CN115536646B

CN115536646B - Nematicidal active compound and its preparation method and use

Info

Publication number: CN115536646B
Application number: CN202110729318.3A
Authority: CN
Inventors: 徐晓勇; 李忠; 曹晓峰; 陈佃聪; 邵旭升; 须志平; 程家高
Original assignee: East China University of Science and Technology
Current assignee: East China University of Science and Technology
Priority date: 2021-06-29
Filing date: 2021-06-29
Publication date: 2025-10-28
Anticipated expiration: 2041-06-29
Also published as: CN115536646A

Abstract

本发明提供式I所示化合物。式I所示化合物具备优异的杀线虫活性，从而能够制备高效、低毒和环境相容性好的杀线虫剂。 The present invention provides a compound represented by formula I. The compound represented by formula I has excellent nematicidal activity, thereby being capable of preparing a nematicide with high efficiency, low toxicity and good environmental compatibility.

Description

Nematicidal active compounds, process for their preparation and their use

Technical Field

The invention belongs to the field of pesticides. In particular, the invention relates to a compound with nematicidal activity, a preparation method and application thereof.

Background

The plant parasitic nematodes have wide distribution range, various types and strong environment adaptability, can be parasitic in root systems, stems, leaves, seeds, buds and fruits of plants, can cause mechanical damage to host plants through feeding activities, and can graze nutrition of the host plants, especially esophageal gland secretion of the plant parasitic nematodes can cause a series of lesions of the host plants, and can also infect the host plants together with other pathogenic microorganisms to cause compound diseases and cause yield loss. The agricultural loss caused by plant parasitic nematodes is up to more than 1000 hundred million dollars each year on a global scale, and the development of agricultural economy is severely restricted.

There are many means for controlling insects in agriculture, and chemical control is the dominant method at present. The widely applied chemical nematicides are mainly high-toxicity and high-residue organophosphorus or carbamate pesticides, such as thiophos, profenofos, bendrophos, fosthiazate, aldicarb, carbofuran and the like, have low safety to human beings and other non-target organisms, and can cause pollution to soil, water sources and agricultural products to different degrees. In addition, due to single species, these nematicides are used excessively and frequently, which has caused serious resistance, so that the difficulty of nematode control is increasing. Therefore, searching for a chemical nematicide with high efficiency, low toxicity and good environmental compatibility and novel structure becomes a technical problem which needs to be solved urgently in the field.

In view of the above, there is a strong need in the art to develop novel compounds having nematicidal activity.

Disclosure of Invention

The invention aims to develop a chemical nematicide with novel structure, high efficiency, low toxicity and good environmental compatibility.

In a first aspect, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a nematicide,

Wherein R ¹ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted amino, substituted or unsubstituted amido, substituted or unsubstituted sulfonamide, substituted or unsubstituted C1-12 (preferably C1-6, more preferably C1-4) alkyl or alkoxy, substituted or unsubstituted C2-12 (preferably C2-6, more preferably C2-4) alkenyl or alkynyl, substituted or unsubstituted-Z-C1-12 (preferably C1-6, more preferably C1-4) alkyl or alkoxy, substituted or unsubstituted-CH ₂ -Z- (C1-12 alkyl or C3-12 (preferably C3-6) cycloalkyl) (wherein Z is O or NH or S), substituted or unsubstituted C5-12 aryl or heteroaryl, substituted or unsubstituted-CH ₂ - (C5-12 aryl or heteroaryl) (preferably substituted or unsubstituted benzyl), or absent;

R ²、R³、R⁴、R⁵ is each independently selected from hydrogen, halogen, substituted or unsubstituted amino, hydroxy, nitro, cyano, substituted or unsubstituted C1-12 (preferably C1-6, more preferably C1-4) alkyl or alkoxy, substituted or unsubstituted C3-12 (preferably C3-6) cycloalkyl, substituted or unsubstituted C2-12 (preferably C2-6, more preferably C2-4) alkenyl or alkynyl, substituted or unsubstituted-CH ₂ -Z- (C1-12 (preferably C1-6, more preferably C1-4) alkyl or C3-12 (preferably C3-6) cycloalkyl) (wherein Z is O or NH or S), substituted or unsubstituted C5-12 aryl or heteroaryl, substituted or unsubstituted-CH ₂ - (C5-12 aryl or heteroaryl) (wherein Z is O or NH or S), or absent;

R ⁶ is hydrogen, substituted or unsubstituted C1-12 (preferably C1-6, more preferably C1-4) alkyl or alkoxy, substituted or unsubstituted C3-12 (preferably C3-6) cycloalkyl, substituted or unsubstituted C2-12 (preferably C2-6, more preferably C2-4) alkenyl or alkynyl, substituted or unsubstituted-CH ₂ -Z- (C1-12 (preferably C1-6, more preferably C1-4) alkyl or C3-12 (preferably C3-6) cycloalkyl) (wherein Z is O or NH or S), substituted or unsubstituted-CH ₂ -Z- (C5-12 aryl or heteroaryl) (wherein Z is O or NH or S), substituted or unsubstituted C5-12 aryl or heteroaryl, substituted or unsubstituted-CH ₂ - (C5-12 aryl or heteroaryl), or absent;

M ¹ is selected from C, CH, S, O or N;

M ²、M³、M⁴ are each independently selected from C, CH, S, O, N;

n is an integer from 0 to 2;

x ¹ is selected from O, N or S;

X ² is selected from N, C, O or S;

Y is selected from-CH ₂-,-CO-,-S(O)_m-,-C(O)NH-,-S(O)₂ NH-, oxime ether group Thiocarbonyl-amino group

M is 0, 1 or 2;

a is a substituted or unsubstituted C5-18 heteroaryl or heterocyclylbiphenyl;

R ⁸ is selected from hydrogen, substituted or unsubstituted C1-12 (preferably C1-6, more preferably C1-4) alkyl, substituted or unsubstituted C3-12 (preferably C3-6) cycloalkyl, substituted or unsubstituted C2-12 (preferably C2-6, more preferably C2-4) alkenyl or alkynyl, substituted or unsubstituted-CH ₂ -Z- (C1-12 (preferably C1-6, more preferably C1-4) alkyl or C3-12 (preferably C3-6) cycloalkyl) (wherein Z is O or NH or S), substituted or unsubstituted C5-12 aryl or heteroaryl, substituted or unsubstituted-CH ₂ - (C5-12 aryl or heteroaryl), substituted or unsubstituted C1-3 alkylene-C5-12 heteroaryl or heterocyclyl.

In a specific embodiment, the compounds of formula I have the structures of formulas I-a and I-b:

Wherein R ¹ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted amino, substituted or unsubstituted amido, substituted or unsubstituted sulfonamide, substituted or unsubstituted C1-12 (preferably C1-6, more preferably C1-4) alkyl or alkoxy, substituted or unsubstituted-Z-C1-12 (preferably C1-6, more preferably C1-4) alkyl or alkoxy (wherein Z is O or NH or S), substituted or unsubstituted-CH ₂ -Z- (C1-12 (preferably C1-6, more preferably C1-4) alkyl or C3-12 (preferably C3-6) cycloalkyl) (wherein Z is O or NH or S), substituted or unsubstituted-C5-12 aryl or heteroaryl, substituted or unsubstituted-CH ₂ - (C5-12 aryl or heteroaryl) (preferably substituted or unsubstituted benzyl), or absent;

Each R ²、R³、R⁴、R⁵ is independently selected from: hydrogen, halogen, substituted or unsubstituted amino, nitro, cyano, substituted or unsubstituted C1-12 (preferably C1-6, more preferably C1-4) alkyl or alkoxy, substituted or unsubstituted C3-12 (preferably C3-6) cycloalkyl, substituted or unsubstituted-CH ₂ -Z- (C1-12 (preferably C1-6, more preferably C1-4) alkyl or C3-12 (preferably C3-6) cycloalkyl) (wherein Z is O or NH or S), substituted or unsubstituted C5-12 aryl or heteroaryl, substituted or unsubstituted-CH ₂ - (C5-12 aryl or heteroaryl), substituted or unsubstituted-Z- (C5-12 aryl or heteroaryl) (wherein Z is O or NH or S), substituted or unsubstituted C2-6 (preferably C2-4) ester;

R ⁶ is hydrogen, substituted or unsubstituted C1-12 (preferably C1-6, more preferably C1-4) alkyl or alkoxy, substituted or unsubstituted C3-12 (preferably C3-6) cycloalkyl, substituted or unsubstituted C2-12 (preferably C2-6, more preferably C2-4) alkenyl or alkynyl, substituted or unsubstituted-CH ₂ -Z- (C1-12 (preferably C1-6, more preferably C1-4) alkyl or C3-12 (preferably C3-6) cycloalkyl) (wherein Z is O or NH or S), substituted or unsubstituted C5-12 aryl or heteroaryl, substituted or unsubstituted-CH ₂ - (C5-12 aryl or heteroaryl);

m ¹ is selected from C or N;

m ²、M³、M⁴ are each independently selected from C, S, O, N;

x ¹ is selected from O, N or S;

X ² is selected from N, C, O or S;

Y is selected from-CH ₂-、-CO-、-S(O_m-、-C(O)NH-、-S(O)₂ NH-, oxime ether group

M is 0, 1 or 2;

a is a substituted or unsubstituted C5-18 heteroaryl;

R ⁸ is selected from hydrogen, substituted or unsubstituted C1-12 (preferably C1-6, more preferably C1-4) alkyl, substituted or unsubstituted C3-12 (preferably C3-6) cycloalkyl, substituted or unsubstituted C2-12 (preferably C2-6, more preferably C2-4) alkenyl, substituted or unsubstituted-CH ₂ -Z- (C1-12 (preferably C1-6, more preferably C1-4) alkyl or C3-12 (preferably C3-6) cycloalkyl) (wherein Z is O or NH or S), substituted or unsubstituted C5-12 aryl or heteroaryl, and substituted or unsubstituted-CH ₂ - (C5-12 aryl or heteroaryl).

In a specific embodiment, the compound of formula I has the structure of formula I-c to I-g:

Wherein R ¹ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted amino, substituted or unsubstituted amido, substituted or unsubstituted sulfonamide, substituted or unsubstituted C1-12 (preferably C1-6, more preferably C1-4) alkyl or alkoxy, substituted or unsubstituted-Z-C1-12 (preferably C1-6, more preferably C1-4) alkyl or alkoxy (wherein Z is O or NH or S), substituted or unsubstituted-CH ₂ -Z- (C1-12 (preferably C1-6, more preferably C1-4) alkyl or C3-12 (preferably C3-6) cycloalkyl) (wherein Z is O or NH or S), substituted or unsubstituted-C5-12 aryl or heteroaryl, or absent;

R ²、R³、R⁴、R⁵ is each independently selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, cyano, substituted or unsubstituted C1-12 (preferably C1-6, more preferably C1-4) alkyl or alkoxy or substituted or unsubstituted C3-12 (preferably C3-6) cycloalkyl, substituted or unsubstituted-CH ₂ -Z- (C1-12 (preferably C1-6, more preferably C1-4) alkyl or C3-12 (preferably C3-6) cycloalkyl) (wherein Z is O or NH or S), substituted or unsubstituted C5-12 aryl or heteroaryl, substituted or unsubstituted-Z- (C5-12 aryl or heteroaryl) (wherein Z is O or NH or S), or absent;

R ⁶ is hydrogen, substituted or unsubstituted C1-12 (preferably C1-6, more preferably C1-4) alkyl or alkoxy, substituted or unsubstituted C3-12 (preferably C3-6) cycloalkyl, substituted or unsubstituted C2-12 (preferably C2-6, more preferably C2-4) alkenyl or alkynyl, substituted or unsubstituted C5-12 aryl or heteroaryl, substituted or unsubstituted-CH ₂ - (C5-12 aryl or heteroaryl), or absent;

m ¹ is selected from C or N;

Each M ²、M³、M⁴ is independently selected from C, S, O or N;

X ¹ is selected from N, O or S;

X ² is selected from N or C;

y is selected from-CH ₂-、-CO-、-S(O)_m-、-C(O)NH-、-S(O)₂ NH-, oxime ether group

M is 0, 1 or 2;

a is a substituted or unsubstituted C5-18 heteroaryl;

r ⁸ is selected from the group consisting of hydrogen, substituted or unsubstituted C1-12 (preferably C1-6, more preferably C1-4) alkyl, substituted or unsubstituted C2-12 (preferably C2-6, more preferably C2-4) alkenyl, substituted or unsubstituted-CH ₂ -Z- (C1-12 (preferably C1-6, more preferably C1-4) alkyl or C3-12 (preferably C3-6) cycloalkyl) (wherein Z is O or NH or S), substituted or unsubstituted C5-12 aryl or heteroaryl, and substituted or unsubstituted-CH ₂ - (C5-12 aryl or heteroaryl).

