Search

US-12617771-B2 - Diphenylpyrazole compound, and preparation method therefor and application thereof

US12617771B2US 12617771 B2US12617771 B2US 12617771B2US-12617771-B2

Abstract

Provided is a diphenylpyrazole-based compound of following formula (I), or its pesticidally acceptable salts, which is a novel inhibitor targeting pest GSTs, has broad inhibitory activities against GSTs in various pests, and can effectively delay the metabolism of insecticides by GSTs in pests, thereby reducing the metabolic resistance of pests to insecticides, and is suitable for use as a synergist for insecticides.

Inventors

  • Jiyuan Liu
  • Yalin Zhang

Assignees

  • NORTHWEST A&F UNIVERSITY

Dates

Publication Date
20260505
Application Date
20210712
Priority Date
20210105

Claims (20)

  1. 1 . A method of inhibiting glutathione S-transferases (GSTs) in pests, comprising applying a diphenylpyrazole-based compound of following formula (I), or its pesticidally acceptable salts to the pests or their habitat, wherein R 1 is: (1) an amido group —NH—CH(O) which is unsubstituted or substituted by one or more of the following substituents; (a) —C 1-6 alkyl-R 3 , —C 3-8 cycloalkyl-R 3 , —C 2-6 alkenyl-R 3 , —C 2-6 alkynyl-R 3 , —NH—R 3 , —N(R 3 ) 2 , —C(O)—R 3 , —NH—C 1-6 alkyl-R 3 , —C 1-6 alkyl-NH—R 3 , —C 1-6 alkyl-N(R 3 ) 2 , —C 1-6 alkyl-OR 3 , —C 3-8 cycloalkyl-OR 3 , —OC 1-6 alkyl-R 3 , —C 1-6 alkyl-OC 1-6 alkyl-R 3 , —C(O)—NH—R 3 , —C(O)—N(R 3 ) 2 , —NH—C(O)—R 3 , —C 1-6 alkyl-NH—C(O)—R 3 , —C 1-6 alkyl-NH—C(O)—OR 3 , —NH—C(O)—C 1-6 alkyl-R 3 , —NH—C(O)—C 1-6 alkyl-OR 3 , —C(O)—NH—C 1-6 alkyl-R 3 or —C 1-6 alkyl-SR 3 ; R 3 is each independently selected from: H, O, S, ═NH, amino, halogen, cyano, —C 1-6 alkyl, —C 3-8 cycloalkyl, —S—C 1-6 alkyl, —S—OH, —SO 2 —C 1-6 alkyl, -6-14 membered aryl, -5-14 membered heterocyclic group, -5-14 membered heteroaryl and -adamantyl; R 3 is unsubstituted or substituted by one or more of the following substituents: O, —OH, halogen, cyano, nitro, —CH(O), amino, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —OC 1-6 alkyl, sulfonic acid group, —C 1-6 alkyl-halogen, —C 1-6 alkyl-HS, —C 1-6 alkyl-NH 3 + , —C 1-6 alkyl-OH, —C 1-6 alkyl-NH—C 1-6 alkyl, or —C 1-6 alkyl-N(C 1-6 alkyl) 2 ; (b) -6-14 membered aryl, -5-14 membered heterocyclic group or -5-14 membered heteroaryl; the 6-14 membered aryl, the 5-14 membered heterocyclic group or the 5-14 membered heteroaryl is unsubstituted or substituted by one or more of the following substituents: O, —OH, halogen, cyano, nitro, —CH(O), amino, —C 1-6 alkyl, —OC 1-6 alkyl, —C 1-6 alkyl-NH—C 1-6 alkyl, —C 1-6 alkyl-N(C 1-6 alkyl) 2 , —C(O)—OC 1-6 alkyl, —NH—C(O)—C 1-6 alkyl, —SO 2 —C 1-6 alkyl, —SO 2 —NH 2 , —SO 2 —NH—C 1-6 alkyl, —SO 2 —N(C 1-6 alkyl) 2 , -6-14 membered aryl, -5-14 membered heterocyclic group, or -5-14 membered heteroaryl; (2) N atom and C atom of the amido group —NH—CH(O) are connected to form a ring structure via —C 3-6 alkylene-, —NH—C 2-6 alkylene-, —NH—C(O)—C 1-6 alkylene-, —C 1-6 alkylene-NH—C(O)—, —NH—C 1-6 alkylene-C(O)— or —C 1-6 alkylene-C(O)—; the ring structure is optionally substituted by the following substituents: —C 1-6 alkyl, —C 3-8 cycloalkyl, —C 3-8 cycloalkyl-C 1-6 alkyl, —OC 1-6 alkyl, -6-14 membered aryl, -5-14 membered heterocyclic group, -5-14 membered heteroaryl, —C 1-6 alkyl-6-14 membered aryl, —C 