CN110511216B

CN110511216B - Isoxazoline derivatives and their use in agriculture

Info

Publication number: CN110511216B
Application number: CN201910422184.3A
Authority: CN
Inventors: 李义涛; 林健; 池伟林; 曾水明; 任佳宁; 邱鹏飞; 郭晓丹
Original assignee: Dongguan Hec Pesticides R&d Co ltd
Current assignee: Ningxia Jianpai Agrochemical Technology Co.,Ltd.
Priority date: 2018-05-22
Filing date: 2019-05-21
Publication date: 2020-09-11
Anticipated expiration: 2039-05-21
Also published as: CN110511216A; WO2019223664A1

Abstract

The invention provides isoxazoline derivatives and their use in agriculture; specifically, the present invention provides a compound represented by formula (Ia) or a stereoisomer, a nitrogen oxide or a salt thereof of the compound represented by formula (Ia), and a method for producing the same; wherein R is¹、R²、R³、R⁴、n、R⁵、R⁶X and Y have the meanings given in the description. Further, the present invention provides compositions containing these compounds and their use in agriculture, particularly as herbicidal active ingredients for controlling unwanted vegetation.

Description

Isoxazoline derivatives and their use in agriculture

Technical Field

The invention provides a novel isoxazoline derivative and a preparation method thereof; compositions containing these compounds and their use in agriculture.

Background

Isoxazolines are a class of compounds with excellent biological activity, and their herbicidal activity is reported, for example, in WO2002062770, WO 2003000686 and WO 2003010165. However, the compounds of the present invention described in detail hereinafter are not described in these documents.

The active ingredients known from the documents cited above have disadvantages in use, for example, (a) no or only insufficient herbicidal action on the weed plants, (b) too narrow a spectrum of weed plants to be controlled or (c) too low a selectivity in crops of useful plants.

Accordingly, there is a need to provide chemically active ingredients that can be advantageously used as herbicides or plant growth regulators.

Disclosure of Invention

The present invention provides a novel isoxazoline compound having excellent herbicidal action and excellent selectivity between crops and weeds.

In one aspect, the invention provides a compound of formula (Ia) or a stereoisomer, a nitroxide or a salt thereof:

wherein:

R¹and R²Each independently is hydrogen, fluoro, chloro, bromo, iodo, amino, nitro, cyano, hydroxy, carboxy, alkyl, haloalkyl, cycloalkyl, or cycloalkylalkyl; or R¹、R²And the carbon atoms to which they are attached form a ring consisting of 3 to 12 atoms;

R³and R⁴Each independently is hydrogen, bromine, iodine, amino, nitroHydroxyl, carboxyl, alkyl, cycloalkyl or cycloalkylalkyl; or R³、R⁴And the carbon atoms to which they are attached form a ring consisting of 3 to 12 atoms;

n is 0, 1 or 2;

R⁵and R⁶Each independently is hydrogen, fluoro, chloro, bromo, iodo, amino, nitro, cyano, hydroxy, carboxy, alkyl, alkenyl, or alkynyl; or R⁵、R⁶And the carbon atoms to which they are attached form a ring consisting of 3 to 12 atoms;

x is fluorine, chlorine or bromine;

y is alkyl, haloalkyl, alkoxyalkyl, alkylaminoalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -C (═ O) -alkyl, -S (═ O)₂-alkyl, -C (═ O) -cycloalkyl, -S (═ O)₂-cycloalkyl, -C (═ O) -heterocyclyl, -S (═ O)₂-heterocyclyl, -C (═ O) -aryl, -S (═ O)₂-aryl, -C (═ O) -heteroaryl or-S (═ O)₂-a heteroaryl group;

wherein Y is optionally selected from Y by 1,2,3, 4,5 or 6^aSubstituted with the substituent(s); each Y is^aIndependently fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocyclyl, aryl or heteroaryl;

with the following conditions:

(1) when Y is methyl, X is chlorine, R⁵And R⁶Are each hydrogen, n is 0, 1 or 2, R³And R⁴Are each hydrogen, R¹When it is methyl, R²Is not methyl or chloromethyl;

(2) when Y is methyl, X is chlorine, R⁵And R⁶Are each hydrogen, n is 0, 1 or 2, R³And R⁴Are each hydrogen, R²When it is methyl, R¹Is not methyl or chloromethyl;

(3) when Y is unsubstituted phenyl, X is chloro,R⁵and R⁶Are each hydrogen, n is 0, 1 or 2, R³And R⁴Are each hydrogen, R¹When it is methyl, R²Is not methyl or chloromethyl;

(4) when Y is unsubstituted phenyl, X is chlorine, R⁵And R⁶Are each hydrogen, n is 0, 1 or 2, R³And R⁴Are each hydrogen, R²When it is methyl, R¹Is not methyl or chloromethyl;

(5) when Y is ethyl or isopropyl, X is chlorine and in the 5-position of the pyrazole ring, R⁵And R⁶Are each hydrogen, n is 0 or 2, R³And R⁴Are each hydrogen, R¹When it is methyl, R²Is not chloromethyl; or

(6) When Y is ethyl or isopropyl, X is chlorine and in the 5-position of the pyrazole ring, R⁵And R⁶Are each hydrogen, n is 0 or 2, R³And R⁴Are each hydrogen, R²When it is methyl, R¹Is not chloromethyl.

In some of these embodiments, the present invention provides a compound that is a compound of formula (II) or a stereoisomer, a nitroxide, or a salt thereof of a compound of formula (II):

wherein:

x is fluorine, chlorine or bromine;

R³and R⁴Each independently is hydrogen, bromo, iodo, amino, nitro, hydroxy, carboxy, alkyl, cycloalkyl, or cycloalkylalkyl; or R³、R⁴And the carbon atoms to which they are attached form a ring consisting of 3 to 12 atoms;

n is 0, 1 or 2;

R⁸、R⁹、R¹⁰、R¹¹and R¹²Each independently is hydrogen, fluoro, chloro, bromo, iodo, amino, nitro, cyano, hydroxy, carboxy, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocyclyl, aryl or heteroaryl;

or R⁸、R⁹And the carbon atoms to which they are attached form an optionally substituted ring of 3 to 12 atoms;

or R⁸、R⁹And the carbon atom to which it is attached, form-C (═ O) -;

or R¹⁰、R¹¹、R¹²Together with the carbon atom to which they are attached form-C.ident.CR¹³or-CR¹⁴＝CR¹⁵R¹⁶(ii) a Wherein R is¹³、R¹⁴、R¹⁵And R¹⁶Each independently is hydrogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl;

or R¹⁰、R¹¹、R¹²Together with the carbon atom to which they are attached form optionally substituted C_6-14Aryl, optionally substituted C_1-9Heteroaryl, optionally substituted C_3-12Cycloalkyl or optionally substituted C_2-12A heterocyclic group;

or-CR⁸R⁹-CR¹⁰R¹¹R¹²Represents optionally substituted C_10-14Aryl, optionally substituted C_1-9Heteroaryl, optionally substituted C_3-12Cycloalkyl, optionally substituted C_2-12Heterocyclyl, unsubstituted phenyl or substituted phenyl;

the number of the substituted or optional substituted groups is 1,2,3, 4,5 or 6; the substituents may be the same or different; wherein the substituent is fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocyclyl, aryl or heteroaryl;

with the following conditions:

(a) when-CR⁸R⁹-CR¹⁰R¹¹R¹²Represents unsubstituted phenyl, X is chlorine, R⁵And R⁶Are each hydrogen, n is 0, 1 or 2, R³And R⁴Are each hydrogen, R¹When it is methyl, R²Is not methyl or chloromethyl;

(b) when-CR⁸R⁹-CR¹⁰R¹¹R¹²Represents unsubstituted phenyl, X is chlorine, R⁵And R⁶Are each hydrogen, n is 0, 1 or 2, R³And R⁴Are each hydrogen, R²When it is methyl, R¹Is not methyl or chloromethyl;

(c) when-CR⁸R⁹-CR¹⁰R¹¹R¹²Represents ethyl or isopropyl, X is chlorine and in the 5-position of the pyrazole ring, R⁵And R⁶Are each hydrogen, n is 0 or 2, R³And R⁴Are each hydrogen, R¹When it is methyl, R²Is not chloromethyl; or

(d) when-CR⁸R⁹-CR¹⁰R¹¹R¹²Represents ethyl or isopropyl, X is chlorine and in the 5-position of the pyrazole ring, R⁵And R⁶Are each hydrogen, n is 0 or 2, R³And R⁴Are each hydrogen, R²When it is methyl, R¹Is not chloromethyl.

In some of these embodiments, the present invention provides a compound that is a compound of formula (IIa) or a stereoisomer, a nitrogen oxide, or a salt thereof, of a compound of formula (IIa):

wherein: r¹、R²、R³、R⁴、R⁵、R⁶、R⁸、R⁹、R¹⁰、R¹¹And R¹²Have the meaning as described in the present invention.

In still other embodiments, the invention provides a compound that is a compound of formula (IIa) or a stereoisomer, a nitrogen oxide, or a salt thereof, of a compound of formula (IIa), wherein:

R¹and R²Each independently is hydrogen, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-6Alkyl, halo C_1-6Alkyl radical, C_3-6Cycloalkyl or C_3-6Cycloalkyl radical C_1-6An alkyl group; or R¹、R²And the carbon atoms to which they are attached form a ring consisting of 3 to 8 atoms;

R³and R⁴Each independently is hydrogen, bromine, iodine, amino, nitro, hydroxyl, carboxyl, C_1-6Alkyl radical, C_3-6Cycloalkyl or C_3-6Cycloalkyl radical C_1-6An alkyl group; or R³、R⁴And the carbon atoms to which they are attached form a ring consisting of 3 to 8 atoms;

R⁵and R⁶Each independently is hydrogen, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-6Alkyl radical, C_2-6Alkenyl or C_2-6An alkynyl group; or R⁵、R⁶And the carbon atoms to which they are attached form a ring consisting of 3 to 8 atoms;

R⁸、R⁹、R¹⁰、R¹¹and R¹²Each independently is hydrogen, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl, halo C_2-6Alkenyl radical, C_2-6Alkynyl, halo C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_3-6Cycloalkyl radical, C_2-8Heterocyclic group, C_6-10Aryl or C_1-9A heteroaryl group;

or R⁸、R⁹And the carbon atoms to which they are attached form an optionally substituted ring of 3 to 10 atoms;

or R⁸、R⁹And the carbon atom to which it is attached, form-C (═ O) -;

or R¹⁰、R¹¹、R¹²Together with the carbon atom to which they are attached form-C.ident.CR¹³or-CR¹⁴＝CR¹⁵R¹⁶(ii) a Wherein R is¹³、R¹⁴、R¹⁵And R¹⁶Each independently is hydrogen, C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl, halo C_2-6Alkenyl radical, C_2-6Alkynyl or halo C_2-6An alkynyl group;

or R¹⁰、R¹¹、R¹²Together with the carbon atom to which they are attached form optionally substituted C_6-14Aryl, optionally substituted C_1-9Heteroaryl, optionally substituted C_3-10Cycloalkyl or optionally substituted C_2-10A heterocyclic group;

or-CR⁸R⁹-CR¹⁰R¹¹R¹²Represents optionally substituted C_10-14Aryl, optionally substituted C_1-9Heteroaryl, optionally substituted C_3-10Cycloalkyl, optionally substituted C_2-10Heterocyclyl, unsubstituted phenyl or substituted phenyl;

the number of the substituted or optional substituted groups is 1,2,3, 4,5 or 6; the substituents may be the same or different; wherein the substituent is fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl, halo C_2-6Alkenyl radical, C_2-6Alkynyl, halo C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_3-8Cycloalkyl radical, C_2-10Heterocyclic group, C_6-14Aryl or C_1-9A heteroaryl group;

with the following conditions:

(a) when-CR⁸R⁹-CR¹⁰R¹¹R¹²Represents unsubstituted phenyl, R⁵And R⁶Are each hydrogen, R³And R⁴Are each hydrogen, R¹When it is methyl, R²Is not methyl or chloromethyl;

(b) when-CR⁸R⁹-CR¹⁰R¹¹R¹²Represents unsubstituted phenyl, R⁵And R⁶Are each hydrogen, R³And R⁴Are each hydrogen, R²When it is methyl, R¹Is not methyl or chloromethyl;

(c) when-CR⁸R⁹-CR¹⁰R¹¹R¹²Represents ethyl or isopropyl, R⁵And R⁶Are each hydrogen, R³And R⁴Are each hydrogen, R¹When it is methyl, R²Is not chloromethyl; or

(d) when-CR⁸R⁹-CR¹⁰R¹¹R¹²Represents ethyl or isopropyl, R⁵And R⁶Are each hydrogen, R³And R⁴Are each hydrogen, R²When it is methyl, R¹Is not chloromethyl.

In some of these embodiments, the present invention provides a compound that is a compound of formula (IIb) or a stereoisomer, a nitroxide, or a salt thereof of a compound of formula (IIb):

In still other embodiments, the present invention provides a compound that is a compound of formula (IIb) or a stereoisomer, a nitroxide or a salt thereof, of a compound of formula (IIb), wherein:

R¹and R²Each independently is hydrogen, fluorine, chlorine, bromine, iodine, amino, nitro, cyanoRadical, hydroxyl, carboxyl, C_1-6Alkyl, halo C_1-6Alkyl radical, C_3-6Cycloalkyl or C_3-6Cycloalkyl radical C_1-6An alkyl group; or R¹、R²And the carbon atoms to which they are attached form a ring consisting of 3 to 8 atoms;

or R⁸、R⁹And the carbon atom to which it is attached, form-C (═ O) -;

with the following conditions:

(a) when-CR⁸R⁹-CR¹⁰R¹¹R¹²Represents unsubstituted phenyl, R⁵And R⁶Are each hydrogen, R³And R⁴Are each hydrogen, R¹When it is methyl, R²Is not methyl or chloromethyl; or

(b) when-CR⁸R⁹-CR¹⁰R¹¹R¹²Represents unsubstituted phenyl, R⁵And R⁶Are each hydrogen, R³And R⁴Are each hydrogen, R²When it is methyl, R¹Not methyl or chloromethyl.

In some of these embodiments, the present invention provides a compound that is a compound of formula (IIc) or a stereoisomer, nitroxide, or salt thereof of a compound of formula (IIc):

In still other embodiments, the present invention provides a compound that is a compound of formula (IIc) or a stereoisomer, a nitroxide or a salt thereof, of a compound of formula (IIc), wherein:

R⁸、R⁹、R¹⁰、R¹¹and R¹²Each independently of the others is hydrogen, fluorine, chlorine, bromineIodine, amino, nitro, cyano, hydroxy, carboxy, C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl, halo C_2-6Alkenyl radical, C_2-6Alkynyl, halo C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_3-6Cycloalkyl radical, C_2-8Heterocyclic group, C_6-10Aryl or C_1-9A heteroaryl group;

or R⁸、R⁹And the carbon atom to which it is attached, form-C (═ O) -;

the number of the substituted or optional substituted groups is 1,2,3, 4,5 or 6; the substituents may be the same or different; wherein the substituent is fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-6Alkyl, halo C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,C_2-6Alkenyl, halo C_2-6Alkenyl radical, C_2-6Alkynyl, halo C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_3-8Cycloalkyl radical, C_2-10Heterocyclic group, C_6-14Aryl or C_1-9A heteroaryl group.

In some of these embodiments, the present invention provides a compound that is a compound of formula (IId) or a stereoisomer, a nitroxide, or a salt thereof of a compound of formula (IId):

In still other embodiments, the present invention provides a compound that is a compound of formula (IId) or a stereoisomer, a nitroxide or a salt thereof, of a compound of formula (IId), wherein:

or R⁸、R⁹And the carbon atom to which it is attached, form-C (═ O) -;

or-CR⁸R⁹-CR¹⁰R¹¹R¹²Represents optionally substituted C_10-14Aryl, optionally substituted C_1-9Heteroaryl, optionally substituted C_3-10Cycloalkyl, optionally substituted C_2-10Heterocyclic radical, notSubstituted phenyl or substituted phenyl;

the number of the substituted or optional substituted groups is 1,2,3, 4,5 or 6; the substituents may be the same or different; wherein the substituent is fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl, halo C_2-6Alkenyl radical, C_2-6Alkynyl, halo C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_3-8Cycloalkyl radical, C_2-10Heterocyclic group, C_6-14Aryl or C_1-9A heteroaryl group.

In some of these embodiments, the present invention provides a compound which is a compound represented by formula (II-1) or a stereoisomer, a nitroxide or a salt thereof of a compound represented by formula (II-1):

wherein:

n is 0, 1 or 2;

x is fluorine, chlorine or bromine;

R⁸and R⁹Each independently is hydrogen, fluoro, chloro, bromo, iodo, amino, nitro, cyano, hydroxy, carboxy, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocyclyl, aryl or heteroaryl;

R¹³is hydrogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl.

In some embodiments, the invention provides a compound that is a compound of formula (IIa-1) or a stereoisomer, nitroxide, or salt thereof of a compound of formula (IIa-1):

wherein: r¹、R²、R³、R⁴、R⁵、R⁶、R⁸、R⁹And R¹³Have the meaning as described in the present invention.

In still other embodiments, the present invention provides a compound that is a compound of formula (IIa-1) or a stereoisomer, nitroxide or salt thereof of a compound of formula (IIa-1), wherein:

R⁸and R⁹Each independently is hydrogen, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl, halo C_2-6Alkenyl radical, C_2-6Alkynyl, halo C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_3-6Cycloalkyl radical, C_2-8Heterocyclic group, C_6-10Aryl or C_1-9A heteroaryl group;

R¹³is hydrogen, C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl, halo C_2-6Alkenyl radical, C_2-6Alkynyl or halo C_2-6Alkynyl.

In some embodiments, the invention provides a compound that is a compound of formula (IIa-2) or a stereoisomer, nitroxide, or salt thereof of a compound of formula (IIa-2):

In still other embodiments, the present invention provides a compound that is a compound of formula (IIa-2) or a stereoisomer, nitroxide or salt thereof of a compound of formula (IIa-2), wherein:

In some of these embodiments, the present invention provides a compound that is a compound represented by formula (II-5) or a stereoisomer, a nitroxide or a salt thereof of a compound represented by formula (II-5):

wherein:

n is 0, 1 or 2;

x is fluorine, chlorine or bromine;

with the following conditions:

(i) when X is chlorine, R⁵And R⁶Are each hydrogen, n is 0, 1 or 2, R³And R⁴When both are hydrogen, R¹And R²Cannot be simultaneously methyl;

(ii) when X is chlorine and is in the 5-position of the pyrazole ring, R⁵And R⁶Are each hydrogen, n is 0, 1 or 2, R³And R⁴Are each hydrogen, R²When it is methyl, R¹Is not chloromethyl; or

(iii) When X is chlorine and is in the 5-position of the pyrazole ring, R⁵And R⁶Are each hydrogen, n is 0, 1 or 2, R³And R⁴Are each hydrogen, R¹When it is methyl, R²Is not chloromethyl.

In some embodiments, the invention provides a compound that is a compound of formula (IIa-17) or a stereoisomer, nitroxide, or salt thereof of a compound of formula (IIa-17):

wherein: r¹、R²、R³、R⁴、R⁵、R⁶And X has the meaning as described in the present invention.

In still other embodiments, the present invention provides a compound that is a compound of formula (IIa-17) or a stereoisomer, nitroxide or salt thereof of a compound of formula (IIa-17), wherein:

x is fluorine, chlorine or bromine;

with the following conditions:

(1) when X is chlorine, R⁵And R⁶Are each hydrogen, R³And R⁴When both are hydrogen, R¹And R²Cannot be simultaneously methyl;

(2) when X is chlorine, R⁵And R⁶Are each hydrogen, R³And R⁴Are each hydrogen, R²When it is methyl, R¹Is not chloromethyl; or

(3) When X is chlorine, R⁵And R⁶Are each hydrogen, R³And R⁴Are each hydrogen, R¹When it is methyl, R²Is not chloromethyl.

In some embodiments, the invention provides a compound that is a compound of formula (IIa-18) or a stereoisomer, nitroxide, or salt thereof of a compound of formula (IIa-18):

In still other embodiments, the present invention provides a compound that is a compound of formula (IIa-18) or a stereoisomer, nitroxide or salt thereof of a compound of formula (IIa-18), wherein:

x is fluorine, chlorine or bromine;

with the following conditions:

(1) when X is chlorine, R⁵And R⁶Are each hydrogen, R³And R⁴When both are hydrogen, R¹And R²And not both methyl groups.

In other embodiments, R¹And R²Each independently is hydrogen, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-4Alkyl, halo C_1-4Alkyl radical, C_3-6Cycloalkyl or C_3-6Cycloalkyl radical C_1-3An alkyl group; or R¹、R²And the carbon atoms to which they are attached form a ring consisting of 3 to 6 atoms;

R³and R⁴Each independently is hydrogen, bromine, iodine, amino, nitro, hydroxyl, carboxyl, C_1-3Alkyl radical, C_3-6Cycloalkyl or C_3-6Cycloalkyl radical C_1-3An alkyl group; or R³、R⁴And the carbon atoms to which they are attached form a ring consisting of 3 to 6 atoms;

R⁵and R⁶Each independently is hydrogen, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-4Alkyl radical, C_2-4Alkenyl or C_2-4An alkynyl group; or R⁵、R⁶And together with the carbon atoms to which they are attached form a ring consisting of 3 to 6 atoms.

In other embodiments, R¹And R²Each independently is hydrogen, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, -CH₂F、-CH₂Cl、-CH₂Br or-CF₃；

R³And R⁴Each independently hydrogen or bromine;

R⁵and R⁶Each independently hydrogen, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl or methyl.

In still other embodiments, the invention provides a compound that is a compound of formula (IIIa) or a stereoisomer, nitroxide, or salt thereof of a compound of formula (IIIa):

wherein: r⁸、R⁹、R¹⁰、R¹¹And R¹²Have the meaning as described in the present invention.

In still other embodiments, the invention provides a compound that is a compound of formula (IIIb) or a stereoisomer, a nitroxide, or a salt thereof of a compound of formula (IIIb):

In still other embodiments, the invention provides a compound that is a compound of formula (IIIc) or a stereoisomer, a nitroxide, or a salt thereof of a compound of formula (IIIc):

In still other embodiments, the invention provides a compound that is a compound of formula (IIId) or a stereoisomer, a nitroxide, or a salt thereof of a compound of formula (IIId):

Other embodimentsIn the scheme, R⁸、R⁹、R¹⁰、R¹¹And R¹²Each independently is hydrogen, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-4Alkyl, halo C_1-4Alkyl radical, C_2-4Alkenyl, halo C_2-4Alkenyl radical, C_2-4Alkynyl, halo C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_1-4Alkylthio radical, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl or C_1-5A heteroaryl group;

or R⁸、R⁹And the carbon atoms to which they are attached form an optionally substituted ring of 3 to 8 atoms;

or R⁸、R⁹And the carbon atom to which it is attached, form-C (═ O) -;

or R¹⁰、R¹¹、R¹²Together with the carbon atom to which they are attached form-C.ident.CR¹³or-CR¹⁴＝CR¹⁵R¹⁶(ii) a Wherein R is¹³、R¹⁴、R¹⁵And R¹⁶Each independently is hydrogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_2-4Alkenyl, halo C_2-4Alkenyl radical, C_2-4Alkynyl or halo C_2-4An alkynyl group;

or R¹⁰、R¹¹、R¹²Together with the carbon atom to which they are attached form optionally substituted C_6-10Aryl, optionally substituted C_1-6Heteroaryl, optionally substituted C_3-8Cycloalkyl or optionally substituted C_2-6A heterocyclic group;

or-CR⁸R⁹-CR¹⁰R¹¹R¹²Represents optionally substituted C_10-14Aryl, optionally substituted C_1-6Heteroaryl, optionally substituted C_3-8Cycloalkyl, optionally substituted C_2-6Heterocyclyl, unsubstituted phenyl or substituted phenyl;

the number of the substituted or optional substituted groups is 1,2,3, 4,5 or 6; the substituents may be the same or different; wherein the substituents areIs fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-6Alkyl, halo C_1-4Alkyl radical, C_2-4Alkenyl, halo C_2-4Alkenyl radical, C_2-4Alkynyl, halo C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_1-4Alkylthio radical, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl or C_1-5A heteroaryl group.

