Isoxazoline compound and use thereof

Abstract

Provided in the present application are an isoxazoline compound as shown in formula (I), a pharmaceutical composition thereof, and the use thereof in the prevention or treatment of infestation or infection by animal parasites. The compound has excellent insecticidal and acaricidal activities against internal or external parasites of mammals, poultry or fishes.

Description

Isoxazoline compounds and uses thereof

[0001] This application claims priority to the Chinese patent application No. CN202410482503.0, filed on April 19, 2024, entitled “Isoxazoline compounds and uses thereof”, the Chinese patent application No. CN202410961683.0, filed on July 17, 2024, entitled “Isoxazoline compounds and uses thereof”, the Chinese patent application No. CN202510285881.4, filed on March 11, 2025, entitled “Isoxazoline compounds and uses thereof”, the Chinese patent application No. CN202510465216.3, filed on April 11, 2025, entitled “Isoxazoline compounds and uses thereof”, all of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0002] The present application relates to a new class of isoxazoline compounds, pharmaceutical compositions thereof and their use in the control of pests in agriculture, non-agriculture, livestock and pet care. BACKGROUND

[0003] Isoxazoline compounds are a class of effective insecticides and acaricides, which can interfere with the transmembrane signal transmission of the nervous system by antagonizing the gamma-aminobutyric acid receptor and glutamate receptor gate-activated chloride ion channels, so that chloride ions cannot penetrate into the postsynaptic membrane, leading to disorder of the insect nervous system and then death. As an important class of antiparasitic drugs, isoxazoline compounds have attracted much attention due to their high insecticidal activity, wide spectrum of antiparasitic spectrum and good safety. In agriculture, non-agriculture, livestock and pet care, isoxazoline drugs are widely used for the prevention and treatment of various parasitic infections or infestations.

[0004] However, due to the wide variety of insecticidal drugs on the market and long-term use, the drug resistance of products is becoming increasingly serious, at the same time, the residue problem of some drugs has also attracted the attention of the public and regulatory agencies, especially in food animals, long-term drug residues can damage the ecosystem and pose a risk to human health. Therefore, there is an urgent need to develop a new type of compound with high efficiency, economy, ease of use, low toxicity and greater safety to the environment. SUMMARY

[0005] The present application aims to provide a new class of isoxazoline compounds, pharmaceutical compositions containing the compounds and their use in the control of pests.

[0006] The first aspect of the present application provides a compound represented by formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0007] wherein,

[0008] Ring A is selected from 5-10 membered aryl, which is optionally substituted with one or more R x substituents;

[0009] R1, R2, R3are each independently selected from H, halogen or C1-C6haloalkyl;

[0010] X is selected from -C(O)-, -S(O)2-;

[0011] R5is selected from hydrogen, C1-C6alkyl, C1-C6alkoxy;

[0012] R6is selected from C3-C8cycloalkyl, which is optionally substituted with halogen, C1-C6alkyl, C1-C6haloalkyl, -CN; or,

[0013] R5, R6together with the nitrogen atom to which they are attached form a 3-6 membered heterocyclic ring, which is optionally substituted with halogen, C1-C6alkyl, C1-C6haloalkyl, -CN;

[0014] R x is selected from H, C1-C6alkyl;

[0015] n is selected from an integer of 0, 1 or 2.

[0016] In some embodiments, the R1, R2, R3are each independently selected from H, halogen or C1-C6haloalkyl; the halogen is preferably F, Cl, and the C1-C6haloalkyl is preferably CF3.

[0017] In some embodiments, the is selected from the following structures:

[0018] In some embodiments, the ring A as described above is selected from 5-6 membered aryl, which is optionally substituted with one or more R x substituents, wherein R x are as defined above.

[0019] In some embodiments, the ring A is selected from the following structures:

[0020] wherein R x and n are as defined above.

[0021] In some embodiments, the ring A is preferably selected from the following structures:

[0022] wherein * represents the connection to X.

[0023] In some embodiments, X is selected from -C(O)-.

[0024] In some embodiments, R1, R2, R3are each independently selected from H, halogen, CF3.

[0025] In some embodiments, R5is selected from hydrogen; R6is selected from C3-C4cycloalkyl, and the C3-C4cycloalkyl is optionally substituted with one or more halogen, CF3, CN.

[0026] In some embodiments, R5, R6together with the nitrogen atom to which they are attached form a four-membered heterocyclic ring, which is optionally substituted with one or more halogen, CF3.

[0027] In some embodiments, R1, R2, R3are each independently selected from H, halogen, CF3. preferably from the following structures:

[0028] In some embodiments, R1, R2, R3are each independently selected from H, halogen, CF3. preferably from the following structures:

[0029] The second aspect of the present application provides a compound represented by formula (II), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0030] wherein R1, R2, R3, R5and R6are as defined in the first aspect of the present application.

[0031] The third aspect of the present application provides a compound represented by formula (III), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0032] The fourth aspect of the present application provides a pharmaceutical composition comprising a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to the first, second or third aspect of the present application and one or more pharmaceutically acceptable carriers.

[0033] The fifth aspect of the present application provides use of a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof according to the first, second or third aspect of the present application, or a pharmaceutical composition according to the fourth aspect of the present application in the manufacture of a medicament for the control of harmful organisms.

[0034] In some embodiments, the medicament in the use described above is for preventing or treating parasitic infestation or infection in an animal.

[0035] In some embodiments, the medicament for use described above can be applied to the locus of the pest or to a plant susceptible to attack by the pest.

[0036] In some embodiments, the medicament for use described above is an antiparasitic agent, preferably an antiparasitic agent against invertebrate parasites.

[0037] In some embodiments, the parasite in the use described above is an ecto- or endoparasitic invertebrate pest; preferably an arthropod; more preferably a fly, mosquito, mite, louse, flea, maggot, tick, bed bug or kissing bug; further preferably a flea, tick, mite or louse.

[0038] In some embodiments, the animal in the use described above is a mammal, an avian or a fish; preferably a canine, a feline, an equine, a poultry or a livestock; more preferably a dog, a cat, a chicken, a sheep, a cow or a pig.

[0039] In some embodiments, the medicament for use described above is for treating flea, tick or mite infestation on the body surface of a dog.

[0040] In some embodiments, the medicament for use described above is for treating mite infestation on the body surface of a poultry. The sixth aspect of the present application provides a method for controlling pests, comprising administering an effective treatment amount of the compound, stereoisomer thereof or pharmaceutically acceptable salt thereof of the first, second or third aspect of the present application or the pharmaceutical composition of the fourth aspect of the present application.

[0041] In some embodiments, the method described above can be applied to the locus of the pest or to a plant susceptible to attack by the pest.

[0042] In some embodiments, the method described above is for preventing or treating a parasitic infestation or infection in an animal.

[0043] In some embodiments, the method described above is for combating parasites, preferably for killing invertebrate parasites.

[0044] In some embodiments, the parasite in the method described above is an ecto- or endoparasitic invertebrate pest; preferably an arthropod; more preferably a fly, mosquito, mite, louse, flea, maggot, tick, bed bug or kissing bug; further preferably a flea, tick, mite or louse.

[0045] In some embodiments, the animal in the method described above is a mammal, an avian or a fish; preferably a canine, a feline, an equine, a poultry or a livestock; more preferably a cat, a dog, a chicken, a sheep, a cow or a pig.

[0046] In some embodiments, the method described above is for treating flea, tick or mite infestation on the body surface of a dog.

[0047] In some embodiments, the above method is used to treat a flea infestation on the body surface of a dog.

[0048] Another aspect of the present application provides the above compound, stereoisomer thereof or pharmaceutically acceptable salt thereof or pharmaceutical composition containing the above compound, stereoisomer thereof or pharmaceutically acceptable salt thereof for use in pest control.

[0049] In some embodiments, the above pest control is for preventing or treating a parasitic infestation or infection in an animal.

[0050] In some embodiments, the above pest control can be applied to the locus of the pest or the plant susceptible to attack by the pest.

[0051] In some embodiments, the above pest control is anti-parasitic, preferably against invertebrate parasitic pests.

[0052] In some embodiments, the above parasite is an ecto- or endo-parasitic invertebrate parasitic pest; preferably an arthropod; more preferably a fly, mosquito, mite, louse, flea, maggot, tick, bed bug or kissing bug; further preferably a flea, tick, mite or louse.

[0053] In some embodiments, the above animal is a mammal, avian, or fish; preferably a canine, feline, equine, poultry or livestock; more preferably a cat, dog, chicken, sheep, cow or pig.

[0054] In some embodiments, the above pest control is for treating a flea, tick or mite infestation on the body surface of a dog.

[0055] In some embodiments, the above pest control is for treating a mite infestation on the body surface of a bird.

[0056] Technical effects:

[0057] The compound of the present application has excellent insecticidal activity against external parasites of mammals, avians or fish, especially for the prevention and killing of mites, fleas and ticks, and has good efficacy; at the same time, it does not produce adverse effects on mammals, avians or fish, and is safer to the environment. BRIEF DESCRIPTION OF DRAWINGS

[0058] The accompanying drawings, which are included to provide a further understanding of the present application and are incorporated in and constitute a part of this application, illustrate embodiments of the present application and serve to explain the present application.

[0059] Figure 1 is a graph showing the mean plasma concentration of compound 1 over time;

[0060] Figure 2 is a plot of mean plasma concentration of Compound 2 versus time;

[0061] Figure 3 is a plot of mean plasma concentration of Compound 3 versus time;

[0062] Figure 4 is a plot of mean plasma concentration of Compound 4 versus time;

[0063] Figure 5 is a plot of mean plasma concentration of Compound 5 versus time;

[0064] Figure 6 is a plot of mean plasma concentration of Compound 6 versus time;

[0065] Figure 7 is a plot of mean plasma concentration of fluoxetine versus time. DETAILED DESCRIPTION

[0066] Explanations and Definitions:

[0067] Unless otherwise indicated, the following terms and phrases used herein have the following meanings. A particular term or phrase should not be construed to be indefinite or unclear unless specifically defined, but should be interpreted in accordance with the ordinary meaning.

[0068] The term "pharmaceutically acceptable" means those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit / risk ratio.

[0069] The term "pharmaceutically acceptable salt" means a derivative of a compound of the present application produced by reaction with a relatively nontoxic acid or base. These salts can be prepared in situ during the synthesis, isolation, and purification of the compound, or separately by reacting the purified compound with a suitable acid or base. When a compound contains relatively acidic functionalities (for example, -COOH, -OH, -SO3H, etc.), base addition salts can be formed with suitable inorganic or organic cations (bases), including alkali or alkaline earth metal salts, ammonium salts, salts with amino acids, and the like. When a compound contains relatively basic functionalities (for example, -NH2, etc.), acid addition salts can be formed with suitable inorganic or organic acids (acids), including inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and the like; and organic acids such as carboxylic acids, glycolic acid, lactic acid, pyruvic acid, oxalic acid, maleic acid, methanesulfonic acid, etc.

[0070] The term "pharmaceutically acceptable carrier" refers to a medium generally accepted in the art for the delivery of biologically active agents to animals, particularly mammals, and includes, as non-limiting examples, adjuvants, excipients or vehicles, such as diluents, preservatives, fillers, flow conditioners, disintegrants, wetting agents, emulsifiers, suspending agents, sweetening agents, flavoring agents, perfuming agents, antibacterial agents, antifungal agents, lubricating agents, and dispersing agents, depending upon the nature of the dosage form and the means of administration. Pharmaceutically acceptable carriers are formulated in accordance with routine procedures, as is understood in the art, and are within the scope of ordinary skill in the art. They include, but are not limited to: the type and nature of the active pharmaceutical 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 therapeutic indication for which the agent is being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media, as well as a variety of solid and semi-solid dosage forms. Such carriers include a number of different ingredients and additives, in addition to the active pharmaceutical agent, which are included in the formulation for a variety of reasons (e.g., to stabilize the active pharmaceutical agent, to bind the agents, etc.), and such additional ingredients are well known to those of ordinary skill in the art. The term "isotopic derivatives" refers to compounds in which at least one atom has been replaced by an atom having the same atomic number but an atomic mass different from the atomic mass of the atom it has replaced. Examples of isotopes of atoms included in the compounds of the present application include, but are not limited to, isotopes of hydrogen, such as deuterium (2H), tritium (3H); isotopes of carbon, such as11C,13C, and14C; isotopes of chlorine, such as36Cl; isotopes of fluorine, such as18F; isotopes of iodine, such as123I and125I; isotopes of nitrogen, such as13N and15N; isotopes of oxygen, such as15O,17O, and18O; isotopes of phosphorus, such as32P; and isotopes of sulfur, such as35S. Isotopically-labeled compounds of the present application can generally be prepared by conventional techniques known to those with ordinary skill in the art, or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent.

