Thiadiazole isoxazoline compound, preparation method and application thereof, and herbicide

文档序号：1884176 发布日期：2021-11-26 浏览：16次中文

阅读说明：本技术 一种噻二唑异噁唑啉类化合物及其制备方法和应用、一种除草剂 (Thiadiazole isoxazoline compound, preparation method and application thereof, and herbicide ) 是由席真张瑞波王大伟于淑一于 2020-05-20 设计创作，主要内容包括：本发明涉及农药领域,公开了一种噻二唑异噁唑啉类化合物及其制备方法和应用、一种除草剂,该噻二唑异噁唑啉类化合物具有式(I)所示的结构。本发明的噻二唑异噁唑啉类化合物具有很好的除草活性；同时,本发明的噻二唑异噁唑啉类化合物具有很高的作物安全性,尤其是对于玉米和小麦等关键农作物具有良好的选择性,能够在保证作物安全生长的前提下,有效去除作物田间的杂草。(The invention relates to the field of pesticides, and discloses a thiadiazole isoxazoline compound, a preparation method and application thereof, and a herbicide. The thiadiazole isoxazoline compound has good herbicidal activity; meanwhile, the thiadiazole isoxazoline compound has high crop safety, particularly has good selectivity on key crops such as corn, wheat and the like, and can effectively remove weeds in crop fields on the premise of ensuring safe growth of crops.)

1. A thiadiazole isoxazoline compound is characterized in that the thiadiazole isoxazoline compound has a structure shown in a formula (I),

wherein, in the formula (I),

R₁、R₂、R₃、R₄each independently selected from H, halogen, -CN, C₁-C₆Alkyl group of (C)₁-C₆Haloalkyl) -O-, (C)₁-C₆Alkyl) -SO of₂-；

R₅Selected from H, -CN, C₁-C₆Alkyl of (C)₁-C₈A haloalkyl group of (a);

R₆selected from H, -CN, C₁-C₆Alkyl of (C)₁-C₈A haloalkyl group of (a);

R₇、R₈each independently selected from H, -CN, C₁-C₆Alkyl of (C)₁-C₆Haloalkyl, -CO-OR₉、-CH₂OR₁₀、-CONR₁₁R₁₂Phenyl, benzyl and (C)₁-C₆Alkyl group of (A) O-, (C)₁-C₆Haloalkyl) -O-, (C)₃-C₆Alkenyl group of (A) O-, (C)₃-C₆Alkynyl) -O-; alternatively, the first and second electrodes may be,

R₆and R₇Are linked together by at least one atom selected from O and S to form a five-membered ringOr a six-membered ring;

R₉selected from H, C₁-C₆Alkyl of (C)₁-C₆Halogenoalkyl of, C₃-C₆Alkenyl of, C₃-C₆Alkynyl (C)₁-C₆Alkyl) -O- (C of₁-C₆Alkyl of (C) -, (C)₁-C₆Alkyl) -CO-O- (C)₁-C₄Alkyl group of (C), (C)₁-C₆Alkyl) -CO-NH- (C)₁-C₄Alkyl of (2), benzyl, having 1 to 4 substituents R¹A benzyl group of,

Each of said substituents R¹Each independently selected from: halogen, -CN, -NO₂、C₁-C₈Alkyl of (C)₁-C₈Haloalkyl of (A), (B), (C)₁-C₈Alkyl group of (A) O-, (C)₁-C₈Haloalkyl) -O-, (C)₁-C₈Alkyl group of (A) O-CO-, (C)₁-C₈Alkyl group of (a) - (C) — S —, (C)₁-C₈Alkyl) -SO of₂-；

R₁₃And R₁₄Not H at the same time; and R is₁₃、R₁₄Each independently selected from the group I_15/16: H. -CN, halogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₁-C₁₀Alkoxy, substituted or unsubstituted C₃-C₁₀Substituted or unsubstituted C containing 0 to 3 heteroatoms selected from at least N, O and S₅-C₁₀Aryl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted-CO- (C)₁-C₁₂Alkyl of (a) -, substituted or unsubstituted- (C)₁-C₅Alkyl) -CO- (C)₁-C₅Alkyl of (a) -, substituted or unsubstituted- (C)₁-C₃Ester group of (1) - (C)₁-C₃Alkyl group of (a),group I_15/16Wherein the substituents optionally present are selected from one or more of halogen, nitro, cyano and amino; alternatively, the first and second electrodes may be,

R₁₃and R₁₄Are respectively selected from the group I_15/16And are connected together to form a ring;

R₁₀selected from H, C₁-C₆Alkyl of (C)₁-C₆Haloalkyl of (A), (B), (C)₁-C₆Alkyl group of (A) O-CO-, (C)₁-C₆Alkyl group of (2) - (C)₁-C₆Haloalkyl) -CO-, (C)₃-C₆Cycloalkyl) -CO-, (C)₃-C₆Halocycloalkyl) -CO-, (C)₁-C₆Alkyl) -SO of₂-、(C₁-C₆Haloalkyl) -SO of₂-、(C₁-C₆Alkyl) -NH-SO of₂-、(C₁-C₆Alkyl of (2)₂-N-SO₂-、(C₁-C₆Alkyl) -NH-CO-, (C)₁-C₆Alkyl of (2)₂-N-CO-、(C₁-C₆Alkyl of (2)₂-N-CS-、(C₁-C₆Alkyl) -S- (C of₂-C₆Alkyl) -CO-, phenyl with 1-4 substituents R²Phenyl and phenyl- (C)₁-C₂Alkyl group of (a) -, with 1-4 substituents R³Phenyl- (C)₁-C₂Alkyl of (2) -, phenyl- (C)₂-C₄Alkenyl) with 1-4 substituents R⁴Phenyl- (C)₂-C₄Alkenyl of (a), phenyl-CO-, with 1-4 substituents R⁵phenyl-CO-, phenyl- (C)₁-C₂Alkyl) -CO-having 1-4 substituents R⁶Phenyl- (C)₁-C₂Alkyl) -CO-, phenyl-O- (C)₁-C₂Alkyl) -CO-having 1-4 substituents R⁷phenyl-O- (C)₁-C₂Alkyl) -CO-, phenyl- (C)₂-C₄Alkenyl) -CO-having 1-4 substituents R⁸Phenyl- (C)₂-C₄Alkenyl) -CO-, heteroaryl having 1-4 substituents R⁹Heteroaryl, heteroaryl- (C) of₁-C₂Alkyl group of (a) -, with 1-4 substituents R¹⁰Heteroaryl of (A) - (C)₁-C₂Alkyl) -, heteroaryl-CO-or with 1-4 substituents R¹¹heteroaryl-CO-of said substituent R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰And R¹¹Each independently selected from halogen, -CN, -NO₂、C₁-C₄Alkyl of (C)₁-C₄Haloalkyl of (A), (B), (C)₁-C₄Alkyl group of (A) O-, (C)₁-C₄Haloalkyl) -O-, (C)₁-C₄Alkyl group of (A) O-CO-, (C)₁-C₄Alkyl group of (a) - (C) — S —, (C)₁-C₄Alkyl) -SO of₂-, phenyl-O-, having 1 to 4 substituents R₁₂phenyl-O-of said substituent R¹²Selected from halogen, -CN, -NO₂、C₁-C₄Alkyl of (C)₁-C₄Haloalkyl of (A), (B), (C)₁-C₄Alkyl group of (A) O-, (C)₁-C₄Haloalkyl) -O-;

R₁₁、R₁₂each independently selected from H, C₁-C₆Alkyl of (C)₁-C₆Halogenoalkyl of, C₁-C₆Alkenyl of, C₁-C₆Alkynyl (C)₁-C₆Alkyl) -O-CO- (C)₁-C₆Alkyl of (b) -, -SO₂-(C₁-C₆Alkyl of (b), -SO)₂-N(C₁-C₆Alkyl of (2)₂(ii) a Alternatively, the first and second electrodes may be,

R₁₁and R₁₂Each independently selected from H, C₁-C₆Alkyl of (C)₁-C₆Haloalkyl of (A), (B), (C)₁-C₆Alkyl) -O-CO- (C)₁-C₆Alkyl of (b) -, -SO₂-(C₁-C₆Alkyl of (b), -SO)₂-N(C₁-C₆Alkyl of (2)₂And R is₁₁And R₁₂Are connected together through an N atom to form a five-membered ring or a six-membered ring.

2. The thiadiazole isoxazoline compound according to claim 1, wherein in the formula (I),

R₁、R₂、R₃、R₄each independently selected from H, halogen, -CN;

R₅selected from H, C₁-C₆Alkyl radical, C₁-C₈A haloalkyl group;

R₆selected from H, C₁-C₆Alkyl radical, C₁-C₈A haloalkyl group; r₇Selected from H, -CN, C₁-C₃Alkyl of-CH₂O(C₁-C₄Alkyl groups of (a); r₈Is selected from-CN, C₁-C₆Alkyl of (C)₁-C₆Haloalkyl, -CO-OR₉、-CH₂OR₁₀、-CONR₁₁R₁₂Phenyl, (C)₁-C₆Alkyl group of (A) O-, (C)₁-C₆Haloalkyl) -O-, (C)₃-C₆Alkenyl group of (A) O-, (C)₃-C₆Alkynyl) -O-; alternatively, the first and second electrodes may be,

R₆and R₇Are linked together by at least one atom selected from O and S to form a five-or six-membered ring, and R₈Is H.

3. The thiadiazole isoxazoline compound according to claim 1, wherein in the formula (I),

R₁selected from H, -F;

R₂is H;

R₃selected from-Cl, -CN;

R₄is H;

R₅selected from H, -CH₃；

R₆Selected from H, -CH₃；R₇Selected from H, -CH₃、-CH₂OCH₃；R₈Selected from-CN, -CO-OR₉、-CH₂OR₁₀、-CONR₁₁R₁₂、(C₁-C₆Alkyl group of (A) O-, (C)₁-C₆Haloalkyl of (1)-O-、(C₃-C₆Alkenyl group of (A) O-, (C)₃-C₆Alkynyl) -O-, C₁-C₆Alkyl groups of (a); alternatively, the first and second electrodes may be,

R₆and R₇Are joined together by an O atom to form a five-or six-membered ring, and R₈Is H;

preferably, in formula (I),

R₁is-F;

R₂is H;

R₃is-Cl;

R₄is H;

R₅is H or-CH₃；

R₆Is H or-CH₃；R₇Is H, -CH₃or-CH₂OCH₃；R₈Selected from-CN, -CO-OR₉、-CH₂OR₁₀、-CONR₁₁R₁₂、(C₁-C₆Alkyl group of (A) O-, (C)₁-C₆Haloalkyl) -O-, (C)₃-C₆Alkenyl group of (A) O-, (C)₃-C₆Alkynyl) -O-, C₁-C₆Alkyl groups of (a); alternatively, the first and second electrodes may be,

R₆and R₇Are joined together by an O atom to form a five-or six-membered ring, and R₈Is H.

