when the concentration of the liquid medicine is 3.13mg/L, the control effect of the compounds 16-7 and the like is 90 percent.
TABLE 147 in vitro inhibitory Activity on Rice blast
Figure DEST_PATH_GDA0000915652240000361
TABLE 148 in vivo protective Activity against cucumber downy mildew
Figure DEST_PATH_GDA0000915652240000362
Figure DEST_PATH_GDA0000915652240000371
TABLE 149 in vivo protective Activity against corn rust
Figure DEST_PATH_GDA0000915652240000372
TABLE 150 Activity for cucumber anthracnose in vivo protection
Figure DEST_PATH_GDA0000915652240000373
Example 17: acaricidal Activity assay
After dissolving a test compound in a mixed solvent of acetone/methanol (1: 1), the test compound was diluted with water containing 0.1% (wt) Tween 80 to a desired concentration. The insecticidal activity is determined by taking tetranychus cinnabarinus as a target and adopting an airrbrush spraying method. The specific determination method comprises the following steps: collecting two bean seedlings of true leaf vegetable, inoculating Tetranychus cinnabarinus, examining the base number, and treating with airrbrush sprayer under 10psi (about 0.7 kg/cm)2) The amount of the sprayed liquid was 5 ml. Each treatment was repeated 3 times, and after treatment, the treated mites were placed in a standard observation room, and after 72 hours, the number of live mites was investigated, and the mortality was calculated.
Partial test results on tetranychus cinnabarinus are as follows:
when the concentration of the liquid medicine is 600mg/L, the lethality of the compounds 16-22, 28-4 and the like to tetranychus cinnabarinus is 100 percent.

Claims (5)

1. An isothiazole compound characterized in that: the compound has the following structure
Compounds having the structure shown in I-A, I-B, I-C, II-A, III-A and III-B:
Figure FDA0003311161350000011
in the general formula I-A, I-B, I-C, II-A, III-A or III-B
R1、R2、R3、R4、R5Can be the same or different and are respectively selected from hydrogen, halogen, cyano, nitro and C1-C4Alkyl, halo C1-C4Alkyl radical, C1-C4Alkoxy or halo C1-C4An alkoxy group;
R6、R6'、R7can be the same or different and are respectively selected from hydrogen, halogen or C1-C4An alkyl group;
R8selected from halogen, C1-C4Alkyl or halo C1-C4An alkyl group;
R9selected from halogen or C1-C4An alkyl group;
a is selected from hydrogen;
Ra、Rbselected from hydrogen.
2. The compound of claim 1, wherein:
in the general formula I-A, I-B, I-C, II-A, III-A or III-B
R1、R2、R3、R4、R5Can be the same or different and are respectively selected from hydrogen, halogen, cyano, nitro and C1-C4Alkyl, halo C1-C2Alkyl radical, C1-C4Alkoxy or halo C1-C2An alkoxy group;
R6、R6'、R7can be the same or different and are respectively selected from hydrogen, halogen or C1-C4An alkyl group;
R8selected from halogen, C1-C2Alkyl or halo C1-C2An alkyl group;
R9selected from halogen or C1-C2An alkyl group;
a is selected from hydrogen;
Ra、Rbselected from hydrogen.
3. The compound of claim 2, wherein:
in the general formula I-A, I-B, I-C, II-A, III-A or III-B
R1、R2、R3、R4、R5Can be the same or different and are respectively selected from hydrogen, halogen, cyano, nitro and C1-C4Alkyl, halo C1-C2Alkyl radical, C1-C4An alkoxy group;
R6、R6'、R7selected from hydrogen;
R8selected from halogens;
R9selected from halogens;
a is selected from hydrogen;
Ra、Rbselected from hydrogen.
4. The use of the compounds of general formula I-A, I-B, I-C, II-A, III-a or III-B according to claim 1 for the preparation of fungicide, insecticide and acaricide in agriculture, forestry or in the hygiene sector.
5. The bactericidal, insecticidal and acaricidal composition is characterized by comprising the following components in parts by weight: contains the compound of the general formula I-A, I-B, I-C, II-A, III-A or III-B as claimed in claim 1 as an active ingredient, wherein the weight percentage of the active ingredient in the composition is 0.5-99%.
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