In particular embodiments, R ¹ is selected from hydrogen, halogen, substituted or unsubstituted amino, substituted or unsubstituted amido, substituted or unsubstituted sulfonamide, substituted or unsubstituted C1-12 (preferably C1-6, more preferably C1-4) alkyl or alkoxy, substituted or unsubstituted-Z-C1-12 (preferably C1-6, more preferably C1-4) alkyl or alkoxy (wherein Z is O or NH or S), substituted or unsubstituted-CH ₂ -Z- (C1-12 (preferably C1-6, more preferably C1-4) alkyl or C3-12 (preferably C3-6) cycloalkyl) (wherein Z is O or NH or S), substituted or unsubstituted-C5-12 aryl or heteroaryl;

R ²、R³、R⁴、R⁵ is each independently selected from hydrogen, halogen, substituted or unsubstituted amino, cyano, trifluoromethyl, trifluoromethoxy, nitro, methyl, methoxy, substituted or unsubstituted C2-4 ester group, substituted or unsubstituted amide group, substituted or unsubstituted C5-12 aryl or heteroaryl or substituted or unsubstituted-Z- (C5-12 aryl or heteroaryl) (wherein Z is O or NH or S);

R ⁶ is selected from hydrogen, substituted or unsubstituted C1-12 (preferably C1-6, more preferably C1-4) alkyl or alkoxy, substituted or unsubstituted C3-12 (preferably C3-6) cycloalkyl, substituted or unsubstituted C2-12 (preferably C2-6, more preferably C2-4) alkenyl or alkynyl, substituted or unsubstituted C5-12 aryl or heteroaryl;

y is selected from-CH ₂-、-S-、-CONH-、-CO-、-CS-、-S(O)₂ -, oxime ether group

R ⁸ is selected from hydrogen, substituted or unsubstituted C1-12 (preferably C1-6, more preferably C1-4) alkyl, substituted or unsubstituted C2-12 (preferably C2-6, more preferably C2-4) alkenyl, substituted or unsubstituted-CH ₂ -Z- (C1-12 (preferably C1-6, more preferably C1-4) alkyl or C3-12 (preferably C3-6) cycloalkyl) (wherein Z is O or NH or S), substituted or unsubstituted-CH ₂ - (C5-12 aryl or heteroaryl).

In a specific embodiment, R ⁸ is selected from hydrogen, substituted or unsubstituted C1-12 (preferably C1-6, more preferably C1-4) alkyl, substituted or unsubstituted C2-12 (preferably C2-6, more preferably C2-4) alkenyl, substituted or unsubstituted-CH ₂ - (C5-12) aryl or heteroaryl.

In specific embodiments, R ⁸ is selected from:

Hydrogen, hydrogen,

In a specific embodiment, the compound of formula I has a structure of formula I-h-I-j:

Wherein ,R¹、R²、R³、R⁴、R⁵、R⁶、M¹、M³、X¹、X² and A are as described above.

In a specific embodiment, the compound of formula I has the structure of formula I-k:

Wherein R ¹ is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted amino, substituted or unsubstituted amido, substituted or unsubstituted sulfonamide, substituted or unsubstituted C1-12 (preferably C1-6, more preferably C1-4) alkyl or alkoxy, substituted or unsubstituted-Z-C1-12 (preferably C1-6, more preferably C1-4) alkyl or alkoxy (wherein Z is O or NH or S), substituted or unsubstituted-CH ₂ -Z- (C1-12 (preferably C1-6, more preferably C1-4) alkyl or C3-12 (preferably C3-6) cycloalkyl) (wherein Z is O or NH or S), substituted or unsubstituted-C5-12 aryl or heteroaryl;

R ²、R³、R⁴、R⁵ is each independently selected from hydrogen, halogen, substituted or unsubstituted amino, nitro, cyano, substituted or unsubstituted C1-12 (preferably C1-6, more preferably C1-4) alkyl or alkoxy, substituted or unsubstituted C3-12 (preferably C3-6) cycloalkyl, substituted or unsubstituted-CH ₂ -Z- (C1-12 (preferably C1-6, more preferably C1-4) alkyl or C3-12 (preferably C3-6) cycloalkyl) (wherein Z is O or NH or S), substituted or unsubstituted C5-12 aryl or heteroaryl, substituted or unsubstituted-Z- (C5-12 aryl or heteroaryl) (wherein Z is O or NH or S);

R ⁶ is selected from the group consisting of hydrogen, substituted or unsubstituted C1-12 (preferably C1-6, more preferably C1-4) alkyl or alkoxy, substituted or unsubstituted C3-12 (preferably C3-6) cycloalkyl, substituted or unsubstituted C2-12 (preferably C2-6, more preferably C2-4) alkenyl or alkynyl, substituted or unsubstituted C5-12 aryl or heteroaryl, substituted or unsubstituted-CH ₂ - (C5-12 aryl or heteroaryl);

m ¹ is selected from C or N;

X ¹ is selected from N, O or S;

X ² is selected from N or C;

A is a substituted or unsubstituted C5-12 heteroaryl group.

In a specific embodiment, the compounds of formula I-k have the structure of formula I-l-q:

wherein R ¹、R²、R³、R⁴、R⁵、R⁶ and A are as described above.

In specific embodiments, a is selected from the following groups, substituted or unsubstituted:

R ⁹ is selected from the group consisting of a substituted or unsubstituted C2-4 ester group, a substituted or unsubstituted amide group, a substituted or unsubstituted C1-12 (preferably C1-6, more preferably C1-4) alkyl or alkoxy group, a substituted or unsubstituted C3-12 (preferably C3-6) cycloalkyl group, a substituted or unsubstituted C2-12 (preferably C2-6, more preferably C2-4) alkenyl or alkynyl group, a substituted or unsubstituted-CH ₂ -Z- (C1-12 (preferably C1-6, more preferably C1-4) alkyl group or C3-12 (preferably C3-6) cycloalkyl group) (wherein Z is O or NH or S), a substituted or unsubstituted C5-12 aryl or heteroaryl group, and a substituted or unsubstituted-CH ₂ - (C5-12 aryl or heteroaryl group).

In specific embodiments, a is selected from:

more preferably, a is selected from:

In a preferred embodiment, the substituents of a are hydrogen, halogen, cyano, trifluoromethyl, trifluoromethoxy, nitro, methyl, methoxy.

In a specific embodiment, the compound is ：I-1、I-2、I-3、I-5、I-20、I-21、I-24、I-25、I-28、I-29、I-32、I-33、I-44、I-96、I-97、I-103、I-111、I-112、I-114、I-115、I-128;

Preferably, the compounds are I-1, I-2, I-3, I-5, I-20, I-21, I-24, I-25, I-28, I-29, I-32, I-33, I-44.

In a second aspect, the present invention provides a nematicide or nematicide composition comprising a compound of the first aspect or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable excipient.

In a third aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof,

M ¹ is selected from C, CH, S, O or N;

M ²、M³、M⁴ are each independently selected from C, CH, S, O, N;

n is an integer from 0 to 2;

x ¹ is selected from O, N or S;

X ² is selected from N, C, O or S;

M is 0, 1 or 2;

a is a substituted or unsubstituted C5-18 heteroaryl or heterocyclylbiphenyl;

m ¹ is selected from C or N;

m ²、M³、M⁴ are each independently selected from C, S, O, N;

x ¹ is selected from O, N or S;

X ² is selected from N, C, O or S;

M is 0, 1 or 2;

a is a substituted or unsubstituted C5-18 heteroaryl;

m ¹ is selected from C or N;

Each M ²、M³、M⁴ is independently selected from C, S, O or N;

X ¹ is selected from N, O or S;

X ² is selected from N or C;

M is 0, 1 or 2;

a is a substituted or unsubstituted C5-18 heteroaryl;

In a specific embodiment, R ⁸ is selected from the group consisting of hydrogen,

m ¹ is selected from C or N;

X ¹ is selected from N, O or S;

X ² is selected from N or C;

A is a substituted or unsubstituted C5-12 heteroaryl group.

wherein R ¹、R²、R³、R⁴、R⁵、R⁶ and A are as described above.

In specific embodiments, a is selected from:

more preferably, a is selected from:

In specific embodiments, the compounds are I-20, I-24, I-28, I-32, I-44.

In a fourth aspect, the present invention provides a method of killing nematodes comprising administering to a plant in need of killing nematodes an effective amount of a nematicide or nematicide composition of the second aspect or a compound of the third aspect or a pharmaceutically acceptable salt thereof.

In preferred embodiments, the nematodes include, but are not limited to, root-knot nematodes such as peanut root-knot nematodes (Meloidogyne arenaria), qigold (Meloidogyne chitwoodi), short root-knot nematodes (Meloidogyne exigua), north root-knot nematodes (Meloidogyne hapla), southern root-knot nematodes (Meloidogyne incognita), java root-knot nematodes (Meloidogyne javanica), and other root-knot nematodes (Meloidogyne), cyst nematodes such as potato golden nematodes (Globodera rostochiensis), Potato Bai Xianchong (Globodera pallida), tobacco cyst nematodes (Globodera tabacum), and other cyst nematodes (Globodera), heterodera, such as cereal cyst nematodes (Heterodera avenae), soybean cyst nematodes (Heterodera glycines), beet cyst nematodes (Heterodera schachtii), trefoil cyst nematodes (Heterodera trifolii), and other Heterodera (hetodera), seed nematodes, such as ragweed nematodes (Anguina funesta), seed nematodes (Anguina funesta), Wheat nematodes (Anguina tritici) and other species of nematodes (Anguina), stem and leaf nematodes, such as Aphelenchus besseyi (Aphelenchoides besseyi), aphelenchus fragilis (Aphelenchoides fragariae), Chrysanthemum aphelenchus (Aphelenchoides ritzemabosi), and other aphelenchus species (Aphelenchoides), spiny nematodes such as weed aphelenchus (Belonolaimus longicaudatus) and other needle aphelenchus species (Belonolaimus), pine nematodes such as pine wood nematodes (Bursaphelenchus xylophilus) and other bursaphelenchus species (Bursaphelenchus), ring nematodes such as ring nematodes (Criconema), The species of the genus Annulus (Criconemella), the genus Meloidogyne (Criconemoides) and the genus Cyclonematode (Mesocriconema), the species of the species corm nematodes such as the species Aphanothece rotting (Ditylenchus destructor), the species sweet potato (Ditylenchus dipsaci), the species Mushroom (Ditylenchus myceliophagus), and the species other than the species Aphanothece (Ditylenchus), the species of the species Trigonella such as the species Trigonella (Dolichodorus), the species of the species Spirulina such as the species double Gong Luoxuan (Helicotylenchus dihystera), the species Trigonella, multi-band nematodes (Helicotylenchus multicintus), and other spiraling nematodes (Helicotylenchus); sheath nematodes such as the genus Sphingoides (Hemicycliophora) and the genus Heterodera (Hemicriconemoides), crown nematodes such as the genus Columbia (Hoploaimus columbus) and other species of Nemacystus (Hoploaimus), pseudoroot-knot nematodes such as the species of Porphyrodes (Nacobbus aberrans) and other species of Porphyrodes (Nacobbus), needle-line nematodes such as the species of Alternaria (Longidorus elongatus) and other species of Alternaria (Longidorus), nail nematodes such as the species of Alternaria (Paratylenchus), root-rot nematodes such as the species of Brevibacterium (Pratylenchus brachyurus), The coffee short body nematode (Pratylenchus coffee), the corn short body nematode (Pratylenchus zeae), Piercing aphelenchus xylophilus (Pratylenchus penetrans), and other aphelenchus species (Pratylenchus), aphelenchus species, such as aphelenchus xylophilus (Radopholus similis) and other aphelenchus species (Radopholus), reniform nematodes, such as reniform nematode (Rotylenchus robustus) and other reniform nematode species (Rotylenchus), residual root nematodes, such as prader (Trichodorus primitivus) and other Bursaphelenchus species (Trichodorus), dwarfing nematodes, such as Leptonchus xylophilus (Tylenchorhynchus claytoni), and, adventitious dwarfing nematodes (Tylenchorhynchus dubius), and other dwarfing nematodes (Tylenchorhynchus), citrus nematodes such as citrus hemipiercing nematodes (Tylenchulus semipenetrans) and other aphelenchus species (Tylenchulus), caenorhabditis elenchus, such as caenorhabditis elenchus (Xiphinema americanum), standard caenorhabditis elenchus (Xiphinema index), caenorhabditis elenchus (Xiphinema diversicaudatum), and other caenorhabditis species (Xiphinema);

Preferably, the nematodes are meloidogyne incognita (Meloidogyne incognita) and pine wood nematodes (Bursaphelenchus xylophilus).

In preferred embodiments, the plants include, but are not limited to, food crops such as peanuts, rice, soybeans, sorghum, wheat, vegetables such as cucumbers, tomatoes, spinach, cabbages, beets and the like, woods such as banana trees, poplar trees, pine trees, cypress trees, coconuts and the like, as well as tobacco, potatoes, citrus and the like.

It is understood that within the scope of the present invention, the above-described technical features of the present invention and technical features specifically described below (e.g., in the examples) may be combined with each other to constitute new or preferred technical solutions. And are limited to a space, and are not described in detail herein.

Detailed Description

Through extensive and intensive research, the inventor unexpectedly discovers a series of chemical nematicides with high efficiency, low toxicity and good environmental compatibility and novel structure, thereby laying a brand new material foundation for developing nematicides and completing the invention on the basis.

Definition of groups

The term "C _1-6 alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.

The term "C _2-6 alkenyl" refers to straight or branched alkenyl groups having 2 to 6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or the like.

The term "C _2-6 alkynyl" refers to straight or branched chain alkynyl groups having 2 to 6 carbon atoms, such as ethynyl, propynyl, or the like.

The term "C _3-7 cycloalkyl" refers to a cyclic alkyl group having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or the like.

The term "C _5-7 cycloalkenyl" refers to a cyclic alkenyl group having 5-7 carbon atoms, having one or more double bonds, such as cyclopentenyl, cyclohexenyl, cycloheptenyl, 1, 3-cyclohexanedienyl, 1, 4-cyclohexanedienyl, or the like.