[0071] The term "prodrug" refers to certain derivatives of compounds of the present application which have little or no pharmacological activity themselves, but which are converted in vivo to the compounds of the present application by, for example, solvolysis or under physiological conditions. The types of prodrugs encompassed are well known in the art (see, e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, N.Y.). Such prodrugs include, but are not limited to, ester, amide, anhydride, salt, and the like. The term "ester" refers to a derivative of a compound of the present application when it contains an acidic group (such as a carboxylic acid) with a suitable alcohol; and a derivative of a compound of the present application when it contains a hydroxyl group with a suitable acid (including an organic or inorganic acid). Methods of making prodrugs are well known to those skilled in the art.

[0072] The term "solvate" refers to an association or complex of one or more solvent molecules and a compound of the present application. When the solvent is water, the term "hydrate" can be used synonymously with solvate. The solvent molecule can be stoichiometrically or non-stoichiometrically associated with the compound of the present application. Methods of making solvates are known in the art.

[0073] The term "nitroso" or "N-oxide" refers to derivatives formed by the further oxidation of a nitrogen atom in a nitrogen-containing group. Common N-oxides include N-oxides of tertiary amines or N-oxides of nitrogen atoms in nitrogen-containing heterocycles. Methods for the synthesis of N-oxides are well known to those skilled in the art and include the oxidation of heterocycles and tertiary amines with peroxy acids such as peroxyacetic acid and meta-chloroperoxybenzoic acid, hydrogen peroxide, alkylhydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane.

[0074] The compounds of the present application and their salts can exist in isotopically- substituted forms, and the compounds of the present application include various isotopically- substituted forms and mixtures thereof.

[0075] The compounds of the present application and their salts can exist in the form of solvates, such as hydrates, and the compounds of the present application include various solvates and mixtures thereof.

[0076] The compounds of the present application and their salts can exist in the form of "N-oxides", and the compounds of the present application include various N-oxides and mixtures thereof.

[0077] The compounds described in the present application, their pharmaceutically acceptable salts, isotopic derivatives, solvates, N-oxides have the same or similar biological activity, and all of them are included in the scope of the present application.

[0078] When the compounds of the present application are used for the prevention or treatment of external or internal parasites of mammals, birds or fish, an effective amount of the compounds of the present application and the formulation additives can be applied by oral administration; parenteral administration such as injection (intramuscular, subcutaneous, intravenous, intraperitoneal); transdermal administration such as dipping, spraying, bathing, pouring-on, pouring-on, spotting-on and dusting; nasal administration. The compounds of the present application can be administered by using shaped articles such as prongs, flakes, plates, tapes, collars, ear tags, neck tags, limb tags, marker devices, trapping devices, and the like. At the time of administration, the compounds of the present application can be formulated into any dosage form suitable for the administration route.

[0079] The term "effective prophylactic or therapeutic treatment" means an amount of a compound, a pharmaceutically acceptable salt thereof, or an isomer thereof of the present application that is therapeutically sufficient to treat a disorder with a reasonable benefit / risk ratio applicable to any medical treatment and / or prophylaxis. It will be understood, however, that the amount of the total daily dose of a compound of this application or a pharmaceutically acceptable salt thereof and composition will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level of this application will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health status of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.

[0080] The term "stereoisomers" includes "enantiomers" and "diastereomers", "enantiomers" means stereoisomers that are mirror images of one another, and "diastereomers" means stereoisomers that are not mirror images of one another.

[0081] Unless otherwise indicated, the bonds and the dashed wedged bonds represent the absolute configuration of a stereocenter, the straight solid bonds and the straight dashed bonds represent the relative configuration of a stereocenter.

[0082] Stereoisomers of the compounds of the present application can be prepared by chiral synthesis or chiral reagents or other conventional techniques. For example, one enantiomer of a compound of the present application can be prepared by asymmetric catalytic techniques or chiral auxiliary derivatization techniques. Alternatively, a single stereoisomer can be obtained from a mixture by chiral resolution techniques. Or directly prepared from chiral starting materials. The separation of optically pure compounds of the present application is typically accomplished using preparative chromatography on chiral columns to achieve separation of the chiral compounds.

[0083] The absolute stereochemistry of the compounds of the present application can be confirmed by conventional techniques. For example, single crystal X-ray diffraction analysis, or by the chiral structure of the starting materials and the reaction mechanism of asymmetric synthesis. Or after resolution, by comparison with the product of absolute configuration. Compounds of the present application marked as "absolute configuration unknown" are typically resolved from racemic compounds by chiral preparative SFC to single isomers, and then characterized and tested.

[0084] The term "parasite" or "parasitic" refers to ectoparasites (e.g., ticks, lice, fleas, biting mites), endoparasites (e.g., mites), endoparasites (e.g., intestinal parasites, blood parasites, and intracellular parasites), intestinal parasites (e.g., roundworms, hookworms, tapeworms, whipworms), blood parasites (e.g., heartworms, Babesia). The compounds of the present application also have an effect on animal pests and plant pests that show normal susceptibility to the compounds of the present application at all or individual stages of development.

[0085] As the pests which can be controlled by using the compounds of the present application, there are insects, mites, crustaceans, mollusks, etc. Specifically, there are black bean weevils, beetles, etc. of Coleoptera; corn borer, rice leaf roller, rice stem borer, melon leaf roller, Spodoptera litura, Spodoptera exigua, Plutella xylostella, Phthirimaea operculella, Pieris rapae, Agrotis segetum, Plutella xylostella, etc. of Lepidoptera; whitefly, brown stink bug, red stink bug, green stink bug, rice green bug, Comstock mealybug, leafhopper, etc. of Hemiptera; palm thrips, tobacco thrips, six-spotted thrips, western flower thrips, onion thrips, Australian thrips, etc. of Thysanoptera; Bactrocera dorsalis, Liriomyza sativae, Liriomyza trifolii, etc. of Diptera; two-spotted spider mite, Panonychus ulmi, Tetranychus urticae, Polyphagotarsonemus latus, etc. of Acarina. However, the present application is not limited to these.

[0086] According to the general understanding in the art, the term "infestation" is synonymous with the term "infection" and includes the presence of a large number of parasites in the environment (e.g., the housing of humans or animals, the surrounding environment, and plants) that are dangerous to humans, animals, or plants, can be present on the skin or fur of animals or on crops and other types of plants, and also includes the phenomenon of the parasites growing, multiplying, etc. in the body of the host (e.g., in the blood or other internal tissues), such as schistosome infection, trichinosis, etc.

[0087] The term "optionally substituted" or "optionally substituted by" as used herein means either one or more hydrogen atoms in a substituent group can be "replaced" or "not replaced" by one or more substituents.

[0088] When a dash ("-") is present in a substituent group, it is used to indicate that the point of attachment of the substituent group is to the adjacent atom. For example, indicates that the atom to which the group is attached is a bonded atom, for example indicates that the C atom on the pyrimidine ring is a bonded atom. The presence of a dash "-" in a substituent group indicates the point of attachment of the substituent group, for example -CH3 is attached through the C atom. indicates the absolute configuration of a stereocenter, i.e., R or S configuration. indicates the cis or trans configuration, a double solid bond or a double dashed bond indicates the cis configuration, and a solid-dashed bond indicates the trans configuration.

[0089] When a bond of a substituent group can cross-link to a ring, it is intended that the substituent group can be bonded to any atom on the ring. For example, the structural element represents that the substituent group R can be substituted at any position on the phenyl ring.

[0090] When n in the structural element is 0, all of the H substituents on ring A are present by default; when n is 1 or 2, the R x substituents are non-H substituents, and the remaining C (non-R x connected C) on ring A are H by default. When a listed substituent group is not designated as to which atom of the given group or given structural formula the substituent group is attached, then the substituent group can be attached by any bond-able atom thereof.

[0091] When any variable (e.g., R d ) occurs more than one time in a compound or structural formula, its definition on each occurrence is independent of its definition at every other occurrence. For example, represents that the cyclopentyl group is substituted with 3 R d groups, and each R d group has an independent option.

[0092] The term "halogen," unless otherwise specified, represents fluorine, chlorine, bromine, or iodine atoms.

[0093] The term "alkyl," unless otherwise specified, refers to a straight or branched chain saturated aliphatic hydrocarbon radical derived from a parent alkane by the removal of one hydrogen atom. For example, "C 1-10 alkyl" refers to C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 alkyl, "C 1-6 alkyl," "C 1-4 alkyl," "C 1-3 alkyl"; specific examples include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, sec-butyl, 2-methylbutyl, 1,1-dimethylbutyl, and the like.

[0094] The term "haloalkyl," unless otherwise specified, refers to an alkyl group in which one or more hydrogen atoms have been replaced with a halogen atom. Preferably, the haloalkyl group is a haloC 1-6 alkyl group, more preferably a haloC 1-4 alkyl group. Examples of haloalkyl groups include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like. Alkyl groups are as previously defined.

[0095] The term "alkoxy," unless otherwise specified, refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen radical, i.e., "alkyl-O-". Included within the term "alkoxy" are "C 1-6 alkoxy" (structure C1-6 alkyl-O-, "C 1-4 "alkoxy", specific examples include, but are not limited to, methoxy, ethoxy, propyloxy, 1-methylethoxy, butyloxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropyloxy, 1,2-dimethylpropyloxy, and the like; preferably, "alkoxy" as used herein is C 1-6 alkoxy, more preferably C 1-4 alkoxy.

[0096] Unless otherwise specified, the term "haloalkoxy" means a group in which one or more hydrogens of an alkoxy group is replaced by a halogen, preferably "haloalkoxy" as used herein is "halo-C 1-6 alkoxy", "halo-C 1-4 alkoxy". Specific examples as used herein are: fluoromethoxy (including monofluoromethoxy, difluoromethoxy, trifluoromethoxy), -OCH2CF3, -OCHFCH3, and the like. Alkoxy is as previously defined.

[0097] Unless otherwise specified, the term "ring" means a saturated, partially saturated, or unsaturated monocyclic and polycyclic ring, "polycyclic" includes spiro, fused, or bridged rings. A group derived from a ring by removal of a hydrogen atom is referred to as a "ring group", which includes monovalent rings, divalent rings (often referred to as ring-alkylenes), trivalent rings, tetravalent rings, and the like, depending on the number of substituents attached to the ring. The description of "ring groups" herein does not specifically distinguish the valence of the ring. Representative "ring groups" include substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl. The term "hetero" means substituted or unsubstituted heteroatoms and oxidized forms of heteroatoms (also referred to as heteroatom groups), which are generally selected from N, O, S, P, and oxidized forms generally include NO, SO, S(O)2, P(O), and the nitrogen atom can be substituted, i.e., NR (R is H or other substituents as defined herein); the number of atoms in a ring is generally defined as the number of atoms in the ring, for example, "3-6 membered heterocycloalkyl" means a ring of 3-6 atoms arranged in a ring, each ring optionally containing 1-3 heteroatoms and / or heteroatom groups, i.e., N, O, S, NO, SO, S(O)2, P(O), or NR, each ring optionally substituted with R groups, R being a group as defined herein.

[0098] Unless otherwise indicated, the term "cycloalkyl" refers to saturated cyclic alkyl groups derived from the removal of a hydrogen atom from a cycloalkane, including monocyclic or polycyclic saturated hydrocarbon groups; the polycyclic saturated hydrocarbon groups refer to polycyclic groups formed by two or more cyclic alkyl structures connected by spiro, bridge, fused, and the like. The carbon atoms in the cycloalkyl groups can be further oxidized, i.e., form C(O). Unless otherwise specified, "cycloalkyl" as used herein is understood to mean monocyclic cycloalkyl groups, and when polycyclic, it is specifically indicated as spiro, fused, or bridged groups. The cycloalkyl groups include "C3-8 cycloalkyl," "C3-6 cycloalkyl," "C3-5 cycloalkyl," "C4-6 cycloalkyl," "C5-6 cycloalkyl," and the like. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. 3-8 The cycloalkyl groups include "C3-8 cycloalkyl," "C3-6 cycloalkyl," "C3-5 cycloalkyl," "C4-6 cycloalkyl," "C5-6 cycloalkyl," and the like. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. 3-6 The cycloalkyl groups include "C3-8 cycloalkyl," "C3-6 cycloalkyl," "C3-5 cycloalkyl," "C4-6 cycloalkyl," "C5-6 cycloalkyl," and the like. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. 3-5 The cycloalkyl groups include "C3-8 cycloalkyl," "C3-6 cycloalkyl," "C3-5 cycloalkyl," "C4-6 cycloalkyl," "C5-6 cycloalkyl," and the like. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl. 3-4 The cycloalkyl groups include "C3-8 cycloalkyl," "C3-6 cycloalkyl," "C3-5 cycloalkyl," "C4-6 cycloalkyl," "C5-6 cycloalkyl," and the like. Specific examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.

[0099] Unless otherwise indicated, the term "heterocycle" refers to saturated cyclic groups derived from the replacement of one or more ring carbon atoms in a cycloalkyl group with a heteroatom and / or a heteroatom group. The heteroatom and / or heteroatom group is typically selected from N, O, S, NO, SO, S(O)2, P(O), and NR, wherein the carbon atoms in the heterocycle are optionally oxidized, i.e., form -C(O); preferably, the heteroatom is 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," and the like. Specific examples include, but are not limited to, azetidine, pyrrolidine, tetrahydrofuran, piperidine, piperazine, tetrahydropyran, morpholine, and the like.

