[go: up one dir, main page]

WO2025218782A1 - Composé d'isoxazoline et son utilisation - Google Patents

Composé d'isoxazoline et son utilisation

Info

Publication number
WO2025218782A1
WO2025218782A1 PCT/CN2025/089797 CN2025089797W WO2025218782A1 WO 2025218782 A1 WO2025218782 A1 WO 2025218782A1 CN 2025089797 W CN2025089797 W CN 2025089797W WO 2025218782 A1 WO2025218782 A1 WO 2025218782A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
trifluoromethyl
stereoisomer
test
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/089797
Other languages
English (en)
Chinese (zh)
Inventor
范传文
孔梅
刘全才
郑欢庆
马庆祝
方明锋
周世宇
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
QILU ANIMAL HEALTH PRODUCTS CO Ltd
Qilu Pharmaceutical Co Ltd
Original Assignee
QILU ANIMAL HEALTH PRODUCTS CO Ltd
Qilu Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by QILU ANIMAL HEALTH PRODUCTS CO Ltd, Qilu Pharmaceutical Co Ltd filed Critical QILU ANIMAL HEALTH PRODUCTS CO Ltd
Publication of WO2025218782A1 publication Critical patent/WO2025218782A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
    • A01N47/30—Derivatives containing the group >N—CO—N aryl or >N—CS—N—aryl
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/08—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having one or more single bonds to nitrogen atoms
    • A01N47/28—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N<
    • A01N47/34—Ureas or thioureas containing the groups >N—CO—N< or >N—CS—N< containing the groups, e.g. biuret; Thio analogues thereof; Urea-aldehyde condensation products
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
    • A01N47/40—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P7/00—Arthropodicides
    • A01P7/04—Insecticides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present application relates to a new class of isoxazoline compounds, pharmaceutical compositions thereof and uses thereof for pest control in agriculture, non-agriculture, animal husbandry and pet care.
  • Isoxazolines are effective insecticides and acaricides that antagonize chloride channels gated by ⁇ -aminobutyric acid (GABA) and glutamate receptors, preventing chloride ions from penetrating the postsynaptic membrane. This interferes with transmembrane signaling in the nervous system, leading to nervous system disorders and ultimately death in insects.
  • GABA ⁇ -aminobutyric acid
  • antiparasitic drugs they are highly valued for their highly effective insecticidal activity, broad antiparasitic spectrum, and excellent safety profile. They are widely used in agriculture, non-agriculture, livestock, and pet care to prevent and treat a variety of parasitic infestations or infections.
  • the purpose of the present application is to provide a new class of isoxazoline compounds, pharmaceutical compositions containing the compounds and their use in pest control.
  • the present application provides a compound represented by formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
  • Ring A is selected from 5-10 membered aryl groups, which are optionally substituted with one or more R x ;
  • R 1 , R 2 , and R 3 are each independently selected from H, halogen, or C 1 -C 6 haloalkyl;
  • X is selected from -C(O)-, -S(O) 2 -;
  • R 6 is selected from C 3 -C 8 cycloalkyl, wherein the C 3 -C 8 cycloalkyl is optionally substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or -CN; or
  • R 5 , R 6 together with the nitrogen atom to which they are attached, form a 3-6 membered heterocyclic ring, wherein the 3-6 membered heterocyclic ring is optionally substituted with halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or -CN;
  • R x is selected from H, C 1 -C 6 alkyl
  • the ring A described above is selected from a 5-6 membered aryl group, which is optionally substituted with one or more R x , wherein R x is as defined above.
  • the ring A is selected from the following structures:
  • R x and n are as defined above.
  • the ring A is preferably selected from the following structures:
  • * represents the connection to the X terminal.
  • said X is selected from -C(O)-.
  • R 1 , R 2 , and R 3 are independently selected from H, halogen, and CF 3 .
  • said R 5 is selected from hydrogen;
  • R 6 is selected from C 3 -C 4 cycloalkyl, and said C 3 -C 4 cycloalkyl is optionally substituted with one or more halogen, CF 3 , or CN.
  • R 5 and R 6 together with the nitrogen atom to which they are attached form a four-membered heterocyclic ring, which is optionally substituted with one or more halogens or CF 3 .
  • the second aspect of the present application provides a compound represented by formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • R 1 , R 2 , R 3 , R 5 and R 6 are as defined in the first aspect of the present application.
  • the third aspect of the present application provides the following compound, its stereoisomer or a pharmaceutically acceptable salt thereof:
  • the fourth aspect of the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound described in the first, second or third aspect of the present application, its stereoisomer or pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers.
  • the fifth aspect of the present application provides the use of the compound described in the first, second or third aspect of the present application, its stereoisomer or pharmaceutically acceptable salt, or the pharmaceutical composition described in the fourth aspect of the present application in the preparation of a drug for pest control.
  • the medicament for the above use is for preventing or treating parasitic infestation or infection in an animal.
  • the drug in the above use can be applied to the locus of the pest or to plants susceptible to attack by the pest.
  • the drug for use above is an antiparasitic drug, preferably an invertebrate parasiticidal agent.
  • the parasite in the above use is an invertebrate parasitic pest that parasitizes externally or internally; preferably, it is an arthropod; more preferably, it is a fly, mosquito, mite, louse, flea, maggot, tick, bedbug or assassin bug; further preferably, it is a flea, tick, mite or louse.
  • the animal in the above use refers to mammals, birds or fish; preferably canines, felines, equines, poultry or livestock; more preferably dogs, cats, chickens, sheep, cattle or pigs.
  • the medicament for use described above is used to treat flea, tick, or mite infestations on the surface of a dog.
  • the drug in the above-mentioned use is used to treat poultry surface mite infestation.
  • the present application provides a method for pest control, comprising administering an effective therapeutic amount of the compound described in the first, second, or third aspect of the present application, its stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition described in the fourth aspect of the present application.
  • the above methods can be applied to the locus of the pest or to plants susceptible to attack by the pest.
  • the above methods are used to prevent or treat parasitic infestation or infection in an animal.
  • the above methods are used to combat parasites, preferably to kill invertebrate parasites.
  • the parasite in the above method is an invertebrate parasitic pest that parasitizes externally or internally; preferably, it is an arthropod; more preferably, it is a fly, mosquito, mite, louse, flea, maggot, tick, bedbug or assassin bug; further preferably, it is a flea, tick, mite or louse.
  • the animal in the above method refers to mammals, birds or fish; preferably canines, felines, equines, poultry or livestock; more preferably cats, dogs, chickens, sheep, cattle or pigs.
  • the above methods are used to treat a flea, tick, or mite infestation on a dog.
  • the above methods are used to treat surface mite infestations in poultry.
  • the present application provides the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt or a pharmaceutical composition containing the above-mentioned compound, its stereoisomer or pharmaceutically acceptable salt, which is used for pest control.
  • the pest control described above is the prevention or treatment of parasitic infestation or infection in animals.
  • the above-mentioned pest control can be applied to the location of the pest or to plants susceptible to attack by the pest.
  • the pest control is antiparasitic, preferably an invertebrate parasiteicide.
  • the parasite is an invertebrate parasitic pest that parasitizes externally or internally; preferably, it is an arthropod; more preferably, it is a fly, mosquito, mite, louse, flea, maggot, tick, bedbug or assassin bug; further preferably, it is a flea, tick, mite or louse.
  • the animal is a mammal, bird, or fish; preferably a canine, feline, equine, poultry, or livestock; more preferably a cat, dog, chicken, sheep, cow, or pig.