As used herein, the term "C _1-4 alkoxy" refers to a straight or branched chain alkoxy group having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, or the like.

The term "halogen" refers to fluorine, chlorine, bromine, or iodine. The term "halogenated" refers to groups substituted with one or more of the above halogen atoms, same or different, such as trifluoromethyl, pentafluoroethyl, heptafluoroisopropyl, or the like.

The term "ring" or "ring system" refers to a carbocyclic or heterocyclic ring.

The term "heterocycle" means that at least one of the atoms forming the heterocyclic backbone is not carbon, is nitrogen, oxygen or sulfur. Typically, the heterocycle contains no more than 4 nitrogens, no more than 2 oxygens, and/or no more than 2 thiols. Unless otherwise indicated, a heterocycle may be a saturated, partially unsaturated, or fully unsaturated ring.

The term "ring system" refers to a fused ring in which two or more rings are joined together.

As used herein, the term "5-or 6-membered heterocyclyl" refers to a five-or six-membered ring containing one or more heteroatoms selected from nitrogen, oxygen, or sulfur, such as pyridyl, thiazolyl, isothiazolyl, thienyl, furyl, pyrrolyl, pyrazolyl, pyrimidinyl, tetrahydrofuranyl, 4, 5-dihydrothiazol-2-yl, 2-cyanoimino-4-oxo-1, 3-thiazolidin-3-yl, 2-cyanoimino-4-oxo-1, 3-thiazinan-3-yl, oxazolyl, isoxazolyl, 1H-tetrazolyl, 1H-1,2, 3-triazolyl, 4H-1,2, 4-triazolyl, 1,2, 3-thiadiazolyl, 1,2, 4-thiadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, tetrazolyl, and the like.

The term "heterocyclic ring system" refers to a ring system in which at least one ring in the ring system is heterocyclic.

The term "heteroaromatic ring system" refers to a system in which at least one ring in the ring system is an aromatic ring.

As used herein, the term "8-to 12-membered heteroaromatic bicyclic ring system" or "8-to 14-membered heteroaromatic bicyclic or tricyclic ring system" may be selected from the group consisting of benzofuran, benzo [ b ] thiophene, indole, quinoline, isoquinoline, 1H-indazole, 1H-benzo [ d ] imidazole, benzo [ d ] thiazole, benzo [ d ] oxazole, benzo [ d ] isoxazole, benzo [ d ] [1,2,3] thiadiazole, 2, 3-dihydroimidazo [1,2-a ] pyridine, quinazoline, quinoxaline, cinnoline, phthalazine, 1, 8-naphthyridine, 4,5,6, 7-tetrahydrobenzo [ b ] thiophene, benzo [ b ] thiophene-1, 1-dioxane, 8H-indeno [2,1-b ] thiophene, 7, 8-dihydro-6H-cyclopenta [4,5] thieno [2,3-d ] pyrimidine, 3,5,6, 7-tetrahydrocyclopenta [4, 3-indoline ] thiophene, 3-dihydro [4, 3-cyclopenta [ 3-4, 3-indoline ] spiro [2, 3-indoline ] thiophene, 3-dihydro [ 3, 3-indoline ] spiro [2, 3-indoline ] or the like.

The term "alkyl" refers to a group of an alkane molecule having one fewer hydrogen atom, and the term "alkylene" refers to a group of an alkane molecule having two fewer hydrogen atoms. Similarly, "alkenylene", "alkynylene", "cycloalkylene", "cycloalkenyl", "phenylene", "naphthylene", "heterocyclylene" or "heteroarylene bi-or tricyclic ring systems" are defined similarly.

Unless otherwise indicated as "substituted or unsubstituted", the radicals of the present invention may be substituted with substituents selected from the group consisting of halogen, cyano, nitro, C _1-6 alkyl, C _1-6 haloalkyl, C _2-6 alkenyl, C _2-6 haloalkenyl, C _2-6 alkynyl, C _2-6 haloalkynyl, hydroxy, C _1-4 alkyl 、OR³、NR³R⁴、C(O)R³、C(O)OR³、C(O)NR³R⁴、SR³、S(O)_mR⁵、S(O)₂NR³R⁴、OC(O)R⁵、OC(O)NR³R⁴、OS(O)₂R⁵、OS(O)₂NR³R⁴、N(R⁶)C(O)R⁵、N(R⁶)C(O)NR³R⁴、N(R⁶)S(O)₂R⁵, and N (R ⁶)S(O)₂NR³R⁴, etc., wherein R ³、R⁴、R⁵、R⁶ is as defined above and m is 1 or 2.

Inert solvents refer to various solvents that do not react with the starting materials, including various straight, branched or cyclic alcohols, ethers or ketones, haloalkanes, 1, 4-dioxane, acetonitrile, tetrahydrofuran, N-Dimethylformamide (DMF), dimethylsulfoxide (DMSO), and the like.

The compounds of the invention may contain one or more asymmetric centers and thus occur as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers. Asymmetric centers that may be present depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers, and all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds are included within the scope of the invention. The present invention includes all isomeric forms of the compounds.

Nematicidal activity of the active substances according to the invention

The term "active substance of the present invention" or "active compound of the present invention" refers to a compound of the structure represented by the general formula (I), an optical isomer, a cis-trans isomer or an agropharmaceutically acceptable salt thereof. The compound contains N, S heterocyclic structures, has obvious nematicidal activity, and has wide nematicidal spectrum and strong stability.

The term "agropharmaceutically acceptable salt" means that the anion of the salt is known and acceptable in forming nematicide pharmaceutically acceptable salts. Preferably, the salt is water soluble. Suitably, the acid addition salts formed with compounds of formula (I) include salts formed with inorganic acids, for example hydrochloride, phosphate, sulphate, nitrate, and salts formed with organic acids, for example acetate, benzoate and the like.

The active substances of the invention can be used for controlling and eliminating a wide range of plant parasitic nematodes in agriculture and forestry. In this specification, a "nematicide" is a generic term for substances having the effect of controlling all plant parasitic nematodes mentioned herein.

Examples of plant parasitic nematodes include, but are not limited to, root-knot nematodes such as peanut root-knot nematodes (Meloidogyne arenaria), root-knot nematodes (Meloidogyne chitwoodi), root-knot nematodes (Meloidogyne exigua), northern root-knot nematodes (Meloidogyne hapla), southern root-knot nematodes (Meloidogyne incognita), root-knot nematodes (Meloidogyne javanica), and other root-knot nematodes (Meloidogyne), cyst nematodes such as potato nematodes (Globodera rostochiensis), plant nematodes, Potato Bai Xianchong (Globodera pallida), tobacco cyst nematodes (Globodera tabacum), and other cyst nematodes (Globodera), heterodera, such as cereal cyst nematodes (Heterodera avenae), soybean cyst nematodes (Heterodera glycines), beet cyst nematodes (Heterodera schachtii), trefoil cyst nematodes (Heterodera trifolii), and other Heterodera (hetodera), seed nematodes, such as ragweed nematodes (Anguina funesta), seed nematodes (Anguina funesta), Wheat nematodes (Anguina tritici) and other species of nematodes (Anguina), stem and leaf nematodes, such as Aphelenchus besseyi (Aphelenchoides besseyi), aphelenchus fragilis (Aphelenchoides fragariae), Chrysanthemum aphelenchus (Aphelenchoides ritzemabosi), and other aphelenchus species (Aphelenchoides), spiny nematodes such as weed aphelenchus (Belonolaimus longicaudatus) and other needle aphelenchus species (Belonolaimus), pine nematodes such as pine wood nematodes (Bursaphelenchus xylophilus) and other bursaphelenchus species (Bursaphelenchus), ring nematodes such as ring nematodes (Criconema), The species of the genus Annulus (Criconemella), the genus Meloidogyne (Criconemoides) and the genus Cyclonematode (Mesocriconema), the species of the species corm nematodes such as the species Aphanothece rotting (Ditylenchus destructor), the species sweet potato (Ditylenchus dipsaci), the species Mushroom (Ditylenchus myceliophagus), and the species other than the species Aphanothece (Ditylenchus), the species of the species Trigonella such as the species Trigonella (Dolichodorus), the species of the species Spirulina such as the species double Gong Luoxuan (Helicotylenchus dihystera), the species Trigonella, multi-band nematodes (Helicotylenchus multicintus), and other spiraling nematodes (Helicotylenchus); sheath nematodes such as the genus Sphingoides (Hemicycliophora) and the genus Heterodera (Hemicriconemoides), crown nematodes such as the genus Columbia (Hoploaimus columbus) and other species of Nemacystus (Hoploaimus), pseudoroot-knot nematodes such as the species of Porphyrodes (Nacobbus aberrans) and other species of Porphyrodes (Nacobbus), needle-line nematodes such as the species of Alternaria (Longidorus elongatus) and other species of Alternaria (Longidorus), nail nematodes such as the species of Alternaria (Paratylenchus), root-rot nematodes such as the species of Brevibacterium (Pratylenchus brachyurus), The coffee short body nematode (Pratylenchus coffee), the corn short body nematode (Pratylenchus zeae), Piercing aphelenchus xylophilus (Pratylenchus penetrans), and other aphelenchus species (Pratylenchus), aphelenchus species, such as aphelenchus xylophilus (Radopholus similis) and other aphelenchus species (Radopholus), reniform nematodes, such as reniform nematode (Rotylenchus robustus) and other reniform nematode species (Rotylenchus), residual root nematodes, such as prader (Trichodorus primitivus) and other Bursaphelenchus species (Trichodorus), dwarfing nematodes, such as Leptonchus xylophilus (Tylenchorhynchus claytoni), and, Adventitious dwarfing nematodes (Tylenchorhynchus dubius), and other dwarfing nematodes (Tylenchorhynchus), citrus nematodes such as citrus hemipiercing nematodes (Tylenchulus semipenetrans) and other aphelenchus species (Tylenchulus), caenorhabditis elenchus, such as caenorhabditis elegans (Xiphinema americanum), standard caenorhabditis elenchus (Xiphinema index), caenorhabditis elenchus (Xiphinema diversicaudatum), and other caenorhabditis species (Xiphinema).

The compound has better control effect on the meloidogyne incognita (Meloidogyne incognita) and the pine wood nematodes (Bursaphelenchus xylophilus).

Nematicidal compositions containing an active substance according to the invention

The active substances according to the invention can be prepared in a conventional manner as nematicidal compositions. These active compounds can be formulated as conventional formulations, such as solutions, emulsions, suspensions, powders, foams, pastes, granules, aerosols, natural and synthetic materials impregnated with the active substance, microcapsules in polymers, coated compounds for seeds, and formulations for use with combustion devices, such as fumigating cartridges, fumigating cans and fumigating trays, and ULV Cold and hot mist (Cold mist) formulations.

These formulations can be produced by known methods, for example by mixing the active compound with extenders, which are liquid or liquefied gas or solid diluents or carriers, and optionally surfactants, i.e. emulsifiers and/or dispersants and/or foam formers. For example, when water is used as the extender, organic solvents may also be used as adjuvants.

When liquid solvents are used as diluents or carriers, it is basically suitable, for example aromatic hydrocarbons, such as xylene, toluene or alkyl naphthalenes, chlorinated aromatic or chlorinated aliphatic hydrocarbons, such as chlorobenzene, vinyl chloride or dichloromethane, aliphatic hydrocarbons, such as cyclohexane or paraffins, such as mineral oil fractions, alcohols, such as ethanol or ethylene glycol and their ethers and lipids, ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone or cyclohexanone, or less frequently polar solvents, such as dimethylformamide and dimethyl sulfoxide, and water.

The diluent or carrier for the liquefied gas refers to a liquid that will become a gas at normal temperature and pressure, such as an aerosol propellant, e.g., halogenated hydrocarbons, as well as butane, propane, nitrogen, and carbon dioxide.

The solid carrier may be ground natural minerals such as kaolin, clay, talc, quartz, activated clay, montmorillonite, or diatomaceous earth, and ground synthetic minerals such as highly dispersed silicic acid, alumina, and silicate. Solid carriers for the particles are crushed and graded natural zircon, such as calcite, marble, pumice, sepiolite and dolomite, as well as particles synthesized from inorganic and organic grits, and particles of organic materials such as sawdust, coconut shells, corn cobs and tobacco stalks, and the like.

Nonionic and anionic emulsifying trains can be used as emulsifiers and/or foam formers. Such as polyoxyethylene-fatty acid esters, polyoxyethylene-fatty alcohol ethers, such as alkylaryl polyglycol ethers, alkyl sulfonates, alkyl sulfates, aryl sulfonates, and albumin hydrolysates. The dispersing agent comprises lignin sulfite waste liquid and methyl cellulose.

Binders such as carboxymethylcellulose and natural and synthetic polymers in the form of powders, granules or emulsions, for example gum arabic, polyvinyl alcohol and polyvinyl acetate, can be used in the formulation.

Colorants such as inorganic dyes, e.g., ferric oxide, british and Prussian blue, organic dyes, e.g., azo dyes or metal phthalocyanine dyes, and trace nutrients, e.g., salts of iron, manganese, boron, copper, cobalt, aluminum and zinc, etc., may be used.

These active compounds according to the invention can be present in their commercial preparations or in the dosage forms used prepared from these preparations in a mixture with other active compounds, which are pesticides, bactericides, fungicides, herbicides, growth control agents and the like. Pesticides include, for example, phosphates, carbamates, chlorinated hydrocarbons, pyrethroids, neonicotinoids, bisamides, and substances produced by microorganisms, such as avermectin, and the like, fungicides include methoxy acrylates, amides, triazoles, succinate dehydrogenase inhibitors, and the like.