4. The thiadiazole isoxazoline according to any one of claims 1 to 3, wherein,

R₉selected from H, C₁-C₆Alkyl of (C)₁-C₃Halogenoalkyl of, C₃-C₅Alkenyl of, C₃-C₄Alkynyl (C)₁-C₆Alkyl) -CO-O- (C)₁-C₄Alkyl of (C) -, (C)₁-C₆Alkyl) -CO-O- (C)₁-C₄Haloalkyl) -, benzyl, with 1-4 substituents R³Phenyl- (C)₁-C₂Alkyl of (C) -, (C)₁-C₆Alkyl) -O- (C of₁-C₄Alkyl of (C) -, (C)₁-C₄Alkyl of (2)Radical) -CO-O- (C₁-C₆Alkyl) -NH-CO- (C)₁-C₄Alkyl of (C) -, (C)₁-C₆Alkyl) -CO-NH- (C)₁-C₄Alkyl) -, or,

Preferably, R₁₀Selected from H, (C)₁-C₂Alkyl group of (2) - (C)₁-C₂Alkyl group of (2) -CO-O-, (C)₁-C₂Haloalkyl) -CO-, phenyl-CO-O-, (C)₁-C₂Alkyl) -phenyl-CO-, (C)₁-C₂Alkyl) -phenyl-CO-O-, (C)₁-C₂Haloalkyl) -phenyl-CO-, phenyl-O- (C)₁-C₂Alkyl) -CO-;

preferably, R₁₁、R₁₂Each independently selected from H, C₁-C₄Alkyl of (C)₁-C₄Halogenoalkyl of, C₃-C₆Alkenyl of, C₃-C₆Alkynyl, benzyl, having 1-4 substituents R³Phenyl- (C)₁-C₂Alkyl of (C) -, (C)₁-C₆Alkyl) -CO-O- (C)₁-C₄Alkyl of (b) -, -SO₂-(C₁-C₆Alkyl of (b), -SO)₂-N(C₁-C₆Alkyl of (2)₂(ii) a Or, R₁₁、R₁₂Are linked together by an N atom to form a substituted or unsubstituted five-membered ring or to form a substituted or unsubstituted six-membered ring, and R₁₁、R₁₂The substituents optionally present when joined together by the N atom to form a five-or six-membered ring are selected from the group consisting of-CO-O- (C)₁-C₆Alkyl group of (a);

preferably, R₁₃And R₁₄Not simultaneously being H, and R₁₃、R₁₄Each independently selected from H, -CN, halogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₁-C₁₀Alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, (C)₁-C₃Alkyl) -O-CO-, pyridyl- (C)₁-C₃Alkyl) -, thienyl- (C)₁-C₃Alkyl of (a) -, substituted or unsubstituted- (C)₁-C₃Ester group of (1) - (C)₁-C₃Alkyl group of) -, R₁₃And R₁₄Wherein the substituents optionally present are each independently selected from halogen, C₁-C₃Alkyl of (C)₁-C₃One or more of haloalkyl, nitro, cyano and amino; or R₁₃And R₁₄Together form a five-membered ring with or without at least one heteroatom selected from O and S or a six-membered ring with or without at least one heteroatom selected from O and S.

5. The thiadiazole isoxazoline compound according to any one of claims 1 to 4, wherein the thiadiazole isoxazoline compound having the structure represented by the formula (I) is selected from any one of the following compounds:

compound 1: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂H；

Compound 2: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₃；

Compound 3: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂C₂H₅；

Compound 4: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂(n-C₃H₇)；

Compound 5: r₁Is F, R₂Is H, R₃Is Cl，R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH(CH₃)₂；

Compound 6: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂(n-C₄H₉)；

Compound 7: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂CH₂F；

Compound 8: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂CHF₂；

Compound 9: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂CH₂CH₂F；

Compound 10: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂CH(CH₃)₂；

Compound 11: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈Is composed of

Compound 12: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈Is composed of

Compound 13: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈Is composed of

Compound 14: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈Is composed of

Compound 15: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂CH＝CH₂；

Compound 16: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂CH＝C(CH₃)₂；

Compound 17: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂C≡CH；

Compound 18: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂CO₂CH₃；

Compound (I)19：R₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂CO₂C₂H₅；

Compound 20: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH(CH₃)CO₂C₂H₅；

Compound 21: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂C(CH₃)₂CO₂C₂H₅；

Compound 22: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CHFCO₂C₂H₅；

Compound 23: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CF₂CO₂C₂H₅；

Compound 24: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂Ph；

Compound 25: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂(4-CF₃-Ph)；

Compound 26: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂(4-F-Ph)；

Compound 27: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂(4-CH₃-Ph)；

Compound 28: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂(4-Br-Ph)；

Compound 29: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂(4-Cl-Ph)；

Compound 30: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂CH₂OCH₃；

Compound 31: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONHCH₃；

Compound 32: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONHC₂H₅；

Compound 33: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONHCH₂CH₂F；

Compound 34: r₁Is F, R₂Is H，R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONH (n-C)₃H₇)；

Compound 35: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONHCH₂CH₂CH₂F；

Compound 36: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONHCH (CH)₃)₂；

Compound 37: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONH (n-C)₄H₉)；

Compound 38: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONH (t-C)₄H₉)；

Compound 39: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈Is composed of

Compound 40: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONHCH₂CH＝CH₂；

Compound 41: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONHCH₂C≡CH；

Compound 42: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CON (CH)₃)₂；

Compound 43: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CON (C)₂H₅)₂；

Compound 44: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CON (n-C)₃H₇)₂；

Compound 45: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONHCH₂Ph；

Compound 46: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONHCH₂(4-CF₃-Ph)；

Compound 47: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONHCH₂(4-CH₃-Ph)；

Compound 48: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈Is composed of

Compound 49: r₁Is F, R₂Is H, R₃Is Cl，R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONHCH₂CH₂CO₂CH₃；

Compound 50: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈Is composed of

Compound 51: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈Is composed of

Compound 52: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈Is composed of

Compound 53: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH(CH₃)CONHCH₂CH₂CO₂CH₃；

Compound 54: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CN;

compound 55: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CH₂CH₃；

Compound 56: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CH₂OH；

Compound 57: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CH₂OCOCH₃；

Compound 58: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CH₂OCOCF₃；

Compound 59: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CH₂OCOCH₂F；

Compound 60: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CH₂OCOCH₂Cl；

Compound 61: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CH₂OCOCH₂Br；

Compound 62: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CH₂OCOPh；

Compound 63: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CH₂OCO(4-CF₃-Ph)；

Compound 64: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CH₂OCO₂(4-CH₃-Ph)；

Compound 65: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CH₂OCO₂CH₃；

Compound 66: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CH₂OCO₂C₂H₅；

Compound 67: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CH₂OCO₂Ph；

Compound 68: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂H；

Compound 69: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂CH₃；；

Compound 70: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂C₂H₅；

Compound 71: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂(n-C₃H₇)；

Compound 72: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂CH(CH₃)₂；

Compound 73: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂(n-C₄H₉)；

Compound 74: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂CH₂CH₂F；

Compound 75: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂CH₂CHF₂；

Compound 76: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂CH₂CH₂CH₂F；

Compound 77: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂CH₂CH(CH₃)₂；

Compound 78: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈Is composed of

Compound 79: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈Is composed of

Compound 80: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂CH₂CH＝CH₂；

Compound 81: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂CH₂CH＝C(CH₃)₂；

Compound 82: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂CH₂C≡CH；

Compound 83: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂CH₂CO₂CH₃；

Compound 84: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂CH₂CO₂C₂H₅；

Compound 85: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂CH(CH₃)CO₂C₂H₅；

Compound 86: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂C(CH₃)₂CO₂C₂H₅；

Compound 87: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂CHFCO₂C₂H₅；

Compound 88: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂CF₂CO₂C₂H₅；

Compound 89: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂CH₂Ph；

Compound 90: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂CH₂(4-CF₃-Ph)；

Compound 91: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂CH₂(4-F-Ph)；

Compound 92: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂CH₂(4-CH₃-Ph)；

Compound 93: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂CH₂CH₂OCH₃；

Compound 94: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CONHCH₃；

Compound 95: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CONHC₂H₅；

Compound 96: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CONHCH₂CH₂F；

Compound 97: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CONH (n-C)₃H₇)；

Compound 98: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CONHCH₂CH₂CH₂F；

Compound 99: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CONHCH (CH)₃)₂；

Compound 100: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CONH (n-C)₄H₉)；

Compound 101: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CONH (t-C)₄H₉)；

Compound 102: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈Is composed of

Compound 103: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CONHCH₂CH＝CH₂；

Compound 104: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CONHCH₂C≡CH；

Compound 105: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CON (CH)₃)₂；

Compound 106: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CON (C)₂H₅)₂；

Compound 107: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CON (n-C)₃H₇)₂；

Compound 108: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CONHCH₂Ph；

Compound 109: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CONHCH₂(4-CF₃-Ph)；

Compound 110: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CONHCH₂(4-CH₃-Ph)；

Compound 111: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈Is composed of

Compound 112: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CONHCH₂CH₂CO₂CH₃；

Compound 113: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈Is composed of

Compound 114: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈Is composed of

Compound 115: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈Is composed of

Compound 116: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CO₂CH(CH₃)CONHCH₂CH₂CO₂CH₃；

Compound 117: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CN;

compound 118: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CH₂CH₃；

Compound 119: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CH₂OH；

Compound 120: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CH₂OCOCH₃；

Compound 121: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CH₂OCOCF₃；

Compound 122: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CH₂OCOC₂H₅；

Compound 123: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CH₂OCOCH₂Cl；

Compound 124: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CH₂OCOCH₂Br；

Compound 125: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇is-CH₂OCH₃，R₈is-CH₂OCOPh；

Compound 126: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂H；

Compound 127: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂CH₃；

Compound 128: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂C₂H₅；

Compound 129: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂(n-C₃H₇)；

Compound 130: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂CH(CH₃)₂；

Compound 131: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂(n-C₄H₉)；

Compound 132: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂CH₂CH₂F；

Compound 133: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂CH₂CHF₂；

Compound 134: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂CH₂CH₂CH₂F；

Compound 135: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂CH₂CH(CH₃)₂；

Compound 136: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈Is composed of

