Search

EP-4741380-A1 - ISOXAZOLINE COMPOUND AND USE

EP4741380A1EP 4741380 A1EP4741380 A1EP 4741380A1EP-4741380-A1

Abstract

Provided are an isoxazoline compound and use thereof. The isoxazoline compound has a structure represented by Formula 1. The compound can be used for preventing and treating parasite infections and killing agricultural pests, has a good prevention and treatment effect, and exhibits good pharmacokinetic properties in mice.

Inventors

  • LI, YI
  • CHEN, CHUN
  • LIN, Hongzhi

Assignees

  • NANJING PETMEDICINE TECHNOLOGY CO., LTD.

Dates

Publication Date
20260513
Application Date
20250402

Claims (20)

  1. An isoxazoline compound having a structure represented by Formula I: wherein X is selected from -CH= or -N=; Y is selected from -CH= or -N=; Z is selected from wherein the wavy line represents a linkage site of the group; R 1 is selected from hydrogen, C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, halogenated C 1 to C 6 alkyl, deuterated C 1 to C 6 alkyl, halogenated C 2 to C 6 alkenyl, halogenated C 2 to C 6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b , -C(O)R a , -C(O)OR a , -OR a , -R a OR b , -OC(O)R a , -OC(O)OR a , -OC(O)NR a R b , -NR a R b , -SR a , -S(O)R a , -S(O) 2 R a , or a 3- to 10-membered saturated or unsaturated ring containing 0 to 3 heteroatoms, wherein the 3- to 10-membered saturated or unsaturated ring containing 0 to 3 heteroatoms is optionally substituted with 1 to 3 R a ; R 2 is selected from hydrogen, halogen, C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, halogenated C 1 to C 6 alkyl, deuterated C 1 to C 6 alkyl, halogenated C 2 to C 6 alkenyl, or halogenated C 2 to C 6 alkynyl; R 3 is selected from hydrogen, halogen, C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, halogenated C 1 to C 6 alkyl, deuterated C 1 to C 6 alkyl, halogenated C 2 to C 6 alkenyl, or halogenated C 2 to C 6 alkynyl; R 4 is selected from hydrogen, C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, halogenated C 1 to C 6 alkyl, deuterated C 1 to C 6 alkyl, halogenated C 2 to C 6 alkenyl, halogenated C 2 to C 6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b , -C(O)R a , -C(O)OR a , -OR a , -R a OR b , -OC(O)R a , -OC(O)OR a , -OC(O)NR a R b , -NR a R b , -SR a , -S(O)R a , -S(O) 2 R a , or a 3- to 10-membered saturated or unsaturated ring containing 0 to 3 heteroatoms, wherein the 3- to 10-membered saturated or unsaturated ring containing 0 to 3 heteroatoms is optionally substituted with 1 to 3 R a ; R 5 is selected from hydrogen, C 1 to C 6 alkyl, C 1 to C 6 alkyl substituted with 1 to 3 R a , C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, halogenated C 1 to C 6 alkyl, deuterated C 1 to C 6 alkyl, halogenated C 2 to C 6 alkenyl, halogenated C 2 to C 6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b , -C(O)R a , -C(O)OR a , -OR a , -R a OR b , -OC(O)R a , -OC(O)OR a , -OC(O)NR a R b , -NR a R b , -SR a , -S(O)R a , -S(O) 2 R a , or a 3- to 10-membered saturated or unsaturated ring containing 0 to 3 heteroatoms, wherein the 3- to 10-membered saturated or unsaturated ring containing 0 to 3 heteroatoms is optionally substituted with 1 to 3 R a ; or R 4 and R 3 , together with the nitrogen atom connecting them, form a 3- to 7-membered saturated or unsaturated ring optionally substituted with 1 to 8 R a ; R 6 is selected from hydrogen, C 1 to C 6 alkyl, C 2 to C 6 alkenyl, halogenated C 1 to C 6 alkyl, C 1 to C 6 alkoxy, or deuterated C 1 to C 6 alkyl; R 7 is selected from hydrogen, halogen, C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, halogenated C 1 to C 6 alkyl, C 1 to C 6 alkoxy, deuterated C 1 to C 6 alkyl, halogenated C 2 to C 6 alkenyl, or halogenated C 2 to C 6 alkynyl; R a and R b are each independently selected from hydrogen, deuterium, C 1 to C 6 alkyl, C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, halogenated C 1 to C 6 alkyl, deuterated C 1 to