In addition, the active compounds according to the invention can also be present in their commercial preparations or in the dosage forms prepared from these preparations in a mixture with synergists, which are compounds which increase the action of the active compounds, since the active compounds themselves are active, it being possible for the synergists not to be necessary.

These formulations generally contain from 0.001 to 99.99% by weight, preferably from 0.01 to 99.9% by weight, more preferably from 0.05 to 90% by weight, of the active compounds of the invention, based on the total weight of the nematicidal composition. The concentration of the active compound in the commercial preparation or use dosage form may vary widely. The concentration of the active compound in the dosage form used may be from 0.0000001 to 100% (g/v), preferably between 0.0001 and 1% (g/v).

Process for the preparation of the compounds of the invention

The compounds represented by the general formula of the present invention can be produced by a method, however, the conditions of the method, such as reactants, solvents, bases, amounts of compounds used, reaction temperature, time required for the reaction, etc., are not limited to the following explanation. The compounds of the present invention may also optionally be conveniently prepared by combining the various synthetic methods described in this specification or known in the art, such combination being readily apparent to those skilled in the art to which the present invention pertains. Reagents may be purchased commercially if available.

Typical embodiments of the compounds of the present invention may be synthesized using the general reaction scheme described below. It is apparent from the description given herein that the general scheme can be modified by substituting other materials having similar structures to obtain correspondingly different products. The synthetic method may be used as desired to provide mass production. The starting materials may be obtained commercially or synthesized using published methods. The characteristics of the final product are generally such that the characteristics of the necessary starting materials are apparent from the examples given herein by simple inspection steps.

Parameters of the synthesis reaction

The compounds of the present invention may be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be appreciated that other process conditions may be used given typical or optimized process conditions (i.e., reaction temperature, time, molar ratios of reactants, solvents, catalysts, pressures, etc.), unless otherwise indicated. The optimal reaction conditions may vary with the particular reactants or solvents used, but such conditions may be determined by one skilled in the art by routine optimization procedures.

The starting materials for the following reactions are generally known compounds or may be prepared by known procedures or obvious modifications thereof. For example, many starting materials are available from commercial suppliers, others may be prepared by steps described in the text of standard references or obvious modifications.

In the preparation method of the present invention, each reaction is usually carried out in an inert solvent at a reaction temperature of-20 to 120 ℃ (preferably-10 to 0 ℃ or 20 to 30 ℃ or 80 to 100 ℃). The reaction time is usually 2 to 24 hours, preferably 4 to 18 hours, and may be appropriately prolonged according to the reaction requirement, and the specific reaction time is determined according to the reaction degree.

Bases used in the reaction include, but are not limited to, triethylamine, diisopropylethylamine, diethylamine, piperidine, piperazine, morpholine, N-methylmorpholine, triethylenediamine (DABCO), 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN), potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, or combinations thereof.

The invention has the advantages that:

1. the invention provides a series of compounds with brand-new structure and nematicide activity, thereby laying a new material foundation for developing nematicides;

2. the compound has better living activity to root-knot nematodes and pine wood nematodes and has broad-spectrum characteristics.

The technical solutions of the present invention are further described below with reference to specific embodiments, but the following examples are not to be construed as limiting the present invention, and all the various methods of application adopted according to the principles and technical means of the present invention are within the scope of the present invention.

The experimental methods, in which specific conditions are not noted in the following examples, are generally conducted under conventional conditions or under conditions recommended by the manufacturer. Percentages and parts are by weight unless otherwise indicated.

Example 1 Synthesis of (1H-indol-2-yl) (thiophen-2-yl) methanone, compound I-3

1.612G (10 mmol) of benzopyrrole-2-carboxylic acid are slowly added dropwise into 100mL of toluene solution containing 1.756g (10 mmol) of 2-chloro-4, 6-dimethoxy-1, 3, 5-triazine and 1.011g (10 mmol) of N-methylmorpholine, the reaction is carried out at room temperature, TLC tracks the progress of the reaction, after the reaction is finished, 1.535g (12 mmol) of 2-thiopheneboronic acid, 0.140g (0.2 mmol) of bis-triphenylphosphine palladium dichloride and 8.490g (40 mmol) of potassium phosphate are added into the reaction system, and the mixture is heated to reflux under the protection of argon, and TLC tracks the progress of the reaction. After the completion of the reaction, the solvent was distilled off under reduced pressure, 100mL of water was added to the residue, the mixture was extracted with methylene chloride (100 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column to give 1.864g of a yellow solid in 84% yield.

¹H NMR(400MHz,DMSO-d₆)δ11.96(s,1H),8.15(dd,J＝3.8,1.0Hz,1H),8.09(dd,J＝5.0,1.0Hz,1H),7.75(d,J＝8.0Hz,1H),7.55–7.48(m,2H),7.36–7.29(m,2H),7.12(t,J＝7.4Hz,1H).¹³C NMR(101MHz,DMSO)δ177.28,142.50,137.81,134.31,133.86,133.35,128.72,127.09,125.59,122.79,120.39,112.66,110.09.HRMS(EI+):m/z Calculated C ₁₃H₉ NOS 227.0405 found 227.0407.

EXAMPLE 2 Synthesis of Compound I-99

Similar procedures were followed using the described synthesis of compound I-3 using the appropriate starting materials to produce compound I-99.

¹H NMR(400MHz,Chloroform-d)δ12.01(s,1H),8.77(s,1H),8.23(d,J＝3.2Hz,1H),7.82(d,J＝7.8Hz,1H),7.79(d,J＝2.8Hz,1H),7.64(d,J＝8.2Hz,1H),7.54(d,J＝8.2Hz,1H),7.33(t,J＝7.4Hz,1H).¹³C NMR(101MHz,CDCl₃)δ173.66,164.32,153.21,150.64,145.43,128.91,127.55,126.27,123.12,122.43,119.22,113.21.HRMS(EI+):m/z Calculated C ₁₂H₈N₂ OS 228.0357, found 228.0356.

EXAMPLE 3 Synthesis of Compound I-92

Similar procedures were followed using the described synthesis of compound I-3 using the appropriate starting materials to produce compound I-92.

¹H NMR(400MHz,Chloroform-d)δ9.21(s,1H),8.76(s,1H),8.06(d,J＝8.0Hz,1H),7.95(d,J＝4.0Hz,1H),7.45-7.42(m,1H),7.20(dd,J＝8.0,4.0Hz,1H)..¹³CNMR(101MHz,CDCl₃)δ184.12,157.23,154.42,149.41,147.91,146.12,136.62,133.44,122.31,119.89,116.51.HRMS(EI+):m/z Calculated C ₁₁H₆N₂O₂ S230.0150, found 230.0151.

EXAMPLE 5 Synthesis of Compound I-7

Similar procedures were followed using the described synthesis of compound I-3 using the appropriate starting materials to produce compound I-7.

¹H NMR(400MHz,Chloroform-d)δ7.93(dd,J＝3.8,1.0Hz,1H),7.88(d,J＝4.0Hz,1H),7.73–7.67(m,2H),7.50–7.34(m,4H),7.20(dd,J＝4.8,4.0Hz,1H).¹³C NMR(101MHz,CDCl₃)δ178.50,152.62,142.86,141.62,140.25,133.28,132.88,129.15,129.07,127.93,126.33,123.86.HRMS(EI+):m/z Calc.Mass:C₁₂H₇NO₂S229.0198,Mass:229.0197

EXAMPLE 5 Synthesis of Compound I-93

Similar procedures were followed using the described synthesis of compound I-3 using the appropriate starting materials to produce compound I-93.

¹H NMR(400MHz,DMSO-d₆)δ11.51(s,1H),7.76(s,1H),7.79(dd,J＝4.8,1.2Hz,1H),7.58(d,J＝1.0Hz,1H),7.36(d,J＝4.6Hz,1H),6.69(s,1H),2.13(s,3H).¹³C NMR(101MHz,DMSO)δ184.51,159.08,154.21.148.51,137.32,129.52,128.15,123.21,116.15.101.13,98.36,11.31;HRMS(EI+):m/z Calculated value C ₁₄H₁₁NO₂ 225.0790, found value 225.0788.

EXAMPLE 6 Synthesis of Compound I-14

Similar procedures were followed using the described synthesis of compound I-3 using the appropriate starting materials to produce compound I-14.

¹H NMR(400MHz,Chloroform-d)δ8.03–7.96(m,1H),7.92–7.83(m,2H),7.79(dd,J＝4.8,1.2Hz,1H),7.59–7.51(m,2H),7.19(dd,J＝4.8,4.0Hz,1H).¹³C NMR(101MHz,CDCl₃)δ179.78,143.64,138.19,136.72,135.68,135.47,132.38,128.20,127.80,125.76,124.10,123.66,122.71.HRMS(EI+):m/z Calculated value C ₁₃H₇ClOS₂ 277.9627, found value 277.9629.

EXAMPLE 7 Synthesis of Compound I-63

Similar procedures were followed using the described synthesis of compound I-3 using the appropriate starting materials to produce compound I-63.

¹H NMR(400MHz,DMSO-d₆)δ11.87(s,1H),8.35(s,1H),8.22(dd,J＝4.2,0.8Hz,1H),7.75(dd,J＝8.4,0.8Hz,1H),7.76(d,J＝8.4Hz,1H),7.45–7.40(m,2H),7.26(s,1H),3.98(s,3H).¹³C NMR(101MHz,DMSO)δ177.98,168,32,143.45,138.71,133.91,133.46,133.22,128.62,127.19,124.89,122.89,121.29,111.54,110.29,54.59.HRMS(EI+):m/z Calculated C ₁₅H₁₁NO₃ S285.0460, found 285.0468.

EXAMPLE 8 Synthesis of Compound I-64

Similar procedures were followed using the described synthesis of compound I-3 using the appropriate starting materials to produce compound I-64.

¹H NMR(400MHz,Chloroform-d)δ8.51(s,1H),7.92(d,J＝8.0Hz,1H),7.84(d,J＝8.4Hz,1H),7.69(d,J＝7.6Hz,2H),7.61(d,J＝8.4Hz,1H),7.49–7.33(m,3H),7.28(t,J＝7.4Hz,1H).¹³C NMR(101MHz,CDCl₃)δ175.25,154.87,151.47,141.57,140.91,138.30,130.77,127.33,126.65,125.93,125.35,124.06,123.08,122.29,121.77,113.99,111.42.HRMS(EI+):m/z Calculated C ₁₇H₁₀O₂ S278.0402, found 278.0403.

EXAMPLE 9 preparation of benzofuran-2-yl (thiophen-2-yl) methanone, compound I-1

1.464G (12 mmol) of salicylaldehyde are added to a solution of 2.050g (10 mmol) of 2- (2-bromoacetyl) thiophene in 100mL of acetonitrile, heated to reflux and TLC followed by reaction progress. After the completion of the reaction, the solvent was distilled off under reduced pressure, 100mL of water was added to the residue, the mixture was extracted with methylene chloride (100 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column to give 1.938g of a white solid in 85% yield.

¹H NMR(400MHz,Chloroform-d)δ8.34(d,J＝4.0Hz,1H),7.80–7.70(m,3H),7.65(d,J＝8.4Hz,1H),7.51(t,J＝8.0Hz,1H),7.35(t,J＝8.0Hz,1H),7.27(t,J＝4.0Hz,1H).¹³C NMR(101MHz,CDCl₃)δ175.03,155.80,152.56,142.30,134.60,134.47,128.38,128.15,127.02,124.02,123.24,114.58,112.40.HRMS(EI+):m/z Calculated C ₁₃H₈O₂ S228.0245 found 228.0246.

EXAMPLE 10 Synthesis of Compound I-11

Similar procedures were followed using the described synthesis of compound I-1 using the appropriate starting materials to produce compound I-11.

¹H NMR(400MHz,DMSO-d₆)δ8.43(dd,J＝3.8,1.0Hz,1H),8.17(dd,J＝5.0,1.0Hz,1H),7.90(d,J＝7.8Hz,1H),7.79(d,J＝8.4Hz,1H),7.65–7.56(m,1H),7.47–7.33(m,2H),2.98(s,3H).¹³C NMR(101MHz,DMSO)δ175.36,153.66,146.16,142.64,135.80,134.78,132.58,128.94,128.68,127.52,123.68,121.69,112.31,16.21.HRMS(EI+):m/z Calculated C ₁₄H₁₀O₂ S242.0402 found 242.0401.

EXAMPLE 11 Synthesis of Compound I-20

Similar procedures were followed using the described synthesis of compound I-1 using the appropriate starting materials to produce compound I-20.

¹H NMR(400MHz,Chloroform-d)δ7.69(dd,J＝4.0,0.8Hz,1H),7.69(dd,J＝4.8,1.0Hz,1H),7.66–7.56(m,2H),7.26(dd,J＝8.6,1.4Hz,1H),7.17(dd,J＝5.0,3.8Hz,1H),7.04(td,J＝9.0,2.2Hz,1H).¹⁹F NMR(376MHz,CDCl₃)δ-110.54.HRMS(EI+):m/z Calculated C ₁₃H₇FO₂ S246.0151 found 246.0148.

EXAMPLE 12 Synthesis of Compound I-25

Similar procedures were followed using the described synthesis of compound I-1 using the appropriate starting materials to produce compound I-25.