  • the pest control is used to treat flea, tick, or mite infestations on dogs.
  • the pest control is used to treat acarid infestation on the poultry surface.
  • the compounds of the present application have excellent insecticidal activity against external parasites of mammals, poultry or fish, especially have good pharmacological effects on the prevention and killing of mites, fleas and ticks; at the same time, they have no adverse effects on mammals, poultry or fish and are safer for the environment.
  • Figure 1 is a graph showing the change of the mean blood concentration of compound 1 over time
  • Figure 2 is a graph showing the change of the mean blood concentration of compound 2 over time
  • FIG3 is a graph showing the change of the mean blood concentration of compound 3 over time
  • FIG4 is a graph showing the change of the mean blood concentration of compound 4 over time
  • FIG5 is a graph showing the change of the mean blood concentration of compound 5 over time
  • Figure 6 is a graph showing the change of the mean blood concentration of compound 6 over time
  • FIG7 is a graph showing the change pattern of the mean blood concentration of flurellan over time.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to derivatives of the compounds of the present invention prepared with relatively nontoxic acids or bases. These salts can be prepared during compound synthesis, isolation, or purification, or by reacting the purified free form of the compound with a suitable acid or base.
  • relatively acidic functional groups e.g., -COOH, -OH, -SO 3 H, etc.
  • bases inorganic or organic cations
  • the compound When the compound contains relatively basic functional groups (e.g., -NH 2 , etc.), it reacts with appropriate inorganic or organic anions (acids) to form acid addition salts, including salts formed with inorganic or organic acids (e.g., carboxylic acids, etc.).
  • relatively basic functional groups e.g., -NH 2 , etc.
  • acids inorganic or organic anions
  • salts formed with inorganic or organic acids e.g., carboxylic acids, etc.
  • pharmaceutically acceptable carrier refers to a medium generally accepted in the art for delivering biologically active agents to animals, particularly mammals, and includes, for example, adjuvants, excipients, or vehicles, such as diluents, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavorings, fragrances, antibacterial agents, antifungal agents, lubricants, and dispersants, depending on the mode of administration and the nature of the dosage form.
  • Pharmaceutically acceptable carriers are formulated within the purview of those skilled in the art based on a wide range of factors.
  • compositions containing the agent include, but are not limited to, the type and nature of the active agent being formulated, the subject to whom the composition containing the agent is to be administered, the intended route of administration of the composition, and the target therapeutic indication.
  • Pharmaceutically acceptable carriers include both aqueous and non-aqueous media, as well as a variety of solid and semisolid dosage forms. In addition to the active agent, such carriers include a variety of different ingredients and additives, and the inclusion of such additional ingredients in a formulation for various reasons (e.g., to stabilize the active agent, as a binder, etc.) is well known to those skilled in the art.
  • isotopic derivative refers to a compound in which at least one atom is replaced by an atom having the same atomic number but a different atomic mass.
  • isotopes in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (2H), tritium (3H)); isotopes of carbon (e.g., 11C, 13C, and 14C); isotopes of chlorine (e.g., 36Cl); isotopes of fluorine (e.g., 18F); isotopes of iodine (e.g., 123I and 125I); isotopes of nitrogen (e.g., 13N and 15N); isotopes of oxygen (e.g., 15O, 17O, and 18O); isotopes of phosphorus (e.g., 32P); and isotopes of sulfur (e.g., 35S).
  • isotopes of hydrogen e.g., deuterium (2H), tritium (3H)
  • isotopes of carbon e.g., 11C, 13C,
  • Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or can be prepared by methods analogous to those described herein using a suitable isotopically labeled reagent instead of an unlabeled reagent.
  • prodrug refers to certain derivatives of the compounds of the present application that have little or no pharmacological activity themselves, which have a cleavable group and decompose into the compounds of the present application through solvent decomposition or under physiological conditions.
  • the types of prodrugs include, but are not limited to, amides, esters, anhydrides, salts, etc.
  • the "ester” refers to a derivative formed by the compounds of the present application when they contain an acidic group (such as a carboxylic acid) and a suitable alcohol; when the compounds of the present application contain a hydroxyl group, they are formed by a suitable acid (including an organic acid or an inorganic acid).
  • the preparation methods of prodrugs are well known to those skilled in the art.
  • solvate refers to an association or complex of one or more solvent molecules with a compound of the present invention.
  • hydrate may be used when the solvent is water.
  • the solvent molecules may be present in stoichiometric or non-stoichiometric amounts. Methods for preparing solvates are known in the art.
  • nitrogen oxide or "N-oxide” refers to a derivative formed by further oxidation of the nitrogen atom in a nitrogen-containing group.
  • Common N-oxides include N-oxides of tertiary amines or nitrogen atoms in nitrogen-containing heterocycles. Synthesis methods of N-oxides are well known to those skilled in the art and include oxidation of heterocycles and tertiary amines using peroxyacids such as peracetic acid and m-chloroperbenzoic acid, hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate, and dioxiranes such as dimethyldioxirane.
  • the compounds of the present application and their salts may exist in the form of isotopic derivatives, and the compounds of the present application include various isotopic derivatives and mixtures thereof.
  • the compounds of the present application and their salts may exist in the form of solvates, such as hydrates, and the compounds of the present application include various solvates and mixtures thereof.
  • the compounds of the present invention and their salts may exist in the form of “N-oxides”, and the compounds of the present invention include various N-oxides and mixtures thereof.
  • the compounds of the present application When the compounds of the present application are used to control external or internal parasites of mammals, birds or fish, they can be administered orally; non-orally by injection (muscular, subcutaneous, intravenous, intraperitoneal); transdermal administration such as dipping, spraying, bathing, pouring, dripping (pouring-on) and dripping (spotting-on) and spraying (dusting); and nasal administration to apply an effective amount of the compounds of the present application and the additives for the preparation.
  • the compounds of the present application can be administered by using a shaped article such as a fork, a thin piece, a plate, a belt, a collar, an ear tag, a collar, a limb band, a marking device, a trapping device, etc.
  • the compounds of the present application can be made into any dosage form suitable for the route of administration.
  • an effective prophylactic or therapeutic amount refers to a sufficient amount of the compound of the present application, its pharmaceutically acceptable salt, or its isomer to treat the disorder at a reasonable benefit/risk ratio applicable to any medical treatment and/or prevention.
  • the total daily dosage of the compound of the present application, its pharmaceutically acceptable salt, and composition should be determined by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dosage level should be determined based on a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound being used; the specific composition being used; the time of administration, route of administration, and excretion rate of the specific compound being used; the duration of treatment; drugs used in combination with or concurrently with the specific compound being used; and similar factors known in the medical field.
  • stereoisomer encompasses “enantiomers” and “diastereomers”.
  • Enantiomers refer to stereoisomers that are mirror images of each other, and “diastereomers” refer to stereoisomers that have two or more chiral centers and are not mirror images of each other.
  • Stereoisomers of the compounds of this application can be prepared by chiral synthesis, chiral reagents, or other conventional techniques.
  • one enantiomer of a compound of this application can be prepared by asymmetric catalysis or chiral auxiliary derivatization.