In other embodiments, R⁸、R⁹、R¹⁰、R¹¹And R¹²Each independently is hydrogen, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxy, carboxy, -CH₃、-CH₂CH₃、-CH₂CH₂CH₃、-CH(CH₃)₂、-CH₂F、-CHF₂、-CH₂Cl、-CH₂Br、-CF₃、-CH₂CF₃、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CH₂Br、-CH₂CHF₂、-CH₂CH₂CF₃、-CH₂CH₂CH₂F、-CH₂CH₂CH₂Cl、-CH₂CH₂CH₂Br、-CHFCH₂CH₃、-CHClCH₂CH₃、-CH＝CH₂、-CH₂CH＝CH₂、CH₃-CH＝CH-、-C≡CH、-C≡CCH₃、-CH₂-C≡CH、-OCH₃、-OCH₂CH₃、-OCH₂CH₂CH₃、-OCH(CH₃)₂、-NHCH₃、-N(CH₃)₂、-SCH₃、-SCH₂CH₃、-SCH₂CH₂CH₃Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl;

or R⁸、R⁹Together with the carbon atom to which they are attached form C_3-6A cycloalkyl group;

or R⁸、R⁹Together with the carbon atom to which they are attached form-C(＝O)-；

Or R¹⁰、R¹¹、R¹²Together with the carbon atom to which they are attached form-C ≡ CH or-CH ═ CH₂；

Or R¹⁰、R¹¹、R¹²Together with the carbon atom to which they are attached form C_3-6Cycloalkyl, phenyl optionally substituted by halogen or C containing one oxygen_2-6A heterocyclic group;

or-CR⁸R⁹-CR¹⁰R¹¹R¹²Is represented by C_3-6Cycloalkyl or halogen substituted phenyl.

In some of these embodiments, the present invention provides a compound that is a compound of formula (IIIe) or a stereoisomer, a nitroxide, or a salt thereof of a compound of formula (IIIe):

wherein:

R⁵and R⁶Each independently is hydrogen or fluorine;

x is fluorine or chlorine;

R^mis hydrogen, C_1-3Alkyl or halo C_1-3An alkyl group;

R^vis hydrogen, C_1-3Alkyl or halo C_1-3An alkyl group;

R^wis C_1-3Alkyl or halo C_1-3An alkyl group.

In still other embodiments, the invention provides a compound that is a compound of formula (IIIe) or a stereoisomer, nitroxide, or salt thereof, of a compound of formula (IIIe), wherein R is^mIs hydrogen or methyl; r^vIs hydrogen or methyl; r^wIs methyl, isopropyl, difluoromethyl or tetrafluoroethyl.

In some of these embodiments, the present invention provides a compound that is a compound of formula (IIIf) or a stereoisomer, a nitroxide, or a salt thereof of a compound of formula (IIIf):

wherein:

R⁵and R⁶Each independently is hydrogen or fluorine;

x is fluorine or chlorine;

R^mis hydrogen, C_1-3Alkyl or halo C_1-3An alkyl group;

R^vis hydrogen, C_1-3Alkyl or halo C_1-3An alkyl group;

R^wis C_1-3Alkyl or halo C_1-3An alkyl group.

In still other embodiments, the invention provides a compound that is a compound of formula (IIIf) or a stereoisomer, nitroxide, or salt thereof, of a compound of formula (IIIf), wherein R is^mIs hydrogen or methyl; r^vIs hydrogen or methyl; r^wIs methyl, isopropyl, difluoromethyl or tetrafluoroethyl.

In some of these embodiments, the present invention provides a compound that is a compound of formula (IIIg) or a stereoisomer, a nitroxide, or a salt thereof of a compound of formula (IIIg):

wherein: x is fluorine or chlorine.

In some of these embodiments, the present invention provides a compound that is a compound of formula (IIIh) or a stereoisomer, a nitroxide, or a salt thereof of a compound of formula (IIIh):

wherein: x is fluorine, chlorine or bromine.

In another aspect, the present invention provides a composition comprising a compound of the present invention or a stereoisomer, a nitrogen oxide or a salt thereof, further optionally comprising at least one pesticidally acceptable adjuvant.

Further, the present invention provides a herbicidal composition comprising the compound of the present invention or a stereoisomer, a nitrogen oxide or a salt thereof as an active ingredient, and further optionally comprising at least one pesticidally acceptable adjuvant.

In another aspect, the invention provides the use of a compound of the invention or a composition comprising a compound of the invention in agriculture.

Further, the present invention provides use of the compound of the present invention or a composition containing the compound of the present invention for controlling a plant disease.

Further, the present invention provides the use of the compound of the present invention or a composition comprising the compound of the present invention for agricultural weeding.

In some of these embodiments, the present invention provides the use of a compound described herein or a composition comprising a compound described herein for controlling unwanted vegetation.

In yet another aspect, the present invention provides a method of controlling weed growth in useful plants comprising pre-emergence application to the locus of the weeds of an effective amount of a compound of the present invention.

In some embodiments, the weeds comprise broadleaf weeds and grasses. Further, the broadleaf weeds comprise piemarker, Amaranthus retroflexus or snakehead intestine; the grassy weeds include large crabgrass, barnyard grass or green bristlegrass.

In some of these embodiments, the useful plant comprises soybean, peanut, or sunflower.

In another aspect, the present invention provides a method for controlling undesired vegetation by applying an effective amount of a compound according to the invention to the plants, to the seeds of the plants, to the soil in or on which the plants are grown, or to the area of cultivation.

The compounds of formula (Ia), formula (II), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (II-1), formula (IIa-2), formula (II-5), formula (IIa-17), formula (IIa-18), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IIIe), formula (IIIf), formula (IIIg) or formula (IIIh) may exist in different stereoisomers or optical isomers or tautomeric forms. The invention encompasses all such isomers and tautomers and mixtures thereof in various ratios, as well as isotopic forms such as heavy hydrogen-containing compounds.

Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H，³H，¹¹C，¹³C，¹⁴C，¹⁵N，¹⁷O，¹⁸O，¹⁸F，³¹P，³²P，³⁵S，³⁶Cl and¹²⁵I。

any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration.

The foregoing has outlined only certain aspects of the present invention and is not intended to be limited in these or other respects to the details described herein.

Definitions for the detailed description of the invention and general terms

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. One skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions, as used herein, should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be found in the descriptions of "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and JerryMarch, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.

The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.

The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.

"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.

"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.

"diastereomer" refers to a stereoisomer that has two or more chiral neutrals and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.

The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hilldictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.

Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.

By "room temperature" is meant a temperature of about 15 ℃ to 35 ℃ or about 20 ℃ to 30 ℃ or about 23 ℃ to 28 ℃ or about 25 ℃. In the context of the present invention, all numbers disclosed herein are approximate values, regardless of whether the word "about" or "approximately" is used. The numerical value of each number may vary by 1%, 2%, 3%, 4% or 5%.

The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention. It is understood that the term "optionally substituted" may be used interchangeably with the term "substituted or unsubstituted". In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein said substituent may be, but is not limited to, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxyl, nitro, amino, carboxyl, alkyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aryloxy, heteroaryloxy, heterocyclyloxy, arylalkoxy, heteroarylalkoxy, heterocyclylalkoxy, cycloalkylalkoxy, alkylamino, alkylaminoalkyl, alkylaminoalkylamino, cycloalkylamino, cycloalkylalkylamino, alkylthio, haloalkyl, haloalkoxy, hydroxyl-substituted alkyl, hydroxyl-substituted alkylamino, cyano-substituted alkyl, cyano-substituted alkoxy, cyano-substituted alkylamino, amino-substituted alkyl, alkanoyl, heteroalkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, arylamino, heteroaryl, heteroarylalkyl, heteroarylamino, amido, sulfonyl, aminosulfonyl, and the like.

In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.

In various parts of this specification, the invention discloses substituents for compoundsAccording to the group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C₁-C₆Alkyl "or" C_1-6Alkyl "means in particular independently disclosed methyl, ethyl, C₃Alkyl radical, C₄Alkyl radical, C₅Alkyl and C₆An alkyl group.

The term "alkyl" or "alkyl group" as used herein, denotes a saturated, straight or branched chain, monovalent hydrocarbon group containing from 1 to 20 carbon atoms; wherein the alkyl group is optionally substituted with one or more substituents described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1 to 12 carbon atoms; in one embodiment, the alkyl group contains 1 to 10 carbon atoms; in one embodiment, the alkyl group contains 1 to 8 carbon atoms; in another embodiment, the alkyl group contains 1 to 6 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms.

Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)₃) Ethyl group (Et, -CH)₂CH₃) N-propyl (n-Pr, -CH)₂CH₂CH₃) Isopropyl group (i-Pr, -CH (CH)₃)₂) N-butyl (n-Bu, -CH)₂CH₂CH₂CH₃) Isobutyl (i-Bu, -CH)₂CH(CH₃)₂) Sec-butyl (s-Bu, -CH (CH)₃)CH₂CH₃) Tert-butyl (t-Bu, -C (CH)₃)₃) N-pentyl (-CH)₂CH₂CH₂CH₂CH₃) 2-pentyl (-CH (CH)₃)CH₂CH₂CH₃) 3-pentyl (-CH (CH)₂CH₃)₂) 2-methyl-2-butyl (-C (CH)₃)₂CH₂CH₃) 3-methyl-2-butyl (-CH (CH)₃)CH(CH₃)₂) 3-methyl-1-butyl (-CH)₂CH₂CH(CH₃)₂) 2-ARadical-1-butyl (-CH)₂CH(CH₃)CH₂CH₃) N-hexyl (-CH)₂CH₂CH₂CH₂CH₂CH₃) 2-hexyl (-CH (CH)₃)CH₂CH₂CH₂CH₃) 3-hexyl (-CH (CH)₂CH₃)(CH₂CH₂CH₃) 2-methyl-2-pentyl (-C (CH))₃)₂CH₂CH₂CH₃) 3-methyl-2-pentyl (-CH (CH)₃)CH(CH₃)CH₂CH₃) 4-methyl-2-pentyl (-CH (CH)₃)CH₂CH(CH₃)₂) 3-methyl-3-pentyl (-C (CH)₃)(CH₂CH₃)₂) 2-methyl-3-pentyl (-CH (CH)₂CH₃)CH(CH₃)₂) 2, 3-dimethyl-2-butyl (-C (CH)₃)₂CH(CH₃)₂) 3, 3-dimethyl-2-butyl (-CH (CH)₃)C(CH₃)₃) N-heptyl, n-octyl, and the like.

The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp²A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "tans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 10 carbon atoms; in one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)₂) Allyl (-CH)₂CH＝CH₂) Allyl (CH)₃-CH＝CH-)，-CH₂CH₂CH＝CH₂、-CH₂CH＝CHCH₃、-CH₂CH₂CH₂CH＝CH₂、-CH₂CH₂CH＝CHCH₃、-CH₂CH₂CH₂CH＝CHCH₃And so on.

The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one carbon-carbon sp triple bond, wherein the alkynyl radical may be optionally substituted with one or more substituents as described herein. In one embodiment, alkynyl groups contain 2-10 carbon atoms; in one embodiment, alkynyl groups contain 2-8 carbon atoms; in another embodiment, alkynyl groups contain 2-6 carbon atoms; in yet another embodiment, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, -C.ident.CH, -C.ident.CCH₃、-CH₂-C≡CH、-CH₂-C≡CCH₃、-CH₂CH₂-C≡CH、-CH₂-C≡CCH₂CH₃、-CH₂CH₂-C≡CH₂CH₃And so on.

The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 10 carbon atoms; in one embodiment, the alkoxy group contains 1 to 8 carbon atoms; in one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.

Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)₃) Ethoxy (EtO, -OCH)₂CH₃) 1-propoxy (n-PrO, n-propoxy, -OCH)₂CH₂CH₃) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)₃)₂) 1-butoxy (n-BuO, n-butoxy, -OCH)₂CH₂CH₂CH₃) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)₂CH(CH₃)₂) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)₃)CH₂CH₃) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)₃)₃) 1-pentyloxy (n-pentyloxy, -OCH)₂CH₂CH₂CH₂CH₃) 2-pentyloxy (-OCH (CH)₃)CH₂CH₂CH₃) 3-pentyloxy (-OCH (CH))₂CH₃)₂) 2-methyl-2-butoxy (-OC (CH))₃)₂CH₂CH₃) 3-methyl-2-butoxy (-OCH (CH)₃)CH(CH₃)₂) 3-methyl-l-butoxy (-OCH)₂CH₂CH(CH₃)₂) 2-methyl-l-butoxy (-OCH)₂CH(CH₃)CH₂CH₃) And so on.

The term "alkylamino" or "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups. In some of these embodiments, the alkylamino group is one or two C_1-6Lower alkylamino groups in which the alkyl group is attached to the nitrogen atom. In other embodiments, the alkylamino group is C_1-3Lower alkylamino groups of (a). Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like.

The term "alkylthio" refers to a straight or branched chain alkyl group attached to a divalent sulfur atom, wherein the alkyl group has the meaning as described herein. Examples of alkylthio groups include, but are not limited to, -SCH₃、-SCH₂CH₃、-SCH₂CH₂CH₃And so on.

The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

The term "haloalkyl" denotes an alkyl group substituted with one or more halogen atoms. Examples of haloalkyl include, but are not limited to, -CH₂F，-CHF₂，-CH₂Cl，-CH₂Br，-CF₃，-CH₂CF₃，-CH₂CH₂F，-CH₂CH₂Cl，-CH₂CH₂Br，-CH₂CHF₂，-CH₂CH₂CF₃，-CH₂CH₂CH₂F，-CH₂CH₂CH₂Cl，-CH₂CH₂CH₂Br，-CHFCH₂CH₃，-CHClCH₂CH₃And so on.

The term "tetrafluoroethyl" denotes-CF₂CHF₂or-CHFCF₃。

The term "haloalkoxy" denotes an alkoxy group substituted with one or more halogen atoms. Examples of haloalkoxy include, but are not limited to, -OCH₂F，-OCHF₂，-OCH₂Cl，-OCH₂Br，-OCF₃，-OCH₂CF₃，-OCH₂CH₂F，-OCH₂CH₂Cl，-OCH₂CH₂Br，-OCH₂CHF₂，-OCH₂CH₂CF₃，-OCH₂CH₂CH₂F，-OCH₂CH₂CH₂Cl，-OCH₂CH₂CH₂Br，-OCHFCH₂CH₃，-OCHClCH₂CH₃And so on.

The term "haloalkylamino" denotes an alkylamino group substituted with one or more halogen atoms.

The term "haloalkylthio" denotes an alkylthio group substituted by one or more halogen atoms.

The term "haloalkenyl" denotes an alkenyl group substituted with one or more halogen atoms.

The term "haloalkynyl" denotes an alkynyl group substituted by one or more halogen atoms.

The term "ring of x atoms", where x is an integer, typically describes the number of ring-forming atoms in a molecule in which the number of ring-forming atoms is x. For example, piperidinyl is a heterocyclic group consisting of 6 atoms.

The term "ring of 3 to 12 atoms" refers to a carbocyclic, heterocyclic or aromatic ring system of 3 to 12 atoms, i.e. a saturated, partially unsaturated or fully unsaturated ring system optionally containing one or more heteroatoms.

The term "ring of 3 to 10 atoms" refers to a carbocyclic, heterocyclic or aromatic ring system of 3 to 10 atoms, i.e. a saturated, partially unsaturated or fully unsaturated ring system optionally containing one or more heteroatoms.

The term "ring of 3 to 8 atoms" refers to a carbocyclic, heterocyclic or aromatic ring system of 3 to 8 atoms, i.e. a saturated, partially unsaturated or fully unsaturated ring system optionally containing one or more heteroatoms.

The term "ring of 3 to 6 atoms" refers to a carbocyclic, heterocyclic or aromatic ring system of 3 to 6 atoms, i.e. a saturated, partially unsaturated or fully unsaturated ring system optionally containing one or more heteroatoms.

The term "carbocyclyl" or "carbocycle" denotes a monovalent or multivalent, non-aromatic, saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring system containing 3 to 12 carbon atoms. Carbobicyclic groups include spirocarbocyclic and fused carbocyclic groups, and suitable carbocyclic groups include, but are not limited to, cycloalkyl, cycloalkenyl and cycloalkynyl groups. Examples of carbocyclyl groups further include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-1-alkenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. In one embodiment, the cycloalkyl group contains 3 to 12 carbon atoms; in one embodiment, the cycloalkyl group contains 3 to 10 carbon atoms; in another embodiment, cycloalkyl contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. The cycloalkyl group is optionally substituted with one or more substituents described herein. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, adamantyl, and the like.

The term "cycloalkylalkyl" denotes an alkyl group substituted by a cycloalkyl group, wherein the alkyl group and the cycloalkyl group have the meaning as described herein.

The term "cycloalkenyl" denotes mono-, bi-or tricyclic ring systems containing 3 to 12 carbon atoms, mono-or polyvalent, comprising at least one carbon-carbon double bond, said ring systems being non-aromatic. In one embodiment, cycloalkenyl groups contain 3 to 10 carbon atoms; in another embodiment, cycloalkenyl groups contain 3 to 8 carbon atoms; in yet another embodiment, cycloalkenyl groups contain 3 to 6 carbon atoms. The cycloalkenyl group is optionally substituted with one or more substituents described herein. Examples include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, and the like.

The term "unsaturated" as used herein means that the group contains one or more unsaturations.

The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state form of P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).

The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic ring containing 3 to 15 ring atoms, wherein no aromatic ring is included in the monocyclic, bicyclic, or tricyclic ring, and at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. In some embodiments, C_2-12Heterocyclyl means a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing 2 to 12 carbon atoms as ring atoms, wherein no aromatic ring is contained in the monocyclic, bicyclic or tricyclic ring, and at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. In other embodiments, C_2-10Heterocyclyl means a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing 2 to 10 carbon atoms as ring atoms, wherein no aromatic ring is contained in the monocyclic, bicyclic or tricyclic ring, and at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. In other embodiments, C₂-8 heterocyclyl means a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing 2 to 8 carbon atoms as ring atoms, wherein no aromatic ring is contained in the monocyclic, bicyclic or tricyclic ring, and at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. In still other embodiments, C_2-6Heterocyclyl means a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing 2 to 6 carbon atoms as ring atoms, wherein no aromatic ring is contained in the monocyclic, bicyclic or tricyclic ring, and at least one ring atom is selected from nitrogen, sulfur and oxygen atoms. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH₂-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclyl groups include, but are not limited to, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g., 2-pyrrolidinyl), 2-pyrrolinyl, 3-pyrrolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl (2-piperidinyl, 3-piperidinyl, 4-piperidinyl), morpholinyl, thiomorpholinyl, (1-oxo) -thiomorpholinyl, (1, 1-dioxo) -thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl, tetrahydropyridinyl. In heterocyclic radicals of-CH₂Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl. Examples of sulfur atoms in heterocyclic groups that are oxidized include, but are not limited to, sulfolane, 1, 1-dioxothiomorpholinyl. Said heterocyclyl group being optionally substitutedSubstituted with one or more substituents as described herein.

The term "C containing an oxygen_2-6The "heterocyclic group" means a heterocyclic group consisting of 2 to 6 carbon atoms and one oxygen atom as ring atoms, and examples thereof include, but are not limited to,

the term "heterocyclylalkyl" refers to a heterocyclyl-substituted alkyl group; wherein heterocyclyl and alkyl groups have the meaning as indicated in the present invention.

The term "heterocyclyloxy" includes optionally substituted heterocyclyl groups, as defined herein, attached to an oxygen atom and linked to the rest of the molecule by an oxygen atom, wherein the heterocyclyl group has the meaning as described herein.

The term "aryl" denotes monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises a ring of 3 to 7 atoms with one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of the aryl group may include phenyl, indenyl, naphthyl and anthryl. The aryl group is optionally substituted with one or more substituents described herein.

The term "arylalkyl" or "aralkyl" means that an alkyl group is substituted with one or more aryl groups, wherein the alkyl and aryl groups have the meanings as described herein.

The term "aryloxy" or "aryloxy" includes optionally substituted aryl groups, as defined herein, attached to and linked from an oxygen atom to the rest of the molecule, wherein the aryl group has the meaning as described herein.

The term "heteroaryl" denotes monocyclic, bicyclic and tricyclic ring systems containing 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring system contains one or more heteroatoms, wherein each ring system contains a ring of 5 to 7 atoms with one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". The heteroaryl group is optionally substituted with one or more substituents described herein.

In one embodiment, a heteroaryl group of 5-10 atoms contains 1,2,3, or 4 heteroatoms independently selected from O, S, and N.

In another embodiment, the ring atoms of the heteroaryl group comprise 1 to 9 carbon atoms and 1 to 4 heteroatoms selected from N, O or S; in another embodiment, the ring atoms of the heteroaryl group comprise 1 to 5 carbon atoms and 1 to 4 heteroatoms selected from N, O or S.

In yet another embodiment, heteroaryl represents a 5-or 6-membered heteroaryl group containing 1-4N heteroatoms; in yet another embodiment, heteroaryl represents a 5 membered heteroaryl group containing 1-3 heteroatoms selected from N, O or S; in yet another embodiment, heteroaryl represents a 5 membered heteroaryl group containing 1-3 heteroatoms selected from N or O; in yet another embodiment, heteroaryl represents a 5 membered heteroaryl group containing 1-3 heteroatoms selected from N or S.

In one embodiment, C_1-9Heteroaryl denotes heteroaryl groups containing 1 to 9 carbon atoms as ring atoms. In another embodiment, C_1-6Heteroaryl denotes heteroaryl groups containing 1 to 6 carbon atoms as ring atoms. In yet another embodiment, C_1-5Heteroaryl means heteroaryl containing 1 to 5 carbon atoms as ring atoms.

Examples of heteroaryl groups include, but are not limited to, 2-furyl, 3-furyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g., 2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl, isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 3-triazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl, pyrimidinonyl, pyridonyl; the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzofuranyl, benzotetrahydrofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), and the like.

The term "heteroarylalkyl" means that an alkyl group is substituted with one or more heteroaryl groups, wherein the alkyl group and heteroaryl groups have the meaning as set forth herein.