¹H NMR(400MHz,DMSO-d₆)δ8.37(d,J＝3.6Hz,1H),8.22(d,J＝5.2Hz,1H),7.92(s,2H),7.85(d,J＝8.8Hz,1H),7.60(dd,J＝9.0,1.8Hz,1H),7.47–7.34(m,1H).¹³C NMR(101MHz,DMSO)δ173.98,153.51,152.49,141.37,136.39,135.05,129.14,128.45,128.36,128.18,122.73,114.26,114.04.HRMS(EI+):m/z Calculated C ₁₃H₇ClO₂ S261.9855 found 261.9858.

EXAMPLE 13 Synthesis of Compound I-33

Similar procedures were followed using the described synthesis of compound I-1 using the appropriate starting materials to produce compound I-33.

¹H NMR(400MHz,Chloroform-d)δ8.25(d,J＝3.8Hz,1H),7.69(d,J＝4.8Hz,1H),7.58(s,1H),7.44(t,J＝4.2Hz,2H),7.24(d,J＝8.6Hz,1H),7.20–7.15(m,2H)2.40(s,3H).¹³C NMR(101MHz,CDCl₃)δ174.03,153.31,151.63,141.32,133.46,133.38,132.62,128.74,127.31,126.08,121.66,113.40,110.86,20.31.HRMS(EI+):m/z Calculated C ₁₃H₇BrO₂ S242.0402 found 242.0397.

EXAMPLE 14 Synthesis of Compound I-37

Similar procedures were followed using the described synthesis of compound I-1 using the appropriate starting materials to produce compound I-37.

¹H NMR(400MHz,Chloroform-d)δ8.31(d,J＝3.6Hz,1H),7.75(d,J＝5.2Hz,1H),7.65(s,1H),7.55–7.48(m,1H),7.24(dd,J＝5.0,3.8Hz,1H),7.15–7.08(m,2H),3.86(s,3H).¹³C NMR(101MHz,CDCl₃)δ174.86,156.70,153.26,150.98,142.30,134.51,134.43,128.34,127.54,118.34,114.57,113.04,103.86,55.87.HRMS(EI+):m/z Calculated C ₁₄H₁₀O₃ S258.0351 found 258.0350.

EXAMPLE 15 Synthesis of Compound I-41

Similar procedures were followed using the described synthesis of compound I-1 using the appropriate starting materials to produce compound I-41.

¹H NMR(400MHz,Chloroform-d)δ8.33(dd,J＝3.8,1.0Hz,1H),8.07(s,1H),7.81(dd,J＝5.0,1.0Hz,1H),7.76(m,3H),7.31–7.23(m,1H).¹⁹F NMR(376MHz,CDCl₃)δ-61.28.HRMS(EI+):m/z Calculated C ₁₄H₇F₃O₂ S296.0119, found 296.0120.

EXAMPLE 16 Synthesis of Compound I-43

Similar procedures were followed using the described synthesis of compound I-1 using the appropriate starting materials to produce compound I-43.

¹H NMR(400MHz,DMSO-d₆)δ8.44(s,1H),8.39(d,J＝3.6Hz,1H),8.23(d,J＝4.8Hz,1H),8.03(dd,J＝17.6,8.4Hz,3H),7.40(t,J＝4.4Hz,1H).¹³C NMR(101MHz,DMSO)δ174.02,156.55,152.86,141.24,136.74,135.37,131.44,129.29,129.21,127.35,118.74,114.42,114.11,107.15.HRMS(EI+):m/z Calculated C ₁₄H₇NO₂ S253.0197, found 253.0200.

EXAMPLE 17 Synthesis of Compound I-44

Similar procedures were followed using the described synthesis of compound I-1 using the appropriate starting materials to produce compound I-44.

¹H NMR(400MHz,Chloroform-d)δ8.29(d,J＝4.0Hz,1H),7.82–7.75(m,2H),7.72(d,J＝4.0Hz,1H),7.65(d,J＝8.4Hz,1H),7.59–7.53(m,1H),7.38(t,J＝7.6Hz,1H).¹⁹F NMR(376MHz,CDCl₃)δ-58.24.HRMS(EI+):m/z Calculated C ₁₄H₇F₃O₃ S312.0068, found 312.0070.

EXAMPLE 18 Synthesis of Compound I-46

Similar procedures were followed using the described synthesis of compound I-1 using the appropriate starting materials to produce compound I-46.

¹H NMR(400MHz,DMSO-d₆)δ8.31(d,J＝3.6Hz,1H),8.14(d,J＝4.8Hz,1H),7.76(s,1H),7.46(d,J＝4.2Hz,1H),7.40–7.31(t,J＝8.8Hz,1H),6.89(m,2H),5.16(s,2H).¹³C NMR(101MHz,DMSO)δ174.03,151.35,148.80,145.69,141.85,135.61,134.43,129.01,127.51,118.07,114.75,112.21,104.11.HRMS(EI+):m/z Calculated C ₁₃H₉NO₂ S243.0354, found 243.0358.

EXAMPLE 19 preparation of (5-phenylbenzofuran-2-yl) (thiophen-2-yl) methanone, compound I-48

To a mixed solvent of dioxane and water containing I-29.307 g (1 mmol), tetraphenylphosphine palladium 57.75mg (0.05 mmol) and 0.276g (2 mmol) of potassium carbonate was added 0.163g (1.2 mmol) of p-tolueneboronic acid, and the reaction was refluxed under the protection of argon, and TLC followed the progress of the reaction. After the completion of the reaction, the filtrate was collected by suction filtration using celite, the solvent was distilled off under reduced pressure, 100mL of water was added to the residue, the residue was extracted with methylene chloride (100 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, concentrated and separated by column to give 0.261g of pale yellow solid in 82% yield.

¹H NMR(400MHz,Chloroform-d)δ8.31(dd,J＝3.8,1.0Hz,1H),7.99–7.89(m,2H),7.85(d,J＝2.0Hz,1H),7.79(dd,J＝5.0,1.0Hz,1H),7.64(d,J＝0.4Hz,1H),7.63–7.57(m,3H),7.52(d,J＝8.8Hz,1H),7.29–7.21(m,1H),2.57(s 3H).¹³CNMR(101MHz,CDCl₃)δ174.69,154.39,153.49,141.99,135.01,134.66,133.91,131.09,129.20,128.88,128.46,126.21,125.70,121.69,117.12,113.91,113.46,25.76.HRMS(EI+):m/z Calculated C ₂₀H₁₄O₂ S318.0715; found 318.0717.

EXAMPLE 20 Synthesis of Compound I-96

Similar procedures were followed using the described synthesis of compound I-1 using the appropriate starting materials to produce compound I-96.

¹H NMR(400MHz,Chloroform-d)δ7.90(m,J＝0.4Hz,1H),7.79–7.73(m,2H),7.70(d,J＝4.0Hz,1H),7.64(d,J＝8.0Hz,1H),7.50(t,J＝8.0Hz,1H),7.34(t,J＝8.0Hz,1H),6.67(dd,J＝3.6,1.6Hz,1H).¹³C NMR(101MHz,CDCl₃)δ170.07,155.74,151.63,151.51,147.15,128.33,127.14,123.99,123.37,120.37,115.46,112.62,112.43.HRMS(EI+):m/z Calculated value C ₁₃H₈O₃ 212.0473, found value 212.0475.

EXAMPLE 21 Synthesis of Compound I-97

Similar procedures were followed using the described synthesis of compound I-1 using the appropriate starting materials to produce compound I-97.

¹H NMR(400MHz,Chloroform-d)δ9.76(s,1H),7.73(d,J＝7.8Hz,1H),7.68(s,1H),7.63(dd,J＝8.4,0.9Hz,1H),7.58(ddd,J＝4.0,2.6,1.3Hz,1H),7.48(ddd,J＝8.4,7.4,1.3Hz,1H),7.37–7.28(m,1H),7.18(td,J＝2.6,1.8Hz,1H),6.43(dt,J＝4.0,2.2Hz,1H).¹³C NMR(101MHz,DMSO)δ166.5,150.4,147.8,125.3,122.4,121.9,120.4,118.6,117.7,113.8,108.0,107.0,106.4.HRMS(EI+):m/z Calculated value C ₁₃H₉NO₂ 211.0633, found value 211.0635.

EXAMPLE 22 Synthesis of Compound I-103

Similar procedures were followed using the described synthesis of compound I-1 using the appropriate starting materials to produce compound I-103.

¹H NMR(400MHz,Chloroform-d)δ8.54(d,J＝3.2Hz,1H),7.82(d,J＝4.8Hz,1H),7.74(d,J＝7.6Hz,1H),7.70–7.60(m,2H),7.50(t,J＝7.2Hz,1H),7.41(dd,J＝5.0,3.0Hz,1H),7.34(t,J＝7.4Hz,1H).¹³C NMR(101MHz,CDCl₃)δ177.01,155.82,153.12,140.21,134.11,128.39,128.15,127.01,126.08,123.99,123.23,114.92,112.43.HRMS(EI+):m/z Calculated C ₁₃H₈O₂ S228.0245 found 228.0244.

EXAMPLE 23 Synthesis of Compound I-112

Similar procedures were followed using the described synthesis of compound I-1 using the appropriate starting materials to produce compound I-112.

¹H NMR(400MHz,Chloroform-d)δ8.16(d,J＝7.6Hz,1H),7.75(d,J＝7.6Hz,1H),7.71(s,1H),7.63(d,J＝8.4Hz,1H),7.51(t,J＝7.8Hz,1H),7.35(t,J＝7.6Hz,1H),7.08(d,J＝4.4Hz,1H).¹³C NMR(101MHz,CDCl₃)δ173.78,155.80,152.25,140.75,140.72,134.32,128.34,127.90,126.89,124.15,123.29,114.68,112.36.HRMS(EI+):m/z Calculated C ₁₃H₇ClO₂ S261.9855, found 261.9854.

EXAMPLE 24 Synthesis of Compound I-115

Compound I-115 was prepared using a similar procedure for the synthesis of compound I-1 using the appropriate starting materials.

¹H NMR(400MHz,Chloroform-d)δ8.09(d,J＝3.8Hz,1H),7.66(d,J＝7.8Hz,1H),7.60(s,1H),7.56(d,J＝8.4Hz,1H),7.42(t,J＝8.4Hz,1H),7.26(t,J＝7.6Hz,1H),6.85(d,J＝4.8Hz,1H),2.53(s,3H).¹³C NMR(101MHz,CDCl₃)δ174.64,155.70,152.76,150.96,140.13,135.30,127.91,127.24,127.05,123.92,123.13,114.07,112.34,16.06.HRMS(EI+):m/z Calculated C ₁₄H₁₀O₂ S242.0402, found 242.0403.

EXAMPLE 25 Synthesis of Compound I-120

Compound I-120 was prepared using a similar procedure for the synthesis of compound I-1 using the appropriate starting materials.

¹H NMR(400MHz,DMSO-d₆)δ8.42(d,J＝3.8Hz,1H),8.20(d,J＝4.2Hz,1H),8.10(s,1H),7.88(d,J＝7.8Hz,1H),7.80(d,J＝8.2Hz,1H),7.66(t,J＝7.4Hz,1H),7.46(t,J＝7.2Hz,1H).¹³C NMR(101MHz,DMSO)δ172.45,156.33,150.51,148.32,140.54,134.05,130.51,127.23,126.43,122.63,117.24,115.36,112.27,111.56.HRMS(EI+):m/z Calculated C ₁₄H₇NO₃, 237.0426, found 237.0428.

EXAMPLE 26 Synthesis of Compound I-148

Compound I-148 was prepared using a similar procedure for the synthesis of compound I-1 using the appropriate starting materials.

¹H NMR(400MHz,DMSO-d₆)δ8.27(dd,J＝4.0,1.2Hz,1H),8.17(dd,J＝5.0,1.4Hz,1H),7.90(d,J＝8.0Hz,1H),7.71–7.65(m,4H),7.53–7.38(m,4H),7.31(dd,J＝4.8,4.0Hz,1H),4.55(s,2H).¹³C NMR(101MHz,DMSO)δ176.12,152.65,144.44,141.25,136.47,134.36,130.26,129.72,128.48,128.24,128.25,128.15,127.33,124.50,121.28,112.14.30.52.HRMS(EI+):m/z Calculated values are C ₂₀H₁₄O₂ S318.0715, found 318.0716.

EXAMPLE 27 preparation of (3-aminobenzofuran-2-yl) (thiophen-2-yl) methanone, compound I-150

To a solution of 0.12g (1 mmol) of o-hydroxybenzonitrile and 0.65g (2 mmol) of cesium carbonate in 5mL of DMF was added 0.21g (1 mmol) of 2-bromo-1- (thiophen-2-yl) ethan-1-one, and the mixture was stirred at room temperature and TLC followed the progress of the reaction. After the reaction is finished, adding the mixture into ice water, separating out solids, carrying out suction filtration, washing with the ice water, taking a filter cake, and separating by a column to obtain 0.103g of pale yellow solid with the yield of 79.5%.

¹H NMR(400MHz,Chloroform-d)δ8.32(d,J＝4.0Hz,1H),7.77-7.71(m,2H),7.64(d,J＝8.4Hz,1H),7.50(t,J＝8.4Hz,1H),7.34(t,J＝8.0Hz,1H),7.25(d,J＝9.0Hz,1H),6.02(s,2H).¹³C NMR(101MHz,CDCl₃)δ175.03,155.80,144.27,142.30,134.60,134.47,128.38,128.15,127.02,124.02,123.24,114.58,112.40.HRMS(EI+):m/z Calculated values are C ₁₃H₉NO₂ S243.0354, found 243.0347.