[0100] Unless otherwise indicated, the term "aryl" refers to unsaturated, typically aromatic hydrocarbon groups, which can be monocyclic or multiple rings fused together, including C 5-10 The aryl groups include "C6-10 aryl," "C6-8 aryl," "C6-4 aryl," and the like. Examples of aryl groups include, but are not limited to, phenyl, naphthyl. 5-8 The aryl groups include "C6-10 aryl," "C6-8 aryl," "C6-4 aryl," and the like. Examples of aryl groups include, but are not limited to, phenyl, naphthyl. 5-6 The aryl groups include "C6-10 aryl," "C6-8 aryl," "C6-4 aryl," and the like. Examples of aryl groups include, but are not limited to, phenyl, naphthyl.

[0101] The structures of the compounds of the present application were determined by nuclear magnetic resonance (NMR) and mass spectrometry. NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker Ascend 400 NMR instrument with deuterated dimethyl sulfoxide (DMSO-d6) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0102] Liquid chromatography-mass spectrometry (LC-MS) was performed using a liquid chromatograph Shimadzu LC-30AD, a mass spectrometer AB QTRAP 4500, and a chromatographic column Waters XBridge C18 (5 μm, 4.6 x 250 mm).

[0103] The HPLC determination used an Agilent 1260 with a Waters XBridge C18 (5 pm, 4.6 x 250 mm) column.

[0104] The preparative HPLC used a NU3000C (DAC 50 x 650 mm).

[0105] The thin layer chromatography silica gel plates used HSGF254 silica gel plates from Yantai Jiangyou Silica Gel Development Co., Ltd., with a specification of 0.20 mm ± 0.03 mm, preparative 20 x 20 cm, and the column chromatography used 200-300 mesh silica gel from Qingdao Hailang Silica Gel Drier Co., Ltd. as the carrier.

[0106] The starting materials in the examples of the present application are known and commercially available or can be synthesized using or according to methods known in the art.

[0107] Example 1:

[0108] 4-[5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-N-(2-(3,3-difluoroazetidin-1-yl)2-oxoethyl)methylbenzamide

[0109] Reaction Scheme:

[0110] Procedure:

[0111] Step 1: To a solution of 72.6 g of N-Boc-glycine in 1800 mL of ethyl acetate, 60.3 g of 3,3-difluoroazetidine hydrochloride, 56.0 g of 1-hydroxybenzotriazole (HOBt) and 98.0 g of triethylamine (TEA) were added with stirring at room temperature, followed by the addition of 100.0 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI). After the addition was complete, stirring was continued at room temperature for 3 h, 1000 mL of purified water was added and stirred for 5 min, the organic phase was separated and the solvent was removed by distillation under reduced pressure to obtain a concentrate.

[0112] Step 2: The concentrate obtained in Step 1 was added to 300 mL of a 4M hydrogen chloride dioxane solution, and the reaction was carried out at room temperature for 2 h. About 300 mL of solvent was removed by distillation under reduced pressure, the reaction mixture was stirred at room temperature, 100 mL of n-heptane was added, stirring was continued for 1 h, and the mixture was filtered. The filter cake was washed with n-heptane and dried at 60°C to obtain 2-amino-1-(3,3-difluoroazetidin-1-yl)ethanone hydrochloride 74.5 g.

[0113] Step 3: In a solution of 106.8 g of 2-methyl-4-acetylbenzoic acid in 500 mL of toluene, stirring was carried out at room temperature, 188.4 g of 3,5-dichloro-4-fluorotrifluoroacetylbenzene and 182.4 g of triethylamine were added, then the temperature was raised to 70°C and the reaction was carried out for 6 h, after which the reaction mixture was allowed to cool to room temperature and was filtered under suction, the filter cake was washed with 100 mL of toluene and was dried in a vacuum at 60°C to give 4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid triethylamine salt, 309.7 g.

[0114] Step 4: In a solution of 50.0 g of 4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid triethylamine salt in 170 mL of toluene, 3.4 g of dimethylaminopyridine and 18.9 g of acetic anhydride were added, stirring was carried out and the temperature was raised to 60°C, the reaction was carried out for 4 h, then the reaction mixture was concentrated in a vacuum, water was added and the mixture was washed, then the mixture was filtered to give 4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluoro-2-enoyl)-2-methylbenzoic acid.

[0115] Step 5: 4-(3-(3,5-dichloro-4-fluorophenyl)-4,4,4-trifluoro-2-enoyl)-2-methylbenzoic acid obtained in Step 3 was added to 200 mL of toluene, 12.9 g of hydroxylamine hydrochloride was added, stirring was carried out in an ice bath, 85 g of sodium hydroxide saturated aqueous solution was added dropwise, and the reaction was carried out for 2 h, then the reaction mixture was allowed to warm to room temperature, 100 mL of 6N hydrochloric acid solution was added, the mixture was allowed to stand and was separated into layers, and the organic phase was concentrated in a vacuum to give 4-[5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid, 30.2 g.

[0116] Step 6: In 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, 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 were added, then stirring was carried out at room temperature for 3 h, then the reaction mixture was quenched with 200 mL of water, the mixture was separated into layers, the organic phase was distilled under reduced pressure to remove the solvent, and the concentrate was purified using a silica gel column to give 4-[5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-(2-(3,3-difluoroazetidin-1-yl)2-oxoethyl)methylbenzamide (Compound 1), 9.1 g.

[0117] MS (ESI) M / Z: 568.0 [M+H] + .

[0118] 1 H-NMR (DMSO-d6, 400MHz) δ 8.64 (t, J = 6.0 Hz, 1H), 7.81 (d, J = 6.4 Hz, 2H), 7.61 (d, J = 6.0 Hz, 2H), 7.47 (d, J = 8.4 Hz, 1H), 4.73 (t, J = 12.4 Hz, 2H), 4.41-4.30 (m, 4H), 3.96 (d, J = 6.0 Hz, 2H), 2.40 (s, 3H).

[0119] Example 2:

[0120] 4-[5-(3,4,5-trichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-(2-(3,3- difluoroazetidin-1-yl)2-oxoethyl)methylbenzamide

[0121] Reaction Scheme:

[0122] Procedure:

[0123] Step 1: In 10.7 g of 2-methyl-4-acetylbenzoic acid in 40 mL of toluene, stirring was dissolved at room temperature, 20.0 g of 3,4,5-trichlorotrifluoroacetylbenzene and 18.2 g of triethylamine were added, then the temperature was raised to 70°C for 6 h, after cooling to room temperature, filtration was performed, the filter cake was washed with 30 mL of toluene, and the filter cake was dried at 60°C to obtain 32.5 g of 4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid triethylamine salt.

[0124] Step 2: In 32.5 g of 4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid triethylamine salt in 110 mL of toluene, 2.1 g of dimethylaminopyridine and 11.9 g of acetic anhydride were added, and the temperature was gradually raised to 60°C for 4 h. Concentration under vacuum, washing with purified water, and filtration yielded 4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluoro-2-enoyl)-2-methylbenzoic acid.

[0125] Step 3: To the 4-(3-(3,4,5-trichlorophenyl)-4,4,4-trifluoro-2-enoic acid from Step 2, was added 130 mL of toluene and 8.1 g of hydroxylamine hydrochloride, stirred in ice bath, and 54 g of sodium hydroxide saturated aqueous solution was added dropwise. The reaction was allowed to proceed for 2 h. After the reaction was completed, the reaction solution was allowed to warm to room temperature, 100 mL of 6N hydrochloric acid solution was added, and the organic phase was separated. The organic phase was concentrated under vacuum to give 4-[5-(3,4,5-trichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid 19.2 g.

[0126] 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 was added 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. After the addition was completed, the reaction was stirred at room temperature for 3 h. After the reaction was completed, the reaction solution was quenched with 80 mL of water, and the organic phase was separated. The solvent was removed from the organic phase under reduced pressure. The concentrate was purified using silica gel column chromatography to give 4-[5-(3,4,5-trichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-(2-(3,3-difluoroazetidin-1-yl)2-oxoethyl)methylbenzamide (Compound 2) 4.6 g.

[0127] MS (ESI) M / Z: 583.9 [M+H] +

[0128] 1 H-NMR (DMSO-d6, 400 MHz) δ 8.65 (t, J = 6.0 Hz, 1H), 7.84 (s, 2H), 7.61 (d, J = 6.4 Hz, 2H), 7.48 (d, J = 6.4 Hz, 1H), 4.73 (t, J = 12.4 Hz, 2H), 4.42-4.30 (m, 4H), 3.96 (d, J = 5.6 Hz, 2H), 2.40 (s, 3H).

[0129] Example 3:

[0130] 4-[5-(3-Chloro-5-trifluoromethylphenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-(2-(3,3-difluoroazetidin-1-yl)2-oxoethyl)methylbenzamide

[0131] Reaction Scheme:

[0132] Operation steps:

[0133] Step 1: In a solution of 20.0 g of 2-methyl-4-acetylbenzoic acid in 60 mL of toluene, stirring and dissolving at room temperature, 37.2 g of 3-chloro-5-trifluoromethyltrifluoroacetylbenzene and 34.1 g of triethylamine were added, then the temperature was raised to 70°C and reacted for 6 h. After cooling to room temperature, filtration was performed, the filter cake was rinsed with 30 mL of toluene, and the filter cake was dried at 60°C to obtain 60.3 g of 4-(3-(3-chloro-5-trifluoromethylphenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid triethylamine salt.

[0134] Step 2: In a solution of 50.0 g of 4-(3-(3-chloro-5-trifluoromethylphenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid triethylamine salt in 170 mL of toluene, 3.3 g of dimethylaminopyridine (DMAP) and 18.4 g of acetic anhydride were added, and the temperature was gradually raised to 60°C and reacted for 4 h. After the reaction was completed, it was concentrated under vacuum, washed with purified water, and filtered to obtain 4-(3-(3-chloro-5-trifluoromethylphenyl)-4,4,4-trifluoro-2-enoyl)-2-methylbenzoic acid.

[0135] Step 3: The 4-(3-(3-chloro-5-trifluoromethylphenyl)-4,4,4-trifluoro-2-enoyl)-2-methylbenzoic acid obtained in Step 2 was added to 200 mL of toluene and 12.5 g of hydroxylamine hydrochloride, and was stirred in an ice bath. 85 g of a saturated aqueous sodium hydroxide solution was added dropwise and reacted for 2 h. After the reaction was completed, the reaction solution was allowed to warm to room temperature, 100 mL of 6N hydrochloric acid solution was added, and it was allowed to stand and separate into layers. The organic phase was concentrated under vacuum to obtain 4-[5-(3-chloro-5-trifluoromethylphenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid 30.6 g.

[0136] 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, 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, 5.5 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) were added. After the addition, the reaction was stirred at room temperature for 3 h. After the reaction was completed, the reaction solution was quenched with 100 mL of water, and the organic phase was separated. The solvent was removed by distillation under reduced pressure. The concentrate was purified using a silica gel column to obtain 4-[5-(3-chloro-5-trifluoromethylphenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-N-(2-(3,3-difluoroazetidin-1-yl)2-oxoethyl)methylbenzamide (Compound 3) 9.1 g.

[0137] MS (ESI) M / Z: 584.0 [M+H] +

[0138] 1 H-NMR (DMSO-d6, 400 MHz) δ 8.65 (t, J = 6.0 Hz, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.63 (d, J = 6.4 Hz, 2H), 7.48 (d, J = 6.4 Hz, 1H), 4.73 (t, J = 12.4 Hz, 2H), 4.48-4.32 (m, 4H), 3.96 (d, J = 6.0 Hz, 2H), 2.41 (s, 3H).

[0139] Example 4:

[0140] 4-[5-(3,5-Dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-(2- ((2,2-difluorocyclopropyl)amino)2-oxoethyl)methylbenzamide

[0141] Reaction Scheme:

[0142] Procedure:

[0143] Step 1: To a solution of 11.0 g of N-Boc-glycine in 300 mL of ethyl acetate, stirred at room temperature, was added 10.0 g of 2,2-difluorocyclopropylamine hydrochloride, 8.8 g of 1-hydroxybenzotriazole (HOBt) and 8.9 g of triethylamine (TEA), followed by the addition of 16.1 g of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI). After the addition was completed, the reaction was stirred at room temperature for 3 h. After the reaction was completed, 200 mL of purified water was added, and the organic phase was separated. The solvent was removed from the organic phase by distillation under reduced pressure to obtain a concentrate.