The term "heteroaryloxy" includes optionally substituted heteroaryl groups, as defined herein, attached to and linked by an oxygen atom to the rest of the molecule, wherein the heteroaryl group has the meaning as described herein.

The pyrazole rings of the present invention are numbered as follows:

when the compounds of the present invention contain an acid moiety, salts of the compounds of the present invention include those derived from alkali or alkaline earth metals as well as those derived from ammonia and amines. Preferred cations include sodium, potassium, magnesium and those of formula N⁺(R¹⁹R²⁰R²¹R²²) Ammonium cation of (2), wherein R is¹⁹、R²⁰、R²¹And R²²Independently selected from hydrogen, C₁-C₆Alkyl and C₁-C₆A hydroxyalkyl group. The salt of the compound represented by the formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (II-1), formula (IIa-2), formula (II-5), formula (IIa-17), formula (IIa-18), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IIIe), formula (IIIf), formula (IIIg) or formula (IIIh) can be prepared by using a metal hydroxide (e.g., sodium hydroxide) or an amine (e.g., ammonia, trimethylamine, diethanolamine, 2-methylthiopropylamine, diallylamine, 2-butylaminoOxyethylamine, morpholine, cyclododecylamine or benzylamine) by treating a compound represented by formula (I), formula (Ia), formula (II), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (II-1), formula (IIa-2), formula (II-5), formula (IIa-17), formula (IIa-18), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IIIe), formula (IIIf), formula (IIIg) or formula (IIIh).

When a compound of the invention comprises a base moiety, acceptable salts can be formed from organic and inorganic acids, such as acetic, propionic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic, toluenesulfonic, camphorsulfonic, and similarly known acceptable acids.

Detailed description of the Compounds of the invention

The invention aims to provide a novel isoxazoline compound, a herbicide composition containing the compound, a preparation and application of the compound.

In one aspect, the invention provides a compound that is a compound of formula (I) or a stereoisomer, a nitroxide, or a salt thereof:

wherein:

R¹and R²Each independently is hydrogen, fluoro, chloro, bromo, iodo, amino, nitro, cyano, hydroxy, carboxy, alkyl, cycloalkyl, or cycloalkylalkyl; or R¹、R²And the carbon atoms to which they are attached form a ring consisting of 3 to 12 atoms;

R³and R⁴Each independently is hydrogen, fluoro, chloro, bromo, iodo, amino, nitro, cyano, hydroxy, carboxy, alkyl, cycloalkyl, or cycloalkylalkyl; or R³、R⁴And the carbon atoms to which they are attached form a ring consisting of 3 to 12 atoms;

n is 0, 1 or 2;

R^aand R^bEach independently is hydrogen, fluoro, chloro, bromo, iodo, amino, nitro, cyano, hydroxy, carboxy, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, alkylamino, alkylthio, cycloalkyl, heterocyclyl, aryl or heteroaryl;

or R⁸、R⁹And the carbon atom to which it is attached, form-C (═ O) -;

or R¹⁰、R¹¹、R¹²Together with the carbon atom to which they are attached form optionally substituted C_6-14Aryl, optionally substituted C_1-9Heteroaryl, optionally substituted C_3-12Cycloalkyl or optionally substituted C_2-12Heterocyclic (i.e. a

To represent

Wherein Ay1 is optionally substituted C_6-14Aryl, optionally substituted C_1-9Heteroaryl, optionally substituted C_3-12Cycloalkyl or optionally substituted C_2-12A heterocyclic group);

or-CR⁸R⁹-CR¹⁰R¹¹R¹²Represents optionally substituted C_10-14Aryl, optionally substituted C_1-9Heteroaryl, optionally substituted C_3-12Cycloalkyl, optionally substituted C_2-12Heterocyclyl, unsubstituted phenyl or substituted phenyl (i.e.

To represent

Wherein Ay2 is optionally substituted C_10-14Aryl, optionally substituted C_1-9Heteroaryl, optionally substituted C_3-12Cycloalkyl, optionally substituted C_2-12Heterocyclyl, unsubstituted phenyl or substituted phenyl);

provided that (i) R^aIs not-CF₃；(ii)R^bIs not-CF₃(ii) a (iii) When R is^aWhen it is phenyl, R^bIs not Cl; (iv) r^aAnd R^bNot both Cl; (v) when R is^aWhen it is an alkyl group, R⁸、R¹⁰The 3-12 membered ring formed with the carbon atoms to which it is attached is not a benzene ring; (vi) when-CR⁸R⁹-CR¹⁰R¹¹R¹²Represents unsubstituted phenyl, R^aIs chlorine, R^bIs difluoromethyl, R⁵And R⁶Are each hydrogen, n is 0, 1 or 2, R³And R⁴Are each hydrogen, R¹When it is methyl, R²Is not methyl or chloromethyl; (vii) when-CR⁸R⁹-CR¹⁰R¹¹R¹²Represents unsubstituted phenyl, R^bIs chlorine, R^aIs difluoromethyl, R⁵And R⁶Are each hydrogen, n is 0, 1 or 2, R³And R⁴Are each hydrogen, R¹When it is methyl, R²Is not methyl or chloromethyl; (viii) when-CR⁸R⁹-CR¹⁰R¹¹R¹²Represents unsubstituted phenyl, R^aIs chlorine, R^bIs difluoromethyl, R⁵And R⁶Are each hydrogen, n is 0, 1 or 2, R³And R⁴Are each hydrogen, R²When it is methyl, R¹Is not methyl or chloromethyl; or (ix) when-CR⁸R⁹-CR¹⁰R¹¹R¹²Represents unsubstituted phenyl, R^bIs chlorine, R^aIs difluoromethyl, R⁵And R⁶Are each hydrogen, n is 0, 1 or 2, R³And R⁴Are each hydrogen, R²When it is methyl, R¹Not methyl or chloromethyl.

In another aspect, the invention provides a compound that is a compound of formula (Ia) or a stereoisomer, a nitroxide or a salt thereof of a compound of formula (Ia):

wherein:

R³and R⁴Each independently is hydrogen, bromine, iodine, amino, nitro, hydroxyl, carboxyl, alkyl, cycloalkylOr cycloalkylalkyl; or R³、R⁴And the carbon atoms to which they are attached form a ring consisting of 3 to 12 atoms;

n is 0, 1 or 2;

x is fluorine, chlorine or bromine;

with the following conditions:

(3) when Y is unsubstituted phenyl, X is chlorine, R⁵And R⁶Are all hydrogenN is 0, 1 or 2, R³And R⁴Are each hydrogen, R¹When it is methyl, R²Is not methyl or chloromethyl;

In some of these embodiments, Y is C_1-8Alkyl, halo C_1-8Alkyl radical, C_1-8Alkoxy radical C_1-8Alkyl radical, C_1-8Alkylamino radical C_1-8Alkyl radical, C_2-8Alkenyl, halo C_2-8Alkenyl radical, C_2-8Alkynyl, halo C_2-8Alkynyl, C_3-10Cycloalkyl radical, C_3-10Cycloalkyl radical C_1-8Alkyl radical, C_2-12Heterocyclic group, C_2-12Heterocyclyl radical C_1-8Alkyl radical, C_6-14Aryl radical, C_6-14Aryl radical C_1-8Alkyl radical, C_1-9Heteroaryl group, C_1-9Heteroaryl C_1-8Alkyl, -C (═ O) -C_1-8Alkyl, -S (═ O)₂-C_1-8Alkyl, -C (═ O) -C_3-10Cycloalkyl, -S (═ O)₂-C_3-10Cycloalkyl, -C (═ O) -C_2-12heterocyclyl-S (═ O)₂-C_2-12Heterocyclyl, -C (═ O) -C_6-14Aryl, -S (═ O)₂-C_6-14Aryl, -C (═ O) -C_1-9Heteroaryl or-S (═ O)₂-C_1-9A heteroaryl group;

wherein Y is optionally selected from Y by 1,2,3, 4,5 or 6^aSubstituted with the substituent(s); each one ofY^aIndependently fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxy, carboxyl, C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl, halo C_2-6Alkenyl radical, C_2-6Alkynyl, halo C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl or C_1-9A heteroaryl group.

In other embodiments, Y is C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_1-6Alkylamino radical C_1-6Alkyl radical, C_2-6Alkenyl, halo C_2-6Alkenyl radical, C_2-6Alkynyl, halo C_2-6Alkynyl, C_3-8Cycloalkyl radical, C_3-8Cycloalkyl radical C_1-6Alkyl radical, C_2-8Heterocyclic group, C_2-8Heterocyclyl radical C_1-6Alkyl radical, C_6-10Aryl radical, C_6-10Aryl radical C_1-6Alkyl radical, C_1-6Heteroaryl group, C_1-6Heteroaryl C_1-6Alkyl, -C (═ O) -C_1-6Alkyl, -S (═ O)₂-C_1-6Alkyl, -C (═ O) -C_3-8Cycloalkyl, -S (═ O)₂-C_3-8Cycloalkyl, -C (═ O) -C_2-8heterocyclyl-S (═ O)₂-C_2-8Heterocyclyl, -C (═ O) -C_6-10Aryl, -S (═ O)₂-C_6-10Aryl, -C (═ O) -C_1-6Heteroaryl or-S (═ O)₂-C_1-6A heteroaryl group;

wherein Y is optionally selected from Y by 1,2,3, 4,5 or 6^aSubstituted with the substituent(s); each Y is^aIndependently fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxy, carboxyl, C_1-4Alkyl, halo C_1-4Alkyl radical, C_2-4Alkenyl, halo C_2-4Alkenyl radical, C_2-4Alkynyl, halo C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_1-4Alkylthio radical, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl or C_1-6A heteroaryl group.

In other embodiments, Y is C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy radical C_1-4Alkyl radical, C_1-4Alkylamino radical C_1-4Alkyl radical, C_2-4Alkenyl, halo C_2-4Alkenyl radical, C_2-4Alkynyl, halo C_2-4Alkynyl, C_3-6Cycloalkyl radical, C_3-6Cycloalkyl radical C_1-3Alkyl radical, C_2-4Heterocyclic group, C_2-4Heterocyclyl radical C_1-3Alkyl radical, C_6-10Aryl radical, C_6-10Aryl radical C_1-4Alkyl radical, C_1-6Heteroaryl group, C_1-6Heteroaryl C_1-3Alkyl, -C (═ O) -C_1-4Alkyl, -S (═ O)₂-C_1-4Alkyl, -C (═ O) -C_3-6Cycloalkyl, -S (═ O)₂-C_3-6Cycloalkyl, -C (═ O) -C_2-4heterocyclyl-S (═ O)₂-C_2-4Heterocyclyl, -C (═ O) -C_6-10Aryl, -S (═ O)₂-C_6-10Aryl, -C (═ O) -C_1-5Heteroaryl or-S (═ O)₂-C_1-5A heteroaryl group;

wherein Y is optionally selected from Y by 1,2,3, 4,5 or 6^aSubstituted with the substituent(s); each Y is^aIndependently fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxy, carboxyl, C_1-3Alkyl, halo C_1-3Alkyl radical, C_2-3Alkenyl, halo C_2-3Alkenyl radical, C_2-3Alkynyl, halo C_2-3Alkynyl, C_1-3Alkoxy radical, C_1-3Alkylamino radical, C_1-3Alkylthio radical, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl or C_1-5A heteroaryl group.

In still other embodiments, Y is-CH₃、-CH₂CH₃、-CH₂CH₂CH₃、-CH(CH₃)₂、-CH₂CH(CH₃)₂、-C(CH₃)₃、-CH₂CHF₂、-CH₂CF₃、-CH₂CF₂CHF₂、-CH₂CH＝CH₂、-CH₂-C≡CH、-C(＝O)CH₃、-CH₂OCH₃、-CH₂OCH₂CH₃Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2, 4-difluorophenyl, benzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, benzoyl or benzenesulfonyl; or

Y is the following subformula:

in some of these embodiments, the present invention provides a compound that is a compound of formula (II) or a stereoisomer, nitroxide, or salt of a compound of formula (II):

wherein: x is fluorine, chlorine or bromine;

R¹、R²、R³、R⁴、n、R⁵、R⁶、R⁸、R⁹、R¹⁰、R¹¹and R¹²Have the meaning as described in the present invention.

In some of these embodiments, the present invention provides a compound that is a compound represented by formula (II-1) or a stereoisomer, a nitroxide or a salt thereof of a compound represented by formula (II-1):

wherein: x is fluorine, chlorine or bromine;

R¹、R²、R³、R⁴、n、R⁵、R⁶、R⁸、R⁹and R¹³Have the meaning as described in the present invention.

In some of these embodiments, the present invention provides a compound which is a compound represented by formula (II-2) or a stereoisomer, a nitroxide or a salt thereof of a compound represented by formula (II-2):

wherein: x is fluorine, chlorine or bromine;

R¹、R²、R³、R⁴、n、R⁵、R⁶、R⁸、R⁹、R¹⁴、R¹⁵and R¹⁶Have the meaning as described in the present invention.

In some of these embodiments, the present invention provides a compound that is a compound represented by formula (II-3) or a stereoisomer, a nitroxide or a salt thereof of a compound represented by formula (II-3):

wherein: x is fluorine, chlorine or bromine;

R¹、R²、R³、R⁴、n、R⁵、R⁶、R⁸、R⁹and Ay1 have the meaning as described herein.

In some of these embodiments, the present invention provides a compound that is a compound represented by formula (II-4) or a stereoisomer, a nitroxide or a salt thereof of a compound represented by formula (II-4):

wherein: x is fluorine, chlorine or bromine;

R¹、R²、R³、R⁴、n、R⁵、R⁶and Ay2 have the meaning as described herein.

wherein: x is fluorine, chlorine or bromine;

R¹、R²、R³、R⁴、n、R⁵and R⁶Have the meaning as described in the present invention.

In some of these embodiments, the present invention provides a compound which is a compound represented by formula (III-1) or a stereoisomer, a nitroxide or a salt thereof of a compound represented by formula (III-1):

wherein: r¹、R²、R³、R⁴、n、R⁵、R⁶、R⁸、R⁹、R¹⁰、R¹¹And R¹²Have the meaning as described in the present invention.

In some of these embodiments, the present invention provides a compound which is a compound represented by formula (III-2) or a stereoisomer, a nitroxide or a salt thereof of a compound represented by formula (III-2):

wherein:R¹、R²、R³、R⁴、R⁵、R⁶、R⁸、R⁹、R¹⁰、R¹¹and R¹²Have the meaning as described in the present invention.

In some embodiments, the invention provides a compound that is a compound of formula (IIa-3) or a stereoisomer, nitroxide, or salt thereof of a compound of formula (IIa-3):

wherein: r¹、R²、R³、R⁴、R⁵、R⁶、R⁸、R⁹、R¹⁴、R¹⁵And R¹⁶Have the meaning as described in the present invention.

In some embodiments, the invention provides a compound that is a compound of formula (IIa-4) or a stereoisomer, nitroxide, or salt thereof of a compound of formula (IIa-4):

In some embodiments, the invention provides a compound that is a compound of formula (IIa-5) or a stereoisomer, nitroxide, or salt thereof of a compound of formula (IIa-5):

wherein: r¹、R²、R³、R⁴、R⁵、R⁶、R⁸、R⁹And Ay1 have the meaning as described herein.

In some embodiments, the invention provides a compound that is a compound of formula (IIa-6) or a stereoisomer, nitroxide or salt thereof of a compound of formula (IIa-6):

In some embodiments, the invention provides a compound that is a compound of formula (IIa-7) or a stereoisomer, nitroxide, or salt thereof of a compound of formula (IIa-7):

wherein: r¹、R²、R³、R⁴、R⁵、R⁶And Ay2 have the meaning as described herein.

In some embodiments, the invention provides a compound that is a compound of formula (IIa-8) or a stereoisomer, nitroxide, or salt thereof of a compound of formula (IIa-8):

In some embodiments, the invention provides a compound that is a compound of formula (IIa-9) or a stereoisomer, nitroxide, or salt thereof of a compound of formula (IIa-9):

In some embodiments, the invention provides a compound that is a compound of formula (IIa-10) or a stereoisomer, nitroxide, or salt thereof of a compound of formula (IIa-10):

In some embodiments, the invention provides a compound that is a compound of formula (IIa-11) or a stereoisomer, nitroxide, or salt thereof of a compound of formula (IIa-11):

In some embodiments, the invention provides a compound that is a compound of formula (IIa-12) or a stereoisomer, nitroxide, or salt thereof of a compound of formula (IIa-12):

In some embodiments, the invention provides a compound that is a compound of formula (IIa-13) or a stereoisomer, nitroxide, or salt thereof of a compound of formula (IIa-13):

In some embodiments, the invention provides a compound that is a compound of formula (IIa-14) or a stereoisomer, nitroxide, or salt thereof of a compound of formula (IIa-14):

In some embodiments, the invention provides a compound that is a compound of formula (IIa-15) or a stereoisomer, nitroxide, or salt of a compound of formula (IIa-15):

In some embodiments, the invention provides a compound that is a compound of formula (IIa-16) or a stereoisomer, nitroxide, or salt thereof of a compound of formula (IIa-16):

wherein: x, R¹、R²、R³、R⁴、R⁵And R⁶Have the meaning as described in the present invention.

In some of these embodiments, the present invention provides a compound that is a compound of formula (IV) or a stereoisomer, nitroxide, or salt of a compound of formula (IV):

wherein:

ay2 is optionally substituted C_10-14Aryl, optionally substituted C_1-9Heteroaryl, optionally substituted C_3-12Cycloalkyl, optionally substituted C_2-12Heterocyclyl, unsubstituted phenyl or substituted phenyl; the number of the substituted or optional substituted groups is 1,2,3, 4,5 or 6; the substituents may be the same or different; wherein the substituent is fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl, halo C_2-6Alkenyl radical, C_2-6Alkynyl, halo C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_3-6Cycloalkyl radical, C_2-8Heterocyclic group, C_6-10Aryl or C_1-9A heteroaryl group;

R¹、R²、R³、R⁴、n、R⁵and R⁶Have the meaning as described herein;

provided that, when Ay2 represents an unsubstituted phenyl group, R⁵And R⁶Are each hydrogen, n is 0, 1 or 2, R³And R⁴Are each hydrogen, R¹When it is methyl, R²Is not methyl or chloromethyl; or when Ay2 represents an unsubstituted phenyl group, R⁵And R⁶Are each hydrogen, n is 0, 1 or 2, R³And R⁴Are each hydrogen, R²When it is methyl, R¹Not methyl or chloromethyl.

In some of these embodiments, R¹And R²Each independently is hydrogen, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-6Alkyl, halo C_1-6Alkyl radical, C_3-6Cycloalkyl or C_3-6Cycloalkyl radical C_1-6An alkyl group; or R¹、R²And together with the carbon atoms to which they are attached form a ring consisting of 3 to 8 atoms.

In some of these embodiments, R³And R⁴Each independently is hydrogen, bromine, iodine, amino, nitro, hydroxyl, carboxyl, C_1-6Alkyl radical, C_3-6Cycloalkyl or C_3-6Cycloalkyl radical C_1-6An alkyl group; or R³、R⁴And together with the carbon atoms to which they are attached form a ring consisting of 3 to 8 atoms.

In some of these embodiments, R⁵And R⁶Each independently is hydrogen, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-6Alkyl radical, C_2-6Alkenyl or C_2-6An alkynyl group; or R⁵、R⁶And together with the carbon atoms to which they are attached form a ring consisting of 3 to 8 atoms.

In some of these embodiments, R⁸、R⁹、R¹⁰、R¹¹And R¹²Each independently is hydrogen, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl, halo C_2-6Alkenyl radical, C_2-6Alkynyl, halo C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_3-6Cycloalkyl radical, C_2-8Heterocyclic group, C_6-10Aryl or C_1-9A heteroaryl group.

Some of which are described inIn, R⁸、R⁹And the carbon atoms to which they are attached form an optionally substituted ring of 3 to 10 atoms; the number of the optional substituent is 1,2,3, 4,5 or 6; the substituents may be the same or different; wherein the substituent is fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl, halo C_2-6Alkenyl radical, C_2-6Alkynyl, halo C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_3-8Cycloalkyl radical, C_2-10Heterocyclic group, C_6-14Aryl or C_1-9A heteroaryl group.

In some of these embodiments, R⁸、R⁹Together with the carbon atom to which they are attached form-C (═ O) -.

In some of these embodiments, R¹⁰、R¹¹、R¹²Together with the carbon atom to which they are attached form-C.ident.CR¹³or-CR¹⁴＝CR¹⁵R¹⁶(ii) a Wherein R is¹³、R¹⁴、R¹⁵And R¹⁶Each independently is hydrogen, C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl, halo C_2-6Alkenyl radical, C_2-6Alkynyl or halo C_2-6Alkynyl.

In some of these embodiments, R¹⁰、R¹¹、R¹²Together with the carbon atom to which they are attached form optionally substituted C_6-14Aryl, optionally substituted C_1-9Heteroaryl, optionally substituted C_3-10Cycloalkyl or optionally substituted C_2-10Heterocyclic (i.e. a

To represent

Wherein Ay1 is optionally substituted C_6-14Aryl, optionally substituted C_1-9Heteroaryl, optionally substituted C_3-10Cycloalkyl or optionally substituted C_2-10Heterocyclic ringsRadical); the number of the optional substituent is 1,2,3, 4,5 or 6; the substituents may be the same or different; wherein the substituent is fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl, halo C_2-6Alkenyl radical, C_2-6Alkynyl, halo C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_3-8Cycloalkyl radical, C_2-10Heterocyclic group, C_6-14Aryl or C_1-9A heteroaryl group.

In some of these embodiments, -CR⁸R⁹-CR¹⁰R¹¹R¹²Represents optionally substituted C_10-14Aryl, optionally substituted C_1-9Heteroaryl, optionally substituted C_3-10Cycloalkyl, optionally substituted C_2-10Heterocyclyl, unsubstituted phenyl or substituted phenyl (i.e.

To represent

Wherein Ay2 is optionally substituted C_10-14Aryl, optionally substituted C_1-9Heteroaryl, optionally substituted C_3-10Cycloalkyl, optionally substituted C_2-10Heterocyclyl, unsubstituted phenyl or substituted phenyl); the number of the substituted or optional substituted groups is 1,2,3, 4,5 or 6; the substituents may be the same or different; wherein the substituent is fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-6Alkyl, halo C_1-6Alkyl radical, C_2-6Alkenyl, halo C_2-6Alkenyl radical, C_2-6Alkynyl, halo C_2-6Alkynyl, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_1-6Alkylthio radical, C_3-8Cycloalkyl radical, C_2-10Heterocyclic group, C_6-14Aryl or C_1-9A heteroaryl group.

In other embodiments, R¹And R²Each independently is hydrogenFluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxy, carboxyl, C_1-4Alkyl, halo C_1-4Alkyl radical, C_3-6Cycloalkyl or C_3-6Cycloalkyl radical C_1-3An alkyl group; or R¹、R²And together with the carbon atoms to which they are attached form a ring consisting of 3 to 6 atoms.

In other embodiments, R³And R⁴Each independently is hydrogen, bromine, iodine, amino, nitro, hydroxyl, carboxyl, C_1-3Alkyl radical, C_3-6Cycloalkyl or C_3-6Cycloalkyl radical C_1-3An alkyl group; or R³、R⁴And together with the carbon atoms to which they are attached form a ring consisting of 3 to 6 atoms.