  • a single stereoisomer of the compound can be obtained from a mixture by chiral resolution techniques.
  • the compound can be prepared directly using chiral starting materials. Separation of optically pure compounds in this application is typically accomplished using preparative chromatography, employing chiral chromatographic columns to achieve the purpose of separating chiral compounds.
  • the absolute stereo configuration of a compound can be confirmed by conventional techniques in the art. For example, single crystal X-ray diffraction can be used, or the absolute configuration of a compound can be confirmed based on the chiral structure of the starting material and the reaction mechanism of asymmetric synthesis. Alternatively, after resolution, the stereo configuration can be determined by comparing it with a product with a determined absolute configuration. Compounds marked as "absolute configuration unknown" in this application are typically resolved into individual isomers by chiral preparative SFC from a racemic compound, followed by characterization and testing.
  • parasite refers to external parasites of the skin (e.g., ticks, lice, fleas, and dermatophagoides mites), internal parasites of the skin (e.g., mites), internal parasites (e.g., intestinal parasites, blood parasites, and intracellular parasites), intestinal parasites (e.g., roundworms, hookworms, tapeworms, and whipworms), and blood parasites (e.g., heartworms and babesia).
  • the compounds of the present application also have effects on animal pests and plant pests to which all or individual developmental stages show normal sensitivity.
  • insects examples include insects, mites, crustaceans, and mollusks.
  • examples include: Coleoptera, such as the black bean weevil and flea beetle; Lepidoptera, such as the corn borer, striped stem borer, yellow stem borer, rice leaf roller, melon borer, fall armyworm, fall armyworm, diamondback moth, noctuid armyworm, spodoptera exigua, cabbage moth, wheat borer, fruit borer, and tobacco caterpillar; Hemiptera, such as the whitefly, brown-winged stink bug, red-banded stink bug, green-bellied stink bug, green stink bug, pear scale, and leafhopper; Thysanoptera, such as palm thrips, tobacco thrips, six-spotted thrips, western flower thrips, sedge flower thrips, and Australian plague thrips; Diptera, such as the citrus fruit fly, lir
  • infestation is synonymous with the term “infection”, including the presence of a large number of parasites that are dangerous to humans, animals or plants in the environment (such as human or animal housing, surrounding objects and plants), which may exist on animal skin or fur or on crops and other types of plants. It also includes the phenomenon that parasites enter the host body (such as in the blood or other internal tissues) to grow and reproduce, such as schistosomiasis infection, trichinosis infection, etc.
  • the substituent When the substituent appears in the structure Indicates that the atom is a bonding atom, for example Indicates that the C atom on the pyrimidine ring is a bonding atom.
  • a dash "—" in a substituent structure indicates the point of attachment for the substituent, for example, -CH3 is attached through a C atom.
  • a substituent's bond can cross-link to a ring, it means that the substituent can be bonded to any atom on the ring.
  • the substituent R can be substituted at any position on the benzene ring.
  • R d When any variable (e.g., R d ) occurs more than once in a compound's composition or structure, its definition on each occurrence is independent. It means that the cyclopentyl group is substituted by 3 R d , and each R d has an independent option.
  • halogen means a fluorine, chlorine, bromine or iodine atom.
  • alkyl refers to a group derived from a branched or straight-chain saturated aliphatic alkane having the specified number of carbon atoms by removing one hydrogen.
  • C1-10 alkyl includes C1 , C2 , C3, C4 , C5 , C6 , C7 , C8 , C9 , and C10 alkyl, " C1-6 alkyl,”” C1-4 alkyl,” and " C1-3 alkyl.”
  • Specific examples include, but are not limited to, methyl , ethyl, n-propyl, isopropyl, sec-butyl, 2-methylbutyl, and 1,1-dimethylbutyl.
  • haloalkyl refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen atom. Halogenated C 1-6 alkyl groups are preferred, and halogenated C 1-4 alkyl groups are more preferred. Examples of haloalkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, and 2,2,2-trichloroethyl. Alkyl is as defined above.
  • alkoxy refers to an alkyl group as defined herein connected to another group through an oxygen atom, i.e., "alkyl-O-.”
  • Specific examples include, but are not limited to, methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, and 1,2-dimethylpropoxy.
  • the "alkoxy” described herein is a C 1-6 alkoxy group, and more preferably a C 1-4 alkoxy group.
  • haloalkoxy refers to a group formed by replacing one or more hydrogen atoms in an alkoxy group with a halogen.
  • the "haloalkoxy” described herein is preferably a "halogenated C 1-6 alkoxy” or a "halogenated C 1-4 alkoxy.”
  • Specific examples described herein include fluoromethoxy (including monofluoromethoxy, difluoromethoxy, and trifluoromethoxy), -OCH 2 CF 3 , and -OCHFCH 3 .
  • Alkoxy is as defined above.
  • ring refers to saturated, partially saturated or unsaturated monocycles and polycycles
  • polycycles include spirocycles, condensed rings or bridged rings.
  • the group derived from the ring by removing hydrogen atoms is called a "cyclyl", which includes a monovalent ring, a divalent ring (commonly referred to as a subring), a trivalent ring, a tetravalent ring, etc., and the specific valence depends on the number of substituents connected to the ring.
  • the description of "cyclyl” in this application no longer specifically distinguishes the valence of the ring.
  • cyclyl includes substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl.
  • hetero refers to substituted or unsubstituted heteroatoms and oxidized forms of heteroatoms (also known as heteroatoms).
  • the heteroatoms are generally selected from N, O, S, and P.
  • Oxidized forms generally include NO, SO, S(O) 2 , and P(O).
  • the nitrogen atom can be substituted, i.e., NR (R is H or other substituents defined herein).
  • the number of atoms in the ring is generally defined as the number of ring members.
  • "3-6 membered heterocycloalkyl” refers to a ring of 3-6 atoms arranged around, each ring optionally containing 1-3 heteroatoms and/or heteroatoms, i.e., N, O, S, NO, SO, S(O) 2 , P(O), or NR, each ring optionally substituted with an R group, where R is a group defined herein.
  • cycloalkyl refers to a saturated cyclic alkyl group derived from a cycloalkane by removing a hydrogen atom, including monocyclic or polycyclic saturated hydrocarbon groups.
  • Polycyclic saturated hydrocarbon groups refer to polycyclic groups formed by two or more cyclic alkyl structures connected by spiro, bridged, or fused structures. Carbon atoms in the cycloalkyl group may be further oxidized, forming C(O).
  • the term “monocyclic cycloalkyl” as used herein refers to a monocyclic cycloalkyl group.
  • Cycloalkyl groups include " C3-8 cycloalkyl,”” C3-6 cycloalkyl,”” C3-5 cycloalkyl,” and “ C3-4 cycloalkyl.”
  • the cycloalkyl group is a monocyclic, saturated structure; specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • heterocycle refers to a saturated ring derived from a cycloalkyl group in which one or more ring carbon atoms are replaced by heteroatoms and/or heteroatomic groups.
  • the heteroatoms and/or heteroatomic groups are generally selected from N, O, S, NO, SO, S(O) 2 , P(O), and NR, wherein the carbon atoms in the heterocycle are optionally oxoed, i.e., forming -C(O); preferably, the heteroatoms are independently selected from 1-3 N and/or O.
  • the heterocycle includes "3-8 membered heterocycle”, “3-6 membered heterocycle”, “3-5 membered heterocycle”, “4-6 membered heterocycle”, “5-6 membered heterocycle”, etc. Specific examples include, but are not limited to, azetidine, pyrrolidine, tetrahydrofuran, piperidine, piperazine, tetrahydropyran, morpholine, etc.
  • aryl refers to an unsaturated, typically aromatic hydrocarbon group, which may be a single ring or multiple rings fused together, including C5-10 aryl, C5-8 aryl, C5-6 aryl, etc. Examples of aryl include, but are not limited to, phenyl and naphthyl.
  • NMR nuclear magnetic resonance
  • ⁇ mass spectroscopy
  • LC-MS Liquid chromatography-mass spectrometry
  • HPLC determination was performed using Agilent 1260 and a Waters XBridge C18 column (5 ⁇ m, 4.6 ⁇ 250mm).
  • the thin layer chromatography silica gel plate used was HSGF254 silica gel plate from Yantai Jiangyou Silica Gel Development Co., Ltd.