Compound 137: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈Is composed of

Compound 138: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂CH₂CH＝CH₂；

Compound 139: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂CH₂CH＝C(CH₃)₂；

Compound 140: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂CH₂C≡CH；

Compound 141: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂CH₂CO₂CH₃；

Compound 142: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂CH₂CO₂C₂H₅；

Compound 143: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂CH(CH₃)CO₂C₂H₅；

Compound 144: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂C(CH₃)₂CO₂C₂H₅；

Compound 145: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂CHFCO₂C₂H₅；

Compound 146: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂CF₂CO₂C₂H₅；

Compound 147: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂CH₂Ph；

Compound 148: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂CH₂(4-CF₃-Ph)；

Compound 149: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂CH₂(4-F-Ph)；

Compound 150: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂CH₂(4-CH₃-Ph)；

Compound 151: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂CH₂CH₂OCH₃；

Compound 152: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CONHCH₃；

Compound 153: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CONHC₂H₅；

Compound 154: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CONHCH₂CH₂F；

Compound 155: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CONH (n-C)₃H₇)；

Compound 156: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CONHCH₂CH₂CH₂F；

Compound 157: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CONHCH (CH)₃)₂；

Compound 158: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CONH (n-C)₄H₉)；

Compound 159: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CONH (t-C)₄H₉)；

Compound 160: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈Is composed of

Compound 161: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CONHCH₂CH＝CH₂；

Compound 162: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CONHCH₂C≡CH；

Compound 163: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CON (CH)₃)₂；

Compound 164: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CON (C)₂H₅)₂；

Compound 165: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CON (n-C)₃H₇)₂；

Compound 166: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CONHCH₂Ph；

Compound 167: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CONHCH₂(4-CF₃-Ph)；

Compound 168: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CONHCH₂(4-CH₃-Ph)；

Compound 169: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈Is composed of

Compound 170: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CONHCH₂CH₂CO₂CH₃；

Compound 171: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈Is composed of

Compound 172: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈Is composed of

Compound 173: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈Is composed of

Compound 174: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CO₂CH(CH₃)CONHCH₂CH₂CO₂CH₃；

Compound 175: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CN;

compound 176: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CH₂CH₃；

Compound 177: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CH₂OH；

Compound 178: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CH₂OCOCH₃；

Compound 179: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CH₂OCOCF₃；

Compound 180: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CH₂OCOC₂H₅；

Compound 181: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CH₂OCOCH₂Cl；

Compound 182: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CH₂OCOCH₂Br；

Compound 183: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-CH₂OCOPh；

Compound 184: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-OCH₃；

Compound 185: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-OCH₂CH₃；

Compound 186: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-O (n-C)₃H₇)；

Compound 187: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-OCH (CH)₃)₂；

Compound 188: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-O (n-C)₄H₉)；

Compound 189: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-OCH₂CH₂F；

Compound 190: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-OCH₂CHF₂；

Compound 191: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-OCH₂CH₂CH₂F；

Compound 192: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-OCH₂CH＝CH₂；

Compound 193: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-OCH₂CH＝C(CH₃)₂；

Compound 194: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is H, R₈is-OCH₂C≡CH；

Compound 195: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂H；

Compound 196: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂CH₃；

Compound 197: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂C₂H₅；

Compound 198: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂(n-C₃H₇)；

Compound 199: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂CH(CH₃)₂；

Compound 200: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂(n-C₄H₉)；

Compound 201: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂CH₂CH₂F；

Compound 202: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂CH₂CHF₂；

Compound 203: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂CH₂CH₂CH₂F；

Compound 204: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂CH₂CH(CH₃)₂；

Compound 205: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈Is composed of

Compound 206: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈Is composed of

Compound 207: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂CH₂CH＝CH₂；

Compound 208: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂CH₂CH＝C(CH₃)₂；

Compound 209: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂CH₂C≡CH；

Compound 210: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂CH₂CO₂CH₃；

Compound 211: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂CH₂CO₂C₂H₅；

Compound 212: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂CH(CH₃)CO₂C₂H₅；

Compound 213: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂C(CH₃)₂CO₂C₂H₅；

Compound 214: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂CHFCO₂C₂H₅；

Compound 215: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂CF₂CO₂C₂H₅；

Compound 216: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂CH₂Ph；

Compound 217: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂CH₂(4-CF₃-Ph)；

Compound 218: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂CH₂(4-F-Ph)；

Compound 219: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂CH₂(4-CH₃-Ph)；

Compound 220: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂CH₂CH₂OCH₃；

Compound 221: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CONHCH₃；

Compound 222: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CONHC₂H₅；

Compound 223: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CONHCH₂CH₂F；

Compound 224: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CONH (n-C)₃H₇)；

Compound 225: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CONHCH₂CH₂CH₂F；

Compound 226: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CONHCH (CH)₃)₂；

Compound 227: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CONH (n-C)₄H₉)；

Compound 228: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CONH (t-C)₄H₉)；

Compound 229: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈Is composed of

Compound 230: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CONHCH₂CH＝CH₂；

Compound 231: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CONHCH₂C≡CH；

Compound 232: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CON (CH)₃)₂；

Compound 233: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CON (C)₂H₅)₂；

Compound 234: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CON (n-C)₃H₇)₂；

Compound 235: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CONHCH₂Ph；

Compound 236: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CONHCH₂(4-CF₃-Ph)；

Compound 237: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CONHCH₂(4-CH₃-Ph)；

Compound 238: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈Is composed of

Compound 239: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CONHCH₂CH₂CO₂CH₃；

Compound 240: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈Is composed of

Compound 241: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈Is composed of

Compound 242: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈Is composed of

Compound 243: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CO₂CH(CH₃)CONHCH₂CH₂CO₂CH₃；

Compound 244: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CN;

compound 245: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CH₂CH₃；

Compound 246: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CH₂OH；

Compound 247: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CH₂OCOCH₃；

Compound 248: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CH₂OCOCF₃；

Compound 249: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CH₂OCOC₂H₅；

Compound 250: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CH₂OCOCH₂Cl；

Compound 251: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CH₂OCOCH₂Br；

Compound 252: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is CH₃，R₆Is CH₃，R₇Is CH₃，R₈is-CH₂OCOPh；

Compound 253: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂H；

Compound 254: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₃；

Compound 255: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂C₂H₅；

Compound 256: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂(n-C₃H₇)；

Compound 257: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH(CH₃)₂；

Compound 258: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂(n-C₄H₉)；

Compound 259: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂CH₂F；

Compound 260: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂CHF₂；

Compound 261: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂CH₂CH₂F；

Compound 262: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂CH(CH₃)₂；

Compound 263: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈Is composed of

Compound 264: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈Is composed of

Compound 265: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂CH＝CH₂；

Compound 266: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂CH＝C(CH₃)₂；

Compound 267: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂C≡CH；

Compound 268: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂CO₂CH₃；

Compound 269: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂CO₂C₂H₅；

Compound 270: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH(CH₃)CO₂C₂H₅；

Compound 271: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂C(CH₃)₂CO₂C₂H₅；

Compound 272: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CHFCO₂C₂H₅；

Compound 273: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CF₂CO₂C₂H₅；

Compound 274: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂Ph；

Compound 275: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂(4-CF₃-Ph)；

Compound 276: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂(4-F-Ph)；

Compound 277: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂(4-CH₃-Ph)；

Compound 278: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂CH₂OCH₃；

Compound 279: (ii) a R₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH₂CH₂OC₂H₅；

Compound 280: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONHCH₃；

Compound 281: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONHC₂H₅；

Compound 282: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONHCH₂CH₂F；

Compound 283: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONH (n-C)₃H₇)；

Compound 284: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONHCH₂CH₂CH₂F；

Compound 285: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONHCH (CH)₃)₂；

Compound 286: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONH (n-C)₄H₉)；

Compound 287: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONH (t-C)₄H₉)；

Compound 288: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈Is composed of

Compound 289: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONHCH₂CH＝CH₂；

Compound 290: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONHCH₂C≡CH；

Compound 291: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CON (CH)₃)₂；

Compound 292: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CON (C)₂H₅)₂；

Compound 293: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CON (n-C)₃H₇)₂；

Compound 294: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONHCH₂Ph；

Compound 295: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONHCH₂(4-CF₃-Ph)；

Compound 296: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONHCH₂(4-CH₃-Ph)；

Compound 297: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈Is composed of

Compound 298: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CONHCH₂CH₂CO₂CH₃；

Compound 299: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈Is composed of

Compound 300: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈Is composed of

Compound 301: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂CH(CH₃)CONHCH₂CH₂CO₂CH₃；

Compound 302: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CN;

compound 303: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CH₂CH₃；

Compound 304: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CH₂OH；

Compound 305: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CH₂OCOCH₃；

Compound 306: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CH₂OCOCF₃；

Compound 307: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CH₂OCOC₂H₅；

Compound 308: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CH₂OCOCH₂Cl；

Compound 309: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CH₂OCOCH₂Br；

Compound 310: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CH₂OCOPh；

Compound 311: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝CHCN；

Compound 312: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝CHCH₃；

Compound 313: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝CHC₂H₅；

Compound 314: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈Is composed of

Compound 315: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈Is composed of

Compound 316: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈Is composed of

Compound 317: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝CHCO₂CH₃；

Compound 318: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝CHCO₂C₂H₅；

Compound 319: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝CFCO₂C₂H₅；

Compound 320: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝CClCO₂C₂H₅；

Compound 321: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝C(CH₃)₂；

Compound 322: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝CHPh；

Compound 323: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝CClPh；

Compound 324: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝CPh₂；

Compound 325: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝CH(2-Cl-Ph)；

Compound 326: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝CH(3-Cl-Ph)；

Compound 327, compound (xxvi): r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝CH(4-Cl-Ph)；

Compound 328: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝CH(2-CH₃-Ph)；

Compound 329: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝CH(3-CH₃-Ph)；

Compound 330: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝CH(4-CH₃-Ph)；

Compound 331: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝CH(2-CF₃-Ph)；

Compound 332: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝CH(3-CF₃-Ph)；

Compound 333: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝CH(4-CF₃-Ph)；

Compound 334: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝CHCH₂Ph；

Compound 335: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝CHCH₂(2-Cl-Ph)；

Compound 336: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝CHCH₂(3-Cl-Ph)；

Compound 337: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝CHCH₂(4-Cl-Ph)；

Compound 338: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈is-CO₂N＝CHCH₂F；

Compound 339: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈Is composed of

Compound 340: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆Is H, R₇Is CH₃，R₈Is composed of

Compound 341: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆And R₇Together form-CH₂OCH₂-，R₈Is H;

compound 342: r₁Is F, R₂Is H, R₃Is Cl, R₄Is H, R₅Is H, R₆And R₇Together form-OCH₂CH₂-，R₈Is H.