1-6 alkyl-5-14 membered heterocyclic group, —C 1-6 alkyl-5-14 membered heteroaryl or trifluoroethyl; the 6-14 membered aryl, the 5-14 membered heterocyclic group and the 5-14 membered heteroaryl are optionally substituted by —OC 1-6 alkyl; or, the ring structure is further combined with 5-8 membered aryl, 5-8 membered heterocyclic group or 5-8 membered heteroaryl to fuse into a fused ring; the heterocyclic group contains 1-4 heteroatoms selected from N, S and O; the heteroaryl contains 1-4 heteroatoms selected from N, S and O; R 2 is selected from: —H, -halogen, -amino, —NO 2 , —CF 3 , —C 1-6 alkyl, —C 1-6 alkyl-OH, —O—R 4 , —C(O)—R 4 , —C(O)—NH 2 , —NH—C(O)—R 4 , —C(O)—O—R 4 or —C(O)—O—N(R 4 ) 2 ; R 4 is selected from: H or C 1-6 alkyl.
  2. 2 . The method according to claim 1 , wherein R 1 is: (1) an amido group —NH—CH(O) which is substituted by one or more of the following substituents, (a) —C 1-3 alkyl-R 3 , —C 3-6 cycloalkyl-R 3 , —C 2-5 alkenyl-R 3 , —C 1-3 alkyl-NH—R 3 , —C 1-3 alkyl-O—R 3 or —O—C 1-3 alkyl-R 3 ; R 3 are each independently selected from: H, O, S, ═NH, amino, halogen, cyano, —C 1-3 alkyl, —C 3-6 cycloalkyl, -6-14 membered aryl, -5-14 membered heterocyclic group or -5-14 membered heteroaryl; R 3 is unsubstituted or substituted by one or more of the following substituents: O, —OH, halogen, cyano, nitro, —CH(O), —S—OH, amino, —C 1-3 alkyl, —C 2-5 alkenyl, —C 2-5 alkynyl, —OC 1-3 alkyl, sulfonic acid group, —C 1-3 alkyl-halogen or —C 1-3 alkyl-OH; (b) -6-14 membered aryl, -5-14 membered heterocyclic group or -5-14 membered heteroaryl; the 6-14 membered aryl, the 5-14 membered heterocyclic group or the 5-14 membered heteroaryl is unsubstituted or substituted by one or more of the following substituents: 0, —OH, halogen, cyano, nitro, —CH(O), amino, —C 1-3 alkyl, —OC 1-3 alkyl, —C 1-3 alkyl-NH—C 1-3 alkyl, —C 1-3 alkyl-N(C 1-3 alkyl) 2 , —C(O)—OC 1-3 alkyl, —NH—C(O)—C 1-3 alkyl, —SO 2 —C 1-3 alkyl, —SO 2 —NH 2 , —SO 2 —NH—C 1-3 alkyl or —SO 2 —N(C 1-3 alkyl) 2 ; (2) N atom and C atom of the amido group —NH—CH(O) are connected to form a ring structure via —C 3-6 alkylene-, —NH—C 2-4 alkylene-, —NH—C(O)—C 1-3 alkylene-, —C 1-3 alkylene-NH—C(O)—, —NH—C 1-3 alkylene-C(O)— or —C 1-3 alkylene-C(O)—; the ring structure is optionally substituted by the following substituents: —C 1-3 alkyl, —C 3-6 cycloalkyl, —C 3-6 cycloalkyl-C 1-3 alkyl, -6-14 membered aryl, -5-14 membered heterocyclic group, -5-14 membered heteroaryl, —C 1-3 alkyl-6-14 membered aryl, —C 1-3 alkyl-5-14 membered heterocyclic group, —C 1-3 alkyl-5-14 membered heteroaryl or trifluoroethyl; the 6-14 membered aryl, the 5-14 membered heterocyclic group and the 5-14 membered heteroaryl are optionally substituted by —OC 1-3 alkyl; the heterocyclic group contains 1-3 heteroatoms selected from N, S and O; the heteroaryl contains 1-3 heteroatoms selected from N, S and O; R 2 is: —H or halogen.