[0144] Step 2: The concentrate obtained in Step 1 was dissolved in 30 mL of dioxane by stirring at room temperature, and then 70 mL of 4 M hydrogen chloride dioxane solution was added. During the reaction, solids gradually precipitated, and gas was generated. The reaction was stirred at room temperature for 2 h, and then about 70 mL of the solvent was removed by distillation under reduced pressure. The reaction mixture was stirred at room temperature, 30 mL of n-heptane was added, and then the mixture was stirred at the same temperature for 1 h. The mixture was filtered. The filter cake was washed with n-heptane, and then dried at 60°C to obtain 2-amino-N-(2,2-difluorocyclopropyl)acetamide hydrochloride 3.2 g.

[0145] 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 was added 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. Then, 3.5 g of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was added. After the addition was completed, the reaction was stirred at room temperature for 3 h. After the reaction was completed, the reaction solution was quenched with 50 mL of water, and then the organic phase was separated. The solvent was removed from the organic phase by distillation under reduced pressure. The concentrate was purified by column chromatography on silica gel to obtain 4-[5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-N-(2-((2,2-difluorocyclopropyl)amino)2-oxoethyl)methylbenzamide (Compound 4) 6.3 g.

[0146] MS (ESI) M / Z: 568.0 [M+H] +

[0147] 1H-NMR (DMSO-d6, 400 MHz) δ 8.57 (t, J = 6.0 Hz, 1H), 8.43 (s, 1H), 7.81 (d, J = 6.4 Hz, 2H), 7.60 (d, J = 6.0 Hz, 2H), 7.49 (d, J = 8.4 Hz, 1H), 4.41-4.29 (m, 2H), 3.94-3.82 (m, 2H), 3.34-3.29 (s, 1H), 2.41 (s, 3H), 1.95-1.85 (m, 1H), 1.53-1.44 (m, 1H).

[0148] Example 5:

[0149] 4-[5-(3,4,5-trichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-N-(2-((2,2- difluorocyclopropyl)amino)2-oxoethyl)methylbenzamide

[0150] Reaction Scheme:

[0151] Procedure:

[0152] To a solution of 6.6 g of 4-[5-(3,4,5-trichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-2-methylbenzoic acid (see Example 2, step 3) in 100 mL of ethyl acetate was added 3.1 g of 2-amino-N-(2,2-difluorocyclopropyl)acetamide hydrochloride (see Example 4, step 2), 1.9 g of 1-hydroxybenzotriazole (HOBt), and 2.1 g of triethylamine. 3.5 g of 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was added. After the addition was completed, the reaction was stirred at room temperature for 3 h. After the reaction was completed, the reaction solution was quenched with 100 mL of water and the layers were separated. The organic phase was distilled under reduced pressure to remove the solvent. The concentrate was purified using a silica gel column to obtain 4-[5-(3,4,5-trichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-N-(2-((2,2-difluorocyclopropyl)amino)2-oxoethyl)methylbenzamide (Compound 5) 6.4 g.

[0153] MS (ESI) M / Z: 584.0 [M+H] +

[0154] 1H-NMR (DMSO-d6, 400 MHz) δ 8.57 (t, J = 6.0 Hz, 1H), 8.43 (s, 1H), 7.85 (s, 2H), 7.60 (d, J = 6.0 Hz, 2H), 7.49 (d, J = 8.8 Hz, 1H), 4.42-4.30 (m, 2H), 3.94-3.82 (m, 2H), 3.36-3.29 (m, 1H), 2.41 (s, 3H), 1.95-1.85 (m, 1H), 1.53-1.45 (m, 1H).

[0155] Example 6:

[0156] 4-[5-(3-Chloro-5-trifluoromethylphenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-N-(2-((2,2-difluorocyclopropyl)amino)2-oxoethyl)methylbenzamide

[0157] Reaction Scheme:

[0158] Procedure:

[0159] To a solution of 5.3 g of 4-[5-(3-chloro-5-trifluoromethylphenyl)-4,5-dihydro-5- (trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid (see Example 3, step 3) in 130 mL of ethyl acetate was added 2.8 g of 2-amino-N-(2,2-difluorocyclopropyl)acetamide hydrochloride (see Example 4, step 2), 1.0 g of 1-hydroxybenzotriazole (HOBt), and 1.7 g of triethylamine. Then 3.7 g of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was added. After the addition, the reaction was stirred at room temperature for 3 h. After the reaction was completed, the reaction solution was quenched with 70 mL of water and the layers were separated. The organic layer was concentrated under reduced pressure to remove the solvent. The concentrate was purified using a silica gel column to give 4-[5-(3-chloro-5-trifluoromethylphenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-N-(2-((2,2-difluorocyclopropyl)amino)2-oxoethyl)methylbenzamide (Compound 6) 3.3 g.

[0160] MS (ESI) M / Z: 584.0 [M+H] +

[0161] 1H-NMR (DMSO-d6, 400 MHz) δ 8.57 (t, J = 6.0 Hz, 1H), 8.43 (s, 1H), 8.10 (s, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.62 (d, J = 6.4 Hz, 2H), 7.50 (d, J = 8.8 Hz, 1H), 4.48-4.35 (m, 2H), 3.94-3.82 (m, 2H), 3.37-3.30 (m, 1H), 2.41 (s, 3H), 1.95-1.86 (m, 1H), 1.53-1.45 (m, 1H).

[0162] Example 7:

[0163] 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-N- (2-oxo-2-((1R,2S)-2-fluorocyclopropylamino)ethyl)benzamide

[0164] Reaction Scheme:

[0165] Procedure:

[0166] Step 1: To a solution of 30.0 g of N-Boc-glycine in 900 mL of ethyl acetate, 50.0 g of (1R,2S)-2-fluorocyclopropylamine p-toluenesulfonate, 12.0 g of 1-hydroxybenzotriazole (HOBt) and 21.0 g of triethylamine (TEA) were added with stirring at room temperature, followed by 51.0 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI). After the addition was completed, stirring was continued at room temperature for 3 h, and the solvent was removed by distillation under reduced pressure to give a concentrate.

[0167] Step 2: The concentrate obtained in Step 1 was added to 200 mL of a 4 M solution of hydrogen chloride in dioxane, and the reaction was carried out at room temperature for 2 h. About 200 mL of the solvent was removed by distillation under reduced pressure, and the reaction mixture was stirred at room temperature. Then, 100 mL of ethyl acetate was added, stirring was continued for 1 h, and the mixture was suction filtered. The filter cake was rinsed with n-heptane, and dried at 60°C to give 2-amino-N-((1R,2S)-2-fluorocyclopropyl)acetamide hydrochloride, 23.5 g.

[0168] Step 3: To a solution of 31.8 g of 2-methyl-4-acetylbenzoic acid in 150 mL of toluene, 52.2 g of 3,5-dichlorotrifluoroacetophenone and 54.2 g of triethylamine were added with stirring at room temperature, and the reaction was carried out at 70°C for 6 h. After the reaction mixture was cooled to room temperature and allowed to stand, the mixture was suction filtered, and the filter cake was rinsed with 30 mL of toluene. The filter cake was dried at 60°C under reduced pressure to give 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid triethylamine salt, 83.1 g.

[0169] Step 4: To a solution of 80.0 g of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3- hydroxybutanoyl)-2-methylbenzoic acid triethylamine salt in 240 mL of toluene, 5.6 g of dimethylaminopyridine and 31.3 g of acetic anhydride were added, and the mixture was stirred to warm to 60 °C for 4 h. Concentration in vacuo was followed by slurry washing with purified water and filtration to give 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-enoic acid)-2-methylbenzoic acid.

[0170] Step 5: To 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-enoic acid)-2-methylbenzoic acid from Step 3 was added 240 mL of toluene, 21.3 g of hydroxylamine hydrochloride, and the mixture was stirred in an ice bath while 130 g of a saturated aqueous sodium hydroxide solution was added dropwise. After 2 h, the reaction was allowed to warm to room temperature, 160 mL of 6 N hydrochloric acid solution was added, and the mixture was allowed to stand to separate into layers. The organic phase was concentrated in vacuo to give 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid, 54.5 g.

[0171] 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. After addition, the mixture was stirred at room temperature for 3 h. After the reaction was complete, the mixture was quenched with 200 mL of water, the layers were separated, and the organic phase was distilled under reduced pressure to remove the solvent. The concentrate was purified using silica gel column chromatography to give 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-N-(2-oxo-2-((1R,2S)-2-fluorocyclopropylamino-1-yl)ethyl)benzamide (Compound 7), 10.7 g.

[0172] MS (ESI) M / Z: 531.9 [M+H] + .

[0173] 1H-NMR (DMSO-d6, 400 MHz) δ 8.52 (t, J = 6.0 Hz, 1H), 8.13 (d, J = 4.0 Hz, 1H), 7.81 (t, J = 2.0 Hz, 1H), 7.64-7.60 (m, 4H), 7.49 (d, J = 8.4 Hz, 1H), 4.80-4.62 (m, 1H), 4.35 (dd, J1= 35.6 Hz, J2= 18.4 Hz, 2H), 3.95-3.83 (m, 2H), 2.72-2.69 (m, 1H), 2.41 (s, 3H), 1.10-1.04 (m, 1H), 0.94-0.85 (m, 1H).

[0174] Example 8:

[0175] 4-[5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-2-methyl-N-(2-oxo-2-((1R,2S)-2-fluorocyclopropylamino)- ethyl)benzamide

[0176] Reaction Scheme:

[0177] Procedure:

[0178] 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. After the addition was complete, the reaction was stirred at room temperature for 3 h. After the reaction was complete, the reaction was quenched with 200 mL of water and the organic phase was separated. The solvent was removed under reduced pressure and the concentrate was purified using silica gel column chromatography to give 4-[5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-2-methyl-N-(2-oxo-2-((1R,2S)-2-fluorocyclopropylamino)-ethyl)benzamide (Compound 8) 25.0 g.

[0179] MS (ESI) M / Z: 550.0 [M+H] +

[0180] 1H-NMR (DMSO-d6, 400 MHz) δ 8.52 (t, J = 6.0 Hz, 1H), 8.14 (d, J = 4.0 Hz, 1H), 7.81 (t, J = 6.4 Hz, 1H), 7.61-7.59 (m, 2H), 7.49 (d, J = 8.4 Hz, 1H), 4.80-4.61 (m, 1H), 4.35 (dd, J1= 27.2 Hz, J2= 18.4 Hz, 2H), 3.95-3.83 (m, 2H), 2.72-2.69 (m, 1H), 2.41 (s, 3H), 1.18-1.04 (m, 1H), 0.94-0.85 (m, 1H).

[0181] Example 9:

[0182] 4-[5-(3,4,5-trichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2- methyl-N-(2-oxo-2-((1R,2S)-2-fluorocyclopropylamino-1-yl)ethyl)benzamide

[0183] Reaction Scheme:

[0184] Procedure:

[0185] 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. After the addition was complete, the reaction was stirred at room temperature for 3 h. After the reaction was complete, the reaction was quenched with 200 mL of water and the organic phase was separated. The solvent was removed by distillation under reduced pressure and the concentrate was purified by column chromatography on silica gel to give 4-[5-(3,4,5-trichlorophenyl)-4,5-dihydro-5- (trifluoromethyl)-3-isoxazolyl]-2-methyl-N-(2-oxo-2-((1R,2S)-2- fluorocyclopropylamino-1-yl)ethyl)benzamide (Compound 9) 8.0 g.

[0186] MS (ESI) M / Z: 565.8 [M+H] +

[0187] 1H-NMR (DMSO-d6, 400 MHz) δ 8.55 (t, J = 6.0 Hz, 1H), 8.16 (d, J = 4.0 Hz, 1H), 7.85 (s, 2H), 7.61-7.59 (m, 2H), 7.49 (d, J = 8.4 Hz, 1H), 4.81-4.61 (m, 1H), 4.36 (dd, J1= 30.0 Hz, J2= 18.4 Hz, 2H), 3.95-3.82 (m, 2H), 2.72-2.68 (m, 1H), 2.41 (s, 3H), 1.10-1.02 (m, 1H), 0.92-0.82 (m, 1H).

[0188] Example 10:

[0189] 4-[5-(3-Chloro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-2-methyl-N-(2-oxo-2-((1R,2S)-2-fluorocyclopropylamino)-ethyl)benzamide

[0190] Reaction Scheme:

[0191] Procedure:

[0192] 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 l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. After the addition was complete, the reaction was stirred at room temperature for 3 h. After the reaction was complete, the reaction was quenched with 500 mL of water and the organic phase was separated. The solvent was removed by distillation under reduced pressure and the concentrate was purified by column chromatography on silica gel to give 4-[5-(3-chloro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-2-methyl-N-(2-oxo-2-((1R,2S)-2-fluorocyclopropylamino)-ethyl)benzamide (Compound 10) 25.5 g.

[0193] MS (ESI) M / Z: 565.8 [M+H] +

[0194] 1H-NMR (DMSO-d6, 400 MHz) δ 8.55 (t, J = 6.0 Hz, 1H), 8.16 (d, J = 4.4 Hz, 1H), 8.09 (s, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.62 (d, J = 6.8 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 4.80-4.63 (m, 1H), 4.42 (dd, J1= 33.2 Hz, J2= 18.4 Hz, 2H), 3.91-3.86 (m, 2H), 2.72-2.68 (m, 1H), 2.41 (s, 3H), 1.10-1.04 (m, 1H), 0.94-0.84 (m, 1H).