6. A process for the preparation of a thiadiazole isoxazoline according to any one of claims 1 to 5, which comprises: in the presence of a first alkaline substance and a first solvent, a compound with a structure shown in a formula (II) and activated carbonic acid are subjected to a first reaction,

wherein each substituent in the formula (II) has the same definition as that of the corresponding substituent in the thiadiazole isoxazoline compound according to any one of claims 1 to 5;

preferably, the conditions of the first reaction include: the temperature is-10 ℃ to 10 ℃ and the time is 1-5 h;

preferably, the activated carbonic acid is selected from at least one of N' N-carbonyldiimidazole, phosgene, diphosgene, triphosgene, methyl chloroformate, ethyl chloroformate, and phenyl chloroformate.

7. The method of claim 6, further comprising preparing the compound having the structure of formula (II) by a process comprising: a second reaction of the compound represented by the formula (IV) with a pyridazine compound in the presence of a second solvent and a second basic substance,

wherein each substituent in formula (IV) has the same definition as the corresponding substituent in the thiadiazole isoxazoline compound according to any one of claims 1 to 5;

preferably, the conditions of the second reaction include: the temperature is-10 ℃ to 30 ℃ and the time is 1-5 h;

preferably, the pyridazine compound is at least one selected from pyridazine, pyridazine monohydrochloride and pyridazine dihydrochloride.

8. The method of claim 7, further comprising preparing the compound having the structure of formula (IV) by a process comprising: a third reaction of the compound of formula (VI) with thiophosgene of formula (VII) in the presence of a third solvent and a third basic substance,

wherein each substituent in formula (VI) is defined as corresponding to the definition of the corresponding substituent in the thiadiazole isoxazoline compound according to any one of claims 1 to 5;

preferably, the conditions of the third reaction include: the temperature is between-10 ℃ and 110 ℃ and the time is between 2 and 8 hours.

9. Use of a thiadiazole isoxazoline compound according to any one of claims 1 to 5 for controlling weeds;

preferably, the weeds are broadleaf weeds and/or grassy weeds.

10. A herbicide containing the thiadiazole isoxazoline compound according to any one of claims 1 to 5;

preferably, the content of the thiadiazole isoxazoline compound is 0.5-90 wt%, preferably 0.5-75 wt% based on the weight of the herbicide; more preferably 5 to 60% by weight.

Technical Field

The invention relates to the field of pesticides, and particularly relates to a thiadiazole isoxazoline compound, a preparation method and application thereof, and a herbicide.

Background

The history of herbicide use dates back to around the 20 th century and in more than half a century, a very wide variety of herbicides have been developed.

However, with the widespread and prolonged use of these herbicides, weeds have developed resistance to more and more herbicides, presenting an increasing trend year by year. An important approach to overcome weed resistance is to synthesize herbicides with new structures and high activity.

U.S. Pat. No. 4, 4885023A and EP0273417A1 disclose a thiadiazole compound of a 9-substituted benzimide-8-thia-1, 6-diazabicyclo- [4.3.0] nonan-7-one derivative of the following general formula.

Wherein: x and Y represent a hydrogen atom, a halogen atom or the like. Z representsWherein R represents a hydrogen atom or an alkyl group, R¹Represents alkyl, cycloalkyl, alkoxycarbonyl, etc.

However, the control of weeds by these known compounds is not always entirely satisfactory.

Disclosure of Invention

The invention aims to overcome the defects of poor herbicidal activity and poor crop safety of herbicidal active substances in the prior art and provide a novel thiadiazole isoxazoline compound.

In order to achieve the above object, a first aspect of the present invention provides a thiadiazole isoxazoline compound having a structure represented by formula (I),

wherein, in the formula (I),

R₁、R₂、R₃、R₄each independently selected from H, halogen, -CN, C₁-C₆Alkyl group of (C)₁-C₆Haloalkyl) -O-, (C)₁-C₆Alkyl) -SO of₂-；

R₅Selected from H, -CN, C₁-C₆Alkyl of (C)₁-C₈A haloalkyl group of (a);

R₆selected from H, -CN, C₁-C₆Alkyl of (C)₁-C₈A haloalkyl group of (a);

R₆and R₇Are connected together by at least one atom selected from O and S to form a five-membered ring or a six-membered ring;

R₁₃And R₁₄Not H at the same time; and R is₁₃、R₁₄Each independently selected from the group I_15/16: H. -CN, halogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₁-C₁₀Alkoxy, substituted or unsubstituted C₃-C₁₀Substituted or unsubstituted C containing 0 to 3 heteroatoms selected from at least N, O and S₅-C₁₀Aryl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted-CO- (C)₁-C₁₂Alkyl of (a) -, substituted or unsubstituted- (C)₁-C₅Alkyl) -CO- (C)₁-C₅Alkyl of (a) -, substituted or unsubstituted- (C)₁-C₃Ester group of (1) - (C)₁-C₃Alkyl of (a) -, the group I_15/16Wherein the substituents optionally present are selected from one or more of halogen, nitro, cyano and amino; alternatively, the first and second electrodes may be,

R₁₃and R₁₄Are respectively selected from the group I_15/16And are connected together to form a ring;

A second aspect of the present invention provides a method for producing the aforementioned thiadiazole isoxazoline compound, which comprises: carrying out a first reaction on a compound with a structure shown in a formula (II) and triphosgene shown in a formula (III) in the presence of a first alkaline substance and a first solvent,

wherein the definition of each substituent in formula (II) corresponds to the same definition as in the aforementioned first aspect.

A third aspect of the present invention provides the use of the thiadiazole isoxazoline compound as described in the first aspect above for controlling weeds.

In a fourth aspect, the present invention provides a herbicide containing the thiadiazole isoxazoline compound.

The thiadiazole isoxazoline compound has good herbicidal activity; meanwhile, the thiadiazole isoxazoline compound has high crop safety, particularly has good selectivity on key crops such as corn, wheat and the like, and can effectively remove weeds in crop fields on the premise of ensuring safe growth of crops.

Detailed Description

The endpoints of the ranges and any values disclosed herein are not limited to the precise range or value, and such ranges or values should be understood to encompass values close to those ranges or values. For ranges of values, between the endpoints of each of the ranges and the individual points, and between the individual points may be combined with each other to give one or more new ranges of values, and these ranges of values should be considered as specifically disclosed herein.

The terms "first", "second", and the like in the present invention do not denote any order or sequence unless otherwise specified, but merely denote that they are different processes (or matters).

“C₁-C₆The "alkyl group" of (a) represents an alkyl group having 1 to 6 carbon atoms in total, and includes a straight-chain alkyl group, a branched-chain alkyl group or a cyclic alkyl group, and may be, for example, a straight-chain alkyl group, a branched-chain alkyl group or a cyclic alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms in total, and may be, for example, a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a n-butyl group, an isobutyl group, a tert-butyl group, a n-pentyl group, an isopentyl group, a n-hexyl group, a cyclopropyl group, a methylcyclopropyl group, an ethylcyclopropyl group, a cyclopentyl group, a methylcyclopentyl group, a cyclohexyl group or the like. For "C_1-4Alkyl of (2), "" C_1-3The "alkyl group" has a similar explanation except that the number of carbon atoms is different.

“C₁-C₈The "haloalkyl group" of (a) means an alkyl group having a total number of carbon atoms of 1 to 8, including straight-chain alkyl groups, branched-chain alkyl groups and cyclic alkyl groups, and at least one H in the alkyl group is substituted with a halogen atom selected from halogens, for example, 1, 2, 3, 4, 5 or 6H in the alkyl group is substituted with any one or more halogen atoms selected from fluorine, chlorine, bromine and iodine, and may be, for example, trifluoromethyl, difluoromethyl, monofluoromethyl, monofluoroethyl, difluoroethyl, trifluoroethyl, etc. "C₁-C₆Of (2)Alkyl-substituted "has similar explanations as this.

“(C₁-C₆Alkyl of (2)₂"means that 2 groups can each independently be selected from C₁-C₆Such as in compound 48.

In the formula (I) of the present invention, the symbol "-" in the selection of each group represents a site at which the group is bonded to the structure of the formula (I), for example, "(C)₁-C₈Alkyl) -O- "of (A) means that the structure is linked to the structure of formula (I) through an oxygen atom; and is as in "(C)₁-C₆Alkyl) -CO-O- (C)₁-C₄Alkyl group of (c)' "does not define a linking site, and indicates both ends. The alkyl, haloalkyl, alkenyl, alkynyl and the like groups are not limited to straight or branched chains.

Other terms in the present invention can be interpreted in a manner conventional in the art.

The thiadiazole isoxazoline compound having the structure represented by the formula (I) according to the present invention has the structure "CO" in the case where it is described in embodiment 4₂"denotes" -CO-O- "for example in Compound 1, R₈is-CO₂H, represents-CO-O-H; as in Compound 2, R₈is-CO₂CH₃Is represented by-CO-O-CH₃。

As described above, the first aspect of the present invention provides a thiadiazole isoxazoline compound having a structure represented by formula (I),

wherein, in the formula (I),

R₁、R₂、R₃、R₄each independently selected from H, halogen, -CN, C₁-C₆Alkyl group of (C)₁-C₆Haloalkyl) -O-, (C)₁-C₆Alkyl) -SO of₂-；

R₅Selected from H, -CN, C₁-C₆Alkyl of (C)₁-C₈A haloalkyl group of (a);

R₆selected from H, -CN, C₁-C₆Alkyl of (C)₁-C₈A haloalkyl group of (a);

R₆and R₇Are connected together by at least one atom selected from O and S to form a five-membered ring or a six-membered ring;

R₁₃And R₁₄Not H at the same time; and R is₁₃、R₁₄Are independently selected fromGroup I consisting of_15/16: H. -CN, halogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₁-C₁₀Alkoxy, substituted or unsubstituted C₃-C₁₀Substituted or unsubstituted C containing 0 to 3 heteroatoms selected from at least N, O and S₅-C₁₀Aryl, substituted or unsubstituted pyridyl, substituted or unsubstituted thienyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, substituted or unsubstituted-CO- (C)₁-C₁₂Alkyl of (a) -, substituted or unsubstituted- (C)₁-C₅Alkyl) -CO- (C)₁-C₅Alkyl of (a) -, substituted or unsubstituted- (C)₁-C₃Ester group of (1) - (C)₁-C₃Alkyl of (a) -, the group I_15/16Wherein the substituents optionally present are selected from one or more of halogen, nitro, cyano and amino; alternatively, the first and second electrodes may be,

R₁₃and R₁₄Are respectively selected from the group I_15/16And are connected together to form a ring;

Preferably, in formula (I), R₁、R₂、R₃、R₄Each independently selected from H, halogen, -CN, C₁-C₃Alkyl group of (C)₁-C₃Haloalkyl) -O-, (C)₁-C₃Alkyl) -SO of₂-; more preferably, R₁、R₂、R₃、R₄Each independently selected from H, halogen, -CN, C₁-C₃Alkyl group of (C)₁-C₃Haloalkyl) -O-; further preferably, R₁、R₂、R₃、R₄Each independently selected from H, halogen, -CN; further preferably, R₁Selected from H, -F; r₂Is H; r₃Selected from-Cl, -CN; r₄Is H; further preferably, R₁is-F; r₂Is H; r₃is-Cl; r₄Is H.