  3. 3 . The method according to claim 1 , wherein R 1 is: (1) —NH—C(O)—C 1-3 alkyl-R 3 ; R 3 is selected from: -6-10 membered aryl, -5-10 membered heterocyclic group, -5-10 membered heteroaryl; R 3 is unsubstituted or substituted by one or more of the following substituents: O, —OH, halogen, cyano, nitro, —CH(O), —S—OH, amino, —C 1-3 alkyl, —OC 1-3 alkyl, sulfonic acid group, —C 1-3 alkyl-halogen, —C 1-3 alkyl-HS, —C 1-3 alkyl-NH 3 + or —C 1-3 alkyl-OH; (2) —NH—C(O)-6-10 membered aryl, —NH—C(O)-5-10 membered heterocyclic group or —NH—C(O)-5-10 membered heteroaryl; the 6-10-membered aryl, the 5-10-membered heterocyclic group or the 5-10-membered heteroaryl is unsubstituted or substituted by one or more of the following substituents: O, —OH, halogen, cyano, nitro, —CH(O), amino, —C 1-3 alkyl or —OC 1-3 alkyl; the heterocyclic group contains 1-3 heteroatoms selected from N, S and O; the heteroaryl contains 1-3 heteroatoms selected from N, S and O; R 2 is —H.
  4. 4 . The method according to claim 1 , wherein R 1 is selected from:
  5. 5 . The method according to claim 1 , wherein the diphenylpyrazole-based compound of formula (I) or its pesticidally acceptable salts is following compound or its pesticidally acceptable salts:
  6. 6 . The method according to claim 1 , wherein the diphenylpyrazole-based compound of formula (I) or its pesticidally acceptable salts is following compound or its pesticidally acceptable salts:
  7. 7 . The method according to claim 1 , wherein the diphenylpyrazole-based compound of formula (I), or its pesticidally acceptable salts is provided in combination with pesticidally acceptable excipients.
  8. 8 . The method according to claim 7 , wherein the diphenylpyrazole-based compound of formula (I), or its pesticidally acceptable salts is provided in combination with one or more other insecticides.
  9. 9 . The method according to claim 1 , wherein the GSTs include PxGSTδ1, PxGSTε3, PxGSTσ1, PxGSTσ2, PxGSTω4, PxGSTθ1, PxGSTζ1 and PxGSTμ1.
  10. 10 . The method according to claim 1 , wherein the GSTs include PxGSTδ1, PxGSTσ1, PxGSTσ2 and PxGSTε3.
  11. 11 . The method according to claim 1 , wherein the GSTs include PxGSTδ1 and PxGSTε3.
  12. 12 . A method of preparing a pesticidal composition, comprising mixing of the diphenylpyrazole-based compound of formula (I), or its pesticidally acceptable salts of claim 1 , with a pesticidally acceptable excipient.
  13. 13 . A method of controlling pests, comprising applying a synergistic pesticidal composition to the pests or their habitat, wherein, the composition comprises the diphenylpyrazole-based compound of formula (I), or its pesticidally acceptable salts of claim 1 , and other insecticides.
  14. 14 . The method according to claim 13 , wherein the composition delays or reduces the resistance of pests to insecticides.
  15. 15 . The method according to claim 13 , wherein the other insecticides include ryanodine receptor modulator insecticides and voltage-dependent sodium ion channel blocker insecticides.
  16. 16 . The method according to claim 13 , wherein the other insecticides include diamide insecticides and oxadiazine insecticides.
  17. 17 . The method according to claim 13 , wherein the other insecticides include chlorantraniliprole and indoxacarb.
  18. 18 . The method according to claim 13 , wherein the pests include field crop pests and economic crop pests.
  19. 19 . The method according to claim 13 , wherein the pests include Plutella xylostella, Mythimna separata, Pyrausta nubilalis, Chilo suppressalis, Nilaparvata lugens, Spodoptera frugiperda, Helicoverpa armigera, Carposina sasakii and Spodoptera litura.
  20. 20 . The method according to claim 12 , wherein the diphenylpyrazole-based compound of formula (I), or its pesticidally acceptable salts inhibits GSTs.