In other embodiments, R⁵And R⁶Each independently is hydrogen, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-4Alkyl radical, C_2-4Alkenyl or C_2-4An alkynyl group; or R⁵、R⁶And together with the carbon atoms to which they are attached form a ring consisting of 3 to 6 atoms.

In other embodiments, R¹And R²Each independently is hydrogen, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, -CH₂F、-CH₂Cl、-CH₂Br or-CF₃。

In other embodiments, R³And R⁴Each independently hydrogen or bromine.

In other embodiments, R⁵And R⁶Each independently hydrogen, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl or methyl.

In some of these embodiments, the present invention provides a compound that is a compound of formula (IIIa) or a stereoisomer, a nitroxide, or a salt thereof of a compound of formula (IIIa):

In some of these embodiments, the present invention provides a compound that is a compound of formula (IIIb) or a stereoisomer, a nitroxide, or a salt thereof of a compound of formula (IIIb):

In some of these embodiments, the present invention provides a compound that is a compound of formula (IIIc) or a stereoisomer, a nitroxide, or a salt thereof of a compound of formula (IIIc):

In some of these embodiments, the present invention provides a compound that is a compound of formula (IIId) or a stereoisomer, a nitroxide, or a salt thereof of a compound of formula (IIId):

In some of these embodiments, R⁸、R⁹、R¹⁰、R¹¹And R¹²Each independently is hydrogen, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-4Alkyl, halo C_1-4Alkyl radical, C_2-4Alkenyl, halo C_2-4Alkenyl radical, C_2-4Alkynyl, halo C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_1-4Alkylthio radical, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl or C_1-5A heteroaryl group.

In some of these embodiments, R⁸、R⁹And the carbon atoms to which they are attached form an optionally substituted ring of 3 to 8 atoms; the number of the optional substituent is 1,2,3, 4,5 or 6; the substituents may be the same or different; wherein the substituent is fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-6Alkyl, halo C_1-4Alkyl radical, C_2-4Alkenyl, halo C_2-4Alkenyl radical, C_2-4Alkynyl, halo C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_1-4Alkylthio radical, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl or C_1-5A heteroaryl group.

In some of these embodiments, R¹⁰、R¹¹、R¹²Together with the carbon atom to which they are attached form-C.ident.CR¹³or-CR¹⁴＝CR¹⁵R¹⁶(ii) a Wherein R is¹³、R¹⁴、R¹⁵And R¹⁶Each independently is hydrogen, C_1-4Alkyl, halo C_1-4Alkyl radical, C_2-4Alkenyl, halo C_2-4Alkenyl radical, C_2-4Alkynyl or halo C_2-4Alkynyl.

In some of these embodiments, R¹⁰、R¹¹、R¹²Together with the carbon atom to which they are attached form optionally substituted C_6-10Aryl, optionally substituted C_1-6Heteroaryl, optionally substituted C_3-8Cycloalkyl or optionally substituted C_2-6Heterocyclic (i.e. a

To represent

Wherein Ay1 is optionally substituted C_6-10Aryl, optionally substituted C_1-6Heteroaryl, optionally substituted C_3-8Cycloalkyl or optionally substituted C_2-6A heterocyclic group); the number of the optional substituent is 1,2,3, 4,5 or 6; the substituents may be the same or different; wherein the substituent is fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-6Alkyl, halo C_1-4Alkyl radical, C_2-4Alkenyl, halo C_2-4Alkenyl radical, C_2-4Alkynyl, halo C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_1-4Alkylthio radical, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl or C_1-5A heteroaryl group.

In some of these embodiments, -CR⁸R⁹-CR¹⁰R¹¹R¹²Represents optionally substituted C_10-14Aryl, optionally substituted C_1-6Heteroaryl, optionally substituted C_3-8Cycloalkyl, optionally substituted C_2-6Heterocyclyl, unsubstituted phenyl or substituted phenyl (i.e.

To represent

Wherein Ay2 is optionally substituted C_10-14Aryl, optionally substituted C_1-6Heteroaryl, optionally substituted C_3-8Cycloalkyl, optionally substituted C_2-6Heterocyclyl, unsubstituted phenyl or substituted phenyl); the number of the substituted or optional substituted groups is 1,2,3, 4,5 or 6; the substituents may be the same or different; wherein the substituent is fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-6Alkyl, halo C_1-4Alkyl radical, C_2-4Alkenyl, halo C_2-4Alkenyl radical, C_2-4Alkynyl, halo C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_1-4Alkylthio radical, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl or C_1-5A heteroaryl group.

In other embodiments, R⁸、R⁹、R¹⁰、R¹¹And R¹²Each independently is hydrogen, fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxy, carboxy, -CH₃、-CH₂CH₃、-CH₂CH₂CH₃、-CH(CH₃)₂、-CH₂F、-CHF₂、-CH₂Cl、-CH₂Br、-CF₃、-CH₂CF₃、-CH₂CH₂F、-CH₂CH₂Cl、-CH₂CH₂Br、-CH₂CHF₂、-CH₂CH₂CF₃、-CH₂CH₂CH₂F、-CH₂CH₂CH₂Cl、-CH₂CH₂CH₂Br、-CHFCH₂CH₃、-CHClCH₂CH₃、-CH＝CH₂、-CH₂CH＝CH₂、CH₃-CH＝CH-、-C≡CH、-C≡CCH₃、-CH₂-C≡CH、-OCH₃、-OCH₂CH₃、-OCH₂CH₂CH₃、-OCH(CH₃)₂、-NHCH₃、-N(CH₃)₂、-SCH₃、-SCH₂CH₃、-SCH₂CH₂CH₃Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl.

In other embodiments, R⁸、R⁹Together with the carbon atom to which they are attached form C_3-6A cycloalkyl group.

In other embodiments, R⁸、R⁹Together with the carbon atom to which they are attached form-C (═ O) -.

In other embodiments, R¹⁰、R¹¹、R¹²Together with the carbon atom to which they are attached form-C ≡ CH or-CH ═ CH₂。

In other embodiments, R¹⁰、R¹¹、R¹²Together with the carbon atom to which they are attached form C_3-6Cycloalkyl, phenyl optionally substituted by halogen or C containing one oxygen_2-6A heterocyclic group.

In other embodiments, -CR⁸R⁹-CR¹⁰R¹¹R¹²Is represented by C_3-6Cycloalkyl or halogen substituted phenyl.

In still other embodiments, the present invention provides a compound that is a compound of formula (IIIe) or a stereoisomer, nitroxide, or salt thereof of a compound of formula (IIIe):

wherein:

R⁵and R⁶Each independently is hydrogen or fluorine;

x is fluorine or chlorine;

R^mis hydrogen, C_1-3Alkyl or halo C_1-3An alkyl group;

R^vis hydrogen, C_1-3Alkyl or halo C_1-3An alkyl group;

R^wis C_1-3Alkyl or halo C_1-3An alkyl group.

In still other embodiments, the invention provides a compound that is a compound of formula (IIIe) or a stereoisomer, nitroxide, or salt thereof of a compound of formula (IIIe), wherein R is^mIs hydrogen or methyl; r^vIs hydrogen or methyl; r^wIs methyl, isopropyl, difluoromethyl or tetrafluoroethyl.

In still other embodiments, the present invention provides a compound that is a compound of formula (IIIf) or a stereoisomer, a nitroxide, or a salt thereof of a compound of formula (IIIf):

wherein:

R⁵and R⁶Each independently is hydrogen or fluorine;

x is fluorine or chlorine;

R^mis hydrogen, C_1-3Alkyl or halo C_1-3An alkyl group;

R^vis hydrogen, C_1-3Alkyl or halo C_1-3An alkyl group;

R^wis C_1-3Alkyl or halo C_1-3An alkyl group.

In still other embodiments, the invention provides a compound that is a compound of formula (IIIf) or a stereoisomer, nitroxide, or salt thereof of a compound of formula (IIIf), wherein R is^mIs hydrogen or methyl; r^vIs hydrogen or methyl; r^wIs methyl, isopropyl, difluoromethyl or tetrafluoroethyl.

In still other embodiments, the invention provides a compound that is a compound of formula (IIIg) or a stereoisomer, a nitroxide, or a salt thereof of a compound of formula (IIIg):

wherein: x is chlorine.

In still other embodiments, the present invention provides a compound that is a compound of formula (IIIh) or a stereoisomer, a nitroxide, or a salt thereof of a compound of formula (IIIh):

wherein: x is chlorine.

In some of these embodiments, the present invention provides a compound that is a compound of formula (IVa) or a stereoisomer, a nitroxide, or a salt thereof of a compound of formula (IVa):

wherein: ay2 has the meaning as described in the present invention.

In some of these embodiments, the present invention provides a compound that is a compound of formula (IVb) or a stereoisomer, a nitroxide or a salt thereof of a compound of formula (IVb):

wherein: ay2 has the meaning as described in the present invention.

In some of these embodiments, Ay2 is optionally substituted C_10-14Aryl, optionally substituted C_1-5Heteroaryl, optionally substituted C_3-8Cycloalkyl, optionally substituted C_2-10Heterocyclyl or substituted phenyl; the number of the substituted or optional substituted groups is 1,2,3, 4,5 or 6; the substituents may be the same or different; wherein the substituent is fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-4Alkyl, halo C_1-4Alkyl radical, C_2-4Alkenyl, halo C_2-4Alkenyl radical, C_2-4Alkynyl, halo C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_1-4Alkylthio radical, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl or C_1-5A heteroaryl group.

In still other embodiments, Ay2 is optionally substituted C_3-6Cycloalkyl, optionally substituted C_2-6Heterocyclyl or substituted phenyl; the number of the substituted or optional substituted groups is 1,2,3, 4,5 or 6; the substituents may be the same or different; wherein the substituent is fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy.

In some of these embodiments, the present invention provides a compound that is a compound of formula (IVc) or a stereoisomer, a nitroxide or a salt thereof of a compound of formula (IVc):

wherein: ay1 has the meaning as described in the present invention.

In some of these embodiments, the present invention provides a compound that is a compound of formula (IVd) or a stereoisomer, nitroxide, or salt of a compound of formula (IVd):

wherein: ay1 has the meaning as described in the present invention.

In some of these embodiments, Ay1 is optionally substituted C_6-10Aryl, optionally substituted C_1-6Heteroaryl, optionally substituted C_3-8Cycloalkyl or optionally substituted C_2-8A heterocyclic group; the number of the optional substituent is 1,2,3, 4,5 or 6; the substituents may be the same or different; wherein the substituent is fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, C_1-4Alkyl, halo C_1-4Alkyl radical, C_2-4Alkenyl, halo C_2-4Alkenyl radical, C_2-4Alkynyl, halo C_2-4Alkynyl, C_1-4Alkoxy radical, C_1-4Alkylamino radical, C_1-4Alkylthio radical, C_3-6Cycloalkyl radical, C_2-6Heterocyclic group, C_6-10Aryl or C_1-5A heteroaryl group.

In still other embodiments, Ay1 is optionally substituted phenyl, optionally substituted C_3-6Cycloalkyl or optionally substituted C_2-6A heterocyclic group; the number of the optional substituent is 1,2,3, 4,5 or 6; the substituents may be the same or different; wherein the substituent is fluorine, chlorine, bromine, iodine, amino, nitro, cyano, hydroxyl, carboxyl, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxyA group, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy.

In still other embodiments, Ay1 is C_3-6Cycloalkyl, phenyl optionally substituted by halogen or C containing one oxygen_2-6A heterocyclic group.

In some of these embodiments, the present invention provides a compound that is a compound having one of the following structures or a stereoisomer, a nitroxide or a salt thereof of a compound having one of the following structures:

or

In another aspect, the invention provides a composition comprising a compound of the invention or a stereoisomer, a nitroxide or a salt thereof.

In some of these embodiments, the compositions of the present invention optionally further comprise at least one pesticidally acceptable adjuvant.

In other embodiments, the compositions of the present invention are herbicidal compositions.

The compound provided by the invention is a novel compound which is more effective to weeds, lower in cost, lower in toxicity and safe to environment.

Compositions and formulations of the compounds of the invention

The compounds of the present invention are generally useful as herbicidal active ingredients in compositions or formulations having at least one pesticidally acceptable adjuvant selected from the group consisting of surfactants, solid diluents and liquid diluents, and the like, all of which meet the requirements of use as a pesticide. The formulation or composition ingredients are selected to be compatible with the physical characteristics of the active ingredient, the mode of application, and environmental factors such as soil type, moisture and temperature.

Useful formulations include liquid compositions and solid compositions. Liquid compositions include solutions (including emulsifiable concentrates), suspensions, emulsions (including microemulsions and/or suspoemulsions), and the like, which may optionally be thickened into gels. Common types of aqueous liquid compositions are soluble concentrates, suspension concentrates, capsule suspensions, concentrated emulsions, microemulsions and suspoemulsions. Common types of non-aqueous liquid compositions are emulsifiable concentrates, microemulsifiable concentrates, dispersible concentrates and oil dispersions.

The general types of solid compositions are powders, granules, pellets, prills, lozenges, tablets, filled films (including seed coatings), and the like, which may be water dispersible ("wettable") or water soluble. Films and coatings formed from film-forming solutions or flowable suspensions are particularly useful for seed treatment. The active ingredient may be (micro) encapsulated and further formed into a suspension or solid formulation; alternatively, the entire active ingredient formulation may be encapsulated (or "coated"). Encapsulation may control or delay the release of the active ingredient. Emulsifiable granules combine the advantages of both emulsifiable concentrate formulations and dry granular formulations. The high concentration compositions are mainly used as intermediates for other formulations.

Sprayable formulations are typically dispersed in a suitable medium prior to spraying. Such liquid and solid formulations are formulated to be readily diluted in a spray medium, typically water. The spray volume may be in the range of about one to several thousand liters per hectare, but more typically in the range of about ten to several hundred liters per hectare. The sprayable formulation may be mixed with water or another suitable medium in a water tank for treatment of the foliage by air or ground application, or applied to the growing medium of the plant. The liquid and dry formulations can be dosed directly into the drip irrigation system or into the furrow during planting.

The formulation will typically comprise effective amounts of active ingredient, diluent and surfactant, the sum being 100% by weight.

Solid diluents include, for example, clays such as bentonite, montmorillonite, attapulgite and kaolin, gypsum, cellulose, titanium dioxide, zinc oxide, starches, dextrins, sugars (e.g., lactose, sucrose), silica, talc, mica, diatomaceous earth, urea, calcium carbonate, sodium carbonate and bicarbonate and sodium sulfate. Typical solid Diluents are described in Handbook of the instruments Dust Diluents and Carriers, 2 nd edition, Dorland Books, Caldwell, new jersey, Watkins et al.

Liquid diluents include, for example, water, N-dimethyl alkanamides (e.g., N-dimethylformamide), limonene, dimethyl sulfoxide, N-alkylpyrrolidones (e.g., N-methylpyrrolidone), ethylene glycol, triethylene glycol, propylene glycol, dipropylene glycol, polypropylene glycol, propylene carbonate, butylene carbonate, paraffins (e.g., white mineral oil, N-paraffins, isoparaffins), alkylbenzenes, alkylnaphthalenes, glycerol, triacetin, sorbitol, aromatic hydrocarbons, dealkylated aliphatics, alkylbenzenes, alkylnaphthalenes, ketones (e.g., cyclohexanone, 2-heptanone, isophorone and 4-hydroxy-4-methyl-2-pentanone), acetates (e.g., isoamyl acetate, hexyl acetate, heptyl acetate, octyl acetate, nonyl acetate, tridecyl acetate, and isobornyl acetate), Other esters (such as alkylated lactates, dibasic esters and gamma-butyrolactones), and may be straight chain, branched chain, saturated or unsaturated alcohols (such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-hexanol, 2-ethylhexanol, n-octanol, decanol, isodecanol, isostearyl alcohol, cetyl alcohol, lauryl alcohol, tridecyl alcohol, oleyl alcohol, cyclohexanol, tetrahydrofurfuryl alcohol, diacetone alcohol and benzyl alcohol). Liquid diluents also include glycerol esters of saturated and unsaturated fatty acids (typically C6-C22), such as vegetable seed and fruit oils (e.g., olive oil, castor oil, linseed oil, sesame oil, corn oil, peanut oil, sunflower oil, grapeseed oil, safflower oil, cottonseed oil, soybean oil, rapeseed oil, coconut oil, and palm kernel oil), animal derived fats (e.g., tallow, lard, cod liver oil, fish oil), and mixtures thereof. Liquid diluents also include alkylated (e.g., methylated, ethylated, butylated) fatty acids, which can be obtained by hydrolysis of vegetable and animal derived glycerides and can be purified by distillation. Typical liquid diluents are described in Marsden's Solvents Guide, 2 nd edition, Interscience, New York, 1950.

The solid and liquid compositions of the present invention typically comprise one or more surfactants. Surfactants (also known as "surface active agents") generally change when added to a liquid, most often lowering the surface tension of the liquid. Surfactants can be used as wetting agents, dispersing agents, emulsifying agents, or defoaming agents, depending on the nature of the hydrophilic and lipophilic groups in the surfactant molecule.

Surfactants can be classified as nonionic, anionic, or cationic surfactants. Nonionic surfactants useful as compositions of the present invention include, but are not limited to: alcohol alkoxylates, such as alcohol alkoxylates based on natural and synthetic alcohols (which are branched or linear) and prepared from alcohols and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof; amine ethoxylation, alkanolamides, and ethoxylated alkanolamides; alkoxylated triglycerides, such as ethoxylated soybean, castor and rapeseed oil; alkylphenol alkoxylates such as octylphenol ethoxylate, nonylphenol ethoxylate, dinonylphenol ethoxylate and dodecylphenol ethoxylate (prepared from phenol and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); a block polymer prepared from ethylene oxide or propylene oxide and a reverse block polymer, wherein the end block is prepared from propylene oxide; ethoxylated fatty acids; ethoxylated fatty esters and oils; ethoxylated methyl esters; ethoxylated tristyrylphenols (including those prepared from ethylene oxide, propylene oxide, butylene oxide, or mixtures thereof); fatty acid esters, glycerides, lanolin-based derivatives, polyethoxylated esters, such as polyethoxylated sorbitan fatty acid esters, polyethoxylated sorbitol fatty acid esters, and polyethoxylated glycerol fatty acid esters; other sorbitan derivatives, such as sorbitan esters; polymeric surfactants such as random copolymers, block copolymers, alkyd PEG (polyethylene glycol) resins, graft or comb polymers, and star polymers; polyethylene glycol (PEG); polyethylene glycol fatty acid esters; a silicone-based surfactant; and sugar derivatives such as sucrose esters, alkyl polyglucosides, and alkyl polysaccharides.

Useful anionic surfactants include, but are not limited to: alkyl aryl sulfonic acids and their salts; carboxylated alcohols or alkylphenol ethoxylates; a diphenyl sulfonate derivative; lignin and lignin derivatives, such as lignosulfonates; maleic or succinic acid or anhydrides thereof; olefin sulfonates; phosphate esters such as phosphate esters of alcohol alkoxylates, phosphate esters of alkylphenol alkoxylates, and phosphate esters of styrylphenol ethoxylates; a protein-based surfactant; a sarcosine derivative; styrylphenol ether sulfate; sulfates and sulfonates of oils and fatty acids; sulfates and sulfonates of ethoxylated alkylphenols; sulfates of alcohols; sulfates of ethoxylated alcohols; amine and amide sulfonates, such as N, N-alkyl taurates; benzene, cumene, toluene, xylene, and sulfonates of dodecylbenzene and tridecylbenzene; a sulfonate of condensed polynaphthalene; sulfonates of naphthalene and alkylnaphthalenes; sulfonates of petroleum fractions; sulfosuccinamates; and sulfosuccinates and their derivatives, such as dialkyl sulfosuccinates.

Useful cationic surfactants include, but are not limited to: amides and ethoxylated amides; amines such as N-alkyl propylene diamine, tripropylene triamine and dipropylene tetramine, and ethoxylated, ethoxylated and propoxylated amines (prepared from amines and ethylene oxide, propylene oxide, butylene oxide or mixtures thereof); amine salts, such as amine acetates and diamine salts; quaternary ammonium salts such as quaternary salts, ethoxylated quaternary salts and diquaternary salts; and amine oxides such as alkyldimethylamine oxide and bis- (2-hydroxyethyl) -alkylamine oxide.

Also useful in the compositions of the present invention are mixtures of nonionic and anionic surfactants or mixtures of nonionic and cationic surfactants. Nonionic, anionic and cationic surfactants and their proposed uses are disclosed in a number of published references, including McCutcheon's emulsions and Detergents published by McCutcheon's Division, The Manufacturing meeting Publishing co, north american and international yearbook versions; the Encyclopedia of Surface active Agents, Chemical Publ.Co., Inc., New York, 1964, by Sisely and Wood; and Synthetic Detergents, seventh edition, John Wiley and Sons, New York, 1987, by a.s.davidson and b.milwidsky.

The compositions of the present invention may also contain formulation adjuvants and additives known to those skilled in the art as co-formulations (some of which may also be considered to act as solid diluents, liquid diluents or surfactants). Such formulation aids and additives may control: pH (buffer), foaming during processing (antifoam such as polyorganosiloxane), sedimentation of the active ingredient (suspending agent), viscosity (thixotropic thickener), microbial growth in the container (biocide), product freezing (antifreeze), color (dye/pigment dispersion), elution (film former or binder), evaporation (anti-evaporation agent), and other formulation attributes. Film formers include, for example, polyvinyl acetate copolymers, polyvinylpyrrolidone-vinyl acetate copolymers, polyvinyl alcohol copolymers, and waxes. Examples of formulation aids and additives include McCutcheon's volume2 published by McCutcheon's division, The Manufacturing conditioner Publishing co: functional Materials, north american and international yearbook versions; and those listed in PCT publication WO 03/024222.

The compounds of the present invention and any other active ingredients are typically incorporated into the compositions of the present invention by dissolving the active ingredient in a solvent or by grinding the active ingredient in a liquid diluent or a dry diluent. Solutions, including emulsifiable concentrates, can be prepared by simply mixing the ingredients. If the solvent of the liquid composition used as an emulsifiable concentrate is water-immiscible, an emulsifier is usually added to emulsify the solvent containing the active ingredient upon dilution with water. A media mill may be used to wet grind an active ingredient slurry having a particle size of up to 2,000 μm to obtain particles having an average diameter of less than 3 μm. The aqueous slurry can be prepared as a finished suspension concentrate (see, e.g., U.S.3,060,084) or further processed by spray drying to form water-dispersible granules. Dry formulations typically require a dry milling step, which results in an average particle size in the range of 2 to 10 μm. Powders and dusts can be prepared by mixing, and usually by grinding (e.g., with a hammer mill or fluid energy mill). Particles and granules can be prepared by spraying the active substance onto preformed particle carriers or by agglomeration techniques. See Browning "agglomerization" (Chemical Engineering, 12.4.1967, pages 147-48; Perry's Chemical Engineering' Handbook, 4 th edition, McGraw-Hill, New York, 1963, pages 8-57 and later and WO 91/13546. the pellets can be prepared as described in u.s.4,172,714. the water dispersible and water soluble particles can be prepared as set forth in u.s.4,144,050, u.s.3,920,442 and de.3,246,493. the tablets can be prepared as set forth in u.s.5,180,587, u.s.5,232,701 and u.s.5,208,030. the films can be prepared as set forth in GB2,095,558 and u.s.3,299,566.