Preferably, R₅Selected from H, -CN, C₁-C₃Alkyl of (C)₁-C₃A haloalkyl group of (a); more preferably, R₅Selected from H, -CN, C₁-C₃Alkyl groups of (a); further preferably, R₅Selected from H, -CH₃。

Preferably, R₆Selected from H, -CN, C₁-C₆Alkyl of (C)₁-C₈Alkyl halides of (2)A group; more preferably, R₆Selected from H, -CN, C₁-C₃Alkyl groups of (a); further preferably, R₆Selected from H, -CH₃。

Preferably, R₇Selected from H, -CN, C₁-C₃Alkyl of-CH₂O(C₁-C₄Alkyl groups of (a); r₈Is selected from-CN, C₁-C₆Alkyl of (C)₁-C₆Haloalkyl, -CO-OR₉、-CH₂OR₁₀、-CONR₁₁R₁₂Phenyl, (C)₁-C₆Alkyl group of (A) O-, (C)₁-C₆Haloalkyl) -O-, (C)₃-C₆Alkenyl group of (A) O-, (C)₃-C₆Alkynyl) -O-; more preferably, R₇Selected from H, -CH₃、-CH₂OCH₃；R₈Selected from-CN, -CO-OR₉、-CH₂OR₁₀、-CONR₁₁R₁₂、(C₁-C₆Alkyl group of (A) O-, (C)₁-C₆Haloalkyl) -O-, (C)₃-C₆Alkenyl group of (A) O-, (C)₃-C₆Alkynyl) -O-, C₁-C₆Alkyl group of (1).

According to another preferred aspect, R₆And R₇Are linked together by at least one atom selected from O and S to form a five-or six-membered ring, and R₈Is H; further preferably, R₆And R₇Are joined together by an O atom to form a five-or six-membered ring, and R₈Is H.

Preferably, in formula (I),

R₁、R₂、R₃、R₄each independently selected from H, halogen, -CN;

R₅selected from H, C₁-C₆Alkyl radical, C₁-C₈A haloalkyl group;

R₆and R₇Are linked together by at least one atom selected from O and S to form a five-or six-membered ring, and R₈Is H.

More preferably, in formula (I),

R₁selected from H, -F;

R₂is H;

R₃selected from-Cl, -CN;

R₄is H;

R₅selected from H, -CH₃；

R₆Selected from H, -CH₃；R₇Selected from H, -CH₃、-CH₂OCH₃；R₈Selected from-CN, -CO-OR₉、-CH₂OR₁₀、-CONR₁₁R₁₂、(C₁-C₆Alkyl group of (A) O-, (C)₁-C₆Haloalkyl) -O-, (C)₃-C₆Alkenyl group of (A) O-, (C)₃-C₆Alkynyl) -O-, C₁-C₆Alkyl groups of (a); alternatively, the first and second electrodes may be,

R₆and R₇Are joined together by an O atom to form a five-or six-membered ring, and R₈Is H.

Further preferably, in the formula (I),

R₁is-F;

R₂is H;

R₃is-Cl;

R₄is H;

R₅is H or-CH₃；

R₆Is H or-CH₃；R₇Is H, -CH₃or-CH₂OCH₃；R₈Selected from-CN, -CO-OR₉、-CH₂OR₁₀、

-CONR₁₁R₁₂、(C₁-C₆Alkyl group of (A) O-, (C)₁-C₆Haloalkyl) -O-, (C)₃-C₆Alkenyl group of (A) O-, (C)₃-C₆Alkynyl) -O-, C₁-C₆Alkyl groups of (a); alternatively, the first and second electrodes may be,

R₆and R₇Are joined together by an O atom to form a five-or six-membered ring, and R₈Is H.

Preferably, R₉Selected from H, C₁-C₆Alkyl of (C)₁-C₃Halogenoalkyl of, C₃-C₅Alkenyl of, C₃-C₄Alkynyl (C)₁-C₆Alkyl) -CO-O- (C)₁-C₄Alkyl of (C) -, (C)₁-C₆Alkyl) -CO-O- (C)₁-C₄Haloalkyl) -, benzyl, with 1-4 substituents R³Phenyl- (C)₁-C₂Alkyl of (C) -, (C)₁-C₆Alkyl) -O- (C of₁-C₄Alkyl of (C) -, (C)₁-C₄Alkyl) -CO-O- (C)₁-C₆Alkyl) -NH-CO- (C)₁-C₄Alkyl of (C) -, (C)₁-C₆Alkyl) -CO-NH- (C)₁-C₄Alkyl) -, or,

Preferably, R₁₁、R₁₂Each independently selected from H, C₁-C₄Alkyl of (C)₁-C₄Halogenoalkyl of, C₃-C₆Alkenyl of, C₃-C₆Alkynyl, benzyl, having 1-4 substituents R³Phenyl- (C)₁-C₂Alkyl of (C) -, (C)₁-C₆Alkyl) -CO-O- (C)₁-C₄Alkyl of (b) -, -SO₂-(C₁-C₆Alkyl of (b), -SO)₂-N(C₁-C₆Alkyl of (2)₂(ii) a Or, R₁₁、R₁₂Are linked together by an N atom to form a substituted or unsubstituted five-membered ring or to form a substituted or unsubstituted six-membered ring, and R₁₁、R₁₂The substituents optionally present when joined together by the N atom to form a five-or six-membered ring are selected from the group consisting of-CO-O- (C)₁-C₆Alkyl group of (2) is used.

Preferably, R₁₃And R₁₄Not simultaneously being H, and R₁₃、R₁₄Each independently selected from H, -CN, halogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₁-C₁₀Alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, (C)₁-C₃Alkyl) -O-CO-, pyridyl- (C)₁-C₃Alkyl) -, thienyl- (C)₁-C₃Alkyl of (a) -, substituted or unsubstituted- (C)₁-C₃Ester group of (1) - (C)₁-C₃Alkyl group of) -, R₁₃And R₁₄Wherein the substituents optionally present are each independently selected from halogen, C₁-C₃Alkyl of (C)₁-C₃One or more of haloalkyl, nitro, cyano and amino; or R₁₃And R₁₄Together form a five-membered ring with or without at least one heteroatom selected from O and S or a six-membered ring with or without at least one heteroatom selected from O and S.

Several preferred embodiments of the thiadiazole isoxazolines of the present invention are provided below.

Embodiment mode 1:

in the formula (I), the compound represented by the formula (I),

R₁、R₂、R₃、R₄each independently selected from H, halogen, -CN;

R₅selected from H, C₁-C₆Alkyl radical, C₁-C₈A haloalkyl group;

R₆and R₇Are linked together by at least one atom selected from O and S to form a five-or six-membered ring, and R₈Is H;

R₉selected from H, C₁-C₆Alkyl of (C)₁-C₃Halogenoalkyl of, C₃-C₅Alkenyl of, C₃-C₄Alkynyl (C)₁-C₆Alkyl) -CO-O- (C)₁-C₄Alkyl of (C) -, (C)₁-C₆Alkyl) -CO-O- (C)₁-C₄Haloalkyl) -, benzyl, with 1-4 substituents R³Phenyl- (C)₁-C₂Alkyl of (C) -, (C)₁-C₆Alkyl) -O- (C of₁-C₄Alkyl of (C) -, (C)₁-C₄Alkyl) -CO-O- (C)₁-C₆Alkyl) -NH-CO- (C)₁-C₄Alkyl of (C) -, (C)₁-C₆Alkyl) -CO-NH- (C)₁-C₄Alkyl) -, or,

R₁₀Selected from H, (C)₁-C₂Alkyl group of (2) - (C)₁-C₂Alkyl group of (2) -CO-O-, (C)₁-C₂Haloalkyl) -CO-, phenyl-CO-O-, (C)₁-C₂Alkyl) -phenyl-CO-, (C)₁-C₂Alkyl) -phenyl-CO-O-, (C)₁-C₂Haloalkyl) -phenyl-CO-, phenyl-O- (C)₁-C₂Alkyl) -CO-;

R₁₁、R₁₂each independently selected from H, C₁-C₄Alkyl of (C)₁-C₄Halogenoalkyl of, C₃-C₆Alkenyl of, C₃-C₆Alkynyl, benzyl, having 1-4 substituents R³Phenyl- (C)₁-C₂Alkyl of (C) -, (C)₁-C₆Alkyl) -CO-O- (C)₁-C₄Alkyl of (b) -, -SO₂-(C₁-C₆Alkyl of (b), -SO)₂-N(C₁-C₆Alkyl of (2)₂(ii) a Or, R₁₁、R₁₂Are linked together by an N atom to form a substituted or unsubstituted five-membered ring or to form a substituted or unsubstituted six-membered ring, and R₁₁、R₁₂The substituents optionally present when joined together by the N atom to form a five-or six-membered ring are selected from the group consisting of-CO-O- (C)₁-C₆Alkyl group of (a);

R₁₃and R₁₄Not simultaneously being H, and R₁₃、R₁₄Each independently selected from H, -CN, halogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₁-C₁₀Alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, (C)₁-C₃Alkyl) -O-CO-, pyridyl- (C)₁-C₃Alkyl) -, thienyl- (C)₁-C₃Alkyl of (a) -, substituted or unsubstituted- (C)₁-C₃Ester group of (1) - (C)₁-C₃Alkyl group of) -, R₁₃And R₁₄Wherein the substituents optionally present are each independently selected from halogen, C₁-C₃Alkyl of (C)₁-C₃One or more of haloalkyl, nitro, cyano and amino; or R₁₃And R₁₄Together form a five-membered ring with or without at least one heteroatom selected from O and S or a six-membered ring with or without at least one heteroatom selected from O and S.