EXAMPLE 28 preparation of N- (2- (thiophene-2-carbonyl) benzofuran-3-yl) acetamide, compound I-151

To a solution of compound I-150.43 g (10 mmol) in 50mL acetic anhydride was added 0.06g (0.5 mmol) of 4-dimethylaminopyridine, stirred at room temperature and TLC followed the reaction progress. The reaction solution was suction-filtered, and the cake was recrystallized from ethanol to give 0.92g of pale yellow solid in 32% yield.

¹H NMR(400MHz,DMSO-d₆)δ10.44(s,1H),8.41(dd,J＝3.8,1.4Hz,1H),8.18(dd,J＝5.2,1.2Hz,1H),8.08(d,J＝8.0Hz,1H),7.77(d,J＝8.4Hz,1H),7.66–7.59(m,1H),7.41–7.34(m,2H),2.22(s,3H).¹³C NMR(101MHz,DMSO-d₆)δ178.04,176.43,158.75,145.37,144.32,133.40,131.67,129.48,128.24,125.42,123.91,123.44,113.91,112.98,23.08.HRMS(EI+):m/z Calculated values are C ₁₅H₁₁NO₃ S285.0460, found:285.0465.

EXAMPLE 29 Synthesis of Compound I-153

Similar procedures were followed using the described synthesis of compound I-151, using the appropriate starting materials, to produce compound I-153.

¹H NMR(400MHz,Chloroform-d)δ8.11(dd,J＝4.0,1.2Hz,1H),7.82–7.72(m,3H),7.33–7.24(m,2H),7.18(dd,J＝5.2,4.0Hz,1H).¹⁹F NMR(376MHz,CDCl₃)δ-72.6.HRMS(EI+):m/z Calculated values are C ₁₄H₈F₃NO₄S₂ 374.9847:374.9847, found:374.9848.

Example 30 preparation of (3- (methoxymethyl) benzofuran-2-yl) (thiophen-2-yl) methanone, compound I-149.

30.1 Preparation of (3- (bromomethyl) benzofuran-2-yl) (thiophen-2-yl) methanone

To a 30mL carbon tetrachloride solution containing 2.43g (10 mmol) of Compound I-11 was added dropwise a 20mL carbon tetrachloride solution containing 1.87g (10.5 mmol) of NBS and 0.24g (1 mmol) of benzoyl peroxide, and the mixture was stirred, heated under reflux and TLC followed the progress of the reaction. After the reaction is finished, suction filtration is carried out, filtrate is taken, and solvent is distilled off under reduced pressure to obtain pale yellow solid which is directly used for the next step without post treatment.

30.2 Preparation of (3- (methoxymethyl) benzofuran-2-yl) (thiophen-2-yl) methanone, compound I-149

To a solution of the intermediate obtained (3.21 g, 10 mmol) in 20mL of methanol was added 0.64g (20 mmol) of sodium methoxide, and the mixture was stirred and heated to reflux, followed by TLC. After completion of the reaction, the solvent was distilled off under reduced pressure, 100mL of water was added to the residue, the mixture was extracted with methylene chloride (100 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column to give 0.847g of a white solid, yield 31.1%.

¹H NMR(400MHz,DMSO-d₆)δ8.32(dd,J＝3.8,1.0Hz,1H),8.12(dd,J＝5.0,1.0Hz,1H),7.84(d,J＝7.8Hz,1H),7.75(d,J＝8.4Hz,1H),7.62–7.53(m,1H),7.45–7.31(m,2H),5.08(s,2H),3.36(s,3H).¹³C NMR(101MHz,DMSO)δ172.32,154.61,143.16,141.24,135.75,134.68,132.38,129.02,128.48,126.59,123.48,122.54,111.21,62.42,58.92.HRMS(EI+):m/z Calculated C ₁₅H₁₂O₃ S272.0507 found 272.0504.

EXAMPLE 31 preparation of thiophen-2-yl (3-vinylbenzofuran-2-yl) methanone, compound I-13

31.1 Preparation of 2- (2-iodophenoxy) -1- (thiophen-2-yl) ethan-1-one

To a solution of 2.54g (10 mmol) of 5-chloro-2-iodophenol and 2.76g (20 mmol) of potassium carbonate in 20mL of DMF was added dropwise a solution of 2.05g (10 mmol) of 2-bromo-1- (thiophen-2-yl) ethan-1-one in 5mL of DMF, stirred at room temperature and TLC followed the progress of the reaction. After completion of the reaction, 200mL of water was added to the reaction mixture, the mixture was extracted with ethyl acetate (100 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column to obtain intermediate I3.21g in a yield of 84.90%.

31.2 Preparation of 2- (2- (3-hydroxypropyl-1-yn-1-yl) phenoxy) -1- (thiophen-2-yl) ethan-1-one

To 40mL (1:1) of a mixed solution of DMF and triethylamine containing 1.89g (5 mmol) of the intermediate and 0.34g (6 mmol) of propiolic alcohol was added 0.18g (0.25 mmol) of bis triphenylphosphine palladium dichloride, followed by 0.10g (0.5 mmol) of cuprous iodide, and stirring was performed at room temperature under argon atmosphere, followed by TLC to follow the progress of the reaction. After the reaction, the reaction mixture was suction-filtered through celite, the solvent was removed under reduced pressure, and the mixture was concentrated and separated by column to obtain 1.03g of intermediate II in 67.23% yield.

31.3 Preparation of (3- (2- (2-oxo-2- (thiophen-2-yl) ethoxy) phenyl) propan-2-yl-1-ethyl) carbonate

To a solution of intermediate II 1.23g (4 mmol), triethylamine 1.62g (16 mmol) and DMAP0.12g (1 mmol) in 20mL of dichloromethane was added dropwise a solution of ethyl chloroformate 1.74g (16 mmol) in 5mL of dichloromethane under ice bath, stirred at room temperature and TLC followed the reaction progress. After completion of the reaction, 50mL of water was added to the reaction mixture, the mixture was extracted with methylene chloride (100 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column to obtain 1.28g of intermediate III in a yield of 84.72%.

31.4 Preparation of thiophen-2-yl (3-vinylbenzofuran-2-yl) methanone, compound I-13

A solution of intermediate III (0.38 g) (1 mmol) and potassium carbonate (0.27 g) (2 mmol) in 5mL DMF was stirred at room temperature for 5 minutes, followed by the addition of palladium on carbon (16.8 mg) (0.02 mmol) and heating to 60 ℃. TLC followed the reaction progress. After completion of the reaction, 50mL of water was added to the reaction mixture, the mixture was extracted with ethyl acetate (100 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column to give 0.22g of pale yellow solid, with a yield of 78.65%.

¹H NMR(400MHz,DMSO-d₆)δ8.43(dd,J＝3.8,1.0Hz,1H),8.17(dd,J＝5.0,1.0Hz,1H),7.90(d,J＝7.8Hz,1H),7.79(d,J＝8.4Hz,1H),7.65–7.56(m,1H),7.47–7.33(m,2H),6.10(d,J＝2.0Hz,1H),5.66(dd,J＝2.4Hz,18.8Hz,1H).¹³C NMR(101MHz,DMSO)δ176.26,152.55,147.35,143.24,138.23,136.78,133.28,131.68,128.68,128.45,127.81,127.06,123.87,120.65,111.21.

Example 32 preparation of (E) -benzofuran-2-yl (thiophen-2-yl) methanone O-ethyloxime, compound I-134.

1.042G (15 mmol) of hydroxylamine hydrochloride are added to a 80% ethanol solution containing 0.799g (20 mmol) of sodium hydroxide and stirred at room temperature for half an hour, followed by 2.280g (10 mmol) of benzofuran-2-yl (thiophen-2-yl) methanone, compound I-2, which is heated to reflux and TLC is taken up. After the completion of the reaction, the solvent was distilled off under reduced pressure, 100mL of water was added to the residue, the mixture was extracted with methylene chloride (100 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, concentrated and separated by a column to obtain 1.628g of a white solid with a yield of 67%.

¹H NMR(400MHz,DMSO-d₆)δ12.53(s,1H),7.85(d,J＝0.8Hz,1H),7.80(d,J＝7.2Hz,1H),7.72–7.68(m,1H),7.66(dd,J＝3.6,1.2Hz,1H),7.61(dd,J＝5.2,1.2Hz,1H),7.45(ddd,J＝8.4,7.4,1.2Hz,1H),7.38–7.31(m,1H),7.18(dd,J＝5.0,3.8Hz,1H).¹³C NMR(101MHz,DMSO)δ152.87,144.77,141.20,137.05,128.48,127.59,127.49,127.11,126.28,123.48,122.25,113.18,111.52.HRMS(EI+):m/z Calculated C ₁₃H₉NO₂ S243.0354, found 243.0352.

EXAMPLE 33 preparation of benzofuran-2-yl (thiophen-2-yl) methanone O- (3, 4-trifluoro-but-3-en-1-yl) oxime, compound I-138

2.430G (10 mmol) of I-134 are added to a solution of 2.268g (12 mmol) of 4-bromo-1, 2-trifluoro-1-butene in 100mL of acetonitrile containing 2.073g (15 mmol) of potassium carbonate, heated to reflux and TLC is used to track the progress of the reaction. After completion of the reaction, the solvent was distilled off under reduced pressure, 100mL of water was added to the residue, the mixture was extracted with methylene chloride (100 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, concentrated and separated by a column to obtain 2.114g of a yellow oily liquid in 78% yield.

¹H NMR(400MHz,Chloroform-d)δ7.56–7.52(m,3H),7.49(d,J＝8.4Hz,1H),7.28(t,J＝4.0Hz,1H),7.19(t,J＝8.2Hz 1H),7.07–7.03(m,1H),6.98(s,1H),4.48(t,J＝6.2Hz,2H),2.82–2.66(m,2H).¹⁹F NMR(376MHz,Chloroform-d)δ-103.32,-123.53,-175.31.HRMS(EI+):m/z Calculated C ₁₇H₁₂F₃NO₂ S,351.0541, found 351.0543.

EXAMPLE 34 preparation of (1-allyl-1H-indol-2-yl) (thiophen-2-yl) methanone, compound I-17

Compound I-3 227mg (1 mmol), iodobenzene 306mg (1.5 mmol), potassium hydroxide 84mg (1.5 mmol) and cuprous oxide 1.43mg (0.001 mmol) were added to 10mL of N, N-dimethylformamide, heated under argon and refluxed, and TLC followed the reaction progress. After the completion of the reaction, 100mL of water was added to the residue, the mixture was extracted with methylene chloride (100 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column to give 45mg of pale yellow solid in 15% yield.

¹H NMR(400MHz,DMSO-d₆)δ8.12(dd,J＝4.0,1.2Hz,1H),8.1(dd,J＝4.2,1.4Hz,1H),7.75-7.63(m,5H),7.54-7.43(m,4H),7.36–7.29(m,1H),7.11(t,J＝6.8Hz,1H).¹³C NMR(101MHz,DMSO)δ180.38,141.43,136.61,134.22,133.76,133.48,132.95,128.72,127.09,126.23,125.59,125.33,123.21,122.79,120.39,112.66,110.09.HRMS(EI+):m/z Calculated C ₁₉H₁₃ NOS 303.0718 found 303.0720.

EXAMPLE 35 preparation of benzo [ d ] thiazol-2-yl (thiophen-2-yl) methanone, compound I-5

35.1 Preparation of benzo [ d ] thiazole-2-carbonyl chloride

1.792G (10 mmol) of benzothiazole-2-carboxylic acid was added to 20mL of thionyl chloride, heated under reflux, the progress of the reaction was monitored by GC, and after the completion of the reaction, the solvent was distilled off under reduced pressure and taken directly to the next step.

35.2 Preparation of benzo [ d ] thiazol-2-yl (thiophen-2-yl) methanone, compound I-5

10ML of the anhydrous dichloromethane solution of the intermediate of the above reaction was added to 50mL of an anhydrous dichloromethane solution containing 1.600g (12 mmol) of anhydrous aluminum trichloride, stirred at room temperature for half an hour, followed by dropwise addition of 1.009g (12 mmol) of thiophene in 50mL of anhydrous dichloromethane, and TLC followed the progress of the reaction. After completion of the reaction, 100mL of water was added to the residue, the mixture was extracted with methylene chloride (100 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column to give 1.104g of pale yellow solid in 45% yield.

¹H NMR(400MHz,Chloroform-d)δ8.77(d,J＝4.4Hz,1H),8.25(d,J＝7.2Hz,1H),8.02(d,J＝7.6Hz,1H),7.85(d,J＝4.8Hz,1H),7.58(m,2H),7.30–7.26(m,1H).¹³C NMR(101MHz,CDCl₃)δ177.01,166.63,153.74,139.74,137.40,137.04,136.79,128.47,127.57,126.96,125.59,122.27.HRMS(EI+):m/z Calculated C ₁₂H₇NOS₂, 244.9969, found 244.9967.

EXAMPLE 36 Synthesis of Compound I-83

Compound I-83 was prepared using a similar procedure for the synthesis of compound I-5 using the appropriate starting materials.

¹H NMR(400MHz,Chloroform-d)δ8.84(d,J＝3.6Hz,1H),7.89(dd,J＝15.4,6.4Hz,2H),7.62(d,J＝7.6Hz,1H),7.48(t,J＝8.0Hz,1H),7.29(t,J＝4.4Hz,1H).¹³C NMR(101MHz,CDCl₃)δ176.51,167.12,150.83,139.47,138.44,137.82,137.30,130.54,128.69,128.10,127.12,120.80.HRMS(EI+):m/z Calculated C ₁₂H₆ClNOS₂, 278.9579, found 278.9576.