  • the specifications used for TLC were 0.20 mm ⁇ 0.03 mm, and the preparative size was 20 ⁇ 20 cm.
  • the column chromatography used 200-300 mesh silica gel from Qingdao Hailang Silica Gel Desiccant Co., Ltd. as the carrier.
  • the starting materials in the examples of the present application are known and can be purchased on the market, or can be synthesized by or according to methods known in the art.
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • Step 1 To a solution of 72.6 g N-Boc-glycine in 1800 mL ethyl acetate, add 60.3 g 3,3-difluoroazetidine hydrochloride, 56.0 g 1-hydroxybenzotriazole (HOBt) and 98.0 g triethylamine (TEA) under stirring at room temperature, and then add 100.0 g 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI). After the addition, maintain stirring at room temperature for 3 hours, add 1000 mL purified water and stir for 5 minutes, separate the layers, and distill the organic phase under reduced pressure to remove the solvent to obtain a concentrate.
  • HOBt 1-hydroxybenzotriazole
  • EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • Step 2 Add 300 mL of 4 M hydrogen chloride in dioxane to the concentrate obtained in Step 1. React at room temperature for 2 h. Remove approximately 300 mL of solvent by distillation under reduced pressure. Stir the reaction mixture at room temperature, add 100 mL of n-heptane, stir for 1 h, and filter. Rinse the filter cake with n-heptane and dry at 60°C to yield 74.5 g of 2-amino-1-(3,3-difluoroazetidin-1-yl)ethanone hydrochloride.
  • Step 3 Dissolve 106.8 g of 2-methyl-4-acetylbenzoic acid in 500 mL of toluene solution with stirring at room temperature, add 188.4 g of 3,5-dichloro-4-fluorotrifluoroacetophenone and 182.4 g of triethylamine, then heat to 70°C and keep warm for 6 hours.
  • Step 4 To a solution of 50.0 g of 4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluoro-3-hydroxybutyryl)-2-methylbenzoic acid triethylamine salt in 170 mL of toluene, add 3.4 g of dimethylaminopyridine and 18.9 g of acetic anhydride, stir, heat to 60°C, and react for 4 h. Concentrate in vacuo, add purified water for slurry washing, and filter to obtain 4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluoro-2-enoyl)-2-methylbenzoic acid.
  • Step 5 Add 200 mL of toluene and 12.9 g of hydroxylamine hydrochloride to the 4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluoro-2-enoyl)-2-methylbenzoic acid obtained in Step 3.
  • the mixture was stirred in an ice bath and 85 g of a saturated aqueous sodium hydroxide solution was added dropwise.
  • the reaction mixture was allowed to react for 2 h. After the reaction was complete, the reaction mixture was warmed to room temperature, 100 mL of 6N hydrochloric acid solution was added, and the mixture was allowed to stand for separation.
  • Step 6 To a solution of 10.0 g of 4-[5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid in 100 mL of ethyl acetate was added 4.9 g of 2-amino-1-(3,3-difluoroazetidin-1-yl)ethanone hydrochloride (prepared in Step 2), 2.9 g of 1-hydroxybenzotriazole (HOBt), 3.1 g of triethylamine, and 5.4 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • 2-amino-1-(3,3-difluoroazetidin-1-yl)ethanone hydrochloride prepared in Step 2
  • 1-hydroxybenzotriazole (HOBt) 1-hydroxybenzotriazole
  • Step 1 Dissolve 10.7 g of 2-methyl-4-acetylbenzoic acid in 40 mL of toluene solution at room temperature with stirring, add 20.0 g of 3,4,5-trichlorotrifluoroacetophenone and 18.2 g of triethylamine, then heat to 70°C and keep warm for 6 hours. After cooling to room temperature, filter and rinse the filter cake with 30 mL of toluene. Dry the filter cake at 60°C to obtain 32.5 g of 4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluoro-3-hydroxybutyryl)-2-methylbenzoic acid triethylamine salt.
  • Step 2 To a solution of 32.5 g of 4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluoro-3-hydroxybutyryl)-2-methylbenzoic acid triethylamine salt in 110 mL of toluene, add 2.1 g of dimethylaminopyridine and 11.9 g of acetic anhydride. Gradually raise the temperature to 60°C and react for 4 h. Concentrate in vacuo, add purified water for slurry washing, and filter to obtain 4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluoro-2-enoyl)-2-methylbenzoic acid.
  • Step 3 Add 130 mL of toluene and 8.1 g of hydroxylamine hydrochloride to the 4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluoro-2-enoyl)-2-methylbenzoic acid obtained in step 2, stir under ice bath, add 54 g of saturated aqueous sodium hydroxide solution dropwise, and keep warm for 2 h. After the reaction is completed, the reaction solution is warmed to room temperature, 100 mL of 6N hydrochloric acid solution is added, and the mixture is allowed to stand for stratification.
  • Step 4 To a solution of 5.0 g of 4-[5-(3,4,5-trichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid in 125 mL of ethyl acetate, add 2.4 g of 2-amino-1-(3,3-difluoroazetidin-1-yl)ethanone hydrochloride (see Example 1, Step 2), 0.7 g of 1-hydroxybenzotriazole, 1.4 g of triethylamine, and 2.6 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Stir at room temperature for 3 h.
  • Step 1 Dissolve 20.0 g of 2-methyl-4-acetylbenzoic acid in 60 mL of toluene solution at room temperature with stirring, add 37.2 g of 3-chloro-5-trifluoromethyltrifluoroacetophenone and 34.1 g of triethylamine, then heat to 70°C and keep warm for 6 hours. After cooling to room temperature, filter and rinse the filter cake with 30 mL of toluene. Dry the filter cake at 60°C to obtain 60.3 g of 4-(3-(3-chloro-5-trifluoromethylphenyl)-4,4,4-trifluoro-3-hydroxybutyryl)-2-methylbenzoic acid triethylamine salt.
  • Step 2 To a 170 mL toluene solution of 50.0 g of 4-(3-(3-chloro-5-trifluoromethylphenyl)-4,4,4-trifluoro-3-hydroxybutyryl)-2-methylbenzoic acid triethylamine salt, add 3.3 g of dimethylaminopyridine (DMAP) and 18.4 g of acetic anhydride, gradually raise the temperature to 60°C, and react for 4 h. After the reaction is complete, concentrate in vacuo, add purified water for pulping and washing, and filter to obtain 4-(3-(3-chloro-5-trifluoromethylphenyl)-4,4,4-trifluoro-2-enoyl)-2-methylbenzoic acid.
  • DMAP dimethylaminopyridine
  • acetic anhydride 18.4 g
  • Step 3 Add 200 mL of toluene and 12.5 g of hydroxylamine hydrochloride to the 4-(3-(3-chloro-5-trifluoromethylphenyl)-4,4,4-trifluoro-2-enoyl)-2-methylbenzoic acid obtained in Step 2, place in an ice bath, and stir while maintaining the mixture. 85 g of a saturated aqueous sodium hydroxide solution is then added dropwise and allowed to react for 2 h. After the reaction is complete, the reaction solution is warmed to room temperature, 100 mL of a 6N hydrochloric acid solution is added, and the mixture is allowed to stand for separation.
  • Step 4 To a solution of 10.5 g of 4-[5-(3-chloro-5-trifluoromethylphenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid in 100 mL of ethyl acetate, add 5.1 g of 2-amino-1-(3,3-difluoroazetidin-1-yl)ethanone hydrochloride (see Example 1, Step 2), 1.5 g of 1-hydroxybenzotriazole (HOBt), and 3.1 g of triethylamine.
  • 2-amino-1-(3,3-difluoroazetidin-1-yl)ethanone hydrochloride see Example 1, Step 2
  • 1.5 g 1-hydroxybenzotriazole (HOBt)
  • 3.1 g of triethylamine To a solution of 10.5 g of 4-[5-(3-chloro-5-trifluoromethylphenyl)
  • Embodiment 4 is a diagrammatic representation of Embodiment 4:
  • Step 1 To a solution of 11.0 g N-Boc-glycine in 300 mL of ethyl acetate, stir at room temperature. Add 10.0 g of 2,2-difluorocyclopropylamine hydrochloride, 8.8 g of 1-hydroxybenzotriazole (HOBt), and 8.9 g of triethylamine (TEA). Add 16.1 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI). Stir at room temperature for 3 h. After the reaction is complete, add 200 mL of purified water, separate the layers, and distill the organic phase under reduced pressure to remove the solvent to obtain a concentrate.
  • HABt 1-hydroxybenzotriazole
  • TEA triethylamine
  • EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • Step 2 Add 30 mL of dioxane to the concentrate obtained in Step 1 and dissolve it with stirring at room temperature. Then, add 70 mL of a 4 M hydrogen chloride solution in dioxane. During the reaction, solids gradually precipitate, accompanied by gas evolution. The reaction is allowed to react at room temperature for 2 h. Approximately 70 mL of solvent is removed by distillation under reduced pressure. The reaction mixture is stirred at room temperature, and 30 mL of n-heptane is added. Stir for an additional 1 h at the same temperature, and filter. The filter cake is rinsed with n-heptane and dried at 60°C to yield 3.2 g of 2-amino-N-(2,2-difluorocyclopropyl)acetamide hydrochloride.