Description

RELATED APPLICATIONS The present application is a U.S. National Phase of International Application Number PCT/CN2021/105643 filed Jul. 12, 2021, and claims priority to Chinese Application Number 202110005578.6, filed Jan. 5, 2021, and Chinese Application Number 202110760647.4 filed Jul. 6, 2021. TECHNICAL FIELD The present invention relates to the technical field of insecticides, in particular to diphenylpyrazole-based compounds, the preparation method therefor and use thereof. BACKGROUND ART Insecticides have long been the primary means of agricultural pest control. Among many insecticides, the ryanodine receptor modulator represented by chlorantraniliprole and the voltage-dependent sodium ion channel blocker represented by indoxacarb have novel structure, unique mechanism of action, quick effect, wide insecticidal spectrum, and environmental friendliness. Thus they have received widespread attention and become a popular variety of insecticides. Chlorantraniliprole belongs to the diamide-based insecticides, and indoxacarb belongs to the oxadiazine-based insecticides. Both types of insecticides can control most pests with chewing mouthparts, particularly, they have good control effects on Pyralidae (Cnaphalocrocis medinalis, Pyrausta nubilalis, Maruca vitrata Fabricius, etc.), Carposinidae (Carposina sasakii, etc.), Noctuidae (Spodoptera frugiperda, Helicoverpa armigera, Spodoptera litura, etc.), Tortricidae (Cydia pomonella, Grapholita molesta, etc.), Gelechiidae (Pectinophora gossypiella, etc.), Plutellidae (Plutella xylostella etc.), Pieridae (Pieris rapae, etc.), Gracilariidae (Lithocolletis ringoniella Mats., etc.), etc. of Lepidoptera, and they also have high activity against Coleoptera (Leptinotarsa decemlineata, etc.), Diptera (Liriomyza sativae Blanchard, etc.), Isoptera (Termite) pests. The market for diamide-based and oxadiazine-based insecticides has grown rapidly in recent years, and still has a large potential for future growth. The most widely used of these two classes of insecticides are chlorantraniliprole and indoxacarb. In 2019, chlorantraniliprole took the leading position in the global insecticide market, with global sales of US$1.581 billion; indoxacarb's also reached US$206 million. However, with the widespread use of these two insecticides, a variety of pests have developed varying degrees of resistance to them, which has become the main limiting factor for both insecticides. Resistance monitoring shows that the population of Plutella xylostella in the field has developed a high level of resistance to chlorantraniliprole, and the population resistance in some areas has even reached more than 1000 times; the resistance to indoxacarb is generally more than 10 times, and resistance of some population is more than 100 times. The intensification of insecticide resistance not only seriously affects the life cycle of pesticides, but also leads to an increase in the frequency and dosage of pesticides use, resulting in huge economic losses. Effective control of pest resistance has become an urgent problem in crop protection worldwide. The resistance mechanisms of pests to insecticides can be basically classified into three categories: metabolic resistance, penetration resistance and target resistance, of which metabolic resistance mediated by detoxification enzymes is more common. Many studies have shown that, glutathione S-transferases (GSTs), as an important detoxification enzyme system in insects, can participate in insects' resistance against commonly used insecticides, such as organochlorines, organophosphates, pyrethroids, neonicotinoids, diamides and abamectin through gene mutation, increased activity, and up-regulated expression. For example, silencing LmGSTs5 and LmGSTu1 in Locusta migratoria significantly increased the sensitivity of its nymphs to malathion and chlorpyrifos. There is also evidence that insect GSTs can directly metabolize a variety of insecticides. For example, the recombinant protein from Helicoverpa armigera HaGST-8 has good metabolic activity to chlorpyrifos, dichlorvos and cypermethrin. GSTs play an important role in the occurrence and development of pest resistance, and reducing their activity will significantly reduce the resistance of pests. Compounds such as S-Hexyl glutathione (GTX) and diethyl maleate (DEM) have been reported to increase control effects by inhibiting GSTs activity and delaying the metabolism of insecticides by pests. As inhibitors of GSTs, these compounds usually have no insecticidal activity by themselves, but when mixed with insecticides, they can significantly improve the toxicity or efficacy of insecticides, and are important pesticide synergists. The research and development of GSTs-targeted inhibitors can not only improve the control of insecticides, but also delay or reduce insecticide resistance and prolong the life cycle of insecticides, which is of great significance to the management of insecticide resistance. SUMMARY OF THE INVE