Embodiment mode 2:

in the formula (I), the compound represented by the formula (I),

R₁selected from H, -F;

R₂is H;

R₃selected from-Cl, -CN;

R₄is H;

R₅selected from H, -CH₃；

R₆and R₇Are joined together by an O atom to form a five-or six-membered ring, and R₈Is H;

R₉selected from H, C₁-C₆Alkyl of (C)₁-C₃Halogenoalkyl of, C₃-C₅Alkenyl of, C₃-C₄Alkynyl (C)₁-C₆Alkyl) -CO-O- (C)₁-C₄Alkyl of (C) -, (C)₁-C₆Alkyl) -CO-O- (C)₁-C₄Haloalkyl) -, benzyl, with 1-4 substituents R³Phenyl- (C)₁-C₂Alkyl of (C) -, (C)₁-C₆Alkyl) -O- (C of₁-C₄Alkyl of (C) -, (C)₁-C₄Alkyl) -CO-O- (C)₁-C₆Alkyl) -NH-CO- (C)₁-C₄Alkyl of (C) -, (C)₁-C₆Alkyl) -CO-NH- (C)₁-C₄Alkyl) -, or,

R₁₃and R₁₄Not simultaneously being H, and R₁₃、R₁₄Each independently selected from H, -CN, halogen, substituted or unsubstituted C₁-C₁₀Alkyl, substituted or unsubstituted C₁-C₁₀Alkoxy, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl,(C₁-C₃Alkyl) -O-CO-, pyridyl- (C)₁-C₃Alkyl) -, thienyl- (C)₁-C₃Alkyl of (a) -, substituted or unsubstituted- (C)₁-C₃Ester group of (1) - (C)₁-C₃Alkyl group of) -, R₁₃And R₁₄Wherein the substituents optionally present are each independently selected from halogen, C₁-C₃Alkyl of (C)₁-C₃One or more of haloalkyl, nitro, cyano and amino; or R₁₃And R₁₄Together form a five-membered ring with or without at least one heteroatom selected from O and S or a six-membered ring with or without at least one heteroatom selected from O and S.

Embodiment mode 3:

in the formula (I), the compound represented by the formula (I),

R₁is-F;

R₂is H;

R₃is-Cl;

R₄is H;

R₅is H or-CH₃；

R₆and R₇Are joined together by an O atom to form a five-or six-membered ring, and R₈Is H;

R₉selected from H, C₁-C₆Alkyl of (C)₁-C₃Halogenoalkyl of, C₃-C₅Alkenyl of, C₃-C₄Alkynyl (C)₁-C₆Alkyl) -CO-O- (C)₁-C₄Alkyl of (C) -, (C)₁-C₆Alkyl) -CO-O- (C)₁-C₄Haloalkyl) -, benzyl, with 1-4 substituents R³Phenyl- (C)₁-C₂Alkyl of (C) -, (C)₁-C₆Alkyl) -O- (C of₁-C₄Alkyl of (C) -, (C)₁-C₄Alkyl) -CO-O- (C)₁-C₆Alkyl) -NH-CO- (C)₁-C₄Alkyl of (C) -, (C)₁-C₆Alkyl) -CO-NH- (C)₁-C₄Alkyl) -, or,

Embodiment 4:

the thiadiazole isoxazoline compound having the structure shown in the formula (I) is selected from any one of the compounds listed in claim 5.

The thiadiazole isoxazoline compound provided by the invention has excellent weed removal effect and good safety to crops.

As mentioned above, a second aspect of the present invention provides a process for preparing the thiadiazole isoxazoline compound according to the first aspect, which comprises: in the presence of a first alkaline substance and a first solvent, a compound with a structure shown in a formula (II) and activated carbonic acid are subjected to a first reaction,

wherein the definition of each substituent in formula (II) corresponds to the same definition as in the aforementioned first aspect.

Preferably, the conditions of the first reaction include: the temperature is-10 ℃ to 10 ℃ and the time is 1-5 h.

According to the process of the present invention, the first basic substance can be selected within the wide range of the art, and is preferably selected from at least one of triethylamine, N-diisopropylethylamine, pyridine, 1, 8-diazabicycloundecen-7-ene, 4-dimethylaminopyridine, more preferably from triethylamine and/or N, N-diisopropylethylamine in order to be combined with the other reaction materials of the present invention to obtain thiadiazole isoxazolines of higher purity, yield and herbicidal activity.

According to the process of the present invention, the first solvent may be selected within a wide range in the art, and is preferably selected from at least one of acetone, toluene, xylene, dioxane, ethyl acetate, tetrahydrofuran and dichloroethane, more preferably from at least one of acetone, ethyl acetate and dioxane, in order to be combined with the other reaction materials of the present invention to obtain the thiadiazole isoxazoline compound having higher purity, yield and herbicidal activity.

According to the method of the present invention, the amount of the first solvent is not particularly limited, and may be an amount that provides a sufficient reaction environment for the contact reaction. Preferably, the first solvent is used in an amount of 1 to 15mL, more preferably 5 to 10mL, relative to 1mmol of formula (II).

According to the method of the present invention, the amounts of the formula (II), the active carbonic acid and the first basic substance can be adjusted within a wide range, and in order to obtain a thiadiazole isoxazoline compound having higher purity, yield and herbicidal activity, it is preferable that the molar ratio of the amounts of the formula (II), the active carbonic acid and the first basic substance is 1: 0.5-3: 1-5, more preferably, the molar ratio of the amounts of said formula (II), said activated carbonic acid and said first basic substance is 1: 0.5-1.5: 1-3.

According to the method of the present invention, the active carbonic acid can be selected within a wide range in the art, and is preferably selected from at least one of N' N-carbonyldiimidazole, phosgene, diphosgene, triphosgene, methyl chloroformate, ethyl chloroformate and phenyl chloroformate in order to be combined with the other reaction materials of the present invention to obtain thiadiazole isoxazolines having higher purity, yield and herbicidal activity.

The triphosgene has a structure represented by the following formula (III):

according to the method of the present invention, in order to obtain thiadiazole isoxazoline compound having higher purity, yield and herbicidal activity, preferably, the first reaction comprises: dissolving the compound with the structure shown in the formula (II) in the first solvent to obtain a first reaction material, dissolving the active carbonic acid and the first alkaline substance in the first solvent to obtain a second reaction material, gradually adding the second reaction material into the first reaction material within 0.1-0.5h to obtain a third reaction material, and contacting the third reaction material at-10-0 ℃ for 1-5 h.

In the process of the first reaction, preferably, the second reaction material is gradually added into the first reaction material to obtain a third reaction material, wherein the gradual addition does not distinguish laboratories, small tests, pilot tests and large tests, and the addition is finished within 0.1-0.5h according to the required dosage; more preferably within 0.1-0.3 h. The stepwise addition may be carried out in portions or at a uniform rate, preferably at a uniform rate. During the first reaction, preferably, the third reaction mass is first prepared and contacted at-10 ℃ to 0 ℃ for 1-5 h.

According to the method of the present invention, preferably, the material obtained by the contact reaction is purified to obtain the thiadiazole isoxazoline compound represented by the formula (I). The purification method is not particularly limited, and may be carried out according to a method conventional in the art, for example, the material obtained by the contact reaction is sequentially subjected to extraction, washing, drying and solvent removal, and the extraction may be carried out, for example, by adding a mixture of water and an organic solvent (e.g., ethyl acetate) and then extracting with an organic solvent; the washing may be performed, for example, with a saturated saline solution; the drying may be carried out, for example, with a solid drying agent (e.g., anhydrous sodium sulfate, anhydrous magnesium sulfate, and molecular sieves); the solvent removal can be carried out, for example, by concentrating the solvent under reduced pressure.

According to a preferred embodiment, the method further comprises preparing a compound having the structure of formula (II) by a process comprising the steps of: a second reaction of the compound represented by the formula (IV) with a pyridazine compound in the presence of a second solvent and a second basic substance,

wherein, the definition of each substituent in the formula (II) is the same as the definition of the corresponding substituent in the thiadiazole isoxazoline compound according to the first aspect.

Preferably, the conditions of the second reaction include: the temperature is-10 ℃ to 30 ℃ and the time is 1-5 h.

According to the process of the present invention, the second basic substance can be selected within a wide range in the art, and is preferably selected from one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, triethylamine, N-diisopropylethylamine, pyridine, 1, 8-diazabicycloundecen-7-ene, 4-dimethylaminopyridine, more preferably sodium hydroxide and/or potassium hydroxide, in order to be combined with the other reaction materials of the present invention to obtain thiadiazole isoxazoline compounds having higher purity, yield and herbicidal activity.

According to the process of the present invention, the second solvent can be selected within a wide range in the art, and is preferably selected from one or more of water, acetone, toluene, xylene, dioxane, ethyl acetate, tetrahydrofuran and dichloroethane, more preferably from one or more of water, acetone, toluene and xylene, in order to be combined with the other reaction materials of the present invention to obtain the thiadiazole isoxazoline compound having higher purity, yield and herbicidal activity.

According to the method of the present invention, the amount of the second solvent is not particularly limited, and may be an amount that provides a sufficient reaction environment for the contact reaction. Preferably, the second solvent is used in an amount of 1 to 15mL, more preferably 5 to 10mL, relative to 1mmol of formula (IV).

According to the method of the present invention, the pyridazine compound may be selected within a wide range in the art, and in order to be mixed with the other reaction materials of the present invention to obtain the thiadiazole isoxazoline compound having higher purity, yield and herbicidal activity, the pyridazine compound is preferably selected from at least one of pyridazine, pyridazine monohydrochloride and pyridazine dihydrochloride.

The pyridazine dihydrochloride has a structure represented by the following formula (V):

according to the method of the present invention, the amounts of the pyridazine compound represented by formula (IV), the pyridazine compound and the second basic substance may be adjusted within a wide range, and in order to obtain a thiadiazole isoxazoline compound having higher purity, yield and herbicidal activity, it is preferable that the molar ratio of the amounts of the pyridazine compound represented by formula (IV), the pyridazine compound and the second basic substance is 1: 1-3: 2-5, more preferably, the molar ratio of the amounts of the formula (IV), the pyridazine compound and the second basic substance used is 1: 1-1.5: 3-4.