[0195] Example 11:

[0196] 4-[5-(3-Chloro-4-fluoro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5- (trifluoromethyl)-3-isoxazolyl]-2-methyl-N-(2-oxo-2-(2,2-difluorocyclopropyl) amino) ethyl)benzamide

[0197] Reaction Scheme:

[0198] Procedure:

[0199] Step 1: In 15.0 g of 2-methyl-4-acetylbenzoic acid in 50 mL of toluene, the solution was stirred to dissolve at room temperature, 29.7 g of 3-chloro-4-fluoro-5- (trifluoromethyl)-2,2,2-trifluoroacetophenone and 25.6 g of triethylamine were added, then the temperature was raised to 70 °C for 6 h, and then the precipitate was filtered after the temperature was lowered to room temperature, the filter cake was washed with 30 mL of toluene, and the filter cake was dried at 60 °C under vacuum to obtain 37.1 g of 4-(3-(3-chloro-4-fluoro-5- (trifluoromethyl)phenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid triethylamine salt.

[0200] Step 2: In 37.0 g of 4-(3-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-4,4,4- trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid triethylamine salt in 100 mL of toluene, 3.1 g of dimethylaminopyridine and 13.2 g of acetic anhydride were added, and the temperature was raised to 60 °C while stirring for 4 h. After vacuum concentration, the slurry was washed with purified water, and filtration was performed to obtain 4-(3-(3-chloro-4-fluoro-5- (trifluoromethyl)phenyl)-4,4,4-trifluoro-2-enoyl)-2-methylbenzoic acid.

[0201] Step 3: To the 4-(3-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-4,4,4- trifluoro-2-enoic acid obtained in Step 3, 100 mL of toluene was added, 9.0 g of hydroxylamine hydrochloride was added, and the mixture was stirred in an ice bath, 60 g of a saturated aqueous sodium hydroxide solution was added dropwise, and the reaction was allowed to proceed for 2 h. After the reaction was completed, the reaction solution was allowed to warm to room temperature, 75 mL of a 6N hydrochloric acid solution was added, and the mixture was allowed to stand to separate into layers. The organic layer was concentrated under vacuum to obtain 4-[5-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5- (trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid 22.7 g.

[0202] 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, 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 were added. After the addition, the mixture was stirred at room temperature for 3 h. After the reaction was completed, the reaction solution was quenched with 100 mL of water, and the mixture was separated into layers. The organic layer was concentrated under reduced pressure, and the concentrate was purified using a silica gel column to obtain 4-[5-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5- (trifluoromethyl)-3-isoxazolyl]-2-methyl-N-(2-oxo-2-(2,2-difluorocyclopropyl)amino) ethyl)benzamide (Compound 11) 5.1 g.

[0203] MS (ESI) M / Z: 601.9 [M+H] + .

[0204] 1 H-NMR (DMSO-d6, 400MHz) δ 8.53 (t, J = 6.0 Hz, 1H), 8.42 (d, J = 6.4 Hz, 1H), 8.19 (dd, J1 = 6.4 Hz, J2 = 2.0 Hz, 1H), 7.88 (d, J = 4.0 Hz, 1H), 7.61-7.60 (m, 2H), 7.51-7.49 (m, 1H), 4.4-4.3 (m, 2H), 3.9-3.8 (m, 2H), 3.3 (m, 1H), 2.4 (s, 3H), 2.0-1.9 (m, 1H), 1.5-1.4 (m, 1H).

[0205] Example 12:

[0206] 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2- methyl-N-(2-oxo-2-(3-fluoroazetidin-1-yl)ethyl)benzamide

[0207] Reaction Scheme:

[0208] Procedure:

[0209] Step 1: To a solution of 40.4 g of N-Boc-glycine in 1000 mL of ethyl acetate, stirred at room temperature, was added 31.0 g of 3-fluoroazetidine hydrochloride, 15.5 g of 1-hydroxybenzotriazole (HOBt) and 32.3 g of triethylamine (TEA). Then 59.6 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was added. After the addition, the reaction was stirred at room temperature for 3 h. The solvent was removed by distillation under reduced pressure to give a concentrate.

[0210] Step 2: The concentrate from Step 1 was added to 270 mL of 4 M hydrogen chloride in dioxane and the reaction was stirred at room temperature for 2 h. About 250 mL of the solvent was removed by distillation under reduced pressure. The reaction mixture was stirred at room temperature and 100 mL of ethyl acetate was added. The mixture was stirred for 1 h and filtered under suction. The filter cake was rinsed with n-heptane and dried at 60 °C to give 2-amino-N-(3-fluoroazetidin-1-yl)acetamide hydrochloride, 33.2 g.

[0211] Step 3: To a solution of 10.0 g of 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5- (trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid (see Example 7, Step 5) in 250 mL of ethyl acetate was added 4.8 g of 2-amino-N-(3-fluoroazetidin-1-yl)acetamide hydrochloride, 1.6 g of 1-hydroxybenzotriazole (HOBt) and 3.4 g of triethylamine. Then 6.0 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was added. After the addition, the reaction was stirred at room temperature for 3 h. After the reaction was completed, the reaction was quenched with 200 mL of water and the layers were separated. The solvent was removed by distillation under reduced pressure. The concentrate was purified by column chromatography on silica gel to give 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-2-methyl-N-(2-oxo-2-(3-fluoroazetidin-1-yl)ethyl)benzamide (Compound 12), 10.8 g.

[0212] MS (ESI) M / Z: 531.9 [M+H] +

[0213] 1H-NMR (DMSO-d6, 400 MHz) δ 8.56 (t, J = 6.0 Hz, 1H), 7.81 (t, J = 2.0 Hz, 1H), 7.64-7.60 (m, 4H), 7.46 (d, J = 8.4 Hz, 1H), 5.53-5.35 (m, 1H), 4.60-4.51 (m, 1H), 4.41-4.19 (m, 4H), 3.99-3.88 (m, 3H), 2.41 (s, 3H).

[0214] Example 13:

[0215] 4-[5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-2-methyl-N-(2-oxo-2-(3-fluoroazetidin-1-yl)ethyl)benzamide

[0216] Reaction Scheme:

[0217] Procedure:

[0218] 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 (see Example 1, step 5) in 250 mL of ethyl acetate was added 4.8 g of 2-amino-N-(3-fluoroazetidin-1-yl)acetamide hydrochloride (see Example 12, step 2), 1.6 g of 1-hydroxybenzotriazole (HOBt), and 3.4 g of triethylamine. 6.0 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was added. After the addition was completed, the reaction was stirred at room temperature for 3 h. After the reaction was completed, the reaction solution was quenched with 200 mL of water, and the organic phase was separated. The solvent was removed from the organic phase by distillation under reduced pressure. The concentrate was purified using a silica gel column to obtain 4-[5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-2-methyl-N-(2-oxo-2-(3-fluoroazetidin-1-yl)ethyl)benzamide (Compound 13) 10.8 g.

[0219] MS (ESI) M / Z: 550.2 [M+H] +

[0220] 1H-NMR (DMSO-d6, 400 MHz) δ 8.58 (t, J = 6.0 Hz, 1H), 7.82 (d, J = 6.0 Hz, 2H), 7.60 (d, J = 6.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 1H), 5.53-5.36 (m, 1H), 4.60-4.51 (m, 1H), 4.41-4.18 (m, 4H), 3.99-3.87 (m, 3H), 2.40 (s, 3H).

[0221] Example 14:

[0222] 4-[5-(3,4,5-trichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2- methyl-N-(2-oxo-2-(3-fluorazetidin-1-yl)ethyl)benzamide

[0223] Reaction Scheme:

[0224] Procedure:

[0225] To a solution of 6.0 g of 4-[5-(3,4,5-trichlorophenyl)-4,5-dihydro-5- (trifluoromethyl)-3-isoxazolyl]-2-methylbenzoic acid (see Example 2, step 3) in 150 mL of ethyl acetate was added 2.7 g of 2-amino-N-(3-fluorazetidin-1-yl)acetamide hydrochloride (see Example 12, step 2), 0.9 g of 1-hydroxybenzotriazole (HOBt), and 1.9 g of triethylamine. 3.3 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was added. After the addition was completed, the reaction was stirred at room temperature for 3 h. After the reaction was completed, the reaction solution was quenched with 150 mL of water, and the organic phase was separated. The solvent was removed from the organic phase by distillation under reduced pressure. The concentrate was purified using a silica gel column to obtain 4-[5-(3,4,5-trichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-N-(2-oxo-2-(3-fluorazetidin-1-yl)ethyl)benzamide (Compound 14) 5.9 g.

[0226] MS (ESI) M / Z: 565.9 [M+H] +

[0227] 1H-NMR (DMSO-d6, 400 MHz) δ 8.59 (t, J = 6.0 Hz, 1H), 7.85 (s, 2H), 7.61 (d, J = 6.4 Hz, 2H), 7.46 (d, J = 6.4 Hz, 1H), 5.52-5.36 (m, 1H), 4.60-4.51 (m, 1H), 4.42-4.25 (m, 4H), 3.99-3.87 (m, 3H), 2.40 (s, 3H).

[0228] Example 15:

[0229] 4-[5-(3-Chloro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-2-methyl-N-(2-oxo-2-(3-fluoroazetidin-1-yl)ethyl)benzamide

[0230] Reaction Scheme:

[0231] Procedure:

[0232] To a solution of 13.2 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 330 mL of ethyl acetate was added 2.7 g of 2-amino-N-(3-fluoroazetidin-1-yl)acetamide hydrochloride (see Example 12, step 2), 1.1 g of 1-hydroxybenzotriazole (HOBt), and 3.1 g of triethylamine. Then 7.3 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was added. After the addition was completed, the reaction was stirred at room temperature for 3 h. After the reaction was completed, the reaction was quenched with 300 mL of water, and the organic phase was separated. The solvent was removed by distillation under reduced pressure. The concentrate was purified by silica gel column chromatography to give 4-[5-(3-chloro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-2-methyl-N-(2-oxo-2-(3-fluoroazetidin-1-yl)ethyl)benzamide (Compound 15) 14.4 g.

[0233] MS (ESI) M / Z: 566.0 [M+H] +

[0234] 1H-NMR (DMSO-d6, 400 MHz) δ 8.59 (t, J = 6.0 Hz, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.62 (d, J = 6.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 1H), 5.53-5.36 (m, 1H), 4.60-4.51 (m, 1H), 4.45-4.19 (m, 4H), 3.99-3.88 (m, 3H), 2.41 (s, 3H).

[0235] Example 16:

[0236] 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2- methyl-N-(2-oxo-2-(3,3-difluoroazetidin-l-yl)ethyl)benzamide

[0237] Reaction Scheme:

[0238] 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, was added 8.0 g of 2-amino-l-(3,3-difluoroazetidin-l- yl)ethanone hydrochloride (see Example 1, Step 2), 2.4 g of 1-hydroxybenzotriazole (HOBt), and 5.1 g of triethylamine, followed by the addition of 9.0 g of l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. After the addition was complete, the reaction was stirred at room temperature for 3 h. After the reaction was complete, the reaction was quenched with the addition of 300 mL of water, and the organic phase was separated. The solvent was removed from the organic phase by distillation under reduced pressure. The concentrate was purified using silica gel column chromatography to give 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5- (trifluoromethyl)-3-isoxazolyl]-2-methyl-N-(2-oxo-2-(3,3-difluoroazetidin-l- yl)ethyl)benzamide (Compound 16) 17.9 g.

[0239] MS (ESI) M / Z: 549.9 [M+H] +1

[0240] 1H-NMR (DMSO-d6, 400 MHz) δ 8.66 (t, J = 6.0 Hz, 1H), 7.80 (t, J = 2.0 Hz, 1H), 7.64-7.60 (m, 4H), 7.46 (d, J = 8.4 Hz, 1H), 5.53-5.35 (m, 1H), 4.60-4.51 (m, 1H), 4.41-4.19 (m, 4H), 3.99-3.88 (m, 3H), 2.41 (s, 3H).

[0241] Example 17:

[0242] 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2- methyl-N-(2-oxo-2-((3,3-difluorocyclobutyl)amino)ethyl)benzamide

[0243] Reaction Scheme:

[0244] Procedure:

[0245] Step 1: To a solution of 9.5 g of N-Boc-glycine in 250 mL of ethyl acetate, stirred at room temperature, was added 9.3 g of 3,3-difluorocyclobutylamine hydrochloride, 3.7 g of 1-hydroxybenzotriazole (HOBt) and 7.6 g of triethylamine (TEA). Then 7.4 g of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was added and after the addition, the reaction was stirred at room temperature for 3 h. The solvent was removed by distillation under reduced pressure to give a concentrate.