For additional information regarding The field of formulation, see "The formulations's Toolbox-Product Forms for model Agriculture" in T.S. woods, The food-environmental Challenge, T.Brooks and T.R. Roberts eds, Proceedings of The9th International conformation on Pesticide Chemistry, The Royal Society of Chemistry, Cambridge, 1999, p.120-. See also U.S.3,235,361, column 6, line 16 to column 7, line 19 and examples 10-41; U.S. Pat. No. 3,309,192, column 5, column 43 to column 7, column 62 and examples 8, 12, 15, 39, 41, 52, 53, 58, 132, 138, 162, 164, 166, 167 and 169, 182; U.S.2,891,855 at column 3, line 66 to column 5, line 17 and examples 1-4; wed Control as a Science by Klingman, John Wiley and Sons, Inc., New York, 1961, pages 81-96; weed Control Handbook, 8 th edition, Blackwell scientific Publications, Oxford, 1989, by Hance et al; and Developments in relational technology, PJB Publications, Richmond, UK, 2000.

Use of the Compounds of the invention

The herbicides of the present invention can be used by spraying plants, applying to soil, applying to the surface of water. The amount of the active ingredient is appropriately determined to meet the purpose of use. The content of the active ingredient is appropriately determined depending on the purpose.

The amount of the compound of the present invention to be used depends on the kind of the compound to be used, the target weed, the tendency of weed to appear, environmental conditions, the kind of herbicide, and the like. When the herbicides of the invention are used as such, for example in the form of powders or granules, the amount is suitably selected from 1g to 50kg, preferably 10g to 10kg, per 1 hectare of active ingredient. When the herbicide of the present invention is used in a liquid form, for example, in the form of an emulsifiable concentrate, a wettable powder or a flowable formulation, the amount thereof is suitably selected from 0.1 to 50,000ppm, preferably from 10 to 10,000 ppm.

The present invention provides a method for controlling weeds in a crop of useful plants, comprising applying to said weeds or to the locus of said weeds, or to said useful plants or to the locus of said useful plants, a compound or composition of the invention.

The invention also provides a method for selectively controlling grasses and/or weeds in crops of useful plants, which comprises applying to the useful plants or to the locus thereof or to the cultivation area a herbicidally effective amount of a herbicide of the formula (I), formula (Ia), formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (III-1), formula (III-2), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIa-1), formula (IIa-2), formula (IIa-3), formula (IIa-4), formula (IIa-5), formula (IIa-6), formula (IIa-7), formula (IIa-8), formula (IIa-9), formula (IIa-10), formula (IIa-11), A compound represented by formula (IIa-12), formula (IIa-13), formula (IIa-14), formula (IIa-15), formula (IIa-16), formula (IIa-17), formula (IIa-18), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IIIe), formula (IIIf), formula (IIIg), formula (IIIh), formula (IV), formula (IVa), formula (IVb), formula (IVc) or formula (IVd), or a stereoisomer, a nitrogen oxide or a salt thereof.

The term "herbicide" means a compound that controls or modifies the growth of plants. The term "herbicidally effective amount" means the amount of such a compound or combination of such compounds that is capable of producing a control or modification of the growth of plants. The effects of control or modification include all deviations from natural development, e.g., kills, delays, leaf burns, albinism, dwarfing, etc. The term "plant" refers to all tangible parts of a plant, including seeds, seedlings, plantlets, roots, tubers, stems, stalks, leaves, and fruits. The term "locus" is intended to include soil, seeds and seedlings, as well as established plants (grassed habitat) and includes not only areas where weeds may have grown, but also areas where weeds have not yet emerged, and also areas for the planting of crops of useful plants. "planted area" includes the land on which crop plants have grown, as well as the land intended for planting such crop plants. The term "weeds" as used herein means any undesirable vegetation and thus includes not only important agronomic weeds as described below, but also volunteer crop plants.

Crops of useful plants in which the compositions according to the invention may be used include, but are not limited to, perennial crops such as citrus fruits, grapevines, nuts, oil palms, olives, pome fruits, stone fruits and rubber, and annual arable crops such as cereals (such as barley and wheat), cotton, oilseed rape, maize, rice, soya, sugar beet, sugar cane, sunflowers, ornamentals, switchgrass, turf and vegetables, especially cereals, maize and soya.

The grasses and weeds to be controlled can be both monocotyledonous species, such as agrostis, alopecurus, avena, brachiaria, bromus, tribulus, cyperus, digitaria, barnyard grass, kojima, lolium, monocrotonia, panicum, poa, cylindron, arrowhead, scirpus, setaria, sida and sorghum, and dicotyledonous species, such as kenaf, amaranthus, chenopodium, chrysanthemum, euphorbia, labra, ipomoea, kochia, eclipta, polygonum, rhodomyrtus, sinapis, solanum, chickweed, veronica, viola and xanthium.

The compounds of the invention may show tolerance to important crops including, but not limited to, alfalfa, barley, cotton, wheat, canola, sugar beet, corn (maize), sorghum, soybean, rice, oats, peanut, vegetables, tomato, potato, perennial plant crops including coffee, cocoa, oil palm, rubber, sugar cane, citrus, grapes, fruit trees, nut trees, bananas, plantains, pineapple, hops, tea and forests such as eucalyptus and conifer (e.g., loblolly pine), and turf varieties (e.g., prairie grass, san augustine grass (st. augustine grass), Kentucky grass and bermudagrass).

If desired, according to the invention, the compounds of the formula (I), formula (Ia), formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (III-1), formula (III-2), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIa-1), formula (IIa-2), formula (IIa-3), formula (IIa-4), formula (IIa-5), formula (IIa-6), formula (IIa-7), formula (IIa-8), formula (IIa-9), formula (IIa-10), formula (IIa-11), formula (IIa-12), formula (IIa-13), formula (IIa-14), formula (IIa-15), formula (IIa-16), The compounds of formula (IIa-17), formula (IIa-18), formula (IIIa), formula (IIIb), formula (IIIc), formula (IIId), formula (IIIe), formula (IIIf), formula (IIIg), formula (IIIh), formula (IV), formula (IVa), formula (IVb), formula (IVc) or formula (IVd) or stereoisomers, nitrogen oxides or salts thereof can also be used in combination with other active ingredients, for example other herbicides and/or insecticides and/or acaricides and/or nematicides and/or molluscicides and/or fungicides and/or plant growth regulators. These mixtures, and the use of these mixtures for controlling the growth of weeds and/or undesired vegetation, form yet further aspects of the invention. For the avoidance of doubt, the mixtures of the invention also include two or more different compounds of the formula (I), formula (Ia), formula (II-1), formula (II-2), formula (II-3), formula (II-4), formula (II-5), formula (III-1), formula (III-2), formula (IIa), formula (IIb), formula (IIc), formula (IId), formula (IIa-1), formula (IIa-2), formula (IIa-3), formula (IIa-4), formula (IIa-5), formula (IIa-6), formula (IIa-7), formula (IIa-8), formula (IIa-9), formula (IIa-10), formula (IIa-11), formula (IIa-12), formula (IIa-13), formula (IIa-14), formula (IIa-15), A compound represented by the formula (IIa-16), the formula (IIa-17), the formula (IIa-18), the formula (IIIa), the formula (IIIb), the formula (IIIc), the formula (IIId), the formula (IIIe), the formula (IIIf), the formula (IIIg), the formula (IIIh), the formula (IV), the formula (IVa), the formula (IVb), the formula (IVc) or the formula (IVd), a stereoisomer thereof, a nitrogen oxide thereof or a mixture of salts thereof. Specifically, the invention also relates to a composition of the invention, which is in addition to the formula (I), the formula (Ia), the formula (II-1), the formula (II-2), the formula (II-3), the formula (II-4), the formula (II-5), the formula (III-1), the formula (III-2), the formula (IIa), the formula (IIb), the formula (IIc), the formula (IId), the formula (IIa-1), the formula (IIa-2), the formula (IIa-3), the formula (IIa-4), the formula (IIa-5), the formula (IIa-6), the formula (IIa-7), the formula (IIa-8), the formula (IIa-9), the formula (IIa-10), the formula (IIa-11), the formula (IIa-12), the formula (IIa-13), the formula (IIa-14), the formula (IIa-15, The compound represented by the formula (IIa-16), the formula (IIa-17), the formula (IIa-18), the formula (IIIa), the formula (IIIb), the formula (IIIc), the formula (IIId), the formula (IIIe), the formula (IIIf), the formula (IIIg), the formula (IIIh), the formula (IV), the formula (IVa), the formula (IVb), the formula (IVc) or the formula (IVd) or a stereoisomer, a nitrogen oxide or a salt thereof, and further comprises at least one herbicide.

General synthetic procedure

In this specification, a structure is dominant if there is any difference between the chemical name and the chemical structure. In general, the compounds of the invention may be prepared by the methods described herein, unless otherwise indicated. The starting materials, reagents and the like used in the preparation of the compounds of the present invention are commercially available or can be prepared by methods conventional in the art.

The test conditions of the nuclear magnetic resonance hydrogen spectrum of the invention are as follows: brookfield (Bruker) nuclear magnetic instrument at 400MHz or 600MHz in CDC1 at room temperature₃，d⁶-DMSO，CD₃OD or d⁶Acetone as solvent (reported in ppm) with TMS (0ppm) or chloroform (7.26ppm) as reference standard. When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet), q (quatet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet)let of triplets, double triplet). Coupling constants are expressed in hertz (Hz).

The mass spectrometry method used in the invention comprises the following steps: agilent 1260HPLC was used; agilent 6120 ESI.

Phase A: water (0.1% formic acid); phase B: acetonitrile (0.1% formic acid).

Gradient elution: 0-3min, 5-100% B; 3-6min, 100% B.

Flow rate: 0.6 mL/min.

Detection wavelength: 254 nm.

MS parameters: ESI positive scan, collision induced ionization: 70V.

Drying nitrogen gas: 12L/min, atomizing gas pressure: 40psi, gas temperature: at 350 ℃.

Taking a proper amount of sample, dissolving in 0.5mL of methanol, injecting a sample, and performing primary MS full scanning in a positive ESI mode to obtain an excimer peak [ M + H ]]⁺And (6) reading.

The following abbreviations are used throughout the present invention:

petroleum ether: petroleum ether

DMF: n, N-dimethylformamide, dimethylformamide

EtOAc: ethyl acetate

HBr: hydrogen bromide

K₂CO₃: potassium carbonate

m-CPBA: meta-chloroperoxybenzoic acid

NFSI: n-fluorobisbenzenesulfonamides

THF: tetrahydrofuran (THF)

TLC: thin layer chromatography

The following synthetic schemes and examples 1-16 serve to further illustrate the context of the present invention.

Synthesis scheme I

The compound of formula (5a) may be prepared by synthetic scheme one, wherein R^cIs C_2-10Alkyl, haloalkyl or cycloalkyl. (a ') reacting the compound with thiourea in HBr to obtain a compound of formula (b'); the ethyl difluoroacetoacetate reacts with hydrazine hydrate and then with phosphorus oxychloride to obtain an intermediate and R^c-I to give a compound of formula (1a) and a compound of formula (1 b); carrying out reduction reaction on the compound of the formula (1a) to obtain a compound of a formula (2 a); reacting the compound of formula (2a) with a bromohydrocarbon (e.g., carbon tetrabromide) to obtain a compound of formula (3 a); under basic conditions (e.g. K) the compounds of formula (3a)₂CO₃Etc.) to produce a compound of formula (4a) by condensation reaction with a compound of formula (b'); the compound of formula (4a) is further oxidized to give the compound of formula (5 a).

Synthesis scheme two

The compound of formula (5b) may be prepared by synthetic scheme one, wherein R^cIs C_2-10Alkyl, haloalkyl or cycloalkyl. The compound of the formula (1b) is subjected to reduction reaction to obtain a compound of a formula (2 b); reacting the compound of formula (2b) with a bromohydrocarbon (e.g., carbon tetrabromide) to obtain a compound of formula (3 b); under basic conditions (e.g. K) the compounds of formula (3b)₂CO₃Etc.) to produce a compound of formula (4b) by condensation reaction with a compound of formula (b'); the compound of formula (4b) is further oxidized to give the compound of formula (5 b).

Examples

Example 1: 3- (((5-chloro-3- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) methyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole

Step 1: synthesis of compound 5, 5-dimethyl-4, 5-dihydroisoxazol-3-ylisothiourea hydrobromide

Thiourea (6g,79mmol) was dissolved in acetonitrile (65mL) at room temperature, hydrobromic acid (48%, 10mL) was added dropwise, and stirred for 1 h. To the above-mentioned mixed solution was added dropwise 3-chloro-5, 5-dimethyl-4, 5-dihydroisoxazole (12.6g,95mmol), and the mixture was stirred overnight while warming to 40 ℃. The solvent was distilled off under pressure, and the resulting solid was recrystallized from ethyl acetate to obtain 19.2g of white crystals, yield: 96.0 percent.

Step 2: synthesis of the compounds 5-chloro-3- (difluoromethyl) -1-ethyl-1H-pyrazole-4-carbaldehyde and 3-chloro-5- (difluoromethyl) -1-ethyl-1H-pyrazole-4-carbaldehyde

Ethyl difluoroacetoacetate (83.06g,0.5mol) was dissolved in absolute ethanol (200mL) and stirred at 0 deg.C, then hydrazine hydrate (37.50g,0.75mol) was slowly added dropwise to the above mixture, after the dropwise addition was completed, the mixture was heated to room temperature for reaction for 4 hours, and then heated to 80 deg.C for reaction overnight, and the reaction was stopped. The ethanol was removed, the mixture was washed with water (300mL), extracted with ethyl acetate (150mL) three times, and the combined organic phases were freed of solvent under reduced pressure to give a pale yellow solid.

Placing DMF (38.01g,0.52mol) at 0 ℃ for stirring, slowly dropwise adding phosphorus oxychloride (239.20g,1.56mol) into the DMF, after dropwise adding, heating to room temperature for stirring, adding the obtained light yellow solid into the mixed solution in batches, then heating the mixed solution to 110 ℃ for refluxing overnight, after the reaction is finished, washing with water (500mL), extracting with ethyl acetate (150mL) for three times, combining organic phases, and removing the solvent under reduced pressure to obtain a reddish brown solid.

Dissolving the reddish brown solid and potassium carbonate (57.96g,0.42mol) in DMF (100mL) and stirring at room temperature, then adding iodoethane (35.78g,0.25mol) into the mixed solution, after the addition is finished, heating to 80 ℃, stirring for 24H, after the reaction is finished, washing with water (200mL), extracting ethyl acetate (100mL) for three times, combining organic phases, removing the solvent under reduced pressure, and performing column chromatography separation and purification (eluent: Petroleum ether/EtOAc (v/v) ═ 10/1) to obtain 15.69g of colorless transparent liquid 5-chloro-3- (difluoromethyl) -1-ethyl-1H-pyrazole-4-formaldehyde with the yield of 15.0%; and 15.92g of colorless transparent liquid 3-chloro-5- (difluoromethyl) -1-ethyl-1H-pyrazole-4-carbaldehyde, yield: 15.3 percent.

5-chloro-3- (difluoromethyl) -1-ethyl-1H-pyrazole-4-carbaldehyde: MS-ESI: M/z 209.0[ M + H ]]⁺；¹H NMR(400MHz,CDCl₃)9.89(s,1H),7.41(t,J＝52.5Hz,1H),4.36(q,J＝7.2Hz,2H),1.52(t,J＝7.2Hz,3H)；¹⁹F NMR(376MHz,CDCl₃)-115.94(s),-116.08(s)；

3-chloro-5- (difluoromethyl) -1-ethyl-1H-pyrazole-4-carbaldehyde: MS-ESI: M/z 209.0[ M + H ]]⁺；¹H NMR(400MHz,CDCl₃)9.97(s,1H),6.90(t,J＝53.6Hz,1H),4.27(q,J＝7.3Hz,2H),1.50(t,J＝7.3Hz,3H)；¹⁹F NMR(376MHz,CDCl₃)-114.04(s),-114.18(s)。

And step 3: synthesis of Compound (5-chloro-3- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) methanol

Dissolving 5-chloro-3- (difluoromethyl) -1-ethyl-1H-pyrazole-4-carbaldehyde (6.0g,28.8mmol) in anhydrous methanol (50mL) and stirring at 0 ℃, then gradually adding sodium borohydride (1.30g,34.5mmol) in portions to the above mixed solution, after the addition is finished, heating to room temperature and stirring for 4H, after the reaction is finished, removing methanol, washing with water (50mL), extracting with ethyl acetate (50mL) for three times, combining organic phases and removing the solvent under reduced pressure to obtain 5.50g of a colorless liquid crude product, wherein the yield is as follows: 90.7 percent.

MS-ESI:m/z 211.0[M+H]⁺。

And 4, step 4: synthesis of compound 4- (bromomethyl) -5-chloro-3- (difluoromethyl) -1-ethyl-1H-pyrazole

Dissolving (5-chloro-3- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) methanol (6.00g,28.5mmol) and triphenylphosphine (14.95g,57.0mmol) in acetonitrile (60mL), stirring at 0 ℃, then dissolving carbon tetrabromide (18.9g,57.0mmol) in acetonitrile (20mL), slowly dropwise adding the mixture to the mixture, controlling the temperature to be not higher than 5 ℃, after the dropwise addition, heating to room temperature, stirring for 3.5H, removing acetonitrile after the reaction is finished, washing with water (300mL), extracting with ethyl acetate (100mL) for three times, combining organic phases, removing the solvent under reduced pressure, and separating and purifying by column chromatography (eluent: Petroleum ether/EtOAc (v/v) ═ 10/1), to obtain 7.50g of a colorless liquid, yield: 96.3 percent.

MS-ESI:m/z 274.9[M+H]⁺。

And 5: synthesis of Compound 3- (((5-chloro-3- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) methyl) thio) -5, 5-dimethyl-4, 5-dihydroisoxazole 4- (bromomethyl) -5-chloro-3- (difluoromethyl) -1-ethyl-1H-pyrazole (7.50g,27.4mmol) and 5, 5-dimethyl-4, 5-dihydroisoxazol-3-yl isothiourea hydrobromide (8.36g,32.9mmol) were dissolved in acetonitrile (100mL), and after stirring at room temperature for 10min, to the above mixture was added potassium carbonate (15.12g,109.6mmol), the reaction was stopped after 12H, the acetonitrile was removed, washed with water (300mL), ethyl acetate (100mL) was extracted three times and the combined organic phases were freed of solvent under reduced pressure to give 7.00g of crude product as a yellow liquid in yield: 79.0 percent.

MS-ESI:m/z 324.0[M+H]⁺。

Step 6: synthesis of Compound 3- (((5-chloro-3- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) methyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole

3- (((5-chloro-3- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) methyl) thio) -5, 5-dimethyl-4, 5-dihydroisoxazole (7.00g,21.6mmol) was dissolved in dichloromethane (100mL), stirred at room temperature, then 85% m-CPBA (8.78g,43.2mmol) was added to the above mixture to react for 5 hours and then the reaction was stopped, then washed with saturated aqueous sodium bisulfite (200mL) and saturated aqueous sodium bicarbonate (200mL), respectively, extracted with dichloromethane (200mL), dried over anhydrous sodium sulfate, the combined organic phases were freed from the solvent under reduced pressure, purified by column chromatography (eluent: Petroleum ether/EtOAc (v/v) ═ 5/1) to give 5.45g of a white solid, yield: 71.0 percent.

MS-ESI:m/z 356.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)6.82(t,J＝54.8Hz,1H),4.62(s,2H),4.26(q,J＝7.3Hz,2H),3.09(s,2H),1.52(s,6H),1.49(t,J＝7.3Hz,3H).

Example 2: 3- (((3-chloro-5- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) methyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole

Step 1: synthesis of Compound (3-chloro-5- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) methanol

Dissolving 3-chloro-5- (difluoromethyl) -1-ethyl-1H-pyrazole-4-carbaldehyde (6.3g,30.2mmol) in anhydrous methanol (50mL) and stirring at 0 ℃, then gradually adding sodium borohydride (1.36g,36.2mmol) in portions to the above mixed solution, after the addition is finished, heating to room temperature and stirring for 4H, after the reaction is finished, removing methanol, washing with water (50mL), extracting with ethyl acetate (50mL) for three times, combining organic phases and removing the solvent under reduced pressure to obtain 6.00g of a colorless liquid crude product, wherein the yield is as follows: 94.3 percent.

MS-ESI:m/z 211.0[M+H]⁺。

Step 2: synthesis of compound 4- (bromomethyl) -3-chloro-5- (difluoromethyl) -1-ethyl-1H-pyrazole

Dissolving (3-chloro-5- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) methanol (6.00g,28.5mmol) and triphenylphosphine (14.95g,57.0mmol) in acetonitrile (60mL), stirring at 0 ℃, then dissolving carbon tetrabromide (18.9g,57.0mmol) in acetonitrile (20mL), slowly dropwise adding the mixture to the mixture, controlling the temperature to be not higher than 5 ℃, after the dropwise addition, heating to room temperature, stirring for 3.5H, removing acetonitrile after the reaction is finished, washing with water (300mL), extracting with ethyl acetate (100mL) for three times, combining organic phases, removing the solvent under reduced pressure, and separating and purifying by column chromatography (eluent: Petroleum ether/EtOAc (v/v) ═ 10/1), to obtain 7.50g of a colorless liquid, yield: 96.3 percent.

MS-ESI:m/z 274.9[M+H]⁺。

And step 3: synthesis of Compound 3- (((3-chloro-5- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) methyl) thio) -5, 5-dimethyl-4, 5-dihydroisoxazole 4- (bromomethyl) -3-chloro-5- (difluoromethyl) -1-ethyl-1H-pyrazole (7.50g,27.4mmol) and 5, 5-dimethyl-4, 5-dihydroisoxazol-3-yl isothiourea hydrobromide (8.36g,32.9mmol) were dissolved in acetonitrile (100mL), and after stirring at room temperature for 10min, to the above mixture was added potassium carbonate (15.12g,109.6mmol), the reaction was stopped after 12H, the acetonitrile was removed, washed with water (300mL), ethyl acetate (100mL) was extracted three times and the combined organic phases were freed of solvent under reduced pressure to give 7.0g of crude product as a yellow liquid in yield: 79.0 percent.

MS-ESI:m/z 324.0[M+H]⁺。

And 4, step 4: synthesis of Compound 3- (((3-chloro-5- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) methyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole

3- (((3-chloro-5- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) methyl) thio) -5, 5-dimethyl-4, 5-dihydroisoxazole (7.00g,21.6mmol) was dissolved in dichloromethane (100mL) and stirred at room temperature, then 85% m-CPBA (8.78g,43.2mmol) was added to the above mixture, the reaction was stopped after 5 hours, and then the mixture was washed with a saturated aqueous sodium bisulfite solution (200mL) and a saturated aqueous sodium bicarbonate solution (200mL), dichloromethane (200mL) was extracted, dried over anhydrous sodium sulfate, the organic phases were combined and the solvent was removed under reduced pressure, and purified by column chromatography (eluent: Petroleum ether/EtOAc (v/v) ═ 5/1) to give 5.40g of a white solid, yield: 70.3 percent.