C 6 alkyl, halogenated C 2 to C 6 alkenyl, halogenated C 2 to C 6 alkynyl, halogen, cyano, nitro, amino, carboxyl, oxo, hydroxyl, hydroxyalkyl, alkoxy, halogenated alkoxy, deuterated alkoxy, C 3 to C 6 cycloalkyl, halogenated C 3 to C 6 cycloalkyl, alkoxy-substituted C 3 to C 6 cycloalkyl, C 3 to C 6 cycloalkyl substituted with 1 to 3 R c , C 3 to C 6 heterocyclyl, halogenated C 3 to C 6 heterocyclyl, alkyl-substituted C 3 to C 6 heteroaryl, -S(O) 2 R c , -OR c OR d , -R c OR a , -C(O)R c , or -OC(O)R c , wherein R c and R d are each independently selected from halogen, C 1 to C 6 alkyl, or halogenated C 1 to C 6 alkyl; m is 0, 1, 2, 3, 4, or 5; and n is 0, 1, 2, 3, or 4.
  2. The isoxazoline compound according to claim 1, wherein the isoxazoline compound has a structure represented by Formula Ia: wherein Z, R 1 , R 2 , R 3 , R 4 , R 5 , m, and n are defined the same as in claim 1.
  3. The isoxazoline compound according to claim 1 or 2, wherein the isoxazoline compound has a structure represented by Formula Ib: wherein R 1 , R 2 , R 3 , m, and n are defined the same as in claim 1; and R a is selected from cyano or trifluoromethyl.
  4. The compound of Formula I according to claim 1, wherein R 1 is selected from hydrogen, halogen, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, halogenated C 1 to C 6 alkyl, or halogenated C 1 to C 6 alkoxy.
  5. The compound of Formula I according to claim 1, wherein R 1 is selected from hydrogen, fluorine, chlorine, methyl, methoxy, trifluoromethyl, or trifluoromethoxy.
  6. The compound of Formula I according to claim 1, wherein R 2 is selected from hydrogen, halogen, C 1 to C 6 alkyl, or halogenated C 1 to C 6 alkyl.
  7. The compound of Formula I according to claim 1, wherein R 2 is trifluoromethyl.
  8. The compound of Formula I according to claim 1, wherein R 3 is selected from hydrogen, halogen, C 1 to C 6 alkyl, or halogenated C 1 to C 6 alkyl.
  9. The compound of Formula I according to claim 1, wherein R 3 is methyl, chlorine, or fluorine.
  10. The compound of Formula I according to claim 1, wherein R 4 is hydrogen.
  11. The compound of Formula I according to claim 1, wherein R 5 is selected from C 1 to C 6 alkyl, halogenated C 1 to C 6 alkyl, C 3 to C 6 cycloalkyl, halogenated C 3 to C 6 cycloalkyl, cyano-substituted C 3 to C 6 cycloalkyl, alkoxy-substituted C 3 to C 6 cycloalkyl, C 3 to C 6 cycloalkyl substituted with halogenated C 1 to C 6 alkyl, or C 3 to C 6 heterocyclyl substituted with halogenated C 1 to C 6 alkyl.
  12. The compound of Formula I according to claim 1, wherein R 5 is selected from trifluoroethyl, cyclopropyl,
  13. The compound of Formula I according to claim 1, wherein is selected from or
  14. The compound of Formula I according to claim 1, wherein R 6 is selected from hydrogen or C 1 to C 6 alkyl.
  15. The compound of Formula I according to claim 1, wherein R 7 is selected from hydrogen or C 1 to C 6 alkyl.
  16. An isoxazoline compound selected from any one of the following compounds: or
  17. The isoxazoline compound according to claim 16, wherein the isoxazoline compound is selected from any one of the following compounds: or
  18. A tautomer, enantiomer, diastereomer, mesomer, racemate, or pharmaceutically acceptable salt of the isoxazoline compound according to any one of claims 1 to 17.
  19. A pharmaceutical composition, comprising a therapeutically effective amount of the isoxazoline compound according to any one of claims 1 to 17 or a tautomer, enantiomer, diastereomer, mesomer, racemate, or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
  20. Use of the isoxazoline compound according to any one of claims 1 to 17, the tautomer, enantiomer, diastereomer, mesomer, racemate, or pharmaceutically acceptable salt thereof according to claim 18, or the pharmaceutical composition according to claim 19 for controlling an infection of a human or an animal with ectoparasites.