[0246] Step 2: The concentrate from Step 1 was added to 150 mL of 4 M hydrogen chloride in dioxane and the reaction was stirred at room temperature for 2 h. About 150 mL of the solvent was removed by distillation under reduced pressure and the reaction mixture was stirred at room temperature. Then 100 mL of ethyl acetate was added and the mixture was stirred for 1 h and filtered under suction. The filter cake was washed with n-heptane and dried at 60 °C to give 2-amino-N-(3,3-difluorocyclobutyl)acetamide hydrochloride, 10.2 g.

[0247] 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 was added 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. 2.4 g of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was added. After the addition was complete, the reaction was stirred at room temperature for 3 h. After the reaction was complete, the reaction was quenched with 100 mL of water and the organic phase was separated. The solvent was removed under reduced pressure. The concentrate was purified using silica gel column chromatography to give 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-2-methyl-N-(2-oxo-2-((3,3-difluorocyclobutyl)amino)ethyl)benzamide (Compound 17) 4.7 g.

[0248] MS (ESI) M / Z: 563.9 [M+H] +

[0249] 1 H-NMR (DMSO-d6, 400 MHz) δ 8.56 (t, J = 6.0 Hz, 1H), 8.45 (d, J = 6.8 Hz, 1H), 7.80 (t, J = 2.0 Hz, 1H), 7.64-7.61 (m, 4H), 7.51 (d, J = 8.8 Hz, 1H), 4.35 (dd, J1= 35.2 Hz, J2= 18.4 Hz, 2H), 4.14-4.06 (m, 1H), 3.85 (d, J = 6.0 Hz, 1H), 2.97-2.86 (m, 2H), 2.66-2.54 (m, 2H), 2.41 (s, 3H).

[0250] Example 18:

[0251] 4-[5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2- methyl-N-(2-oxo-2-((3,3-difluorocyclobutyl)amino)ethyl)benzamide

[0252] Procedure:

[0253] 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 was added 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. 3.3 g of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was added. After the addition was complete, the reaction was stirred at room temperature for 3 h. After the reaction was complete, the reaction was quenched with 100 mL of water and the organic layer was separated. The solvent was removed under reduced pressure. The concentrate was purified using silica gel column chromatography to give 4-[5-(3,5-dichloro-4-fluorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-2-methyl-N-(2-oxo-2-((3,3-difluorocyclobutyl)amino)ethyl)benzamide (Compound 18) 6.0 g.

[0254] MS (ESI) M / Z: 582.0 [M+H] +

[0255] 1 H-NMR (DMSO-d6, 400 MHz) δ 8.54 (t, J = 6.0 Hz, 1H), 8.43 (d, J = 6.4 Hz, 1H), 7.81 (d, J = 6.0 Hz, 2H), 7.60 (d, J = 6.0 Hz, 2H), 7.50 (d, J = 8.4 Hz, 1H), 4.35 (dd, J1= 27.6 Hz, J2= 18.4 Hz, 2H), 4.11-4.04 (m, 1H), 3.83 (d, J = 6.0 Hz, 2H), 2.97-2.86 (m, 2H), 2.68-2.55 (m, 2H), 2.41 (s, 3H).

[0256] Example 19:

[0257] 4-[5-(3,4,5-trichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-N- (2-oxo-2-((3,3-difluorocyclobutyl)amino)ethyl)benzamide

[0258] Procedure:

[0259] 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 was added 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. 3.3 g of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was added. After addition, the reaction was stirred at room temperature for 3 h. After the reaction was completed, the reaction solution was quenched with 100 mL of water and the organic phase was separated. The solvent was removed by distillation under reduced pressure. The concentrate was purified using silica gel column chromatography to obtain 4-[5-(3,4,5-trichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-2-methyl-N-(2-oxo-2-((3,3-difluorocyclobutyl)amino)ethyl)benzamide (Compound 19) 6.6 g.

[0260] MS (ESI) M / Z: 597.9 [M+H] +

[0261] 1 H-NMR (DMSO-d6, 400 MHz). δ 8.54 (t, J = 6.0 Hz, 1H), 8.43 (d, J = 6.8 Hz, 1H), 7.85 (s, 2H), 7.60 (d, J = 6.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 1H), 4.36 (dd, J1= 30.4 Hz, J2= 18.4 Hz, 2H), 4.13-4.06 (m, 1H), 3.84 (d, J = 6.0 Hz, 2H), 2.97-2.86 (m, 2H), 2.65-2.52 (m, 2H), 2.41 (s, 3H).

[0262] Example 20:

[0263] 4-[5-(3-Chloro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-2-methyl-N-(2-oxo-2-((3,3-difluorocyclobutyl)amino)ethyl)benzamide

[0264] Procedure:

[0265] Step 1: To a solution of 4.6 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 120 mL of ethyl acetate was added 2.4 g of 2-amino-N-((3,3-difluorocyclobutyl)acetamide hydrochloride (see Example 17, Step 2), 0.7 g of 1-hydroxybenzotriazole (HOBt), and 1.4 g of triethylamine. 2.5 g of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was added. After addition, the reaction was stirred at room temperature for 3 h. After the reaction was completed, the reaction was quenched with 100 mL of water, and the organic phase was separated. The solvent was removed under reduced pressure. The concentrate was purified using silica gel column chromatography to give 4-[5-(3-chloro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-2-methyl-N-(2-oxo-2-((3,3-difluorocyclobutyl)amino)ethyl)benzamide (Compound 20) 5.3 g.

[0266] MS (ESI) M / Z: 597.6 [M+H] +

[0267] 1 H-NMR (DMSO-d6, 400 MHz) δ 8.54 (t, J = 6.0 Hz, 1H), 8.43 (d, J = 6.8 Hz, 1H), 8.10 (s, 1H), 7.98 (s, 1H), 7.86 (s, 1H), 7.62 (d, J = 6.4 Hz, 2H), 7.50 (d, J = 8.4 Hz, 1H), 4.41 (dd, J1= 33.6 Hz, J2= 18.4 Hz, 2H), 4.11-4.02 (m, 1H), 3.83 (d, J = 6.0 Hz, 2H), 2.97-2.86 (m, 2H), 2.68-2.53 (m, 2H), 2.41 (s, 3H).

[0268] Example 21:

[0269] 4-[5-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-2-methyl-N-(2-oxo-2-((3,3-difluorocyclobutyl)amino)ethyl)benzamide

[0270] Procedure:

[0271] 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 Example 11, Step 3) in 120 mL of ethyl acetate was added 2.4 g of 2-amino-N-((3,3-difluorocyclobutyl)acetamide hydrochloride (see Example 17, Step 2), 0.7 g of 1-hydroxybenzotriazole (HOBt), and 1.4 g of triethylamine. 2.5 g of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was added. After the addition was complete, the reaction was stirred at room temperature for 3 h. After the reaction was complete, the reaction was quenched with 100 mL of water and the organic layer was separated. The solvent was removed under reduced pressure. The concentrate was purified using silica gel column chromatography to give 4-[5-(3-chloro-4-fluoro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-2-methyl-N-(2-oxo-2-((3,3-difluorocyclobutyl)amino)ethyl)benzamide (Compound 21) 4.3 g.

[0272] MS (ESI) M / Z: 615.8 [M+H] +

[0273] 1 H-NMR (DMSO-d6, 400 MHz) δ 8.54 (t, J = 6.0 Hz, 1H), 8.43 (d, J = 6.8 Hz, 1H), 8.19 (dd, J1= 6.4 Hz, J2= 1.6 Hz, 1H), 7.89 (d, J = 4.4 Hz, 1H), 7.61 (d, J = 5.6 Hz, 2H), 7.50 (dd, J1= 4.8 Hz, J2= 3.2 Hz, 1H), 4.41 (dd, J1= 18.4 Hz, J2= 10.4 Hz, 2H), 4.11-4.07 (m, 1H), 3.84 (d, J = 5.6 Hz, 2H), 2.97-2.86 (m, 2H), 2.68-2.53 (m, 2H), 2.41 (s, 3H).

[0274] Example 22:

[0275] 4-[5-(3,5-Dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-N-(2- oxo-2-(3-(trifluoromethyl)azetidin-l-yl)ethyl)benzamide

[0276] Reaction Scheme:

[0277] Procedure:

[0278] Step 1: To a solution of 4.0 g of N-Boc-glycine in 100 mL of ethyl acetate, stirred at room temperature, was added 4.1 g of 3-(trifluoromethyl)azetidine hydrochloride, 1.5 g of 1-hydroxybenzotriazole (HOBt) and 3.2 g of triethylamine (TEA). Then 5.7 g of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was added. After the addition, the reaction was stirred at room temperature for 3 h. The solvent was removed by distillation under reduced pressure to give a concentrate.

[0279] Step 2: The concentrate from Step 1 was added to 100 mL of 4 M hydrogen chloride in dioxane and the reaction was stirred at room temperature for 2 h. About 100 mL of the solvent was removed by distillation under reduced pressure. The reaction mixture was stirred at room temperature. 70 mL of ethyl acetate was added and stirred for 1 h. The mixture was filtered. The filter cake was washed with n-heptane and dried at 60 °C to give 2-amino-N-(3-(trifluoromethyl)azetidin-l-yl)acetamide hydrochloride, 4.2 g.

[0280] 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 was added 2.5 g of 2-amino-N-(3-(trifluoromethyl)azetidin-l-yl)acetamide hydrochloride, 0.6 g of 1-hydroxybenzotriazole (HOBt) and 1.4 g of triethylamine. 2.4 g of l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was added. After the addition, the reaction was stirred at room temperature for 3 h. After the reaction was completed, the reaction was quenched with 100 mL of water. The organic phase was separated and the solvent was removed by distillation under reduced pressure. The concentrate was purified by column chromatography on silica gel to give 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-N-(2-oxo-2-(3-(trifluoromethyl)azetidin-l-yl)ethyl)benzamide (Compound 22), 4.9 g.

[0281] MS (ESI) M / Z: 581.5 [M+H] +

[0282] 1 H-NMR (DMSO-d6, 400 MHz) δ 8.60 (t, J = 6.0 Hz, 1H), 7.81 (t, J = 2.0 Hz, 1H), 7.64-7.61 (m, 4H), 7.46 (d, J = 8.4 Hz, 1H), 4.49 (t, J = 8.8 Hz, 1H), 4.42-4.26 (m, 3H), 4.14 (t, J = 9.6 Hz, 1H), 3.90-3.87 (m, 3H), 3.72-3.65 (m, 1H), 2.40 (s, 3H).

[0283] Example 23:

[0284] 4-[5-(3-Chloro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-2-methyl-N-(2-oxo-2-(3-(trifluoromethyl)azetidin-l-yl)ethyl)benzamide

[0285] Reaction Scheme:

[0286] Procedure:

[0287] 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 was added 1.0 g of 2-amino-N-(3-(trifluoromethyl)azetidin-l- yl)acetamide hydrochloride (see Example 22, Step 2), 0.3 g of 1-hydroxybenzotriazole (HOBt), and 0.6 g of triethylamine. 1.0 g of l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI) was added. After the addition was complete, the reaction was stirred at room temperature for 3 h. After the reaction was complete, the reaction was quenched with 50 mL of water and the organic layer was separated. The solvent was removed under reduced pressure. The concentrate was purified using silica gel column chromatography to give 4-[5-(3-chloro-5-(trifluoromethyl)phenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-2-methyl-N-(2-oxo-2-(3-(trifluoromethyl)azetidin-l-yl)ethyl)benzamide (Compound 23) 1.9 g.

[0288] MS (ESI) M / Z: 581.5 [M+H] +

[0289] 1 H-NMR (DMSO-d6, 400 MHz) δ 8.60 (t, J = 6.0 Hz, 1H), 8.08 (s, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.63-7.62 (m, 2H), 7.46 (d, J = 8.4 Hz, 1H), 4.51-4.35 (m, 3H), 4.28 (dd, Ji = 9.2 Hz, J2 = 5.6 Hz, 1H), 4.15 (t, J = 9.6 Hz, 1H), 3.90-3.87 (m, 3H), 3.72-3.65 (m, 1H), 2.41 (s, 3H).

[0290] Example 24:

[0291] 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2- methyl-N-(2-oxo-2-((1-(trifluoromethyl)cyclopropyl)amino)ethyl)benzamide

[0292] Reaction Scheme:

[0293] Procedure:

[0294] Step 1 : To a solution of 10.0 g of N-Boc-glycine in 250 mL of ethyl acetate, 11.1 g of 1-trifluoromethylcyclopropylamine hydrochloride, 3.8 g of 1- hydroxybenzotriazole (HOBt) and 8.0 g of triethylamine (TEA) were added with stirring at room temperature. Then 14.3 g of 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI) was added and the reaction was stirred at room temperature for 3 h. The solvent was removed by distillation under reduced pressure to give a concentrate.