According to the method of the present invention, in order to obtain thiadiazole isoxazoline compound having higher purity, yield and herbicidal activity, preferably, the second reaction comprises: dissolving the formula (IV) in the second solvent to obtain a first reaction material I, dissolving the pyridazine compound and the second basic substance in the second solvent to obtain a second reaction material II, gradually adding the second reaction material II into the first reaction material I within 0.1-0.5h to obtain a third reaction material III, and contacting the third reaction material III at 0-30 ℃ for 1-5 h.

In the process of the second reaction, preferably, the second reaction material II is gradually added into the first reaction material I to obtain a third reaction material III, and the gradual addition does not distinguish laboratories, small tests, middle tests and large tests, and the addition is finished within 0.1-0.5h according to the required dosage; more preferably within 0.1-0.3 h. The stepwise addition may be carried out in portions or at a uniform rate, preferably at a uniform rate.

During the second reaction, the third reaction material III is preferably prepared and contacted for 1-5h at 0-30 ℃.

According to the method of the present invention, preferably, the material obtained from the second reaction is purified to obtain a compound having a structure represented by formula (II). The purification method is not particularly limited, and may be carried out according to a method conventional in the art, for example, the material obtained by the second reaction is sequentially subjected to extraction, washing, drying and solvent removal, and the extraction may be carried out, for example, by adding a mixture of water and an organic solvent (e.g., ethyl acetate) and then extracting with an organic solvent; the washing may be performed, for example, with a saturated saline solution; the drying may be carried out, for example, with a solid drying agent (e.g., anhydrous sodium sulfate, anhydrous magnesium sulfate, and molecular sieves); the solvent removal can be carried out, for example, by concentrating the solvent under reduced pressure.

According to the process of the present invention, the compound represented by the formula (IV) can be obtained commercially or by the laboratory.

Preferably, the method further comprises preparing a compound having the structure shown in formula (IV) by a method comprising: a third reaction of the compound of formula (VI) with thiophosgene of formula (VII) in the presence of a third solvent and a third basic substance,

wherein, the definition of each substituent in the formula (II) is the same as the definition of the corresponding substituent in the thiadiazole isoxazoline compound described in the first aspect.

Preferably, the conditions of the third reaction include: the temperature is between-10 ℃ and 110 ℃ and the time is between 2 and 8 hours.

In the third reaction process, the amounts of the third basic substance, the formula (VI) and the formula (VII) may be adjusted within a wide range, and in order to obtain the thiadiazole isoxazoline compound having better purity and yield of the formula (IV) and higher herbicidal activity, it is preferable that the molar ratio of the amounts of the formula (VI), the formula (VII) and the third basic substance is 1: 1-3: 1-5, more preferably 1: 2-3: 2-4.

During the third reaction, the third basic substance may be selected within the scope of the art, and in order to obtain a thiadiazole isoxazoline compound of formula (IV) having better purity and yield and higher herbicidal activity in combination with the other reaction materials of the present invention, the third basic substance is preferably selected from one or more of triethylamine, N-diisopropylethylamine, pyridine, 1, 8-diazabicycloundece-7-ene, 4-dimethylaminopyridine, and more preferably from one or more of triethylamine, N-diisopropylethylamine, and pyridine.

In the third reaction, the amount of the third solvent used is not particularly limited, and may be sufficient to provide a reaction environment for the reaction of preparing the formula (IV). Preferably, the third solvent is used in an amount of 1 to 10mL, more preferably 5 to 10mL, relative to 1mmol of formula (VI).

In the above process for preparing formula (IV), in order to obtain formula (IV) with better purity and yield and to obtain thiadiazole isoxazoline compound with higher herbicidal activity, preferably, the third reaction process comprises: dissolving the formula (VII) in the third solvent to obtain a reaction material 1-II, mixing the formula (VI) with the third alkaline substance to obtain a reaction material 1-I, gradually adding the reaction material 1-I into the reaction material 1-II within 0.1-0.5h, and then sequentially carrying out three-stage reaction: the first stage of reaction, the contact reaction is carried out for 0.2 to 0.8h at the temperature of between 4 ℃ below zero and 10 ℃; the second stage reaction, the contact reaction is carried out for 0.2 to 0.8h at the temperature of between 15 and 30 ℃; and (3) carrying out a third stage of reaction, namely heating for reflux reaction for 2-8 h.

In the above process for preparing formula (IV), preferably, the reaction mass 1-II is gradually added to the reaction mass 1-I, the gradual addition does not distinguish between laboratory, pilot plant and pilot plant, and is completed within 0.1-0.5h according to the required amount; more preferably within 0.2-0.3 h. The stepwise addition may be carried out in portions or at a uniform rate, preferably at a uniform rate.

In the above process for preparing formula (IV), in order to obtain formula (IV) with better purity and yield and to obtain thiadiazole isoxazoline compounds with higher herbicidal activity, it is preferable to sequentially perform three-stage reactions at different temperatures and times.

More preferably, the conditions of the first stage reaction include: the contact reaction is carried out for 0.1 to 2 hours at the temperature of between 10 ℃ below zero and 20 ℃.

More preferably, the conditions for the second stage reaction include: the contact reaction is carried out for 0.1 to 2 hours at the temperature of between 10 and 50 ℃.

More preferably, the conditions for the third stage reaction include: the contact reaction is carried out for 2 to 8 hours at the temperature of between 50 and 110 ℃.

The compound shown in the formula (VI) can be obtained commercially or by preparation, and can be obtained by using reducing agents such as iron, zinc, palladium carbon, stannous oxide and the like according to a conventional method, and specifically, reference can be made to EP 2044006; US20070155738 and the like.

The method for preparing thiadiazole isoxazoline compounds provided by the invention can further comprise post-treatment means known in the art, such as filtration, recrystallization, column chromatography, washing, drying and the like, preferred embodiments are exemplified in the subsequent examples of the invention, and a person skilled in the art should not be understood as limiting the scheme of the invention.

As mentioned above, the third aspect of the present invention provides the use of the thiadiazole isoxazoline compound according to the first aspect described above for controlling weeds.

The weeds of the present invention are plants that grow in a place that is harmful to human survival and activity, and may be non-cultivated wild plants or plants that are not useful to humans. For example, various wild plants in the field in which the crop is planted may be used.

Preferably, the weeds are broadleaf weeds and/or grassy weeds. The thiadiazole isoxazoline compound has good herbicidal activity when being used for controlling broadleaf weeds and/or grassy weeds.

Preferably, the broadleaf weeds are at least one selected from abutilon, amaranth retroflexus, amaranth with concave head, purslane, seedling of pig vine, garden sorrel, field thistle, shepherd's purse, rice tile, sow thistle, endive, lawy grass (larval seedling), cocklebur, sowthistle, polygonum leaf, bindweed, and thrashing flower.

Preferably, the grassy weeds are at least one selected from the group consisting of barnyard grass, large crabgrass, green bristlegrass, wild oat, arthroncus, alopecurus, carex, bluegrass, beckmannia, eleusine indica, and the like.

According to the use of the present invention, in order to achieve a better weed control effect, the thiadiazole isoxazoline compound is preferably used in an amount of 5 to 100 g/ha, more preferably 10 to 37.5 g/ha.

According to the application of the invention, in order to achieve better weed control effect, the thiadiazole isoxazoline compound is preferably dissolved in an organic solvent to prepare an organic solution for use. The solvent for dissolving the isoxazoline fragment-containing thiadiazole compound is preferably one or more selected from the group consisting of N, N-dimethylformamide, dimethyl sulfoxide, toluene, xylene and acetone.

Preferably, the concentration of the organic solution of the thiadiazole isoxazoline compound obtained by dissolution is 0.005 to 0.2g/L, more preferably 0.03 to 0.08 g/L.

According to the use of the present invention, in order to achieve a better effect of controlling weeds, it is preferable to use an organic solution of the above thiadiazole isoxazoline compound diluted with water or an aqueous solution. Further preferably, the volume ratio of the organic solution of the thiadiazole isoxazoline compound to water or the aqueous solution is 1: 1-100, more preferably 1: 5-60.

The thiadiazole isoxazoline compound can be used alone or used in combination with other additives or herbicides.

As described above, the fourth aspect of the present invention provides a herbicide containing the thiadiazole isoxazoline compound according to the first aspect.

Preferably, the content of the thiadiazole isoxazoline compound is 0.5-90 wt% based on the weight of the herbicide; more preferably, the content of the thiadiazole isoxazoline compound is 0.5 to 75 wt%; more preferably, the content of the thiadiazole isoxazoline compound is 5 to 60% by weight.

According to the herbicide, other common additives in the field, such as carriers, surfactants and the like, can also be contained in the herbicide. The amount of adjuvant may be selected in a manner conventional in the art.

The herbicide according to the invention may also contain other active ingredients, for example selected from 2, 4-D-butyl ester, clodinafop-propargyl, pinoxaden, carfentrazone-ethyl, butafenacil, isoprothiolane, diflufenzopyr, cyhalofop-butyl, indoxyl, flumiclorac-methyl, oxadiazon, oxadiargyl, clomazone, mesotrione, bisphenoxydim, pendimethalin, trifluralin, benazolin, acifluorfen-ethyl, aclonifen, metofen-ethyl, fluroxypyr, oxyfluorfen, pyrithiobac-sodium, fomesafen, fluoroglycofen-ethyl, pyrithiobac-methyl, pyribenzoxim, pyraclonil, florasulam, alachlor, metolachlor, pretilachlor, butachlor, mefenacet, quinclorac, lactofen, halofop-ethyl, haloxyfop-p-ethyl, and pyraflufen-ethyl, Oxadiargyl, quizalofop-p-ethyl, haloxyfop-p-methyl, cyhalofop-butyl, prometryn, ametryn, atrazine, clethodim, mesotrione, amicarbazone, sethoxydim, isoproturon, nicosulfuron, rimsulfuron, pyrazosulfuron-ethyl, bensulfuron-methyl, ethametsulfuron-methyl, thifensulfuron-methyl, imazasulfuron, trifloxysulfuron sodium, sulfosulfuron-methyl, cyclosulfamuron, amidosulfuron, flupyrsulfuron-methyl, broadleaf blight, paraquat, benazolin, wheatgrass, diquat, diuron, imazethapyr, 2-methyl-4-sodium chloride, arba, saflufenacil, propyzamide, phoxim, sulfofop, glufosinate, glyphosate and glufosinate.

When the thiadiazole isoxazoline compound disclosed by the invention is matched with one or more active ingredients, a good compounding effect can be realized, so that the effect of the activity, safety and application range (the type of the weed to be controlled) of controlling the weed is far more than the sum of the activity, safety and application range of the weed to be controlled, namely, an obvious synergistic effect is realized.