MS-ESI:m/z 356.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)6.89(t,J＝52.3Hz,1H),4.55(s,2H),4.31(q,J＝7.2Hz,2H),3.02(s,2H),1.49(s,9H)。

Example 3: 3- (((5-chloro-3- (difluoromethyl) -1-isopropyl-1H-pyrazol-4-yl) methyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole

Step 1: synthesis of the compound 5-chloro-3- (difluoromethyl) -1-isopropyl-1H-pyrazole-4-carbaldehyde and 3-chloro-5- (difluoromethyl) -1-isopropyl-1H-pyrazole-4-carbaldehyde

The above reddish brown solid product and potassium carbonate (57.96g,0.42mol) were dissolved in DMF (100mL) and stirred at room temperature, then 2-iodopropane (42.50g,0.25mol) was added to the above mixture, after completion of the addition, the mixture was heated to 80 ℃ and stirred for 24H, after completion of the reaction, washed with water (200mL), extracted with ethyl acetate (100mL) in three portions, the organic phases were combined and the solvent was removed under reduced pressure, and separated by column chromatography (eluent: Petroleum ether/EtOAc (v/v) ═ 10/1) to obtain 27.8g of 5-chloro-3- (difluoromethyl) -1-isopropyl-1H-pyrazole-4-carbaldehyde as a colorless transparent liquid, yield: 25.0 percent; and 28.16g of colorless transparent liquid 3-chloro-5- (difluoromethyl) -1-isopropyl-1H-pyrazole-4-carbaldehyde, yield: 25.3 percent.

5-chloro-3- (difluoromethyl) -1-isopropyl-1H-pyrazole-4-carbaldehyde: MS-ESI: M/z 223.1[ M + H ]]⁺；¹HNMR(400MHz,CDCl₃)9.89(s,1H),7.44(t,J＝52.5Hz,1H),4.86(hept,J＝6.6Hz,1H),1.54(d,J＝6.6Hz,6H)；¹⁹F NMR(376MHz,CDCl₃)-115.54(s),-115.68(s)；

3-chloro-5- (difluoromethyl) -1-isopropyl-1H-pyrazole-4-carbaldehyde: MS-ESI: M/z 223.1[ M + H ]]⁺；¹HNMR(400MHz,CDCl₃)9.99(s,1H),6.88(t,J＝53.6Hz,1H),4.79(hept,J＝6.6Hz,1H),1.53(d,J＝6.7Hz,6H)；¹⁹F NMR(376MHz,CDCl₃)-113.49(s),-113.64(s)。

Step 2: synthesis of Compound (5-chloro-3- (difluoromethyl) -1-isopropyl-1H-pyrazol-4-yl) methanol

Dissolving 5-chloro-3- (difluoromethyl) -1-isopropyl-1H-pyrazole-4-carbaldehyde (2.25g,10.1mmol) in anhydrous methanol (20mL) and stirring at 0 ℃, then gradually adding sodium borohydride (0.45g,12.1mmol) in portions to the above mixed solution, after the addition is finished, heating to room temperature and stirring for 4H, after the reaction is finished, removing methanol, washing with water (50mL), extracting with ethyl acetate (50mL) for three times, combining organic phases, and removing the solvent under reduced pressure to obtain 2.00g of a colorless liquid crude product, wherein the yield is as follows: 88.5 percent.

MS-ESI:m/z 225.1[M+H]⁺。

And step 3: synthesis of compound 4- (bromomethyl) -5-chloro-3- (difluoromethyl) -1-isopropyl-1H-pyrazole

Dissolving (5-chloro-3- (difluoromethyl) -1-isopropyl-1H-pyrazol-4-yl) methanol (2.00g,8.9mmol) and triphenylphosphine (4.67g,17.8mmol) in acetonitrile (20mL), stirring at 0 ℃, then dissolving carbon tetrabromide (5.90g,17.8mmol) in acetonitrile (10mL), slowly dropwise adding the mixture into the mixture, controlling the temperature to be not higher than 5 ℃, after dropwise adding, heating to room temperature, stirring for 3.5H, removing acetonitrile after reaction, washing with water (100mL), extracting with ethyl acetate (50mL) for three times, combining organic phases, removing the solvent under reduced pressure, and separating and purifying (eluent: Petroleum ether/EtOAc (v/v) ═ 10/1) to obtain 2.20g of colorless liquid, yield: 86.3 percent.

MS-ESI:m/z 288.9[M+H]⁺。

And 4, step 4: synthesis of the Compound 3- (((5-chloro-3- (difluoromethyl) -1-isopropyl-1H-pyrazol-4-yl) methyl) thio) -5, 5-dimethyl-4, 5-dihydroisoxazole

4- (bromomethyl) -5-chloro-3- (difluoromethyl) -1-isopropyl-1H-pyrazole (2.20g,7.6mmol) and 5, 5-dimethyl-4, 5-dihydroisoxazol-3-ylisothiourea hydrobromide (2.33g,9.2mmol) were dissolved in acetonitrile (30mL) and after stirring at room temperature for 10min, potassium carbonate (4.20g,30.4mmol) was then added to the above mixture and the reaction was stopped after 12H, the acetonitrile was then removed, washed with water (100mL), ethyl acetate (30mL) was extracted three times and the combined organic phases were freed from solvent under reduced pressure to give 2.48g of crude yellow liquid, yield: 96.5 percent.

MS-ESI:m/z 338.1[M+H]⁺。

And 5: synthesis of the Compound 3- (((5-chloro-3- (difluoromethyl) -1-isopropyl-1H-pyrazol-4-yl) methyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole

3- (((5-chloro-3- (difluoromethyl) -1-isopropyl-1H-pyrazol-4-yl) methyl) thio) -5, 5-dimethyl-4, 5-dihydroisoxazole (2.78g,8.2mmol) was dissolved in dichloromethane (50mL) and stirred at room temperature, then 85% m-CPBA (3.34g,16.4mmol) was added to the above mixture, the reaction was stopped after 5 hours of reaction, and then washed with a saturated aqueous sodium bisulfite solution (100mL) and a saturated aqueous sodium bicarbonate solution (100mL), dichloromethane (50mL) was extracted, dried over anhydrous sodium sulfate, the organic phases were combined and the solvent was removed under reduced pressure, and purified by column chromatography (eluent: Petreum ether/EtOAc (v/v) ═ 5/1) to obtain 2.30g of a white solid, yield: 84.8 percent.

MS-ESI:m/z 370.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)6.79(t,J＝54.7Hz,1H),4.73(dt,J＝13.3,6.6Hz,1H),4.62(s,2H),3.07(s,2H),1.50(t,J＝3.3Hz,12H)。

Example 4: 3- (((3-chloro-5- (difluoromethyl) -1-isopropyl-1H-pyrazol-4-yl) methyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole

Step 1: synthesis of Compound (3-chloro-5- (difluoromethyl) -1-isopropyl-1H-pyrazol-4-yl) methanol

Dissolving 3-chloro-5- (difluoromethyl) -1-isopropyl-1H-pyrazole-4-carbaldehyde (1.60g,7.2mmol) in anhydrous methanol (20mL) and stirring at 0 ℃, then gradually adding sodium borohydride (0.32g,8.6mmol) in portions to the above mixed solution, after the addition is finished, heating to room temperature and stirring for 4H, after the reaction is finished, removing methanol, washing with water (50mL), extracting with ethyl acetate (50mL) for three times, combining organic phases, and removing the solvent under reduced pressure to obtain 1.55g of a colorless liquid crude product, wherein the yield is as follows: 95.8 percent.

MS-ESI:m/z 225.1[M+H]⁺。

Step 2: synthesis of compound 4- (bromomethyl) -3-chloro-5- (difluoromethyl) -1-isopropyl-1H-pyrazole

Dissolving (3-chloro-5- (difluoromethyl) -1-isopropyl-1H-pyrazol-4-yl) methanol (1.55g,6.9mmol) and triphenylphosphine (3.62g,13.8mmol) in acetonitrile (20mL), stirring at 0 ℃, then dissolving carbon tetrabromide (4.58g,13.8mmol) in acetonitrile (10mL), slowly dropwise adding the mixture into the mixture, controlling the temperature to be not higher than 5 ℃, after dropwise adding, heating to room temperature, stirring for 3.5H, removing acetonitrile after reaction, washing with water (100mL), extracting with ethyl acetate (50mL) for three times, combining organic phases, removing the solvent under reduced pressure, and separating and purifying (eluent: Petroleum ether/EtOAc (v/v) ═ 10/1) to obtain 1.46g of colorless liquid, yield: 74.0 percent.

MS-ESI:m/z 288.9[M+H]⁺。

And step 3: synthesis of the Compound 3- (((3-chloro-5- (difluoromethyl) -1-isopropyl-1H-pyrazol-4-yl) methyl) thio) -5, 5-dimethyl-4, 5-dihydroisoxazole

4- (bromomethyl) -3-chloro-5- (difluoromethyl) -1-isopropyl-1H-pyrazole (1.46g,5.1mmol) and 5, 5-dimethyl-4, 5-dihydroisoxazol-3-ylisothiourea hydrobromide (1.55g,6.1mmol) were dissolved in acetonitrile (30mL) and after stirring at room temperature for 10min, potassium carbonate (2.82g,20.4mmol) was then added to the above mixture and the reaction was stopped after 12H, the acetonitrile was then removed, washed with water (100mL), ethyl acetate (30mL) was extracted three times and the combined organic phases were freed from solvent under reduced pressure to give a crude yellow liquid 1.65g, yield: 96.0 percent.

MS-ESI:m/z 338.1[M+H]⁺。

And 4, step 4: synthesis of Compound 3- (((3-chloro-5- (difluoromethyl) -1-isopropyl-1H-pyrazol-4-yl) methyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole

3- (((3-chloro-5- (difluoromethyl) -1-isopropyl-1H-pyrazol-4-yl) methyl) thio) -5, 5-dimethyl-4, 5-dihydroisoxazole (1.64g,4.85mmol) was dissolved in methylene chloride (30mL), stirred at room temperature, 85% m-CPBA (1.97g,9.7mmol) was added to the above mixture, the reaction was stopped after 5 hours of reaction, and then washed with a saturated aqueous sodium bisulfite solution (100mL) and a saturated aqueous sodium bicarbonate solution (100mL), methylene chloride (50mL) was extracted, dried over anhydrous sodium sulfate, the organic phases were combined and the solvent was removed under reduced pressure, and purified by column chromatography (eluent: Petreum ether/EtOAc (v/v) ═ 5/1) to give 1.30g of a white solid, yield: 72.6 percent.

MS-ESI:m/z 370.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)6.87(t,J＝52.2Hz,1H),4.77(dt,J＝13.2,6.5Hz,1H),4.54(s,2H),3.00(s,2H),1.52(d,J＝6.6Hz,6H),1.48(s,6H)。

Example 5: 3- (((5-chloro-1- (2, 2-difluoroethyl) -3- (difluoromethyl) -1H-pyrazol-4-yl) methyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole

Step 1: synthesis of the compounds 5-chloro-1- (2, 2-difluoroethyl) -3- (difluoromethyl) -1H-pyrazole-4-carbaldehyde and 3-chloro-1- (2, 2-difluoroethyl) -5- (difluoromethyl) -1H-pyrazole-4-carbaldehyde

Ethyl difluoroacetoacetate (83.06g,0.50mol) is dissolved in absolute ethyl alcohol (200mL) and stirred at 0 ℃, then hydrazine hydrate (37.50g,0.75mol) is slowly dripped into the mixed solution, after the dripping is finished, the mixed solution is heated to room temperature for reaction for 4 hours, and then the mixed solution is heated to 80 ℃ for reaction overnight, and the reaction is stopped. The ethanol was removed, the mixture was washed with water (300mL), extracted with ethyl acetate (150mL) three times, and the combined organic phases were freed of solvent under reduced pressure to give a pale yellow solid.

Dissolving the reddish brown solid and potassium carbonate (57.96g,0.42mol) in DMF (100mL) and stirring at room temperature, then adding 1, 1-difluoro-2-iodoethane (48.00g,0.25mol) into the mixed solution, after the addition is finished, heating to 80 ℃ and stirring for 24H, after the reaction is finished, washing with water (200mL), extracting by ethyl acetate (100mL) for three times, combining organic phases, removing the solvent under reduced pressure, and carrying out column chromatography separation and purification (eluent: Petroleum ether/EtOAc (v/v) ═ 10/1) to obtain colorless transparent liquid 5-chloro-1- (2, 2-difluoroethyl) -3- (difluoromethyl) -1H-pyrazole-4-formaldehyde 20.03g, and the yield is 16.4%; and colorless transparent liquid 3-chloro-1- (2, 2-difluoroethyl) -5- (difluoromethyl) -1H-pyrazole-4-carbaldehyde 19.93g, yield: 16.3 percent.

5-chloro-1- (2, 2-difluoroethyl) -3- (difluoromethyl) -1H-pyrazole-4-carbaldehyde: MS-ESI of M/z 245.0[ M + H ]]⁺；¹H NMR(400MHz,CDCl₃)9.92(s,1H),7.42(t,J＝52.3Hz,1H),6.23(tt,J＝55.0,4.4Hz,1H),4.65(td,J＝12.3,4.4Hz,2H)；¹⁹F NMR(376MHz,CDCl₃)-114.83(t,J＝3.6Hz),-114.96(t,J＝3.5Hz),-122.48(tt,J＝12.2,3.6Hz),-122.63(tt,J＝12.2,3.6Hz)；

3-chloro-1- (2, 2-difluoroethyl) -5- (difluoromethyl) -1H-pyrazole-4-carbaldehyde: MS-ESI of M/z 245.0[ M + H ]]⁺；¹H NMR(400MHz,CDCl₃)9.92(s,1H),7.42(t,J＝52.3Hz,1H),6.22(tt,J＝55.0,4.4Hz,1H),4.65(td,J＝12.3,4.4Hz,2H)；¹⁹F NMR(376MHz,CDCl₃)-114.80(t,J＝3.6Hz),-114.94(t,J＝3.5Hz),-122.46(tt,J＝12.2,3.6Hz),-122.60(tt,J＝12.2,3.6Hz)。

Step 2: synthesis of the compound (5-chloro-1- (2, 2-difluoroethyl) -3- (difluoromethyl) -1H-pyrazol-4-yl) methanol

Dissolving 5-chloro-1- (2, 2-difluoroethyl) -3- (difluoromethyl) -1H-pyrazole-4-carbaldehyde (0.61g,2.5mmol) in anhydrous methanol (20mL) and stirring at 0 ℃, then gradually adding sodium borohydride (0.11g,3.0mmol) to the above mixed solution in portions, after the addition is finished, heating to room temperature and stirring for 4H, after the reaction is finished, removing methanol, washing with water (50mL), extracting with ethyl acetate (50mL) for three times, combining organic phases and removing the solvent under reduced pressure to obtain 0.60g of a colorless liquid crude product, and obtaining the yield: 96.8 percent.

MS-ESI:m/z 247.1[M+H]⁺。

And step 3: synthesis of compound 4- (bromomethyl) -5-chloro-1- (2, 2-difluoroethyl) -3- (difluoromethyl) -1H-pyrazole

Dissolving (5-chloro-1- (2, 2-difluoroethyl) -3- (difluoromethyl) -1H-pyrazol-4-yl) methanol (0.60g,2.4mmol) and triphenylphosphine (1.26g,4.8mmol) in acetonitrile (20mL), stirring at 0 ℃, then dissolving carbon tetrabromide (1.60g,4.8mmol) in acetonitrile (10mL), slowly dropwise adding into the above mixture while controlling the temperature to be not higher than 5 ℃, after dropwise adding, stirring at room temperature for 3.5H, removing acetonitrile after the reaction is finished, washing with water (100mL), extracting with ethyl acetate (50mL) for three times, combining organic phases, removing the solvent under reduced pressure, and purifying by column chromatography (eluent: peleluometer/EtOAc (v/v) ═ 10/1), to obtain colorless liquid 0.70g, yield: 94.6 percent.

MS-ESI:m/z 310.9[M+H]⁺。

And 4, step 4: synthesis of the Compound 3- (((5-chloro-1- (2, 2-difluoroethyl) -3- (difluoromethyl) -1H-pyrazol-4-yl) methyl) thio) -5, 5-dimethyl-4, 5-dihydroisoxazole

4- (bromomethyl) -5-chloro-1- (2, 2-difluoroethyl) -3- (difluoromethyl) -1H-pyrazole (0.70g,2.3mmol) and 5, 5-dimethyl-4, 5-dihydroisoxazol-3-ylisothiourea hydrobromide (0.70g,2.76mmol) were dissolved in acetonitrile (30mL), stirred at room temperature for 10min, then potassium carbonate (1.27g,9.2mmol) was added to the above mixture, the reaction was stopped after 12H, then acetonitrile was removed, washed with water (100mL), ethyl acetate (30mL) was extracted three times, the organic phases were combined and the solvent was removed under reduced pressure to give a yellow liquid crude product 0.79g, yield: 95.2 percent.

MS-ESI:m/z 360.1[M+H]⁺。

And 5: synthesis of the Compound 3- (((5-chloro-1- (2, 2-difluoroethyl) -3- (difluoromethyl) -1H-pyrazol-4-yl) methyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole

3- (((5-chloro-1- (2, 2-difluoroethyl) -3- (difluoromethyl) -1H-pyrazol-4-yl) methyl) thio) -5, 5-dimethyl-4, 5-dihydroisoxazole (0.79g,2.2mmol) was dissolved in dichloromethane (30mL), stirred at room temperature, then 85% m-CPBA (0.89g,4.4mmol) was added to the above mixture, the reaction was stopped after 5 hours of reaction, then washed with a saturated aqueous sodium bisulfite solution (50mL) and a saturated aqueous sodium bicarbonate solution (50mL), dichloromethane (50mL) was extracted, dried over anhydrous sodium sulfate, the organic phases were combined and the solvent was removed under reduced pressure, and separation and purification were carried out (eluent: Petroleum ether/EtOAc (v/v) ═ 5/1), 0.72g of white solid was obtained, yield: 83.7 percent.

MS-ESI:m/z 392.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)6.83(t,J＝54.6Hz,1H),6.35–5.94(m,1H),4.62(s,2H),4.60–4.50(m,2H),3.07(s,2H),1.50(s,6H)。

Example 6: 3- (((3-chloro-1- (2, 2-difluoroethyl) -5- (difluoromethyl) -1H-pyrazol-4-yl) methyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole

Step 1: synthesis of compound (3-chloro-1- (2, 2-difluoroethyl) -5- (difluoromethyl) -1H-pyrazol-4-yl) methanol

Dissolving 3-chloro-1- (2, 2-difluoroethyl) -5- (difluoromethyl) -1H-pyrazole-4-carbaldehyde (0.60g,2.45mmol) in anhydrous methanol (20mL) and stirring at 0 ℃, then gradually adding sodium borohydride (0.11g,2.94mmol) to the above mixed solution in portions, after the addition is finished, heating to room temperature and stirring for 4H, after the reaction is finished, removing methanol, washing with water (50mL), extracting with ethyl acetate (50mL) for three times, combining organic phases and removing the solvent under reduced pressure to obtain 0.55g of a colorless liquid crude product, and obtaining the yield: 91.7 percent.

MS-ESI:m/z 247.1[M+H]⁺。

Step 2: synthesis of compound 4- (bromomethyl) -3-chloro-1- (2, 2-difluoroethyl) -5- (difluoromethyl) -1H-pyrazole

Dissolving (3-chloro-1- (2, 2-difluoroethyl) -5- (difluoromethyl) -1H-pyrazol-4-yl) methanol (0.55g,2.2mmol) and triphenylphosphine (1.15g,4.4mmol) in acetonitrile (20mL), stirring at 0 ℃, then dissolving carbon tetrabromide (1.46g,4.4mmol) in acetonitrile (10mL), slowly dropwise adding into the above mixture while controlling the temperature to be not higher than 5 ℃, after dropwise adding, stirring at room temperature for 3.5H, removing acetonitrile after the reaction is finished, washing with water (100mL), extracting with ethyl acetate (50mL) for three times, combining organic phases, removing the solvent under reduced pressure, and purifying by column chromatography (eluent: peleluometer/EtOAc (v/v) ═ 10/1), to obtain colorless liquid 0.71g, yield: 95.1 percent.

MS-ESI:m/z 310.9[M+H]⁺。

And step 3: synthesis of the Compound 3- (((3-chloro-1- (2, 2-difluoroethyl) -5- (difluoromethyl) -1H-pyrazol-4-yl) methyl) thio) -5, 5-dimethyl-4, 5-dihydroisoxazole

4- (bromomethyl) -3-chloro-1- (2, 2-difluoroethyl) -5- (difluoromethyl) -1H-pyrazole (0.58g,1.87mmol) and 5, 5-dimethyl-4, 5-dihydroisoxazol-3-ylisothiourea hydrobromide (0.56g,2.2mmol) were dissolved in acetonitrile (30mL), stirred at room temperature for 10min, then potassium carbonate (1.03g,7.48mmol) was added to the above mixture, the reaction was stopped after 12H, then acetonitrile was removed, washed with water (100mL), ethyl acetate (30mL) was extracted three times, the organic phases were combined and the solvent was removed under reduced pressure to give a yellow liquid crude product 0.77g, yield: 93.2 percent.

MS-ESI:m/z 360.1[M+H]⁺。

And 4, step 4: synthesis of the Compound 3- (((3-chloro-1- (2, 2-difluoroethyl) -5- (difluoromethyl) -1H-pyrazol-4-yl) methyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole

3- (((3-chloro-1- (2, 2-difluoroethyl) -5- (difluoromethyl) -1H-pyrazol-4-yl) methyl) thio) -5, 5-dimethyl-4, 5-dihydroisoxazole (0.77g,2.1mmol) is dissolved in dichloromethane (30mL), stirred at room temperature, then 85% m-CPBA (0.87g,4.2mmol) is added to the above mixture to react for 5H, the reaction is stopped, then the mixture is washed with saturated aqueous sodium bisulfite (50mL) and saturated aqueous sodium bicarbonate (50mL), dichloromethane (50mL) is extracted, anhydrous sodium sulfate is dried, the organic phases are combined and decompressed to remove the solvent, and the column chromatography is separated and purified (eluent: Petroleum ether/EtOAc (v/v) ═ 5/1), 0.70g of white solid was obtained, yield: 85.4 percent.

MS-ESI:m/z 392.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)6.96(t,J＝52.4Hz,1H),6.18(tt,J＝55.1,4.3Hz,1H),4.63(dd,J＝12.6,4.3Hz,2H),4.58(s,2H),3.02(s,2H),1.49(s,6H)。

Example 7: 3- ((1- (3-chloro-5- (difluoromethyl) -1-isopropyl-1H-pyrazol-4-yl) ethyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole

3- (((3-chloro-5- (difluoromethyl) -1-isopropyl-1H-pyrazol-4-yl) methyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole (0.63g,1.70mmol) and potassium carbonate (0.47g,3.4mmol) were dissolved in DMF (10mL) and stirred at room temperature. To the mixture was added dropwise methyl iodide (0.29g,2.0mmol), and the mixture was stirred at room temperature. The reaction was monitored by TLC, after completion of the reaction, the reaction mixture was washed with water (100mL), extracted with ethyl acetate (30mL) three times, the organic phases were combined and the solvent was removed under reduced pressure, purified by column chromatography (eluent: Petroleum ether/EtOAc (v/v) ═ 5/1) to give 0.23g yellow oily liquid, yield: 35.3 percent.