  • Step 3 To a solution of 6.1 g of 4-[5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid (see Example 1, Step 5) in 70 mL of ethyl acetate, add 3.1 g of 2-amino-N-(2,2-difluorocyclopropyl)acetamide hydrochloride, 1.9 g of 1-hydroxybenzotriazole (HOBt), and 2.1 g of triethylamine. Add 3.5 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI).
  • EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • Step 1 To a solution of 30.0 g N-Boc-glycine in 900 mL ethyl acetate, add 50.0 g (1R, 2S)-2-fluorocyclopropylamine p-toluenesulfonate, 12.0 g 1-hydroxybenzotriazole (HOBt) and 21.0 g triethylamine (TEA) under stirring at room temperature, and then add 51.0 g 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI). After the addition is completed, maintain stirring at room temperature for 3 hours, and remove the solvent by distillation under reduced pressure to obtain a concentrate.
  • HOBt 1-hydroxybenzotriazole
  • TEA triethylamine
  • Step 2 Add 200 mL of 4 M hydrogen chloride in dioxane to the concentrate obtained in Step 1 and react at room temperature for 2 h. Remove approximately 200 mL of solvent by distillation under reduced pressure. Stir the reaction mixture at room temperature, add 100 mL of ethyl acetate, stir for 1 h, and filter. Rinse the filter cake with n-heptane and dry at 60°C to yield 23.5 g of 2-amino-N-((1R,2S)-2-fluorocyclopropyl)acetamide hydrochloride.
  • Step 3 Dissolve 31.8 g of 2-methyl-4-acetylbenzoic acid in 150 mL of toluene solution under stirring at room temperature, add 52.2 g of 3,5-dichlorotrifluoroacetophenone and 54.2 g of triethylamine, then heat to 70°C and keep warm for 6 hours. After cooling to room temperature for precipitation, filter with suction, rinse the filter cake with 30 mL of toluene, and dry the filter cake in a vacuum at 60°C to obtain 83.1 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutyryl)-2-methylbenzoic acid triethylamine salt.
  • Step 4 To a solution of 80.0 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutyryl)-2-methylbenzoic acid triethylamine salt in 240 mL of toluene, add 5.6 g of dimethylaminopyridine and 31.3 g of acetic anhydride, stir, warm to 60°C, and react for 4 h. Concentrate in vacuo, add purified water for slurry washing, and filter to obtain 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-enoyl)-2-methylbenzoic acid.
  • Step 5 Add 240 mL of toluene and 21.3 g of hydroxylamine hydrochloride to the 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-enoyl)-2-methylbenzoic acid obtained in Step 3, place in an ice bath and stir, then add dropwise 130 g of a saturated aqueous sodium hydroxide solution and react for 2 h.
  • reaction solution is warmed to room temperature, 160 mL of a 6N hydrochloric acid solution is added, the mixture is allowed to stand and separate, and the organic phase is concentrated in vacuo to obtain 54.5 g of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid.
  • Step 6 To a solution of 10.0 g of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid in 100 mL of ethyl acetate was added 4.8 g of 2-amino-N-((1R,2S)-2-fluorocyclopropyl)acetamide hydrochloride (prepared in Step 2), 1.6 g of 1-hydroxybenzotriazole (HOBt), 3.4 g of triethylamine, and 6.0 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • 2-amino-N-((1R,2S)-2-fluorocyclopropyl)acetamide hydrochloride prepared in Step 2
  • 1-hydroxybenzotriazole (HOBt) 1-hydroxybenzotriazole
  • triethylamine
  • Step 1 To a solution of 21.7 g of 4-[5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid (see Example 1, Step 5) in 600 mL of ethyl acetate was added 10.1 g of 2-amino-N-((1R,2S)-2-fluorocyclopropyl)acetamide hydrochloride (see Example 7, Step 2), 3.8 g of 1-hydroxybenzotriazole (HOBt), 7.0 g of triethylamine, and 12.4 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • HOBt 1-hydroxybenzotriazole
  • Step 1 To a solution of 9.0 g of 4-[5-(3,4,5-trichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid (see Example 2, Step 3) in 225 mL of ethyl acetate was added 4.0 g of 2-amino-N-((1R,2S)-2-fluorocyclopropyl)acetamide hydrochloride (see Example 7, Step 2), 1.4 g of 1-hydroxybenzotriazole (HOBt), 2.8 g of triethylamine, and 5.8 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • HOBt 1-hydroxybenzotriazole
  • Embodiment 10 is a diagrammatic representation of Embodiment 10:
  • Step 1 To a solution of 22.9 g of 4-[5-(3-chloro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid (see Example 3, Step 3) in 570 mL of ethyl acetate was added 10.3 g of 2-amino-N-((1R,2S)-2-fluorocyclopropyl)acetamide hydrochloride (see Example 7, Step 2), 3.4 g of 1-hydroxybenzotriazole (HOBt), 7 g of triethylamine, and 12.7 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • HOBt 1-hydroxybenzotriazole
  • Step 1 Dissolve 15.0 g of 2-methyl-4-acetylbenzoic acid in 50 mL of toluene solution under stirring at room temperature, add 29.7 g of 3-chloro-4-fluoro-5-(trifluoromethyl)-2,2,2-trifluoroacetophenone and 25.6 g of triethylamine, then heat to 70°C and keep warm for 6 hours.
  • Step 2 To a solution of 37.0 g of 4-(3-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-4,4,4-trifluoro-3-hydroxybutyryl)-2-methylbenzoic acid triethylamine salt in 100 mL of toluene, add 3.1 g of dimethylaminopyridine and 13.2 g of acetic anhydride, stir, heat to 60°C, and react for 4 h.
  • Step 3 Add 100 mL of toluene and 9.0 g of hydroxylamine hydrochloride to the 4-(3-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-4,4,4-trifluoro-2-enoyl)-2-methylbenzoic acid obtained in step 3, place under ice bath and stir, add 60 g of saturated aqueous sodium hydroxide solution dropwise, and react for 2 h. After the reaction is completed, the reaction solution is warmed to room temperature, 75 mL of 6N hydrochloric acid solution is added, and the mixture is allowed to stand for stratification.
  • Step 4 To a solution of 5.0 g of 4-[5-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid in 130 mL of ethyl acetate was added 2.4 g of 2-amino-N-(2,2-difluorocyclopropyl)acetamide hydrochloride (prepared in Step 2), 0.7 g of 1-hydroxybenzotriazole (HOBt), 1.5 g of triethylamine, and 2.7 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
  • 2-amino-N-(2,2-difluorocyclopropyl)acetamide hydrochloride prepared in Step 2
  • 1-hydroxybenzotriazole (HOBt) 1.5 g
  • triethylamine triethy
  • Step 1 To a solution of 15.0 g of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid (see Example 7, Step 5) in 370 mL of ethyl acetate, add 8.0 g of 2-amino-1-(3,3-difluoroazetidin-1-yl)ethanone hydrochloride (see Example 1, Step 2), 2.4 g of 1-hydroxybenzotriazole (HOBt), and 5.1 g of triethylamine.
  • 2-amino-1-(3,3-difluoroazetidin-1-yl)ethanone hydrochloride see Example 1, Step 2
  • Step 1 To a solution of 9.5 g of N-Boc-glycine in 250 mL of ethyl acetate, add 9.3 g of 3,3-difluorocyclobutylamine hydrochloride, 3.7 g of 1-hydroxybenzotriazole (HOBt), and 7.6 g of triethylamine (TEA) while stirring at room temperature. Then, add 7.4 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI). Stir at room temperature for 3 h. Remove the solvent by distillation under reduced pressure to obtain a concentrate.
  • HABt 1-hydroxybenzotriazole
  • EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • Step 2 Add 150 mL of 4 M hydrogen chloride in dioxane to the concentrate obtained in Step 1. React at room temperature for 2 h. Remove approximately 150 mL of solvent by distillation under reduced pressure. Stir the reaction mixture at room temperature, add 100 mL of ethyl acetate, stir for 1 h, and filter. Rinse the filter cake with n-heptane and dry at 60°C to yield 10.2 g of 2-amino-N-(3,3-difluorocyclobutyl)acetamide hydrochloride.
  • Step 3 To a solution of 4.0 g of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid (see Example 7, Step 5) in 100 mL of ethyl acetate, add 2.3 g of 2-amino-N-(3,3-difluorocyclobutyl)acetamide hydrochloride, 0.6 g of 1-hydroxybenzotriazole (HOBt), and 1.4 g of triethylamine. Add 2.4 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI).
  • EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • Step 1 To a solution of 5.3 g of 4-[5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid (see Example 1, Step 5) in 140 mL of ethyl acetate, add 2.7 g of 2-amino-N-(3,3-difluorocyclobutyl)acetamide hydrochloride (see Example 17, Step 2), 0.9 g of 1-hydroxybenzotriazole (HOBt), and 1.5 g of triethylamine.
  • 2-amino-N-(3,3-difluorocyclobutyl)acetamide hydrochloride see Example 17, Step 2
  • Step 1 To a solution of 5.5 g of 4-[5-(3,4,5-trichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid (see Example 2, Step 3) in 140 mL of ethyl acetate, 2.7 g of 2-amino-N-((3,3-difluorocyclobutyl)acetamide hydrochloride (see Example 17, Step 2), 0.9 g of 1-hydroxybenzotriazole (HOBt) and 1.5 g of triethylamine were added. 3.3 g of 1-(3-dimethylamino)-1-nitropropane was added.