EXAMPLE 37 Synthesis of Compound I-113

Compound I-113 was prepared using a similar procedure for the synthesis of compound I-5 using the appropriate starting materials.

¹H NMR(400MHz,Chloroform-d)δ7.72(d,J＝8.0Hz,2H),7.63(d,J＝8.8Hz,1H),7.58–7.54(m,2H),7.43–7.37(m,1H).¹³C NMR(101MHz,CDCl₃)δ178.25,168.31,154.14,134.05,128.94,128.25,127.08,127.01,123.87,122.26,114.12,111.27.HRMS(EI+):m/z Calculated value C ₁₂H₆ClNOS₂ 278.9579, found value 278.9582.

EXAMPLE 38 preparation of benzo [ d ] oxazol-2-yl (thiophen-2-yl) methanone, I-4

38.1 Preparation of 2-bromo-1- (thiophen-2-yl) ethan-1-one and 2, 2-dibromo-1- (thiophen-2-yl) ethan-1-one

1.262G (10 mmol) of 2-acetylthiophene and 3.350g (15 mmol) of bromoketone are added to 100mL of acetonitrile, heated to reflux and TLC is followed by reaction progress. After the completion of the reaction, the solvent was distilled off under reduced pressure, 50mL of water was added to the residue, the mixture was extracted with methylene chloride (80 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give two tan liquids each of 0.693g, yield 34%, 1.127g, yield 40%.

¹H NMR(400MHz,Chloroform-d)δ8.02(dd,J＝4.0,0.8Hz,1H),7.80(dd,J＝4.8,0.8Hz,1H),7.22(t,J＝4.4Hz,1H),6.51(s,1H).

38.2 Preparation of benzo [ d ] oxazol-2-yl (thiophen-2-yl) methanone, compound I-4

0.218G (2 mmol) of o-aminophenol are added to 40mL of N, N-dimethylformamide solution containing 0.585g (8 mmol) of diethylamine, 10mL of N, N-dimethylformamide solution containing 0.676g (2.4 mmol) of 2, 2-dibromo-1- (thiophen-2-yl) ethan-1-one are added dropwise at room temperature, heated to 90℃and TLC tracks the progress of the reaction. After the completion of the reaction, the solvent was distilled off under reduced pressure, 50mL of water was added to the residue, the mixture was extracted with methylene chloride (100 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, concentrated and separated by column chromatography to give 0.220g of a yellow solid in 48% yield.

¹H NMR(400MHz,Chloroform-d)δ8.69(d,J＝3.6Hz,1H),7.89(d,J＝8.0Hz,1H),7.80(d,J＝4.6Hz,1H),7.65(d,J＝8.2Hz,1H),7.49(t,J＝7.4Hz,1H),7.42(t,J＝7.6Hz,1H),7.21(t,J＝4.4Hz,1H).¹³C NMR(101MHz,CDCl₃)δ171.17,155.85,149.59,139.71,139.58,136.56,135.95,127.69,127.36,124.74,121.29,110.90.HRMS(EI+):m/z Calculated C ₁₂H₈N₂ OS,229.0198, found 229.0197.

EXAMPLE 39 preparation of (6-methyl-1H-benzo [ d ] imidazol-2-yl) (thiophen-2-yl) methanone, I-78

0.660G (5 mmol) of 6-methyl-1H-benzo [ d ] imidazole and 2.0mL of triethylamine are added dropwise to 5mL of pyridine at 0℃and stirred at low temperature for half an hour, followed by 1.460g (10 mmol) of 2-thiophenoyl chloride slowly dropwise at room temperature and the reaction is followed by TLC. After the reaction, 5mL of a sodium hydroxide solution with a concentration of 6mmol/L is added, the solution is heated to 100 ℃ and stirred, the reaction solution is cooled to room temperature after one hour, then the pH value of the reaction solution is neutralized to 6-7 by using a hydrochloric acid solution with a concentration of 1mmol/L, the reaction solution is extracted by methylene dichloride (100 mL multiplied by 3), an organic phase is dried by anhydrous sodium sulfate and concentrated, and a light yellow solid of 0.508g is obtained after column separation, and the yield is 42%.

¹H NMR(400MHz,DMSO-d₆)δ10.72(s,0.5H),10.61(s,0.5H),8.93–8.91(m,1H),7.84–7.82(m,1H),7.74(s,1H),7.49(d,J＝8.3Hz,0.5H),7.38(s,0.5H),7.28–7.26(m,1H),7.20(d,J＝8.3Hz,1H),2.52(s,2H),2.51(s,1H);¹³C NMR(101MHz,DMSO)δ177.21,147.32,144.21,141.21,137.71,136.85,136.35,133.61,128.55,125.73,121.52,111.61,21.87.HRMS(EI+):m/z Calculated C ₁₃H₁₀N₂ OS,242.0514, found 242.0512.

EXAMPLE 40 preparation of 2- (thiophen-2-ylmethyl) benzo [ b ] thiophene, compound I-2

40.1 Preparation of 3- (2-iodophenyl) -1- (thiophen-2-yl) propan-1-one

To 10mL of anhydrous tetrahydrofuran containing 1.479g (5 mmol) of 2-iodobenzyl bromide was added dropwise a 10mL anhydrous tetrahydrofuran solution containing 1.189g (6 mmol) of ethyl 2-thiophenecarboxylacetate, followed by stirring at room temperature by dropwise a 10mL anhydrous tetrahydrofuran solution containing 0.180g (0.65 mmol) of sodium hydrogen, and TLC followed the progress of the reaction. After the reaction, the reaction was quenched by adding saturated ammonium chloride solution, the mixed solution was extracted with ethyl acetate (100 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, concentrated, and the concentrated material was added to 8mL (2 mol/L) of sodium hydroxide solution and 8mL of ethanol, heated to reflux, and TLC followed the progress of the reaction. After the completion of the reaction, the reaction solution was cooled to room temperature, then 10mL of a hydrochloric acid solution (10%) was added thereto, then the mixed solution was extracted with ethyl acetate (100 ml×3), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by a column to obtain a product.

40.2 Preparation of benzo [ b ] thiophen-2-yl (thiophen-2-yl) methanone, compound I-2

0.684G (2 mmol) of 3- (2-iodophenyl) -1- (thiophen-2-yl) propan-1-one, 0.662g (6 mmol) of potassium sulphide and 0.038g (0.2 mmol) of cuprous iodide are added to 5mL of N, N-dimethylformamide, heated to 130℃and TLC tracks the progress of the reaction. After the reaction was completed, the reaction solution was cooled to room temperature, suction filtration was performed, the filtrate was extracted with ethyl acetate (50 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to obtain 0.415g of pale yellow solid in 85% yield.

¹H NMR(400MHz,Chloroform-d)δ8.13(s,1H),7.98(d,J＝3.8Hz,1H),7.91(t,J＝7.2Hz,2H),7.74(d,J＝5.0Hz,1H),7.51–7.40(m,2H),7.22(dd,J＝4.8,4.0Hz,1H).¹³C NMR(101MHz,CDCl₃)δ180.11,142.66,142.48,142.28,138.97,133.89,133.57,130.28,128.09,127.34,125.96,125.10,122.82.HRMS(EI+):m/z Calculated value C ₁₃H₈OS₂ 244.0017, found value 244.0018.

EXAMPLE 41 Synthesis of Compound I-95

Similar procedures were followed using the described synthesis of compound I-2 using the appropriate starting materials to produce compound I-95.

¹H NMR(400MHz,Chloroform-d)δ9.17(d,J＝1.8Hz,1H),8.89(dd,J＝4.8,1.4Hz,1H),8.21-8.16(m,1H),8.04-7.84(m,3H),7.56-7.44(m,3H).¹³C NMR(101MHz,CDCl₃)δ183.32,157.22,154.45,150.15,149.21,136.45,133.72,129.02,127.21,124.07,123.64,123.29,116.44,113.41.HRMS(EI+):m/z Calculated C ₁₄H₉ NOS 239.0405, found 239.0407.

EXAMPLE 42 Synthesis of Compound I-51

Compound I-51 was prepared using the appropriate starting materials and using a procedure similar to that described for compound I-2.

¹H NMR(400MHz,Chloroform-d)δ8.15(s,1H),8.02(d,J＝4.2Hz,1H),7.95(t,J＝7.8Hz,2H),7.78(s,1H),7.43(d,J＝7.8Hz,1H),7.22(dd,J＝4.8,4.0Hz,1H).¹³C NMR(101MHz,CDCl₃)δ180.11,142.66,142.48,142.28,138.97,133.89,133.57,130.28,128.09,127.34,125.96,125.10,122.82.¹³C NMR(101MHz,CDCl₃)δ181.21,143.57,142.95,142.78,139.51,134.32,134.05,131.45,127.83,125.27,125.45,123.41,121.98.HRMS(EI+):m/z Calculated value C ₁₃H₇ClOS₂ 277.9627, found value 277.9628.

EXAMPLE 43 preparation of 2- (thiophen-2-ylmethyl) benzofuran, I-128

To a solution of 2.280g (10 mmol) of benzofuran-2-yl (thiophen-2-yl) methanone and 5.430g (50 mmol) of trimethylchlorosilane in 50mL of anhydrous acetonitrile under ice bath was added dropwise an ether solution containing 0.227g (6 mmol) of sodium borohydride, followed by 3.142g (50 mmol) of sodium cyanoborohydride, the reaction mixture was warmed to room temperature and reacted at room temperature, and TLC followed the progress of the reaction. After the completion of the reaction, 50mL of a 2mmol/L aqueous hydrochloric acid solution was added, the mixed solution was then extracted with ethyl acetate (100 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by a column to give 1.669g of a pale yellow solid in 78% yield.

¹H NMR(400MHz,Chloroform-d)δ7.48(d,J＝7.2Hz,1H),7.42(d,J＝8.0Hz,1H),7.25-7.14(m,3H),6.95(t,J＝3.6Hz,1H),6.46(s,1H),4.30(s,2H).¹³C NMR(101MHz,CDCl₃)δ156.62,154.91,139.22,128.64,126.91,126.02,124,38,123.58,122.56,111.08,103.32,29.21.HRMS(EI+):m/z Calculated C ₁₃H₁₀ OS 214.0452, found 214.0455.

EXAMPLE 44 Synthesis of Compound I-132

Compound I-132 was prepared using a procedure similar to that described for compound I-128 using the appropriate starting materials.

¹H NMR(400MHz,Chloroform-d)δ8.03(d,J＝8.0Hz,1H),7.80(d,J＝7.8Hz,1H),7.50(dd,J＝8.2,7.4Hz,1H),7.31(dd,J＝7.8,7.4Hz,1H),7.25(d,J＝5.0Hz,1H),7.06(d,J＝3.6Hz,1H),6.99(dd,J＝5.0,3.6Hz,1H),4.65(s,2H).¹³C NMR(101MHz,CDCl₃)δ170.28,153.11,138.73,135.62,127.13,126.91,126.01,125.34,124.87,122.76,121.61,34.65.HRMS(EI+):m/z Calculated value C ₁₂H₉NS₂ 231.0176, found value 231.0175.

EXAMPLE 45 preparation of 2- (thiophen-2-ylsulfonyl) benzofuran, compound I-142

45.1 Preparation of 2- (thiophen-2-ylsulfanyl) benzofuran (i.e., compound I-141)

0.985G (5 mmol) of 2-bromobenzofuran, 0.697g (6 mmol) of 2-thiophenethiol and 0.561g (10 mmol) of potassium hydroxide are added to 10mL of dimethyl sulfoxide, heated to 110℃and TLC followed by reaction progress. After the completion of the reaction, the reaction mixture was cooled to room temperature, extracted with ethyl acetate (50 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography to give 0.951g of a yellow liquid in 82% yield.

¹H NMR(400MHz,DMSO-d₆)δ8.25(dd,J＝4.8,1.2Hz,1H),8.01(dd,J＝4.0,1.2Hz,1H),7.97(s,1H),7.85(d,J＝8.0Hz,1H),7.72(d,J＝8.4Hz,1H),7.53(t,J＝7.8Hz,1H),7.41–7.32(m,1H),7.33–7.31(m,1H).¹³C NMR(101MHz,DMSO)δ152.57,145.11,138.42,136.99,132.44,129.23,128.56,125.22,125.12,122.55,112.11,111.11.HRMS(EI+):m/z Calculated value C ₁₂H₈O₁S₂ 232.0017, found value 232.0019.

45.2 Preparation of 2- (thiophen-2-ylsulfonyl) benzofuran, compound I-142

To 10mL of methylene chloride containing 0.232g (1 mmol) of I-144 at 0℃was added dropwise 10mL of methylene chloride containing 0.345g (2 mmol) of m-chloroperoxybenzoic acid, and the reaction was gradually warmed to room temperature and TLC followed the progress of the reaction. After the completion of the reaction, 10mL of a 10% sodium thiosulfate solution was added to the reaction mixture, the mixture was extracted with methylene chloride (50 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, concentrated and separated by column chromatography to give 0.214g of a white solid in 81% yield.