MS-ESI:m/z 384.1[M+H]⁺；

¹H NMR(400MHz,DMSO-d₆)7.33(t,J＝50.6Hz,1H),5.03(s,1H),4.78(dt,J＝12.9,6.4Hz,1H),3.07(d,J＝17.5Hz,2H),1.77(d,J＝7.2Hz,3H),1.47–1.32(m,12H).

Example 8: 3- ((1- (3-chloro-1- (2, 2-difluoroethyl) -5- (difluoromethyl) -1H-pyrazol-4-yl) ethyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole

3- (((3-chloro-1- (2, 2-difluoroethyl) -5- (difluoromethyl) -1H-pyrazol-4-yl) methyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole (0.48g,1.2mmol) and potassium carbonate (0.33g,2.4mmol) were dissolved in DMF (10mL) and stirred at room temperature. To the mixture was added dropwise methyl iodide (0.21g,1.5mmol), and the mixture was stirred at room temperature. The reaction was monitored by TLC, after completion of the reaction, the reaction mixture was washed with water (100mL), extracted three times with ethyl acetate (30mL), the combined organic phases were freed of solvent under reduced pressure and purified by column chromatography (eluent: Petroleum ether/EtOAc (v/v) ═ 5/1) to give 0.18g of a yellow solid, yield: 37.0 percent.

MS-ESI:m/z 406.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)7.12(d,J＝51.6Hz,1H),6.19(tt,J＝55.3,4.4Hz,1H),4.75(q,J＝7.4Hz,1H),4.63(td,J＝12.4,4.4Hz,2H),2.84(dd,J＝150.7,17.4Hz,2H),1.85(d,J＝7.4Hz,3H),1.42(d,J＝31.5Hz,6H).

Example 9: 3- (((5-fluoro-3- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) methyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole

Step 1: synthesis of compound 3- (difluoromethyl) -1-ethyl-5-fluoro-1H-pyrazole-4-carbaldehyde

5-chloro-3- (difluoromethyl) -1-ethyl-1H-pyrazole-4-carbaldehyde (0.74g,3.5mmol) and anhydrous potassium fluoride (0.51g,8.8mmol) were dissolved in ultra-dry DMF (20mL), heated to 150 ℃ and stirred for 12H, after the reaction was complete, washed with water (100mL), extracted with ethyl acetate (100mL) three times, and the combined organic phases were freed from the solvent under reduced pressure to give the crude product. Column chromatography (eluent: petroleumiether/EtOAc (v/v) ═ 15/1) afforded 0.30g of a colorless liquid, yield: 44.8 percent.

MS-ESI:m/z 193.1[M+H]⁺。

Step 2: synthesis of Compound (5-fluoro-3- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) methanol

Dissolving 5-fluoro-3- (difluoromethyl) -1-ethyl-1H-pyrazole-4-carbaldehyde (0.30g,1.6mmol) in anhydrous methanol (20mL) and stirring at 0 ℃, then gradually adding sodium borohydride (0.15g,3.9mmol) in portions to the above mixed solution, after the addition is finished, heating to room temperature and stirring for 4H, after the reaction is finished, removing methanol, washing with water (50mL), extracting with ethyl acetate (50mL) for three times, combining organic phases and removing the solvent under reduced pressure to obtain 0.24g of light yellow liquid, and obtaining the yield: 77.4 percent.

MS-ESI:m/z 195.1[M+H]⁺。

And step 3: synthesis of compound 4- (bromomethyl) -5-fluoro-3- (difluoromethyl) -1-ethyl-1H-pyrazole

Dissolving (5-fluoro-3- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) methanol (0.24g,1.2mmol) and triphenylphosphine (0.65g,2.4mmol) in acetonitrile (20mL), stirring at 0 ℃, then dissolving carbon tetrabromide (0.82g,2.4mmol) in acetonitrile (5mL), slowly dropwise adding into the above mixed solution, controlling the temperature to be not higher than 5 ℃, after dropwise adding, heating to room temperature, stirring for 3.5H, after the reaction is finished, removing acetonitrile, washing with water (100mL), extracting with ethyl acetate (50mL) for three times, combining organic phases, removing the solvent under reduced pressure, and performing column chromatography (eluent: pelimum ether/EtOAc (v/v) ═ 15/1) to obtain 0.20g of a light yellow liquid, wherein the yield: and (4) 64.9%.

MS-ESI:m/z 257.0[M+H]⁺。

And 4, step 4: synthesis of Compound 3- (((5-fluoro-3- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) methyl) thio) -5, 5-dimethyl-4, 5-dihydroisoxazole 4- (bromomethyl) -5-fluoro-3- (difluoromethyl) -1-ethyl-1H-pyrazole (0.20g,0.8mmol) and 5, 5-dimethyl-4, 5-dihydroisoxazol-3-ylisothiourea hydrobromide (0.24g,0.9mmol) were dissolved in acetonitrile (20mL), stirred at room temperature for 10min, then potassium carbonate (0.43g,3.1mmol) was added to the above mixture, the reaction was stopped after 12H, then the acetonitrile was removed, washed with water (100mL), ethyl acetate (50mL) was extracted three times, and the combined organic phases were freed of solvent under reduced pressure to give 0.21g of a yellow liquid, yield: 87.5 percent.

MS-ESI:m/z 308.1[M+H]⁺。

And 5: synthesis of Compound 3- (((5-fluoro-3- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) methyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole

3- (((5-fluoro-3- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) methyl) thio) -5, 5-dimethyl-4, 5-dihydroisoxazole (0.21g,0.7mmol) was dissolved in dichloromethane (30mL), stirred at room temperature, then 85% m-CPBA (0.28g,1.4mmol) is added into the mixed solution, the reaction is stopped after 5h of reaction, then washed with saturated aqueous sodium bisulfite (50mL) and saturated aqueous sodium bicarbonate (50mL) in that order, extracted with dichloromethane (50mL), dried over anhydrous sodium sulfate, the combined organic phases were freed of solvent under reduced pressure, and purified by column chromatography (eluent: Petroleum ether/EtOAc (v/v) ═ 5/1) to give 0.10g of a yellow solid, yield: 43.5 percent.

MS-ESI:m/z 340.1[M+H]⁺；

¹H NMR(400MHz,CDCl₃)6.70(t,J＝54.6Hz,1H),4.54(s,2H),4.12(q,J＝7.2Hz,2H),3.08(s,2H),1.58–1.41(m,9H)。

Example 10: 3- (((5-chloro-3- (difluoromethyl) -1- (prop-2-yn-1-yl) -1H-pyrazol-4-yl) methyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole

Step 1: synthesis of compound 5-chloro-3- (difluoromethyl) -1- (prop-2-yn-1-yl) -1H-pyrazole-4-carbaldehyde

Ethyl difluoroacetoacetate (83.06g,0.5mol) was dissolved in absolute ethanol (200mL) and stirred at 0 deg.C, then hydrazine hydrate (37.50g,0.75mol) was slowly added dropwise to the above mixture, after the dropwise addition was completed, the mixture was heated to room temperature for reaction for 4 hours, and then heated to 80 deg.C for reaction overnight, and the reaction was stopped. The ethanol was removed, the mixture was washed with water (300mL), extracted with ethyl acetate (150mL) three times, and the combined organic phases were freed of solvent under reduced pressure to give the product as a pale yellow solid.

Placing DMF (38.01g,0.52mol) at 0 ℃ for stirring, slowly dropwise adding phosphorus oxychloride (239.20g,1.56mol) into the DMF, after dropwise adding, heating to room temperature for stirring, adding the obtained light yellow solid into the mixed solution in batches, then heating the mixed solution to 110 ℃ for refluxing overnight, after the reaction is finished, washing with water (500mL), extracting with ethyl acetate (150mL) for three times, combining organic phases, and removing the solvent under reduced pressure to obtain a reddish brown solid product.

Taking the reddish brown solid product (1g,1.85mmol) and potassium carbonate (2.3g,16.6mmol) to dissolve in DMF (15mL) and stirring at room temperature, then adding 3-bromopropyne (1.1g,9.1mmol) into the mixed solution, stirring at room temperature for 24H after the addition is finished, after the reaction is finished, washing with water (20mL), extracting by ethyl acetate (40mL) for three times, combining organic phases, removing the solvent under reduced pressure, and carrying out column chromatography separation (eluent: Petroleum ether/EtOAc (v/v) ═ 10/1) to obtain a colorless transparent liquid 5-chloro-3- (difluoromethyl) -1- (prop-2-yn-1-yl) -1H-pyrazole-4-formaldehyde 0.83g, yield: 46 percent; and colorless transparent liquid 3-chloro-5- (difluoromethyl) -1- (prop-2-yn-1-yl) -1H-pyrazole-4-carbaldehyde 0.65g, yield: 36.0 percent.

5-chloro-3- (difluoromethyl) -1- (prop-2-yn-1-yl) -1H-pyrazole-4-carbaldehyde: MS-ESI of M/z 219.0[ M + H ]]⁺；¹H NMR(400MHz,CDCl₃)9.91(s,1H),7.40(t,J＝53.5Hz,1H),5.09(d,J＝2.4Hz,2H),2.52(t,J＝2.5Hz,1H)；¹⁹F NMR(376MHz,CDCl₃)-115.59(s),-115.73(s)；

3-chloro-5- (difluoromethyl) -1- (prop-2-yn-1-yl) -1H-pyrazole-4-carbaldehyde: MS-ESI of M/z 219.0[ M + H ]]⁺；¹H NMR(400MHz,CDCl₃)9.99(s,1H),6.90(t,J＝53.5Hz,1H),5.01(d,J＝2.4Hz,2H),2.51(t,J＝2.5Hz,1H)；¹⁹F NMR(376MHz,CDCl₃)-113.99(s),-114.13(s)。

Step 2: synthesis of the compound (5-chloro-3- (difluoromethyl) -1- (prop-2-yn-1-yl) -1H-pyrazol 4-yl) methanol

5-chloro-3- (difluoromethyl) -1- (prop-2-yn-1-yl) -1H-pyrazole-4-carbaldehyde (0.83g,3.80mmol) was dissolved in anhydrous methanol (15mL) and stirred at 0 ℃, then sodium borohydride (0.29g,7.6mmol) was gradually added to the above mixture in portions, the addition was completed, the mixture was stirred at room temperature for 4H, after the reaction was completed, methanol was removed, washed with water (20mL), ethyl acetate (20mL) was extracted three times, the organic phases were combined and the solvent was removed under reduced pressure to give 0.68g of a pale yellow liquid, yield: 82.0 percent.

MS-ESI:m/z 221.0[M+H]⁺。

And step 3: synthesis of the compound 4- (bromomethyl) -5-chloro-3- (difluoromethyl) -1- (prop-2-yn-1-yl) -1H-pyrazole

Dissolving (5-chloro-3- (difluoromethyl) -1- (prop-2-yn-1-yl) -1H-pyrazole 4-yl) methanol (0.68g,3.08mmol) in dichloromethane (20mL), stirring at 0 ℃, then dissolving phosphorus tribromide (1.0g,3.70mmol) in dichloromethane (10mL), slowly dropwise adding the mixture into the mixture, controlling the temperature to be not higher than 5 ℃, after dropwise adding, heating to room temperature, stirring for 3.5H, after the reaction is finished, quenching with ice water (30mL), extracting ethyl acetate (40mL) for three times, combining organic phases, removing the solvent under reduced pressure, and carrying out column chromatography (eluent: Petroleum ether/EtOAc (v/v) ═ 10/1) to obtain 0.54g of colorless liquid, wherein the yield: 65.5 percent.

MS-ESI:m/z 282.9[M+H]⁺。

And 4, step 4: synthesis of the Compound 3- (((5-chloro-3- (difluoromethyl) -1- (prop-2-yn-1-yl) -1H-pyrazol-4-yl) methyl) thio) -5, 5-dimethyl-4, 5-dihydroisoxazole

4- (bromomethyl) -5-chloro-3- (difluoromethyl) -1- (prop-2-yn-1-yl) -1H-pyrazole (0.54g,1.90mmol) and 5, 5-dimethyl-4, 5-dihydroisoxazol-3-ylisothiourea hydrobromide (0.58g,2.28mmol) were dissolved in acetonitrile (20mL) and after stirring at room temperature for 10min, potassium carbonate (1.05g,7.60mmol) was added to the above mixture and the reaction was stopped after 12H, the acetonitrile was then removed, washed with water (20mL), extracted with ethyl acetate (50mL) in three portions, the combined organic phases were freed from the solvent under reduced pressure to give 0.62g of a yellow liquid, yield: 97.0 percent.

MS-ESI:m/z 334.0[M+H]⁺。

And 5: synthesis of the Compound 3- (((5-chloro-3- (difluoromethyl) -1- (prop-2-yn-1-yl) -1H-pyrazol-4-yl) methyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole

3- (((5-chloro-3- (difluoromethyl) -1- (prop-2-yn-1-yl) -1H-pyrazol-4-yl) methyl) thio) -5, 5-dimethyl-4, 5-dihydroisoxazole (0.62g,1.85mmol) was dissolved in dichloromethane (20mL), stirred at room temperature, then 85% m-CPBA (0.94g,4.63mmol) was added to the above mixture, the reaction was stopped after 5 hours, then washed with a saturated aqueous sodium bisulfite solution (20mL) and a saturated aqueous sodium bicarbonate solution (20mL) in this order, extracted with dichloromethane (30mL), dried over anhydrous sodium sulfate, the combined organic phases were removed from the solvent under reduced pressure, purified by column chromatography (eluent: Petroleum ether/EtOAc (v/v) ═ 5/1), 0.43g of a colorless transparent liquid was obtained, yield: 70.2 percent.

MS-ESI:m/z 366.4[M+H]⁺；

¹H NMR(400MHz,CDCl₃)6.82(t,J＝54.6Hz,1H),4.99(d,J＝2.2Hz,2H),4.62(s,2H),3.07(s,2H),2.47(d,J＝2.2Hz,1H),1.50(s,6H)。

Example 11: 3- (((3-chloro-5- (difluoromethyl) -1- (prop-2-yn-1-yl) -1H-pyrazol-4-yl) methyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole

Step 1: synthesis of the compound (3-chloro-5- (difluoromethyl) -1- (prop-2-yn-1-yl) -1H-pyrazol-4-yl) methanol

3-chloro-5- (difluoromethyl) -1- (prop-2-yn-1-yl) -1H-pyrazole-4-carbaldehyde (0.65g,2.95mmol) was dissolved in anhydrous methanol (20mL) and stirred at 0 ℃, then sodium borohydride (0.23g,5.90mmol) was gradually added to the above mixture in portions, the addition was completed, the mixture was stirred at room temperature for 4H, after the reaction was completed, methanol was removed, washed with water (30mL), ethyl acetate (30mL) was extracted three times, the organic phases were combined and the solvent was removed under reduced pressure to give 0.70g of a pale yellow solid, yield: 98 percent.

MS-ESI:m/z 221.0[M+H]⁺。

Step 2: synthesis of the compound 4- (bromomethyl) -3-chloro-5- (difluoromethyl) -1- (prop-2-yn-1-yl) -1H-pyrazole

Dissolving (3-chloro-5- (difluoromethyl) -1- (prop-2-yn-1-yl) -1H-pyrazol-4-yl) methanol (0.64g,2.90mmol) in dichloromethane (30mL), stirring at 0 ℃, then dissolving phosphorus tribromide (0.95g,3.48mmol) in dichloromethane (15mL), slowly dropwise adding the mixture into the mixture, controlling the temperature to be not higher than 5 ℃, completing dropwise adding, heating to room temperature, stirring for 3.5H, after the reaction is completed, quenching with ice water (40mL), extracting ethyl acetate (40mL) for three times, combining organic phases, removing the solvent under reduced pressure, and performing column chromatography (eluent: Petroleum ether/EtOAc (v/v) ═ 10/1) to obtain 0.50g of a light yellow solid, wherein the yield: 65.0 percent.

MS-ESI:m/z 283.9[M+H]⁺。

And step 3: synthesis of the Compound 3- (((3-chloro-5- (difluoromethyl) -1- (prop-2-yn-1-yl) -1H-pyrazol-4-yl) methyl) thio) -5, 5-dimethyl-4, 5-dihydroisoxazole

4- (bromomethyl) -3-chloro-5- (difluoromethyl) -1- (prop-2-yn-1-yl) -1H-pyrazole (0.50g,1.76mmol) and 5, 5-dimethyl-4, 5-dihydroisoxazol-3-ylisothiourea hydrobromide (0.97g,7.04mmol) were dissolved in acetonitrile (30mL) and after stirring at room temperature for 10min, potassium carbonate (0.52g,2.04mmol) was added to the above mixture and the reaction was stopped after 12H, the acetonitrile was removed, washed with water (40mL), extracted with ethyl acetate (50mL) three times, the combined organic phases were freed from the solvent under reduced pressure to give a tan solid 0.55g, yield: 93.0 percent.

MS-ESI:m/z 334.0[M+H]⁺。

And 4, step 4: synthesis of the Compound 3- (((3-chloro-5- (difluoromethyl) -1- (prop-2-yn-1-yl) -1H-pyrazol-4-yl) methyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole

3- (((3-chloro-5- (difluoromethyl) -1- (prop-2-yn-1-yl) -1H-pyrazol-4-yl) methyl) thio) -5, 5-dimethyl-4, 5-dihydroisoxazole (0.55g,1.65mmol) was dissolved in dichloromethane (40mL), stirred at room temperature, then 85% m-CPBA (0.77g,3.80mmol) was added to the above mixture to react for 5H and then the reaction was stopped, then washed with a saturated aqueous sodium bisulfite solution (20mL) and a saturated aqueous sodium bicarbonate solution (20mL) in this order, extracted with dichloromethane (50mL), dried over anhydrous sodium sulfate, the combined organic phases were decompressed to remove the solvent, purified by column chromatography (eluent: Petroleum ether/EtOAc (v/v) ═ 6/1), 0.30g of a white solid was obtained, yield: 51.3 percent.

MS-ESI:m/z 366.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)6.99(t,J＝52.7Hz,1H),5.05(d,J＝2.4Hz,2H),4.58(s,2H),3.03(s,2H),2.50(t,J＝2.4Hz,1H),1.50(s,6H)。

Example 12: 3- (((3-chloro-5- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) difluoromethyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole

In a three-necked flask, 3- (((3-chloro-5- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) methyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole (1.42g,4mmol) was weighed out and dissolved in anhydrous THF (20mL), and stirred at-78 ℃. To the mixture was added dropwise a tetrahydrofuran solution of sodium bis (trimethylsilyl) amide (1M,7.2mL), and after completion, stirring was continued for 10 min. NFSI (2.52g,8mmol) was added and reacted for 20 min. After completion of the reaction, the reaction mixture was quenched by adding saturated aqueous ammonium chloride (20 mL). Water (100mL) was added, the mixture was washed with water, and extracted with ethyl acetate (50mL) three times, dried over anhydrous magnesium sulfate, the solvent was removed, and the mixture was purified by column chromatography (eluent: Petroleum ether/EtOAc (v/v) ═ 10/1) to give 0.80g of a pale yellow solid in 51.3% yield.

MS-ESI:m/z 392.0[M+H]⁺；

¹H NMR(400MHz,CDCl₃)6.86(t,J＝51.6Hz,1H),4.39(q,J＝7.2Hz,2H),3.17(s,2H),1.56(s,6H),1.53(d,J＝7.2Hz,3H)。

Example 13: 3- (((3-chloro-5- (difluoromethyl) -1-methyl-1H-pyrazol-4-yl) methyl) sulfonyl) -5-ethyl-5-methyl-4, 5-dihydroisoxazole

Step 1: synthesis of Compound 5-Ethyl-5-methyl-3- (methylsulfonyl) -4, 5-dihydroisoxazole

3-chloro-5-ethyl-5-methyl-4, 5-dihydroisoxazole (10.00g,67.80mmol) was weighed in a three-necked flask, dissolved in DMF (50mL), stirred at 0 ℃ and an aqueous solution of sodium thiomethoxide (20%, 28.50g,81.30mmol) was added dropwise to the mixture and, after completion of the addition, stirred at room temperature for 12 hours. After completion of the reaction, water (100mL) was added to the reaction mixture and stirred. Ethyl acetate (50mL) was extracted three times, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to give 10.00g of 5-ethyl-5-methyl-3- (methylthio) -4, 5-dihydroisoxazole as a yellow liquid, yield: 92.7 percent.

MS-ESI:m/z 160.3[M+H]⁺。

Dissolving intermediate 5-ethyl-5-methyl-3- (methylthio) -4, 5-dihydroisoxazole (10.00g,62.80mmol) in dichloromethane (100mL), stirring at room temperature, then adding 85% m-CPBA (25.50g,125.60mmol) to the above mixture, reacting for 5h, stopping the reaction, filtering, washing the filtrate with saturated aqueous sodium bisulfite (100mL) and saturated aqueous sodium bicarbonate (100mL), extracting dichloromethane (100mL), drying over anhydrous sodium sulfate, combining the organic phases, removing the solvent under reduced pressure, purifying by column chromatography (eluent: Petroleum ether/EtOAc (v/v) ═ 5/1) to obtain 8.00g of yellow solid, yield: 66.6 percent.

MS-ESI:m/z 192.3[M+H]⁺。

Step 2: synthesis of the compounds 5-chloro-3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carbaldehyde and 3-chloro-5- (difluoromethyl) -1-methyl-1H-pyrazole-4-carbaldehyde

Ethyl difluoroacetoacetate (5.00g,30.1mmol) is dissolved in absolute ethyl alcohol (100mL) and stirred at 0 ℃, then hydrazine hydrate (1.45g,45.2mmol) is slowly dripped into the mixed solution, after the dripping is finished, the mixed solution is heated to room temperature for reaction for 4 hours, then the mixed solution is heated to 80 ℃ for reaction overnight, and the reaction is stopped. The ethanol was removed, the mixture was washed with water (50mL), extracted with ethyl acetate (50mL) three times, and the combined organic phases were freed of solvent under reduced pressure to give the product as a pale yellow solid.

DMF (2.20g,30.1mmol) is stirred at 0 ℃, then phosphorus oxychloride (13.8g,90.3mmol) is slowly dripped into DMF, after the dripping is finished, the mixture is heated to room temperature and stirred, the obtained light yellow solid is added into the mixed solution in batches, then the mixed solution is heated to 110 ℃ and refluxed overnight, after the reaction is finished, the mixed solution is washed by water (50mL), ethyl acetate (50mL) is extracted for three times, and the organic phases are combined and the solvent is removed under reduced pressure to obtain a reddish brown solid product.