  • Step 1 To a solution of 4.6 g 4-[5-(3-chloro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid (see Example 3, Step 3) in 120 mL of ethyl acetate, 2.4 g 2-amino-N-((3,3-difluorocyclobutyl)acetamide hydrochloride (see Example 17, Step 2), 0.7 g 1-hydroxybenzotriazole (HOBt) and 1.4 g triethylamine were added. 2.5 g 1-(3-dimethylaminopropyl)propanediol were added.
  • Step 1 To a solution of 4.8 g of 4-[5-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid (see Step 3 of Example 11) in 120 mL of ethyl acetate, 2.4 g of 2-amino-N-((3,3-difluorocyclobutyl)acetamide hydrochloride (see Step 2 of Example 17), 0.7 g of 1-hydroxybenzotriazole (HOBt) and 1.4 g of triethylamine were added.
  • HOBt 1-hydroxybenzotriazole
  • Step 2 Add 100 mL of 4 M hydrogen chloride in dioxane to the concentrate obtained in Step 1 and react at room temperature for 2 h. Remove approximately 100 mL of solvent by distillation under reduced pressure. Stir the reaction mixture at room temperature, add 70 mL of ethyl acetate, stir for 1 h, and filter. Rinse the filter cake with n-heptane and dry at 60°C to obtain 4.2 g of 2-amino-N-(3-(trifluoromethyl)azetidin-1-yl)acetamide hydrochloride.
  • Step 3 To a solution of 4.0 g of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid (see Example 7, Step 5) in 100 mL of ethyl acetate, add 2.5 g of 2-amino-N-(3-(trifluoromethyl)azetidin-1-yl)acetamide hydrochloride, 0.6 g of 1-hydroxybenzotriazole (HOBt), and 1.4 g of triethylamine. Add 2.4 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI).
  • EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • Step 1 To a solution of 1.8 g of 4-[5-(3-chloro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid (see Example 3, Step 3) in 50 mL of ethyl acetate, add 1.0 g of 2-amino-N-(3-(trifluoromethyl)azetidin-1-yl)acetamide hydrochloride (see Example 22, Step 2), 0.3 g of 1-hydroxybenzotriazole (HOBt), and 0.6 g of triethylamine.
  • 2-amino-N-(3-(trifluoromethyl)azetidin-1-yl)acetamide hydrochloride see Example 22, Step 2
  • HOBt 1-hydroxybenzotriazole
  • triethylamine triethylamine
  • Step 1 To a solution of 10.0 g of N-Boc-glycine in 250 mL of ethyl acetate, add 11.1 g of 1-trifluoromethylcyclopropylamine hydrochloride, 3.8 g of 1-hydroxybenzotriazole (HOBt), and 8.0 g of triethylamine (TEA) while stirring at room temperature. Then, add 14.3 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI). Stir at room temperature for 3 h. Remove the solvent by distillation under reduced pressure to obtain a concentrate.
  • 1-trifluoromethylcyclopropylamine hydrochloride 3.8 g of 1-hydroxybenzotriazole (HOBt)
  • TEA 1-hydroxybenzotriazole
  • EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • Step 2 Add the concentrate obtained in Step 1 to 250 mL of 4 M hydrogen chloride in dioxane and react at room temperature for 2 h. Remove approximately 250 mL of solvent by distillation under reduced pressure. Stir the reaction mixture at room temperature, add 150 mL of ethyl acetate, stir for 1 h, and filter. Rinse the filter cake with n-heptane and dry at 60°C to yield 9.6 g of 2-amino-N-(1-(trifluoromethyl)cyclopropyl)acetamide hydrochloride.
  • Step 3 To a solution of 5.0 g of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid (see Example 7, Step 5) in 130 mL of ethyl acetate, add 3.2 g of 2-amino-N-(1-(trifluoromethyl)cyclopropyl)acetamide hydrochloride, 0.8 g of 1-hydroxybenzotriazole (HOBt), and 1.7 g of triethylamine. Add 2.4 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI).
  • EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • Step 1 To a solution of 8.0 g of N-Boc-glycine in 200 mL of ethyl acetate, add 6.5 g of 1-amino-1-cyclopropylcyanide hydrochloride, 3.1 g of 1-hydroxybenzotriazole (HOBt), and 6.5 g of triethylamine (TEA) while stirring at room temperature. Then, add 11.4 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI). After the addition is complete, stir at room temperature for 3 h. Remove the solvent by distillation under reduced pressure to obtain a concentrate.
  • 1-amino-1-cyclopropylcyanide hydrochloride 3.1 g of 1-hydroxybenzotriazole (HOBt)
  • TEA 1-hydroxybenzotriazole
  • EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • Step 2 Add the concentrate obtained in Step 1 to 200 mL of 4 M hydrogen chloride in dioxane and allow to react at room temperature for 2 h. Remove approximately 200 mL of solvent by distillation under reduced pressure. Stir the reaction mixture at room temperature, add 120 mL of ethyl acetate, stir for 1 h, and filter. Rinse the filter cake with n-heptane and dry at 60°C to yield 6.5 g of 2-amino-N-(1-cyanocyclopropyl)acetamide hydrochloride.
  • Step 3 To a solution of 11.9 g of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid (see Example 7, Step 5) in 300 mL of ethyl acetate, add 6.0 g of 2-amino-N-(1-cyanocyclopropyl)acetamide hydrochloride, 1.9 g of 1-hydroxybenzotriazole (HOBt), and 4.0 g of triethylamine. Add 7.1 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI).
  • EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
  • Test Example 1 In vitro mite contact activity inhibition test at different concentrations
  • the contact killing effect and effective concentration of the compound of the present invention on Dermanyssus gallinae were evaluated by the filter paper film method.
  • Test drugs Compounds 1, 2, 3, 4, 5, and 6, and fluralaner (99.6%). First, mix propylene glycol and Tween 80 at a ratio of 1:3 (w/w) at 40°C. Then, weigh a certain amount of compound to prepare a 1% (w/v) solution. Dilute with water to the target concentration before use.
  • Test materials Neutral filter paper (size: 7 ⁇ 10 cm). Dermanyssus gallinae were obtained from clinical sources and cultured to a consistent physiological state.
  • test compounds 1-6 and flurellanine were diluted with purified water to 5 ⁇ g/mL, 10 ⁇ g/mL, and 20 ⁇ g/mL, respectively. The solution was then soaked in neutral filter paper, air-dried, folded, and bound to prepare filter paper bags. Three replicates were used for each concentration. Approximately 20 Dermanysus gallinae mites were selected using a liner pen and placed into each filter paper bag. The bags were sealed and incubated in a climate chamber for 48 hours. The mortality of the mites in the filter paper bags at different concentrations was then observed and the mortality rate was calculated.
  • Mortality rate (%) (treatment mortality rate - blank control mortality rate) / (1 - blank control mortality rate) ⁇ 100%.
  • the compounds of the present application exhibited significant contact killing activity against Dermanyssus gallinae at various concentrations, and this activity was dose-dependent, with the highest killing activity at 20 ⁇ g/mL. Compared to the control compound, flurralan, the compounds of the present application exhibited superior contact killing activity.
  • Test Example 2 In vitro mite contact activity inhibition test at the same concentration
  • Test drug Compound 1-25. First, mix propylene glycol and Tween 80 at a ratio of 1:3 (w/w) at 40°C. Then, weigh a certain amount of compound to prepare a 1% (w/v) solution. Dilute with water to the target concentration before use.
  • Test materials Neutral filter paper (size: 7 ⁇ 10 cm). Dermanyssus gallinae were obtained from clinical sources and cultured to a consistent physiological state.
  • test compound 1-25 was diluted with purified water to 20 ⁇ g/mL. The solution was then soaked in neutral filter paper, air-dried, folded, and bound to prepare filter paper bags. Three replicates were used for each concentration. Approximately 20 Dermanysus gallinae mites were selected using a liner pen and placed into each filter paper bag. The bags were sealed and incubated in a climate chamber for 48 hours. The mortality of the mites in the filter paper bags at different concentrations was observed and the mortality rate was calculated. The mortality rate was calculated using the same formula as in Test Example 1.
  • the compound of the present application has a high contact killing activity against Dermanyssus gallinae at a concentration of 20 ⁇ g/mL.
  • Test Example 3-1 Chicken Mite Killing Test of Compound 1-6
  • Test drugs Compounds 1, 2, 3, 4, 5 and 6, dosage: 0.5 mg/kg or 0.3 mg/kg.
  • Test Animals Laying hens. Approximately 200 laying hens were used for each compound. (Laying hens and eggs were managed and recovered uniformly.)
  • Test Example 3-2 Comparative test of compound 4 and flurella in killing chicken mites
  • Test drug Compound 4, dosage: 0.2 mg/kg, 0.15 mg/kg, 0.1 mg/kg or 0.05 mg/kg. Flurella, dosage: 0.5 mg/kg
  • Test Animals Laying hens. Approximately 200 laying hens were used for each compound. (Laying hens and eggs were managed and recovered uniformly.)
  • Test Example 4 Test on killing fleas on dogs and cats
  • Test animals 6 dogs naturally infested with fleas. Each dog was counted for fleas using a comb cleaner, and the number of fleas on each dog was more than 10.