¹H NMR(400MHz,DMSO-d₆)δ8.23(dd,J＝4.8,1.2Hz,1H),7.98(dd,J＝4.0,1.2Hz,1H),7.93(s,1H),7.84(d,J＝8.0Hz,1H),7.74(d,J＝8.4Hz,1H),7.57(t,J＝7.8Hz,1H),7.46–7.39(m,1H),7.34–7.30(m,1H).¹³C NMR(101MHz,DMSO)δ155.56,151.01,138.97,137.56,135.74,129.03,128.69,125.62,124.71,123.75,113.51,112.32.HRMS(EI+):m/z Calculated value C ₁₂H₈O₃S₂ 263.9915, found value 263.9918.

EXAMPLE 46 preparation of 1-methyl-2- (thiophen-2-ylsulfonyl) -1H-indole, compound I-143

Compound I-143 was prepared using the appropriate starting materials and using a procedure similar to that described for compound I-142.

¹H NMR(400MHz,Chloroform-d)δ7.73(d,J＝4.0Hz,1H),7.69(d,J＝8.0Hz,1H),7.66(d,J＝8.0Hz,1H),7.37(t,J＝9.0Hz,2H),7.33(d,J＝8.0Hz),7.19(t,J＝8.0Hz,1H),7.09(d,J＝7.0Hz,1H),3.95(s,3H);¹³C NMR(101MHz,CDCl₃)δ143.21,139.62,135.53,134.01,133.44,127.92,125.93,125.24,123.01,121.33,110.53,110.32,31.01.HRMS(EI+):m/z Calculated value C ₁₃H₁₁NO₂S₂ 277.0231, found value 277.0233.

EXAMPLE 47 preparation of N- (5-methylthiophene-2-yl) benzofuran-2-carboxamide, compound I-144

47.1 Preparation of benzofuran-2-carbonyl chloride

1.621G (10 mmol) of benzofuran-2-carboxylic acid are added to 20mL of thionyl chloride, heated under reflux, the progress of the reaction is monitored by GC, and after the reaction is finished, the solvent is distilled off under reduced pressure and is directly put into the next step.

47.2 Preparation of N- (5-methylthiophene-2-yl) benzofuran-2-carboxamide, compound I-144

To a solution of 0.565g (5 mmol) of 5-methylthiophene-2-amine and 2.024g (20 mmol) of triethylamine in 80mL of acetonitrile was added dropwise 10mL of acetonitrile solution of the intermediate of the one-step reaction at 0℃and the reaction was completed at room temperature, followed by TLC. After the completion of the reaction, the solvent was distilled off under reduced pressure, 50mL of water was added to the residue, the mixture was extracted with methylene chloride (80 mL. Times.2), and the organic phase was dried over anhydrous sodium sulfate, concentrated and separated by column chromatography to give 0.925g of a white solid in 72% yield.

¹H NMR(400MHz,DMSO-d₆)δ11.94(s,1H),7.84(d,J＝8.0Hz,1H),7.77(m,1H),7.73(d,J＝8.4Hz,1H),7.55–7.49(m,1H),7.39(t,J＝7.6Hz,1H),7.04(d,J＝3.8,1H),6.94(dd,J＝3.8Hz,1H),2.38(s,3H).¹³C NMR(101MHz,DMSO)δ162.72,157.22,150.02,140.21,126.92,124.75,124.32,121.33,120.91,117.02,111.51,111.22,13.28.HRMS(EI+):m/z Calculated C ₁₄H₁₁NO₂ S,257.0510, found 257.0511.

EXAMPLE 48 Synthesis of Compound I-146

Compound I-146 was prepared using a procedure similar to that described for compound I-144 using the appropriate starting materials.

¹H NMR(400MHz,Chloroform-d)δ12.81(s,1H),9.78(s,1H),9.31(s,1H),8.01(d,J＝1.8Hz,1H),7.41(s,1H),7.20(d,J＝3.4Hz,1H),6.78(dd,J＝3.3,1.6Hz,1H).¹³C NMR(101MHz,CDCl₃)δ163.61,154.72,144.27,143.87,133.77,128.31,126.41,125.54,121.45,117.43.HRMS(EI+):m/z Calculated C ₁₀H₇N₃OS₂, 249.0031, found 249.0033.

EXAMPLE 49 preparation of 4-methyl-N- (thiophen-2-yl) benzofuran-2-sulfonamide, compound I-154

0.26G (2 mmol) of 2-nitrothiophene, (4-methylbenzofuran-2-yl) boronic acid 0.42g (2.4 mmol), 0.33g (1.2 mmol) of tetrabutylammonium chloride, 0.34g (2.4 mmol) of potassium carbonate and 0.89g (4 mmol) of potassium metabisulfite are introduced into a pressurized reaction flask containing 10mL of acetonitrile and reacted at 130℃with TLC tracking the progress of the reaction. After the completion of the reaction, the mixture was filtered through celite, concentrated and separated by column chromatography to give 0.32g of a white solid with a yield of 55.21%.

¹H NMR(400MHz,DMSO-d₆)δ10.92(s,1H)8.25(dd,J＝5.0,1.0Hz,1H),7.97(dd,J＝3.8,1.0Hz,1H),7.94(s,1H),7.82(d,J＝8.0Hz,1H),7.78(d,J＝8.2Hz,1H),7.56(t,J＝7.6Hz,1H),7.45–7.37(m,1H),7.33–7.29(m,1H).¹³CNMR(101MHz,DMSO)δ155.62,152.11,139.02,137.45,136.04,128.93,128.79,126.22,124.51,123.65,112.11,111.42,12.31.HRMS(EI+):m/z Calculated value C ₁₃H₁₁NO₃S₂ 293.0180, found value 293.0184.

EXAMPLE 50 preparation of N-phenylbenzofuran-2-carbosulfanamide, compound I-108

To 10mL of anhydrous tetrahydrofuran containing 0.24g (2 mmol) of benzofuran was added a solution of 1.6M n-butyllithium in 0.13g (2 mmol) of n-hexane with stirring at-78 ℃. After one hour of reaction at this temperature, 5mL of an anhydrous tetrahydrofuran solution containing 0.27g (2 mmol) of phenyl thioisocyanate was added, the reaction was gradually warmed to room temperature, and TLC followed the progress of the reaction. After the reaction, 50mL of n-pentane was added, the solid was precipitated, the reaction solution was suction-filtered, concentrated, and separated by column chromatography to obtain 0.45g of solid with a yield of 89.21%.

¹H NMR(400MHz,DMSO-d₆)δ9.75(s,1H),8.21(d,J＝4.0Hz,1H),7.84(d,J＝8.2Hz),7.74(s,1H),7.61(d,J＝8.0Hz,1H),7.44(d,J＝8.4Hz,1H),,7.28(d,J＝8.4Hz,1H),7.01(dd,J＝8.8,4.0Hz,1H).¹³C NMR(101MHz,DMSO)δ182.42,154.84,153.52,139.04,129.44,128.72,127.98,126.15,124.07,123.45,114.12,111.23,107.21.HRMS(EI+):m/z Calculated C ₁₃H₉NO₂ S243.0354, found 243.0358.

EXAMPLE 51 in vivo nematicidal Activity test of Compounds of the invention

Root-knot nematodes belong to the genera nematoda, aphelenchida (tyrenchida), aphelenchida, heterodermaceae (Heteroderidea), root-knot nematode subfamily (Meloidogyninae), root-knot nematodes, a serious hazard plant parasitic nematode.

The method is characterized in that the southern root-knot nematode (Meloidogyne incognita) is used as a test object, cucumber seedlings are used as test hosts, and a test tube planting method is used for testing.

The operation process is that acetone and deionized water are used for preparing the sample to be tested into liquid according to the required concentration, and enough root-knot nematode second-instar larvae are prepared. After cucumber seedlings of one week of age are planted in the test tubes, a proper amount of prepared liquid medicine is added into each test tube, and about 2000 larvae are inoculated into each test tube. And (5) placing the test tube at 20-25 ℃ for culturing under the illumination of 10 hours, and counting the root knot number on each plant root system after 45 days of investigation results. Each sample was tested 3 times in duplicate, with 4 replicates per sample tested.

Distilled water is used as a blank control, distilled water and root knot nematode are used as negative control, and tioxazafen and abamectin solution are used as positive control.

TABLE 1 in vivo nematode inhibition Activity of Compounds of formula (I)

EXAMPLE 52 in vitro nematicidal Activity test of Compounds of the invention

The two-instar larvae of the meloidogyne incognita (Meloidogyne incognita) and the pine wood nematodes (Bursaphelenchus xylophilus) are used as test objects, and the test is carried out by adopting a pore plate method.

The operation process is that the sample to be tested is prepared into liquid according to the required concentration, and enough root-knot nematode second-instar larvae or pine wood nematodes are prepared. And (3) taking a 96-well plate, taking 50 mu L of test reagent liquid, placing the test reagent liquid in the well, adding an equal volume of nematode suspension, ensuring that the number of the second-instar nematodes in each well is 80-100, and covering the cover plate to prevent water evaporation. The 96-well plate was placed in a 25 ℃ incubator protected from light. Each treatment was repeated 4 times. Distilled water is used as a blank control, distilled water and root knot nematode are used as negative control, and avermectin solution is used as positive control. The number of surviving and dead nematode second-instar larvae was checked 72 hours after treatment, and mortality and corrected mortality were calculated.

TABLE 2 in vitro nematicidal Activity of Compounds of formula (I)

All documents mentioned in this disclosure are incorporated by reference in this disclosure as if each were individually incorporated by reference. Further, it will be appreciated that various changes and modifications may be made by those skilled in the art after reading the above teachings, and such equivalents are intended to fall within the scope of the application as defined in the appended claims.

Claims

1. Use of the following compounds or their pesticide-acceptable salts in the preparation of nematicides:

The numbers of the compounds are: I-1, I-2, I-3, I-5, I-20, I-21, I-24, I-25, I-28, I-29, I-32, I-33, I-44, I-96, I-97, I-103, I-111, I-112, I-114, I-115, I-128

2. The use according to claim 1, wherein the compounds are numbered: I-1, I-2, I-3, I-5, I-20, I-21, I-24, I-25, I-28, I-29, I-32, I-33, I-44;

3. A nematicide or a nematicidal pesticide composition, comprising the compound according to claim 1 or 2 or a pesticidally acceptable salt thereof and optionally a pesticidally acceptable excipient.

4. The following compounds or their pesticide-acceptable salts, characterized in that the compound numbers are: I-20, I-24, I-28, I-32, I-44;

5. A method for killing nematodes, characterized in that an effective amount of the nematocide or nematode pesticide composition according to claim 3 or the compound according to claim 4 or a pesticide-acceptable salt thereof is administered to a plant in which nematodes need to be killed.

6. The method according to claim 5, wherein the nematode is selected from the group consisting of: root-knot nematodes; cyst nematodes; heterodermal nematodes; grain nematodes; stem and leaf bud nematodes; thorn nematodes; pine nematodes; ring nematodes; bulb nematodes; cone nematodes; spiral nematodes; sheath nematodes; crown nematodes; pseudo-root-knot nematodes; needle nematodes; nail nematodes; root-rot nematodes; piercing nematodes; reniform nematodes; stump nematodes; dwarf nematodes; citrus nematodes; and Xiphinema nematodes.

7. The method of claim 6, wherein the root-knot nematode is Meloidogynearenaria, Meloidogyne chitwoodi, Meloidogyneexigua, Meloidogyne hapla, Meloidogyne incognita, or Meloidogyne javanica; the cyst nematode is Globodera arostochiensis, Globodera pallida, or Globodera abacum; and the heterodermal nematode is Heterodera avenae, Heterodera glycines, Heterodera schachtii, or Heterodera truncatula. trifolii); the grain nematode is Anguina funesta or Anguina tritici; the stem and leaf bud nematode is Aphelenchoides besseyi, Aphelenchoides fragariae or Aphelenchoides ritzemabosi; the thorn nematode is Belonolaimus longicaudatus; the pine nematode is Bursaphelenchus xylophilus; the ring nematode is of the genus Criconema, Criconemella, Criconemoides or Mesocriconema; the bulb nematode is Ditylenchus destructor, Ditylenchus dipsaci or Ditylenchus myceliophagus; the cone nematode is of the genus Dolichodorus; the spiral nematode is Helicotylenchus dihystera or Helicotylenchus multicintus; the sheath nematode is of the genus Hemicycliophora or Hemicriconemoides; the crown nematode is Hoploaimus columbus; the pseudo-root knot nematode is Nacobbus aberrans; the needle nematode is Longidoruse longatus; the nail nematode is of the genus Paratylenchus; the root rot nematode is Pratylenchus brachyurus, Pratylenchus coffee, Pratylenchus corn zeae) or Pratylenchus penetrans; the boring nematode is Radopholus similis; the reniform nematode is Rotylenchus robustus; the stump nematode is Trichodorus primitivus; the dwarf nematode is Tylenchorhynchus claytoni or Tylenchorhynchus dubius; the citrus nematode is Tylenchulus semipenetrans; the Xiphinema americanum, Xiphinema index or Xiphinema diversicaudatum.

8. The method of claim 7, wherein the nematode is the southern root-knot nematode (Meloidogyne incognita) or the pine wood nematode (Bursaphelenchus xylophilus).

9. The method according to claim 5, wherein the plant is selected from the group consisting of food crops, vegetables, trees, tobacco, citrus, and banana trees.

10. The method according to claim 9, wherein the food crops are peanuts, rice, soybeans, sorghum, wheat or potatoes; the vegetables are cucumbers, tomatoes, spinach, cabbage or sugar beets; and the trees are poplars, pine trees, cypress trees or coconut trees.