The resulting reddish brown solid product and potassium carbonate (4.16g,30.1mmol) were dissolved in DMF (50mL) and stirred at room temperature, methyl iodide (2.14g,15.1mmol) was then added to the above mixture, after completion of the addition, the mixture was heated to 80 ℃ and stirred for 12H, after completion of the reaction, washed with water (50mL), extracted with ethyl acetate (50mL) in three portions, the organic phases were combined and the solvent was removed under reduced pressure, and separated by column chromatography (eluent: Petroleum ether/EtOAc (v/v) ═ 10/1) to give 5-chloro-3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carbaldehyde as a colorless transparent liquid product, 1.00g, yield: 17.1 percent; and 3-chloro-5- (difluoromethyl) -1-methyl-1H-pyrazole-4-carbaldehyde 0.96g, yield: 16.4 percent.

5-chloro-3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carbaldehyde: MS-ESI of M/z 195.6[ M + H ]]⁺；¹H NMR(400MHz,CDCl₃)9.96(s,1H),6.90(t,J＝53.6Hz,1H),3.93(s,3H)；¹⁹F NMR(376MHz,CDCl₃)-114.16(s),-114.30(s)；

3-chloro-5- (difluoromethyl) -1-methyl-1H-pyrazole-4-carbaldehyde: MS-ESI of M/z 195.6[ M + H ]]⁺；¹H NMR(400MHz,CDCl₃)9.89(s,1H),7.38(t,J＝52.4Hz,1H),4.06(s,3H)；¹⁹F NMR(376MHz,CDCl₃)-116.74(s),-116.88(s)。

And step 3: synthesis of Compound (3-chloro-5- (difluoromethyl) -1-methyl-1H-pyrazol-4-yl) methanol

Dissolving 3-chloro-5- (difluoromethyl) -1-methyl-1H-pyrazole-4-carbaldehyde (1.00g,5.14mmol) in anhydrous methanol (20mL) and stirring at 0 ℃, then gradually adding sodium borohydride (389mg,10.3mmol) to the above mixed solution in batches, after the addition is finished, heating to room temperature and stirring for 4H, after the reaction is finished, removing methanol, washing with water (20mL), extracting with ethyl acetate (20mL) for three times, combining organic phases, and removing the solvent under reduced pressure to obtain 1.00g of a colorless liquid product, wherein the yield is as follows: 99.0 percent.

MS-ESI:m/z 197.6[M+H]⁺。

And 4, step 4: synthesis of compound 4- (bromomethyl) -3-chloro-5- (difluoromethyl) -1-methyl-1H-pyrazole

Dissolving (3-chloro-5- (difluoromethyl) -1-methyl-1H-pyrazol-4-yl) methanol (1.00g,5.09mmol) in DCM (20mL), stirring at 0 ℃, slowly dropwise adding phosphorus tribromide (1.38g,5.09mmol) into a reaction bottle, after dropwise adding, heating to room temperature, stirring for 3.5 hours, after the reaction is finished, washing with water (20mL), extracting with dichloromethane (20mL) for 2 times, combining organic phases, and removing the solvent under reduced pressure to obtain 1.00g of yellow liquid, wherein the yield is 75.8%.

MS-ESI:m/z 260.5[M+H]⁺。

And 5: synthesis of the Compound 3- (((3-chloro-5- (difluoromethyl) -1-methyl-1H-pyrazol-4-yl) methyl) thio) -5-ethyl-5-methyl-4, 5-dihydroisoxazole

4- (bromomethyl) -3-chloro-5- (difluoromethyl) -1-methyl-1H-pyrazole (0.50g,1.93mmol) was dissolved in methanol (10mL), thiourea (147mg,1.93mmol) was added at room temperature, and after stirring for 2 hours, potassium carbonate (533mg,3.85mmol) and 5-ethyl-5-methyl-3- (methylsulfonyl) -4, 5-dihydroisoxazole (368mg,1.93mmol) were then added to the above mixture, respectively, and after warming to 75 ℃ and stirring for 12 hours, the reaction was stopped, then methanol was removed, washing with water (30mL), ethyl acetate (20mL) was extracted three times, the organic phases were combined and the solvent was removed under reduced pressure, column chromatography (eluent: Petroleum ether/EtOAc (v/v) ═ 10/1) was performed to obtain 0.40g of a yellow liquid, yield: 64.1 percent.

MS-ESI:m/z 324.8[M+H]⁺。

Step 6: synthesis of the Compound 3- (((3-chloro-5- (difluoromethyl) -1-methyl-1H-pyrazol-4-yl) methyl) sulfonyl) -5-ethyl-5-methyl-4, 5-dihydroisoxazole

3- (((3-chloro-5- (difluoromethyl) -1-methyl-1H-pyrazol-4-yl) methyl) thio) -5-ethyl-5-methyl-4, 5-dihydroisoxazole (0.40g,1.24mmol) was dissolved in dichloromethane (10mL), stirred at room temperature, then 85% m-CPBA (503mg,2.48mmol) was added to the above mixture to react for 12H, the reaction was stopped, then washed with a saturated aqueous sodium bisulfite solution (20mL) and a saturated aqueous sodium bicarbonate solution (20mL) in this order, dichloromethane (20mL) was extracted twice, dried over anhydrous sodium sulfate, the organic phases were combined under reduced pressure to remove the solvent, and column chromatography (eluent: Petroleum ether/EtOAc (v/v) ═ 5/1) was performed to obtain 0.30g of a white solid, yield: 68.3 percent.

MS-ESI:m/z 356.8[M+H]⁺；

¹H NMR(400MHz,CDCl₃)6.90(t,J＝52.3Hz,1H),4.55(s,2H),4.01(s,3H),3.01(dd,J＝63.4,17.3Hz,2H),1.76(q,J＝7.4Hz,2H),1.45(s,3H),0.95(t,J＝7.4Hz,3H)。

Example 14: 3- (((5-chloro-3- (difluoromethyl) -1-methyl-1H-pyrazol-4-yl) methyl) sulfonyl) -5-ethyl-5-methyl-4, 5-dihydroisoxazole

Step 1: synthesis of Compound (5-chloro-3- (difluoromethyl) -1-methyl-1H-pyrazol-4-yl) methanol

Dissolving 5-chloro-3- (difluoromethyl) -1-methyl-1H-pyrazole-4-carbaldehyde (1.00g,5.14mmol) in anhydrous methanol (20mL) and stirring at 0 ℃, then gradually adding sodium borohydride (389mg,10.3mmol) to the above mixed solution in portions, after the addition is completed, heating to room temperature and stirring for 4H, after the reaction is completed, removing methanol, washing with water (20mL), extracting with ethyl acetate (20mL) in three times, combining the organic phases and removing the solvent under reduced pressure to obtain 1.00g of colorless liquid, yield: 99.0 percent.

MS-ESI:m/z 197.6[M+H]⁺。

Step 2: synthesis of compound 4- (bromomethyl) -5-chloro-3- (difluoromethyl) -1-methyl-1H-pyrazole

Dissolving (5-chloro-3- (difluoromethyl) -1-methyl-1H-pyrazol-4-yl) methanol (1.00g,5.09mmol) in DCM (20mL), stirring at 0 ℃, slowly dropwise adding phosphorus tribromide (1.38g,5.09mmol) into a reaction bottle, after dropwise adding, heating to room temperature, stirring for 3.5 hours, after the reaction is finished, washing with water (20mL), extracting with dichloromethane (20mL) for 2 times, combining organic phases, and removing the solvent under reduced pressure to obtain 1.00g of yellow liquid, wherein the yield is 75.8%.

MS-ESI:m/z 260.5[M+H]⁺。

And step 3: synthesis of the Compound 3- (((5-chloro-3- (difluoromethyl) -1-methyl-1H-pyrazol-4-yl) methyl) thio) -5-ethyl-5-methyl-4, 5-dihydroisoxazole

4- (bromomethyl) -5-chloro-3- (difluoromethyl) -1-methyl-1H-pyrazole (0.50g,1.93mmol) was dissolved in methanol (10mL), thiourea (147mg,1.93mmol) was added at room temperature, and after stirring for 2 hours, potassium carbonate (533mg,3.85mmol) and 5-ethyl-5-methyl-3- (methylsulfonyl) -4, 5-dihydroisoxazole (368mg,1.93mmol) were then added to the above mixture, respectively, and after warming to 75 ℃ and stirring for 12 hours, the reaction was stopped, then methanol was removed, washing with water (30mL), ethyl acetate (20mL) was extracted three times, the organic phases were combined and the solvent was removed under reduced pressure, column chromatography (eluent: Petroleum ether/EtOAc (v/v) ═ 10/1) was performed to obtain 0.40g of a yellow liquid, yield: 64.1 percent.

MS-ESI:m/z 324.8[M+H]⁺。

And 4, step 4: synthesis of the Compound 3- (((5-chloro-3- (difluoromethyl) -1-methyl-1H-pyrazol-4-yl) methyl) sulfonyl) -5-ethyl-5-methyl-4, 5-dihydroisoxazole

3- (((5-chloro-3- (difluoromethyl) -1-methyl-1H-pyrazol-4-yl) methyl) thio) -5-ethyl-5-methyl-4, 5-dihydroisoxazole (0.40g,1.24mmol) was dissolved in dichloromethane (10mL), stirred at room temperature, then 85% m-CPBA (503mg,2.48mmol) was added to the above mixture to react for 12H, the reaction was stopped, then washed with a saturated aqueous sodium bisulfite solution (20mL) and a saturated aqueous sodium bicarbonate solution (20mL) in this order, dichloromethane (20mL) was extracted twice, dried over anhydrous sodium sulfate, the organic phases were combined under reduced pressure to remove the solvent, and column chromatography (eluent: Petroleum ether/EtOAc (v/v) ═ 5/1) was performed to obtain 0.32g of a white solid product, yield: 72.8 percent.

MS-ESI:m/z 356.8[M+H]⁺；

Example 15: 3- (((5-chloro-3- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) fluoromethyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole

Example 16: 3- (((5-chloro-3- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) difluoromethyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole

The compounds shown in example 15 and example 16 were prepared as follows:

3- (((5-chloro-3- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) methyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole (1.07g,3mmol) was dissolved in anhydrous THF (20mL) and stirred at-78 ℃. To the mixture was added dropwise a tetrahydrofuran solution of sodium bis (trimethylsilyl) amide (1M,5.4mL), and after completion, stirring was continued for 10 min. NFSI (1.14g,3.6mmol) was added, the reaction was monitored by TLC, and after completion of the reaction, the reaction mixture was quenched by adding saturated aqueous ammonium chloride (20 mL). Water (100mL) was added, washed with water, ethyl acetate (50mL) was extracted three times, dried over anhydrous magnesium sulfate, and the solvent was removed to give a yellow liquid product, which was purified by column chromatography (eluent: Petroleum ether/EtOAc (v/v) ═ 10/1) to give compound 3- (((5-chloro-3- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) fluoromethyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole as a white solid, 150mg, yield 13.6%; and the compound 3- (((5-chloro-3- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) difluoromethyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole, 100mg of white solid, yield 8.5%.

3- (((5-chloro-3- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) fluoromethyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole: MS-ESI: M/z374.0[ M + H ]]⁺；

¹H NMR(400MHz,CDCl₃)6.83(t,J＝53.8Hz,1H),6.53(d,J＝44.6Hz,1H),4.28(q,J＝7.3Hz,2H),3.18(d,J＝2.7Hz,2H),1.54(s,6H),1.49(t,J＝7.3Hz,3H)；

3- (((5-chloro-3- (difluoromethyl) -1-ethyl-1H-pyrazol-4-yl) difluoromethyl) sulfonyl) -5, 5-dimethyl-4, 5-dihydroisoxazole: MS-ESI: M/z 392.0[ M + H ]]⁺；

¹H NMR(400MHz,CDCl₃)6.75(t,J＝53.4Hz,1H),4.32–4.27(m,2H),3.18(s,2H),1.56(s,6H),1.51(t,J＝7.3Hz,3H)。

Biological examples

Compound preparation: weighing a certain mass of original drug by using an analytical balance (0.0001g), dissolving the original drug by using DMF containing 1 wt% of Tween-80 emulsifier to prepare 1.0 wt% of mother liquor, and then diluting the mother liquor by using distilled water for later use.

The test method comprises the following steps: the potting method comprises the test targets of piemarker, redroot amaranth, snakehead intestine, crab grass, cockspur grass and green bristlegrass. A flowerpot with the inner diameter of 7.5cm is taken, composite soil (vegetable garden soil: seedling raising matrix, 1:2, v/v) is filled to 3/4 positions, the six weed targets are directly sown (the germination rate is more than or equal to 85 percent), the soil is covered by 0.2cm, and water is added to keep the soil moist for 24 hours for later use. After each compound is applied to an automatic spraying tower (model: 3WPSH-700E) according to the dosage of 150g a.i./ha, 75g a.i./ha and 37.5g a.i./ha, the compound is moved to a greenhouse for culture after the liquid medicine on the surface of the soil is dried, and the activity (%) of the compound on weeds is checked after 25 days; where 0 means no damage or normal growth process and 100 means no emergence or at least complete death of the aerial parts.

The test results are shown in tables a and B.

TABLE A Pre-emergent herbicidal activity of the compounds of the invention at a dose of 150g a.i./ha

The results in Table A show that the compounds of the invention all have better herbicidal activity than Pyroxasulfone at 150g a.i./ha against abutilon, Amaranthus retroflexus, snakehead intestine, crab grass, Echinochloa crusgalli and/or Setaria viridis.

TABLE B Pre-emergent herbicidal activity of the compounds of the invention at doses of 75g a.i./ha and 37.5g a.i./ha

The results in table B show that the compounds of the present invention still have excellent control effects on the gramineous weeds, large crabgrass, barnyard grass and green bristlegrass at low doses, while having certain control effects on broadleaf weeds, piemarker, Amaranthus retroflexus and snakehead intestine; the compound of the invention can prevent and control gramineous weeds and broadleaf weeds simultaneously.

Crop safety testing

The test method comprises the following steps: potting methods, the test targets were soybean, peanut, cotton, canola, sunflower, corn, wheat and rice. A flowerpot with the inner diameter of 7.5cm is taken, composite soil (vegetable garden soil: seedling raising matrix, 1:2, v/v) is filled to 3/4 positions, the eight crop targets are directly sown (the bud rate is more than or equal to 85 percent), the soil is covered by 0.2cm, and water is added to keep the soil moist for 24 hours for later use. After the compounds are applied to an automatic spray tower (model: 3WPSH-700E) according to the specified dosage, transferring the liquid medicine on the soil surface to a greenhouse for culture after the liquid medicine is dried, and checking the phytotoxicity (%) of crops after 25 days; where 0 means no damage or normal growth process and 100 means no emergence or at least complete death of the aerial parts.

The test results are shown in table C.

TABLE C crop safety of the compounds of the invention

The results in Table C show that the compounds according to the invention are present at 150g a.i./hm²、300g a.i./hm²And 600g a.i./hm²Has good safety to soybean, peanut and sunflower.

In addition, the compounds of the invention are also very safe for cotton, oilseed rape, maize, wheat and rice, for example, in the case of 150g a.i./hm in examples 1,2,3 and 4 of the invention²The phytotoxicity to rape is 0; the concentration of the active ingredients in the compositions of the invention in examples 1,2,3 and 4 is 150g a.i./hm²The damage to cotton is below 20; the concentration of the active ingredients in the invention in the examples 2,3 and 4 is 150g a.i./hm²The damage to wheat is below 20.

The compound has good control effect on broadleaf weeds (such as abutilon, Amaranthus retroflexus and snakehead gut) and grassy weeds (such as crab grass, cockspur grass and green bristlegrass), and the control effect on the weeds is superior to that of a commercial herbicide Pyroxasulfofone and an isoxazoline compound with similar structure. The compound is safe to crops such as soybean, peanut, sunflower, rape, cotton and wheat, and has a good application prospect.

Claims

1. A compound which is a compound of formula (Ia) or a salt of a compound of formula (Ia):

wherein:

R¹and R²Each independently is C_1-6An alkyl group;

R³and R⁴Each independentlyIs hydrogen or bromine;

n is 2;

R⁵and R⁶Each independently of the others is hydrogen, fluorine, chlorine, bromine, iodine or C_1-6An alkyl group;

x is fluorine, chlorine or bromine;

y is C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy radical C_1-6Alkyl radical, C_2-6Alkenyl, halo C_2-6Alkenyl radical, C_2-6Alkynyl, halo C_2-6Alkynyl or-C (═ O) -C_1-6An alkyl group;

with the following conditions:

(1) when Y is methyl, X is chlorine, R⁵And R⁶Are each hydrogen, n is 0, 1 or 2, R³And R⁴Are each hydrogen, R¹When it is methyl, R²Is not methyl;

(2) when Y is methyl, X is chlorine, R⁵And R⁶Are each hydrogen, n is 0, 1 or 2, R³And R⁴Are each hydrogen, R²When it is methyl, R¹Is not methyl.

2. The compound of claim 1, which is a compound of formula (II) or a salt of a compound of formula (II):

wherein:

x is fluorine, chlorine or bromine;

R¹and R²Each independently is C_1-6An alkyl group;

R³and R⁴Each independently hydrogen or bromine;

n is 2;

R⁸、R⁹、R¹⁰、R¹¹and R¹²Each independently is hydrogen, fluorine, chlorine, bromine or iodine;

or R⁸、R⁹And the carbon atom to which it is attached, form-C (═ O) -;

or R¹⁰、R¹¹、R¹²Together with the carbon atom to which they are attached form-C.ident.CR¹³or-CR¹⁴＝CR¹⁵R¹⁶(ii) a Wherein R is¹³、R¹⁴、R¹⁵And R¹⁶Each independently hydrogen.

3. The compound according to claim 1 or 2, which is a compound of formula (IIa) or a salt of a compound of formula (IIa); or a salt of a compound of formula (IIb):

4. a compound according to claim 1 or 2, which is a compound of formula (IIc) or a salt of a compound of formula (IIc); or a salt of a compound represented by the formula (IId):

5. the compound according to claim 1 or 2, which is a compound represented by the formula (II-1) or a salt of a compound represented by the formula (II-1):

wherein:

R¹and R²Each independently is C_1-6An alkyl group;

R³and R⁴Each independently hydrogen or bromine;

n is 2;

R⁵and R⁶Each independently of the otherIs hydrogen, fluorine, chlorine, bromine, iodine or C_1-6An alkyl group;

x is fluorine, chlorine or bromine;

R⁸and R⁹Each independently is hydrogen, fluorine, chlorine, bromine or iodine;

R¹³is hydrogen.

6. The compound of claim 5, which is a compound of formula (IIa-1) or a salt of a compound of formula (IIa-1); or a salt of a compound represented by the formula (IIa-2) or a compound represented by the formula (IIa-2):

wherein:

R¹and R²Each independently is C_1-6An alkyl group;

R³and R⁴Each independently hydrogen or bromine;

R¹³is hydrogen.

7. The compound of claim 1, which is a compound of formula (II-5) or a salt of a compound of formula (II-5):

wherein:

R¹and R²Each independently is C_1-6An alkyl group;

R³and R⁴Each independently hydrogen or bromine;

n is 2;

R⁵and R⁶Each independently of the others is hydrogen, fluorine, chlorine,Bromine, iodine or C_1-6An alkyl group;

x is fluorine, chlorine or bromine;

with the following conditions:

(i) when X is chlorine, R⁵And R⁶Are each hydrogen, n is 2, R³And R⁴When both are hydrogen, R¹And R²And not both methyl groups.

8. The compound of claim 7, which is a compound of formula (IIa-17) or a salt of a compound of formula (IIa-17); or

Which is a compound shown in a formula (IIa-18) or a salt of the compound shown in the formula (IIa-18):

wherein:

R¹and R²Each independently is C_1-6An alkyl group;

R³and R⁴Each independently hydrogen or bromine;

x is fluorine, chlorine or bromine;

with the following conditions:

9. The compound of claim 1 or 8, wherein

R¹And R²Each independently is C_1-4An alkyl group;

R³and R⁴Each independently hydrogen or bromine;

R⁵and R⁶Each independently of the others is hydrogen, fluorine, chlorine, bromine, iodine or C_1-4An alkyl group.

10. The compound of claim 9, wherein

R¹And R²Each independently is methyl, ethyl, n-propyl or isopropyl;

R³and R⁴Each independently hydrogen or bromine;

R⁵and R⁶Each independently hydrogen, fluorine, chlorine, bromine, iodine or methyl.

11. The compound of claim 2, which is a compound of formula (IIIa) or a salt of a compound of formula (IIIa):

12. the compound of claim 2, which is a compound of formula (IIIb) or a salt of a compound of formula (IIIb):

13. the compound of claim 2, which is a compound of formula (IIIc) or a salt of a compound of formula (IIIc):

14. the compound of claim 2, which is a compound of formula (IIId) or a salt of a compound of formula (IIId):

15. a compound according to any one of claims 11 to 14, wherein

or R⁸、R⁹And the carbon atom to which it is attached, form-C (═ O) -;

16. The compound of claim 15, wherein

or R⁸、R⁹And the carbon atom to which it is attached, form-C (═ O) -;

or R¹⁰、R¹¹、R¹²Together with the carbon atom to which they are attached form-C ≡ CH or-CH ═ CH₂。

17. The compound of claim 1, which is a compound of formula (IIIe) or a salt of a compound of formula (IIIe):

wherein:

R⁵and R⁶Each independently is hydrogen or fluorine;

x is fluorine or chlorine;

R^mis hydrogen or methyl;

R^vis hydrogen or methyl;

R^wis C_1-3Alkyl or halo C_1-3An alkyl group.

18. The compound of claim 17, wherein:

R^mis hydrogen or methyl;

R^vis hydrogen or methyl;

R^wis methyl, isopropyl, difluoromethyl or tetrafluoroethyl.

19. The compound of claim 1, which is a compound of formula (IIIf) or a salt of a compound of formula (IIIf):

wherein:

R⁵and R⁶Each independently is hydrogen or fluorine;

x is fluorine or chlorine;

R^mis hydrogen or methyl;

R^vis hydrogen or methyl;

R^wis C_1-3Alkyl or halo C_1-3An alkyl group.

20. The compound of claim 19, wherein:

R^mis hydrogen or methyl;

R^vis hydrogen or methyl;

R^wis methyl, isopropyl, difluoromethyl or tetrafluoroethyl.

21. The compound of claim 1 or 2, which is a compound of formula (IIIg) or a salt of a compound of formula (IIIg):

wherein: x is fluorine or chlorine.

22. The compound of claim 1, which is a compound of formula (IIIh) or a salt of a compound of formula (IIIh):

wherein: x is fluorine, chlorine or bromine.

23. The compound of claim 1, which is a compound having one of the following structures or a salt of a compound having one of the following structures:

or

24. A herbicidal composition in which the compound or the salt of the compound according to any one of claims 1 to 23 is used as an active ingredient.

25. Use of a compound according to any one of claims 1 to 23 or a herbicidal composition according to claim 24 for agricultural weeding.

26. A method of controlling weed growth in useful plants comprising pre-emergence application to the locus of the weeds of an effective amount of a compound of any one of claims 1 to 23.

27. The method of claim 26, wherein the weeds are broadleaf weeds and grass weeds.

28. The method of claim 27, wherein the broadleaf weeds are abutilon, amaranthus retroflexus, snakehead intestine; the grassy weeds are large crabgrass, barnyard grass and green bristlegrass herb.

29. The method of claim 26, wherein the useful plants are soybean, peanut, and sunflower.