  • test dogs were weighed and an appropriate amount of the test solution was orally administered at one time based on their body weight. Two dogs were given compound 1, compound 2, and compound 4 respectively. The number of fleas on the body surface of each test dog was counted using a comb cleaner 3 days, 10 days, and 30 days after administration.
  • Test Example 4-2 Flea Killing Test on Dogs and Cats
  • Test animals Two dogs and two cats naturally infested with fleas. The flea count on each dog was performed using a comb cleaner, and the number of fleas on each dog was more than 10.
  • test dogs and cats were weighed and an appropriate amount of the test solution of Compound 4 was orally administered once according to their body weight.
  • the number of fleas on the body surface of two dogs and two cats was counted using a comb cleaner 3 days, 10 days, 30 days, and 60 days after administration.
  • Test drugs Compounds 1, 2, 3, 4, 5 and 6, and flurbiprofen.
  • the test drug was administered orally at a single dose of 0.5 mg/kg. Chickens were restrained in lateral recumbency and blood was collected from the subwing vein. Blood (1.5 mL) was collected before and at 0.5, 1, 2, 4, 8, 24, 48, 72, 96, 120, 144, 168, 240, 336, 408, and 504 hours after dosing. The blood was placed in a centrifuge tube containing sodium heparin and centrifuged at 4000 rpm for 10 minutes. The supernatant was collected and stored at -20°C. After thawing, 0.2 mL of plasma was accurately pipetted into a 10 mL centrifuge tube.
  • the compound of the present application is rapidly absorbed orally, has a rapid onset of action, and a long half-life. Compared with flurellan, it has higher peak concentrations, higher blood exposure, and a longer elimination half-life, offering advantages such as a smaller dosage and longer-lasting efficacy.
  • the leaf tube pellicle method was used to evaluate the killing effect of the compounds of the present application on Thrips palmi.
  • Test drugs Compounds 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 13, 14, 15, and 19.
  • Test materials Fresh cabbage leaves. Adult Thrips palmi were obtained from a clinical setting and cultured to a consistent physiological state.
  • Test Example 1 Prepare a 1% stock solution according to Test Example 1, and dilute the test compound solution with purified water to 50 mg/L, 10 mg/L, and 2 mg/L, respectively.
  • leaf tube film method use a hole punch to punch round fresh cabbage leaves and immerse them in the drug solution. After the drug solution on the leaf surface has dried naturally, place them in a centrifuge tube. Connect a sucker to the perforated centrifuge tube to suck out adult palm thrips, seal the tube, and place it in a light incubator. After 48 hours, check and record the mortality of palm thrips in each treatment.
  • the test uses clean water as a blank control. Each treatment and control is replicated three times, with approximately 40 palm thrips adults in each replicate. Calculate the insect mortality rate using the same formula as Test Example 1.
  • the leaf dip method was used to evaluate the killing effect of the compounds of the present application on Asian corn borer.
  • Test drugs Compounds 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 13, 14, 15, 17, 19, and 22.
  • Test materials Fresh young corn leaves. Second-instar larvae of Ostrinia furnacalis were obtained from a clinic and cultured to a consistent physiological state.
  • Test Example 1 Prepare a 1% stock solution as in Test Example 1 and dilute the test compound solution with purified water to 50 mg/L, 10 mg/L, and 2 mg/L, respectively.
  • leaf-dip method dip fresh corn leaves into the drug solution at varying concentrations. After drying in the shade, place them in 12-well plates. Inoculate one second-instar corn borer larva into each well and place them in a lighted incubator. After 48 hours, examine and record the number of dead O. corn borers from each treatment. Insects that fail to move after being gently touched with a brush tip are considered dead. Use the water treatment as a blank control. Each treatment is replicated three times, with 15 larvae tested per replicate. Calculate mortality using the same formula as in Test Example 1.
  • the compounds with a corn borer mortality rate greater than 95% are 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 13, 14, 15, and 19; when the concentration is 10 mg/L, the compounds with a corn borer mortality rate greater than 90% are 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 14, 15, and 19; when the concentration is 2 mg/L, the compounds with a corn borer mortality rate greater than 90% are 2, 4, 5, 8, 9, 11, and 15.
  • the leaf dipping method was used to evaluate the killing effect of the compounds of the present application on fall armyworm.
  • Test drugs Compounds 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 13, 14, 15, and 19.
  • Test materials Fresh young corn leaves. Second-instar larvae of Spodoptera frugiperda were obtained from a clinical setting and cultured to a consistent physiological state.
  • Test Example 1 Prepare a 1% stock solution according to Test Example 1, and dilute the test compound solution with purified water to 4 mg/L, 1 mg/L, and 0.25 mg/L, respectively.
  • the leaf immersion method immerse fresh corn leaves in different concentrations of the solution, take them out and dry them in the shade, and place them in 12-well plates. Inoculate one second-instar larva of the fall armyworm into each well and place them in a light incubator. After 48 hours, check and record the number of dead fall armyworms in each treatment. Those that cannot crawl when lightly touched with a brush tip are considered dead. Use clean water as a blank control, and set up 3 replicates for each treatment, with 15 fall armyworm larvae tested in each replicate. Calculate the insect mortality rate using the same calculation formula as in Test Example 1.
  • the compounds with a mortality rate of more than 90% for fall armyworm are 3, 4, 5, 6, 8, 9, 10, 11, 15, and 19; when the concentration is 1 mg/L, the compounds with a mortality rate of more than 90% for fall armyworm are 3, 4, 5, 6, 8, 9, 10, and 19; when the concentration is 0.25 mg/L, the compounds with a mortality rate of more than 90% for fall armyworm are 3, 4, 5, and 10.
  • the agar moisturizing leaf dip method was used to evaluate the killing effect of the compounds of the present application on Bemisia tabaci.
  • Test drugs Compounds 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 13, 14, 15, 17, and 19.
  • Test materials Fresh cotton leaves. Adult Bemisia tabaci were obtained from a clinical setting and cultured to a consistent physiological state.
  • the compounds with a mortality rate of more than 80% for whiteflies are 1, 2, 4, 5, 6, 8, 10, 11, and 13; when the concentration is 4 mg/L, the compounds with a mortality rate of more than 80% for whiteflies are 11 and 13; when the concentration is 1 mg/L, the compounds with a mortality rate of more than 80% for whiteflies are 11 and 13.
  • Test Example 10 Insecticidal test on Bactrocera dorsalis
  • the killing effect of the compound of the present application on Bactrocera dorsalis was evaluated by the finger-shaped tube drug film method.
  • Test drugs Compounds 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 13, 14, 15, and 19.
  • Test materials Fresh apple slices. Adult Bactrocera dorsalis flies were obtained from a clinical setting and cultured to a consistent physiological state.
  • Test Example 1 Prepare a 1% stock solution as in Test Example 1 and dilute the test compound solution with purified water to 4 mg/L, 1 mg/L, and 0.25 mg/L, respectively.
  • Using the finger tube pellicle method add the test solution to a glass finger tube and roll thoroughly on a tube roller until dry to form a uniform pellicle tube. Soak sliced apples in the test solution and place them in the glass finger tube. Place adult Bactrocera dorsalis in the tube and seal the tube tightly. Observe the adults for mortality after 48 hours. Immobility is considered fatal if gently touched with tweezers. Each replicate consists of 10 individuals, with three replicates per treatment. Calculate mortality using the same formula as in Test Example 1.
  • the compounds with mortality rates of more than 95% for the oriental fruit fly are 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 13, 14, 15, and 19; when the concentration is 1 mg/L, the compounds with mortality rates of more than 90% for the oriental fruit fly are 1, 2, 3, 4, 6, 9, 10, 11, 13, 14, and 19; when the concentration is 0.25 mg/L, the compounds with mortality rates of more than 80% for the oriental fruit fly are 1, 6, 9, and 10.