[0295] Step 2: The concentrate from Step 1 was added to 250 mL of 4 M hydrogen chloride in dioxane and the reaction was stirred at room temperature for 2 h. About 250 mL of the solvent was removed by distillation under reduced pressure. The reaction mixture was stirred at room temperature and 150 mL of ethyl acetate was added. The mixture was stirred for 1 h and filtered under suction. The filter cake was washed with n-heptane and dried at 60 °C to give 2-amino-N-(1-(trifluoromethyl)cyclopropyl)acetamide hydrochloride, 9.6 g.

[0296] 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, 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 were added. Then 2.4 g of 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI) was added and the reaction was stirred at room temperature for 3 h. After completion of the reaction, the reaction mixture was quenched with 100 mL of water and the layers were separated. The solvent was removed by distillation under reduced pressure. The concentrate was purified by column chromatography on silica gel to give 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-2-methyl-N-(2-oxo-2-((1-(trifluoromethyl)cyclopropyl)amino)ethyl)benzamide (Compound 24), 5.6 g.

[0297] MS (ESI) M / Z: 581.9 [M+H] +

[0298] 1H-NMR (DMSO-d6, 400 MHz) δ 8.78 (s, 1H), 8.55 (t, J = 6.0 Hz, 1H), 7.81 (t, J = 2.0 Hz, 1H), 7.64-7.60 (m, 4H), 7.49 (d, J = 8.4 Hz, 1H), 4.35 (dd, J1= 35.2 Hz, J2= 18.0 Hz, 2H), 3.84 (d, J = 6.0 Hz, 2H), 2.40 (s, 3H), 1.27-1.23 (m, 2H), 1.04-1.02 (m, 2H).

[0299] Example 25:

[0300] 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2- methyl-N-(2-oxo-2-((1-cyanocyclopropyl)amino)ethyl)benzamide

[0301] Reaction Scheme:

[0302] Procedure:

[0303] Step 1 : To a solution of 8.0 g of N-Boc-glycine in 200 mL of ethyl acetate, stirred at room temperature, was added 6.5 g of 1-amino-1-cyclopropylcyanide hydrochloride, 3.1 g of 1-hydroxybenzotriazole (HOBt) and 6.5 g of triethylamine (TEA). Then 11.4 g of 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI) was added and after the addition, the reaction was stirred at room temperature for 3 h. The solvent was removed by distillation under reduced pressure to give a concentrate.

[0304] Step 2: The concentrate from Step 1 was added to 200 mL of 4M hydrogen chloride in dioxane and the reaction was allowed to proceed at room temperature for 2 h. About 200 mL of the solvent was removed by distillation under reduced pressure and the reaction mixture was stirred at room temperature. Then 120 mL of ethyl acetate was added and the mixture was stirred for 1 h and filtered under suction. The filter cake was washed with n-heptane and dried at 60 °C to give 2-amino-N-(1-cyanocyclopropyl)acetamide hydrochloride 6.5 g.

[0305] 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 was added 6.0 g of 2-amino-N-(1-cyanocyclopropyl)acetamide hydrochloride, 1.9 g of 1-hydroxybenzotriazole (HOBt) and 4.0 g of triethylamine. 7.1 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) was added. After the addition was complete, the reaction was stirred at room temperature for 3 h. After the reaction was complete, the reaction was quenched with 200 mL of water and the organic phase was separated. The solvent was removed under reduced pressure. The concentrate was purified using silica gel column chromatography to give 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3- isoxazolyl]-2-methyl-N-(2-oxo-2-((1-cyanocyclopropyl)amino)ethyl)benzamide (Compound 25) 12.1 g.

[0306] MS (ESI) M / Z: 539.0 [M+H] +

[0307] 1 H-NMR (DMSO-d6, 400MHz) δ 8.94 (s, 1H), 8.62 (t, J = 6.0 Hz, 1H), 7.81 (t, J = 2.0 Hz, 1H), 7.64-7.61 (m, 4H), 7.51 (d, J = 8.8 Hz, 1H), 4.36 (dd, J1 = 36.0 Hz, J2 = 18.4 Hz, 2H), 3.85 (d, J = 6.0 Hz, 2H), 2.41 (s, 3H), 1.52-1.48 (m, 2H), 1.16-1.13 (m, 2H).

[0308] Biological activity experiment

[0309] Test Example 1: In vitro mite contact toxicity inhibition test at different concentrations

[0310] 1. Purpose of the test:

[0311] The contact killing effect and effective concentration of the compounds of the present application on chicken skin mites were evaluated by filter paper drug film method.

[0312] 2. Test materials:

[0313] 2.1 Test drug: Compound 1, 2, 3, 4, 5 and 6, Fluralaner (content 99.6%). First, mix propylene glycol and Tween 80 at 1:3 (w / w) at 40°C to make them uniform, then weigh a certain amount of compound to prepare a 1% (w / v) solution for standby. Before use, dilute with water to the target concentration.

[0314] 2.2 Test material: Neutral filter paper (size: 7 x 10 cm). Chicken mite was derived from clinical and cultured to physiological state.

[0315] 2.3 Instrument: PRX700 series intelligent artificial climate chamber.

[0316] 3. Test method:

[0317] The test compound 1-6 solution, and the fluralaner solution were diluted with purified water to 5 μg / mL, 10 μg / mL and 20 μg / mL respectively, infiltrated into the neutral filter paper, naturally dried, folded and bound, and prepared into filter paper bags, with three repeats for each concentration of drug. About 20 chicken mites were selected by a hook pen into each filter paper bag, sealed, and placed in an artificial climate chamber for 48 h of culture, after which the mortality of chicken mites in the filter paper bags of different concentrations was observed and the mortality rate was counted.

[0318] Mortality rate (%) = (treatment mortality rate - blank control mortality rate) / (1 - blank control mortality rate) x 100%.

[0319] 4. Test results:

[0320] Table 1 Statistics of the mortality of chicken mites at different concentrations

[0321] 5. Test conclusion:

[0322] As shown in Table 1, the compounds of the present application have good knock-killing effect on chicken mites at different concentrations, and show dose-dependent effect, with higher killing activity at 20 μg / mL. Compared with the control compound fluralaner, the compounds of the present application have better knock-killing effect.

[0323] Test Example 2: In vitro mite knock-killing activity inhibition test at the same concentration

[0324] 1. Test purpose:

[0325] The filter paper drug film method was used to evaluate the knock-killing effect of the compounds of the present application on chicken mites at a concentration of 20 μg / mL.

[0326] 2. Test materials:

[0327] 2.1 Test drug: Compounds 1-25. First, mix propylene glycol and Tween 80 at 1:3 (w / w) at 40°C, then weigh a certain amount of compound to prepare a 1% (w / v) solution for standby. Before use, dilute with water to the target concentration.

[0328] 2.2 Test material: Neutral filter paper (size: 7 x 10 cm). Chicken mite was derived from clinical and cultured to physiological state.

[0329] 2.3 Instruments: PRX700 series intelligent artificial climate box.

[0330] 3. Test method:

[0331] Each test compound 1-25 solution was diluted with purified water to 20 μg / mL, infiltrated into neutral filter paper, naturally dried, folded and bound to prepare filter paper bags. About 20 chicken mites were selected by a hook pen into each filter paper bag, sealed, and placed in an artificial climate box for 48 h. The mortality of chicken mites in filter paper bags at different concentrations was observed and the mortality rate was counted. The mortality rate of the mites was calculated according to the same calculation formula as in Test Example 1.

[0332] 4. Test results:

[0333] Table 2 Statistics of the mortality of chicken mites at a concentration of 20 μg / mL

[0334] 5. Test conclusion:

[0335] As shown in Table 2, the compounds of the present application have high contact killing activity against chicken mites at a concentration of 20 μg / mL.

[0336] Test Example 3: Chicken mite killing test

[0337] Test Example 3-1: Chicken mite killing test of compound 1-6

[0338] 1. Purpose of the test:

[0339] To evaluate the therapeutic effect of representative compound 1-6 of the present application on chicken mites of laying hens at different doses.

[0340] 2. Test materials:

[0341] 2.1 Test drugs: compounds 1, 2, 3, 4, 5 and 6, dosages: 0.5 mg / kg or 0.3 mg / kg.

[0342] 2.2 Test animals: laying hens. About 200 laying hens for each compound. (Laying hens and eggs are managed and recycled together)

[0343] 3. Test method:

[0344] a) Preparation before test: One week before the test, mite collectors were evenly arranged in the henhouse, and the number of mite collectors for each drug group was greater than or equal to five.

[0345] b) Start the test: All drug solutions are prepared before the test, (1) Blank solvent: First, stir the propylene glycol and polysorbate 80 uniformly at 40°C in a ratio of 1:3 (V / V) to make a blank solvent for standby. (2) Drug solution: Prepare the raw materials, add the prescribed amount of the above blank solvent to make a 1% (m / v) solution, and stir uniformly at 40°C.

[0346] c) Calculate the volume of each test drug according to the number of test animals, mix with a small amount of drinking water, and add to the appropriate amount of drinking water, which is consumed within 3-5 hours. The same method is used to administer the drug once a week.

[0347] d) Data statistics: Count the number of chicken mites in each group of mite collectors before the first and second administrations, and observe the number of chicken mites in each group of mite collectors once a week or once every two weeks after the second administration.

[0348] 4. Test results:

[0349] The number of chicken mites in each group of mite collectors is shown in Table 3.

[0350] Table 3: Chicken mite statistics in the farm

[0351] Test Example 3-2: Comparison of chicken mite killing by compound 4 and fluralaner

[0352] 1. Purpose of the test:

[0353] To evaluate the therapeutic effect of representative compounds of the present application at different doses compared with fluralaner on chicken mites of laying hens.

[0354] 2. Test materials:

[0355] 2.1 Test drug: Compound 4, administered at a dose of 0.2 mg / kg, 0.15 mg / kg, 0.1 mg / kg, or 0.05 mg / kg. Fluralaner, administered at a dose of 0.5 mg / kg

[0356] 2.2 Test animals: Laying hens. About 200 laying hens per compound. (Laying hens and eggs are managed and recovered together)

[0357] 3. Test method:

[0358] a) Preparation before the test: One week before the test, evenly arrange the mite collectors in the henhouse, with the number of drug mite collectors in each group being greater than or equal to five.

[0359] b) Start the test: all drug solutions are prepared before the test, (1) blank solvent: first stir the propylene glycol and polysorbate 80 at 1:3 (V / V) at 40°C, make a blank solvent for standby. (2) drug solution: prepare the raw material, add the prescribed amount of the above blank solvent to prepare a 1% (m / v) solution, stir evenly at 40C°.

[0360] c) According to the number of test animals, calculate the volume of each test drug, mix with a small amount of drinking water, and add to the appropriate amount of drinking water, so that it is consumed within 3-5 hours, and the same method is used to administer once a week.

[0361] d) Data statistics: count the number of chicken mites in each group of mite collectors before the first administration and before the second administration, and observe the number of chicken mites in each group of mite collectors once a week or every two weeks after the second administration.

[0362] 4. Test results:

[0363] The number of chicken mites in each group of mite collectors is shown in Table 4.

[0364] Table 4: Chicken mite statistics

[0365] Test Example 4: Dog and cat body surface flea killing test

[0366] Test Example 4-1: Dog body surface flea killing test

[0367] 1. Purpose of the test:

[0368] To evaluate the efficacy of Compound 1, Compound 2, and Compound 4 in treating dog fleas.

[0369] 2. Test materials:

[0370] 2.1 Test drugs: Compound 1, Compound 2, and Compound 4.

[0371] 2.2 Dose: Compound 1 and Compound 2 are 5 mg / kg; Compound 4 is 2 mg / kg.

[0372] 2.3 Test animals: 6 dogs naturally infected with fleas, each dog using a comb cleaner to count fleas, all more than 10.

[0373] 3. Test method:

[0374] Weigh the test dogs, according to the weight, a suitable amount of test solution is fed orally at one time, Compound 1, Compound 2, and Compound 4, each 2 dogs, respectively, 3 days, 10 days, and 30 days after administration, using a comb cleaner to count the number of fleas on the surface of each test dog.

[0375] 4. Test results

[0376] No fleas were found on each of the test dogs at 3 days, 10 days after administration. No fleas were found on each of the test dogs at 30 days after administration, and no further observation was made. Test Example 4-2: Dog, cat body surface flea killing test

[0377] 1. Purpose of the test

[0378] To evaluate the flea killing effect of Compound 4 of the present application on dogs and cats.

[0379] 2. Test materials

[0380] 2.1 Test drug: Compound 4.

[0381] 2.2 Dose: Compound 4 was 4 mg / kg.

[0382] 2.3 Test animals: 2 dogs and 2 cats naturally infected with fleas, each dog using a comb cleaner for flea counting, all more than 10.

[0383] 3. Test method

[0384] The test dogs and cats were weighed, and according to the body weight, an appropriate amount of test solution was orally administered once to Compound 4, 2 dogs and 2 cats, and the number of fleas on the body surface of each test dog was counted using a comb cleaner at 3 days, 10 days, 30 days, and 60 days after administration.