The method of use of the herbicide of the present invention may be according to conventional methods in the art, for example, spraying the herbicide onto the stems and/or leaves of weeds, or onto the soil surface.

The herbicide has good safety to crops, and does not need to specially avoid the crops during spraying.

The thiadiazole isoxazoline compound provided by the invention also has the following specific advantages:

(1) can be used at ultra-low dosage to generate very excellent weeding effect;

(2) the crop safety is higher, and the weeds in the crop field can be effectively removed on the premise of ensuring the safe growth of the crops.

Therefore, the thiadiazole isoxazoline compound provided by the invention is particularly suitable for preventing and removing weeds in crop fields during the growth of crops.

The present invention will be described in detail below by way of examples. In the following examples, the various starting materials used in the examples are commercially available and are of analytical grade, unless otherwise specified.

The room temperature in the following examples represents 25. + -. 3 ℃ unless otherwise specified.

Example 1: preparation of Compound 3

The specific process comprises the following steps:

0.206mol of a3-1 compound was dissolved in 200mL of ethanol, cooled to 0 ℃ and added dropwise with stirring to 0.25mol of an aqueous solution of hydroxylamine hydrochloride, followed by warming to room temperature and stirring to react. After 2 hours, the reaction was complete by TLC, poured into water and filtered to give a3-2 as a solid.

The a3-2 compound was dissolved in 150mL of N, N-dimethylformamide, warmed to 35 deg.C, at which temperature 0.24mol of NCS (N-chlorosuccinimide) was added in portions, and the solution was allowed to react for 1 hour while maintaining at 35 deg.C to give a material containing the a3-3 compound. Then, the temperature was lowered to room temperature, 300mL of ethyl acetate was added, followed by washing twice with 1N hydrochloric acid, washing twice with saturated brine, drying over anhydrous magnesium sulfate, suction filtration, lowering the ethyl acetate solution to 0 ℃ and dropwise adding a mixture of 0.3mol of ethyl methacrylate and 0.3mol of triethylamine, and the reaction was maintained at that temperature for 1 hour. Washing with 1N hydrochloric acid and saturated saline sequentially, drying the organic phase with anhydrous magnesium sulfate, desolventizing, and performing column chromatography to obtain a solid containing a3-4 compound.

Dissolving the a3-4 compound in 300mL of 90 vol% ethanol/water solution, heating to 60 ℃, adding 0.3mol of reduced iron powder in 3 batches, carrying out heat preservation reaction for 4 hours, cooling to room temperature after the reaction is finished, filtering, adding 200mL of saturated saline and 300mL of ethyl acetate after the filtrate is dried by spinning, violently stirring for 10min, separating an organic layer, washing the water layer once with 200mL of ethyl acetate, and combining the organic layers. Drying the organic layer, and removing the solvent under reduced pressure to obtain a3-5 compound.

0.009mol of thiophosgene is dissolved in 10mL of toluene and cooled to 0 ℃. A mixed solution of 0.003mol of the compound a3-5 prepared as described above and 0.003mol of triethylamine was added dropwise with stirring. Continuously controlling the temperature to be 0 ℃ for reaction for 0.5h, transferring to room temperature for reaction for 0.5h, then heating to reflux reaction for 4h, and monitoring the reaction completion by TLC. Cooling to room temperature, and concentrating under reduced pressure to remove the solvent to obtain a3-6 compound.

The a3-6 compound was dissolved in 10mL toluene and cooled to 0 ℃. A mixed solution of 0.003mol of pyridazine dihydrochloride, 0.009mol of sodium hydroxide and 20mL of water was added dropwise while stirring. After the dropwise addition, the reaction was carried out for 2 hours at room temperature, and the completion of the reaction was monitored by TLC. 100mL of saturated brine and 100mL of ethyl acetate were added, and the mixture was vigorously stirred for 10min, the organic layer was separated, the aqueous layer was washed once with 50mL of ethyl acetate, and the organic layers were combined. Drying the organic layer, and removing the solvent under reduced pressure to obtain a3-7 compound. Directly feeding the next step for reaction.

0.003mol of a3-7 compound was dissolved in 20mL of acetone and the temperature was reduced to 0 ℃. A mixed solution of 0.003mol of triphosgene, 0.0045mol of triethylamine and 10mL of acetone was added dropwise with stirring. The reaction was continued for 2h at 0 ℃ and monitored by TLC for completion. 100mL of saturated brine and 100mL of ethyl acetate were added, and the mixture was vigorously stirred for 10min, the organic layer was separated, the aqueous layer was washed once with 50mL of ethyl acetate, and the organic layers were combined. Drying with anhydrous sodium sulfate, concentrating under reduced pressure, and performing column chromatography to obtain solid, i.e. compound 3. The nuclear magnetic characterization is shown in Table 1.

Other embodiments

The process is carried out according to the method of example 1, except that the raw materials used are different, and for avoiding redundancy, the specific preparation method is not described in the remaining examples, and the characterization data of the obtained compounds are shown in table 1.

Comparative example

Compound a was prepared according to the procedure described in CN 105777733A.

A compound A:

TABLE 1

Test example 1: this test example serves to illustrate the effect of the compounds according to the invention on controlling weeds.

The herbicidal activity inhibition (%) (dose of 9.375 to 37.5 g/ha).

Test methods (potting method):

(1) inhibition of weed growth at a dose of 37.5 g/ha

The test targets are as shown in table 2, and the specific test method includes:

and (3) taking a flowerpot with the inner diameter of 6cm, filling composite soil (vegetable garden soil: seedling culture medium is 1:2, v/v) to the position 3/4 of the flowerpot, directly sowing the weed target (the bud rate is more than or equal to 85%), covering 0.2cm of soil, and waiting until weeds grow to about 3-leaf stage for later use. The compounds of the examples and comparative examples were dissolved in N, N-dimethylformamide and diluted with distilled water at a dose of 37.5 g/ha, respectively, to prepare a 0.2g/L solution, which was applied by an automatic spray tower (model: 3WPSH-700E, manufactured by Nanjing agricultural mechanization research institute), and after the solution on the leaf surface of weeds was dried in the air, the solution was transferred to a greenhouse for cultivation, and the inhibition rate of weed growth was investigated after 15 days. The method for calculating the inhibition rate of the growth of the weeds comprises the following steps

Wherein E is₁For inhibition of weed growth (%), C₁Fresh weight (in g) of aerial parts of control weed plants, T₁To treat the fresh weight (in g) of the aerial parts of the weed plants.

E₁The higher the value of (a), the stronger the inhibitory effect of the compound on weeds.

(2) Inhibition of weed growth at a dose of 18.75 g/ha

The test was conducted by referring to the test method in (1) above, except that the amount of the compound used in the examples and comparative examples was changed to 37.5 g/ha.

(3) Inhibition of weed growth at a dose of 9.375 g/ha

The test was conducted by referring to the test method in the above (1), except that the amount of the compound used in the examples and comparative examples was changed to 9.375 g/ha.

The test results are classified as follows and are recorded in table 2, and the classification method is as follows:

when 90% < E₁When the content is less than or equal to 100 percent, grade A is evaluated;

when 80% < E₁When the content is less than or equal to 90 percent, the grade B is evaluated;

when 60% < E₁When the content is less than or equal to 80 percent, the grade C is evaluated;

when 40% < E₁When the content is less than or equal to 60 percent, evaluating the grade D;

when E is₁And when the content is less than or equal to 40 percent, evaluating the grade E.

TABLE 2

From the results in table 2 it can be seen that the compounds according to the invention have a comparable or even better inhibition of weeds than the control compound a and methyl oxazinecarboxylate.

Test example 2: this test serves to illustrate the safety of the compounds of the invention against crop plants.

Corn, sorghum, and wheat were selected as test targets. The specific test method for the safety of the post-emergence crop comprises the following steps:

a flowerpot with the inner diameter of 9cm is taken, composite soil (vegetable garden soil: seedling raising matrix is 1:2, v/v) is filled to the 3/4 height of the flowerpot, and a crop target (the bud rate is more than or equal to 85%) is directly sowed for later use. After the application of the compounds of examples and comparative examples at a dose of 75 g/ha, respectively, in an automatic spray tower, the plants were transferred to a greenhouse and the inhibition of the growth of the plants was examined after 30 days.

The method for calculating the inhibition rate of the growth of the crops comprises the following steps:

wherein E is₂Inhibition of crop growth (% by C)₂Fresh weight in g, T of aerial parts of control crop plants₂For the treatment of the fresh weight (in g) of the aerial parts of the crop plants.

The test results are classified as follows and are shown in table 3, and the classification method is as follows:

when the content is less than or equal to 0 percent and less than or equal to E₂When the content is less than or equal to 5 percent, grade A is evaluated;

when 5% < E₂Rating B when the content is less than or equal to 10%;

when 10% < E₂When the content is less than or equal to 20 percent, the grade C is evaluated;

when 20% < E₂When the content is less than or equal to 30 percent, evaluating the grade D;

when 30% < E₂When the content is less than or equal to 50 percent, the grade E is evaluated;

when 50% < E₂When the content is less than or equal to 70 percent, evaluating the grade F;

when 70% < E₂When the content is less than or equal to 90 percent, evaluating the G grade;

when 90% < E₂When the content is less than or equal to 95 percent, evaluating the grade H;

when 95% < E₂And when the content is less than or equal to 100 percent, evaluating the grade I.

TABLE 3

Compound numbering	Corn (corn)	(sorghum)	Wheat (Triticum aestivum L.)
				2	A	D	A
3	B	-	A
				4	B	-	A
7	A	C	A
				9	B	C	A
16	-	D	A
				17	A	D	A
20	B	B	A
				23	B	-	A
24	B	D	A
				29	B	C	A
31	A	C	A
				32	B	C	A
Oxazine oxalic acid methyl ester	A	G	C

As can be seen from Table 3, the compounds of the present invention have good crop safety and show weak inhibition of the growth of corn and wheat, and are therefore particularly suitable for use in crop fields during crop growth. The contrast agent, methyl oxazinate, has very strong inhibitory effect on sorghum and therefore cannot be used on crops. Therefore, it can be seen that the compound of the present invention can achieve wider applications than oxazine methyl oxalate, and thus has strong practicability.

The preferred embodiments of the present invention have been described above in detail, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, many simple modifications can be made to the technical solution of the invention, including combinations of various technical features in any other suitable way, and these simple modifications and combinations should also be regarded as the disclosure of the invention, and all fall within the scope of the invention.

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