Description

TECHNICAL FIELD The present application belongs to the technical field of pharmaceutical compounds and, in particular, relates to an isoxazoline compound and use thereof. BACKGROUND Ectoparasites for animals cause great harm to the health of companion animals and the production performance of livestock and poultry. Effective control of the infection of animals with ectoparasites has long been a goal of the agricultural and veterinary sectors (WOODS D J, KNAUER C S. Discovery of veterinary antiparasitic agents in the 21st century: a view from industry [J]. Int J Parasitol, 2010, 40(10): 1177-81.). Isoxazoline insecticides are a new type of pest control drugs, and such drugs primarily act on the γ-aminobutyric acid (GABA)-gated chloride channels of invertebrates (MITA T, KIKUCHI T, MIZUKOSHI T, et al. Isoxazoline-substituted benzamide compound and noxious organism control agent [J]. WO Patent, 2005, 2005085216: A1. & OZOE Y, ASAHI M, OZOE F, et al. The antiparasitic isoxazoline A1443 is a potent blocker of insect ligand-gated chloride channels [J]. Biochemical and biophysical research communications, 2010, 391(1): 744-9.). The action sites of the isoxazoline insecticides differ from those of other insecticides acting on the chloride channels (such as dieldrin and fipronil), and the isoxazoline insecticides can overcome the resistance to existing insecticides. The Insecticide Resistance Action Committee (IRAC) classifies the isoxazoline insecticides into Group 30 (IRAC Group 30). After researchers from Nissan Chemical (Japan) and DuPont (USA) developed an insecticidal active ingredient, fluralaner, (CASIDA J E. Golden age of RyR and GABA-R diamide and isoxazoline insecticides: common genesis, serendipity, surprises, selectivity, and safety [J]. Chemical research in toxicology, 2015, 28(4): 560-6.), afoxolaner, sarolaner, and lotilaner were subsequently developed. Currently, the four isoxazoline drugs are used for ectoparasite control in pets, and the global annual sales of such antiparasitic drugs (including compound preparations) exceed 2 billion dollars. The isoxazoline drugs have become the mainstream products for routine parasite control in companion animals. Among the currently marketed "-laner" drugs, three share the same N-trifluoroethyl glycinamide tail chain. With an enhanced metabolic capability towards this fragment, insects may generate multi-drug resistance to "-laner" insecticides. Therefore, the development of a new generation of "-laner" insecticides that are safer, more convenient, more effective, and more environmentally friendly can provide new therapeutic options for pet owners while overcoming common resistance to antiparasitic drugs. Additionally, isoxazoline compounds act on the GABA-gated chloride channels and also have a significant killing effect on agricultural pests, demonstrating a wide application potential in the field of pesticides. SUMMARY The following is a summary of the subject matter described herein in detail. This summary is not intended to limit the scope of the claims. In view of the defects in the existing art, an object of the present application is to provide an isoxazoline compound and use thereof. To achieve the object, the present application adopts the technical solutions below. In one aspect, the present application provides an isoxazoline compound. The isoxazoline compound has a structure represented by Formula I: wherein X is selected from -CH= or -N=;Y is selected from -CH= or -N=;Z is selected from wherein the wavy line represents a linkage site of the group;R1 is selected from hydrogen, C1 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, halogenated C1 to C6 alkyl, deuterated C1 to C6 alkyl, halogenated C2 to C6 alkenyl, halogenated C2 to C6 alkynyl, halogen, cyano, nitro, -C(O)NRaRb, -C(O)Ra, -C(O)ORa, -ORa, -RaORb, -OC(O)Ra, -OC(O)ORa, -OC(O)NRaRb, -NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, or a 3- to 10-membered saturated or unsaturated ring containing 0 to 3 heteroatoms, wherein the 3- to 10-membered saturated or unsaturated ring containing 0 to 3 heteroatoms is optionally substituted with 1 to 3 Ra;R2 is selected from hydrogen, halogen, C1 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, halogenated C1 to C6 alkyl, deuterated C1 to C6 alkyl, halogenated C2 to C6 alkenyl, or halogenated C2 to C6 alkynyl;R3 is selected from hydrogen, halogen, C1 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, halogenated C1 to C6 alkyl, deuterated C1 to C6 alkyl, halogenated C2 to C6 alkenyl, or halogenated C2 to C6 alkynyl;R4 is selected from hydrogen, C1 to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, halogenated C1 to C6 alkyl, deuterated C1 to C6 alkyl, halogenated C2 to C6 alkenyl, halogenated C2 to C6 alkynyl, halogen, cyano, nitro, -C(O)NRaRb, -C(O)Ra, -C(O)ORa, -ORa, -RaORb, -OC(O)Ra, -OC(O)ORa, -OC(O)NRaRb, -NRaRb, -SRa, -S(O)Ra, -S(O)2Ra, or a 3- to 10-membered saturated or unsaturated ring containing 0 to 3 heteroatoms, wherein the 3- to 10-membered saturated or uns