Landscapes

  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plant Pathology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Pest Control & Pesticides (AREA)
  • Wood Science & Technology (AREA)
  • Agronomy & Crop Science (AREA)
  • Health & Medical Sciences (AREA)
  • Dentistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Insects & Arthropods (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente demande concerne un composé d'isoxazoline tel que représenté dans la formule (I), une composition pharmaceutique de celui-ci, et son utilisation dans la prévention ou le traitement d'une infestation ou d'une infection par des parasites animaux. Le composé présente d'excellentes activités insecticides et acaricides contre les parasites internes ou externes des mammifères, de la volaille ou des poissons.
PCT/CN2025/089797 2024-04-19 2025-04-18 Composé d'isoxazoline et son utilisation Pending WO2025218782A1 (fr)

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
CN202410482503.0 2024-04-19
CN202410482503 2024-04-19
CN202410961683.0 2024-07-17
CN202410961683 2024-07-17
CN202510285881 2025-03-11
CN202510285881.4 2025-03-11
CN202510465216 2025-04-11
CN202510465216.3 2025-04-11

Publications (1)

Publication Number Publication Date
WO2025218782A1 true WO2025218782A1 (fr) 2025-10-23

Family

ID=97403004

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2025/089797 Pending WO2025218782A1 (fr) 2024-04-19 2025-04-18 Composé d'isoxazoline et son utilisation

Country Status (1)

Country Link
WO (1) WO2025218782A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1930136A (zh) * 2004-03-05 2007-03-14 日产化学工业株式会社 异噁唑啉取代苯甲酰胺化合物及有害生物防除剂
CN101815706A (zh) * 2007-06-13 2010-08-25 杜邦公司 异*唑啉杀昆虫剂
CN103705509A (zh) * 2007-08-17 2014-04-09 英特威国际有限公司 异噁唑啉组合物及其作为抗寄生虫药的用途
CN106459019A (zh) * 2014-02-26 2017-02-22 巴斯夫欧洲公司 唑啉类化合物
WO2023037253A1 (fr) * 2021-09-08 2023-03-16 Pi Industries Ltd Composés d'isoxazoline et leur utilisation en tant qu'agents de lutte contre les nuisibles
CN116874440A (zh) * 2023-06-21 2023-10-13 贵州大学 含异噁唑啉类衍生物的合成及其应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1930136A (zh) * 2004-03-05 2007-03-14 日产化学工业株式会社 异噁唑啉取代苯甲酰胺化合物及有害生物防除剂
CN101815706A (zh) * 2007-06-13 2010-08-25 杜邦公司 异*唑啉杀昆虫剂
CN103705509A (zh) * 2007-08-17 2014-04-09 英特威国际有限公司 异噁唑啉组合物及其作为抗寄生虫药的用途
CN106459019A (zh) * 2014-02-26 2017-02-22 巴斯夫欧洲公司 唑啉类化合物
WO2023037253A1 (fr) * 2021-09-08 2023-03-16 Pi Industries Ltd Composés d'isoxazoline et leur utilisation en tant qu'agents de lutte contre les nuisibles
CN116874440A (zh) * 2023-06-21 2023-10-13 贵州大学 含异噁唑啉类衍生物的合成及其应用

Similar Documents

Publication Publication Date Title
JP6117815B2 (ja) ホウ素含有小分子
JP6118812B2 (ja) 外部寄生生物の制御に使用されるイソキサゾリン誘導体
JP5806743B2 (ja) 抗寄生虫薬としてのスピロ環式イソオキサゾリン誘導体
ES2632265T3 (es) Azinas sustituidas como plaguicidas
JP2016505536A (ja) 駆虫性化合物及び組成物並びにこれらの使用方法
TW201024289A (en) Organic compounds
JP2013523805A (ja) 殺虫剤および殺ダニ剤としての置換３，５−ジフェニル−イソオキサゾリン誘導体
EA023711B1 (ru) Антипаразитарные соединения, способы и составы
JP2008514610A (ja) 新規トリフルオロメタンスルホンアニリドオキシムエーテル誘導体の使用による動物における寄生虫の制御
AU2018204015B2 (en) Novel sulfonylaminobenzamide compounds as anthelmintics
EP2900065A1 (fr) Dérivés d&#39;isoxazoline spirocyclique pour le traitement des poux de mer
JP2015505560A (ja) 抗寄生虫薬としてのキラルイソオキサゾリンアゼチジン誘導体の製造法
CN112424170A (zh) 用于控制节肢动物的新型化合物
JP2014510095A (ja) 抗寄生虫薬としてのイソオキサゾリン誘導体
JP5997779B2 (ja) 抗寄生虫薬としてのジヒドロフランアゼチジン誘導体
CA2779563C (fr) Composes d&#39;amidoacetonitrile dotes d&#39;une activite pesticide
JP4242156B2 (ja) ハロゲン置換キノリン誘導体および外部寄生虫防除剤
WO2025218782A1 (fr) Composé d&#39;isoxazoline et son utilisation
JP6140373B2 (ja) 新規化合物
AU2009324074B2 (en) Amidoacetonitrile compounds and pesticidal composition thereof
CN120172906B (zh) 含有三氟烷硫苯基杂环衍生物的制备与应用
JP2016505587A (ja) 新規化合物
JP4759679B2 (ja) テトラヒドロベンゾトリアジン誘導体
CN120682190A (zh) 一种防治动物体外寄生虫的方法
JPH0692935A (ja) Ｎ置換インドール誘導体、その製造方法およびそれを有効成分とする殺虫組成物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25790042

Country of ref document: EP

Kind code of ref document: A1