[0385] 4. Test results

[0386] No fleas were found on each of the test dogs and cats at 3 days, 10 days, 30 days, and 60 days after administration.

[0387] Test Example 5: Pharmacokinetic test on chickens

[0388] 1. Purpose of the test

[0389] To determine the time-dependent variation of blood drug concentration of Compound 1, 2, 3, 4, 5, and 6, and the control fipronil in chickens.

[0390] 2. Test materials

[0391] 2.1 Test animals: 3 healthy laying hens per group.

[0392] 2.2 Test drug: Compound 1, 2, 3, 4, 5, and 6, fipronil.

[0393] 2.3 Instruments and equipment: Shimadzu high-performance liquid chromatograph, AB SCIEX QTRAP 4500 mass spectrometer.

[0394] 3. Test method

[0395] The test drug was orally administered at a dose of 0.5 mg / kg. The chickens were laterally restrained and blood was collected from the wing vein. Blood samples of 1.5 mL were collected before administration and at 0.5, 1, 2, 4, 8, 24, 48, 72, 96, 120, 144, 168, 240, 336, 408 and 504 h after administration, and were placed in centrifuge tubes containing sodium heparin. The blood plasma was separated by centrifugation at 4000 r / min for 10 min, and was stored at -20°C. After the plasma sample was thawed, 0.2 mL of the plasma was accurately pipetted into a 10 mL centrifuge tube, 0.8 mL of acetonitrile was added, and the mixture was vortexed for 5 min, centrifuged at 10000 r / min for 10 min, and the supernatant was passed through a 0.22 μm organic filter membrane, and was detected by HPLC-MS / MS.

[0396] 4. Test results

[0397] The blood plasma concentration of compounds 1, 2, 3, 4, 5 and 6, and fluoxetine in chickens after oral administration was as shown in Tables 5-11 and Figures 1-7.

[0398] 4.1 The blood plasma concentration detection results of compound 1 are shown in Table 5 and Figure 1.

[0399] Table 5 Change in blood plasma concentration of compound 1 in chickens Note: "ND" indicates that the drug was not detected.

[0400] 4.2 The blood plasma concentration detection results of compound 2 are shown in Table 6 and Figure 2.

[0401] Table 6 Change in blood plasma concentration of compound 2 in chickens Note: "ND" indicates that the drug was not detected.

[0402] 4.3 The blood plasma concentration detection results of compound 3 are shown in Table 7 and Figure 3.

[0403] Table 7 Change in blood plasma concentration of compound 3 in chickens Note: "ND" indicates that the drug was not detected.

[0404] 4.4 The blood plasma concentration detection results of compound 4 are shown in Table 8 and Figure 4.

[0405] Table 8 Change in blood plasma concentration of compound 4 in chickens Note: "ND" indicates that the drug was not detected.

[0406] 4.5 The blood plasma concentration detection results of compound 5 are shown in Table 9 and Figure 5.

[0407] Table 9 Change in blood plasma concentration of compound 5 in chickens Note: "ND" indicates that the drug was not detected.

[0408] 4.6 The blood concentration detection results of compound 6 are shown in Table 10 and Figure 6.

[0409] Table 10 Changes of blood concentration of compound 6 in chicken Note: "ND" means that the drug is not detected.

[0410] 4.7 The blood concentration detection results of fluclorolone are shown in Table 11 and Figure 7.

[0411] Table 11 Changes of blood concentration of fluclorolone in chicken Note: "ND" means that the drug is not detected.

[0412] Conclusion: The compound of the present application is rapidly absorbed orally, has a fast onset, and has a long half-life. Compared with fluclorolone, the peak concentration is high, the blood exposure is high, the elimination half-life is long, and there is an advantage of small drug dosage and more long-acting drug.

[0413] Test Example 6 Insecticidal test on palm thrips

[0414] 1. Purpose of the test:

[0415] The killing effect of the compound of the present application on palm thrips was evaluated by the leaf tube drug film method.

[0416] 2. Test materials:

[0417] 2.1 Test drugs: compounds 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 13, 14, 15, 19.

[0418] 2.2 Test materials: Fresh cabbage leaves. Palm thrips adults were derived from the clinic and cultured to be in a physiological state.

[0419] 2.3 Instruments and equipment: puncher (d = 0.5 cm), suction device, light incubator.

[0420] 3. Test method:

[0421] According to Test Example 1, 1% stock solution was prepared, and the test compound drug solution was diluted with purified water to 50 mg / L, 10 mg / L, and 2 mg / L, respectively. According to the leaf tube drug film method, fresh cabbage leaves were punched into a circle with a puncher, and then immersed in the drug solution. After the drug solution on the surface of the leaves was naturally dried, the leaves were placed in a centrifuge tube. Palm thrips adults were sucked into the centrifuge tube with a suction device, and then placed in a light incubator after sealing. After 48 h, the death of palm thrips in each treatment was checked and recorded. The blank control was treated with water, and each treatment and control was set in triplicate, with about 40 palm thrips adults per replicate. The mortality of the thrips was calculated according to the same calculation formula as in Test Example 1.

[0422] The test results are shown in Table 12.

[0423] Table 12 In vitro toxicity test of compounds on Thrips palmi adults

[0424] As can be seen from Table 12, the mortality rates of the thrips were 100% at the concentrations of 50 mg / L, 10 mg / L and 2 mg / L, respectively, for the compounds 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 13, 14, 15, 19 of the present application.

[0425] Test Example 7 Insecticidal test on Ostrinia furnacalis

[0426] 1. Purpose of the test:

[0427] The killing effect of the compounds of the present application on Ostrinia furnacalis was evaluated by the leaf dipping method.

[0428] 2. Test materials:

[0429] 2.1 Test drugs: compounds 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 13, 14, 15, 17, 19, 22.

[0430] 2.2 Test materials: fresh corn leaves. The 2nd instar larvae of Ostrinia furnacalis were obtained from the clinic and cultured to the same physiological state.

[0431] 2.3 Instruments and equipment: light incubator.

[0432] 3. Test method:

[0433] According to Test Example 1, 1% stock solution was prepared, and the test compound drug solution was diluted with purified water to 50 mg / L, 10 mg / L and 2 mg / L, respectively. According to the leaf dipping method, fresh corn leaves were dipped in different concentrations of drug solution, and after being taken out and dried, 1 head of Ostrinia furnacalis 2nd instar larvae was introduced into each hole of a 12-hole plate, and placed in a light incubator. After 48 h, the number of dead Ostrinia furnacalis in each treatment was checked and recorded. Those that could not move by gently touching the insect body with a brush tip were considered dead. The water treatment was used as a blank control, and 3 replicates were set for each treatment, with 15 Ostrinia furnacalis larvae provided for each replicate. The mortality rate of the insects was calculated according to the same calculation formula as in Test Example 1.

[0434] The test results are shown in Table 13.

[0435] Table 13 In vitro toxicity test of compounds on Ostrinia furnacalis larvae

[0436] As can be seen from Table 13, at a concentration of 50 mg / L, the compounds with a corn borer mortality rate of more than 95% are 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 13, 14, 15, and 19; at a concentration of 10 mg / L, the compounds with a corn borer mortality rate of more than 90% are 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 14, 15, and 19; at a concentration of 2 mg / L, the compounds with a corn borer mortality rate of more than 90% are 2, 4, 5, 8, 9, 11, and 15.

[0437] Test Example 8: Insecticidal test on Spodoptera exigua

[0438] 1. Purpose of the test:

[0439] The killing effect of the compounds of the present application on Spodoptera exigua was evaluated by the leaf dipping method.

[0440] 2. Test materials:

[0441] 2.1 Test drugs: Compounds 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 13, 14, 15, and 19.

[0442] 2.2 Test materials: Fresh corn leaves. The 2nd instar larvae of Spodoptera exigua were obtained from the clinic and cultured to the same physiological state.

[0443] 2.3 Instruments and equipment: Light incubator.

[0444] 3. Test method:

[0445] Prepare a 1% stock solution according to Test Example 1, and dilute the test compound drug solution with purified water to 4 mg / L, 1 mg / L, and 0.25 mg / L, respectively. According to the leaf dipping method, immerse fresh corn leaves in different concentrations of drug solution, and after taking them out and air-drying, place them in a 12-well plate, with 1 head of Spodoptera exigua 2nd instar larvae in each well, and place them in a light incubator. After 48 h, check and record the number of dead Spodoptera exigua in each treatment. Those that cannot move when touched with a brush tip are considered dead. The water treatment is used as a blank control, 3 replicates are set for each treatment, and 15 Spodoptera exigua larvae are provided for each replicate. The mortality rate of the insects is calculated according to the same calculation formula as in Test Example 1.

[0446] The test results are shown in Table 14.

[0447] Table 14: In vitro toxicity determination of compounds on Spodoptera exigua larvae

[0448] As can be seen from Table 14, at a concentration of 4 mg / L, compounds 3, 4, 5, 6, 8, 9, 10, 11, 15, and 19 had a mortality rate of greater than 90%; at a concentration of 1 mg / L, compounds 3, 4, 5, 6, 8, 9, 10, and 19 had a mortality rate of greater than 90%; at a concentration of 0.25 mg / L, compounds 3, 4, 5, and 10 had a mortality rate of greater than 90%.

[0449] Test Example 9: Insecticidal test on Bemisia tabaci

[0450] 1. Purpose of the test:

[0451] The killing effect of the compounds of the present application on Bemisia tabaci was evaluated by the agar moistening leaf immersion method.

[0452] 2. Test materials:

[0453] 2.1 Test drugs: compounds 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 13, 14, 15, 17, and 19.

[0454] 2.2 Test materials: Fresh cotton leaves. Bemisia tabaci adults were derived from the field and cultured to a physiological state.

[0455] 2.3 Instruments and equipment: puncher (d = 2.2 cm), insect sucking device, light incubator.

[0456] 3. Test method:

[0457] According to Test Example 1, 1% stock solution was prepared, and the test compound drug solution was diluted with purified water to 16 mg / L, 4 mg / L, and 1 mg / L, respectively. According to the agar moistening leaf immersion method, fresh cotton leaves were punched into leaf discs with a puncher, immersed in the drug solution, dried, and clamped into a glass tube with agar. Bemisia tabaci adults were moved into the glass tube with an insect sucking device, the glass tube was sealed with a cotton plug, and then inverted in a light incubator. After 48 h, the number of dead Bemisia tabaci in each treatment was checked and recorded. Those that could not move with a light touch of a brush were considered dead. The blank control was treated with water, and each treatment had 3 replicates, with about 35 Bemisia tabaci adults per replicate. The mortality rate of the insects was calculated according to the same calculation formula as in Test Example 1.

[0458] The test results are shown in Table 15.

[0459] Table 15: In vitro toxicity determination of compounds on Bemisia tabaci adults

[0460] As can be seen from Table 15, at a concentration of 16 mg / L, the compounds with a mortality rate of Bemisia tabaci greater than 80% are 1, 2, 4, 5, 6, 8, 10, 11, 13; at a concentration of 4 mg / L, the compounds with a mortality rate of Bemisia tabaci greater than 80% are 11, 13; at a concentration of 1 mg / L, the compounds with a mortality rate of Bemisia tabaci greater than 80% are 11, 13.

[0461] Test Example 10 Insecticidal test on Bactrocera dorsalis

[0462] 1. Purpose of the test:

[0463] The killing effect of the compounds of the present application on Bactrocera dorsalis was evaluated by the glass tube drug film method.

[0464] 2. Test materials:

[0465] 2.1 Test drugs: compounds 1, 2, 3, 4, 5, 6, 8, 9, 10, 11, 13, 14, 15, 19.

[0466] 2.2 Test materials: Fresh apple slices. Bactrocera dorsalis adults were obtained from the field and cultured to a physiological state.

[0467] 2.3 Instruments and equipment: rolling tube machine, light incubator.

[0468] 3. Test method:

[0469] According to Test Example 1, prepare a 1% stock solution, and dilute the test compound drug solution with purified water to 4 mg / L, 1 mg / L, and 0.25 mg / L, respectively. According to the glass tube drug film method, add the test drug solution to the glass tube, roll it on the rolling tube machine until it is dry to form a uniform drug film tube, soak the cut apple slices in the test drug solution, place them in the glass tube, and introduce Bactrocera dorsalis adults into the tube. Seal the tube opening. After 48 h, observe the mortality of the adults. If the adult does not move when touched with a pair of tweezers, it is considered dead. There are 10 adults per replicate, and 3 replicates per treatment. The mortality rate of the insects is calculated according to the same calculation formula as in Test Example 1.

[0470] The test results are shown in Table 16.

[0471] Table 16 In vitro toxicity determination of compounds on Bactrocera dorsalis adults

[0472] As can be seen from Table 16, when the concentration is 4 mg / L, the compounds with the death rate of B. dorsalis greater than 95% 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 the death rate of B. dorsalis greater than 90% are 1, 2, 3, 4, 6, 9, 10, 11, 13, 14 and 19; when the concentration is 0.25 mg / L, the compounds with the death rate of B. dorsalis greater than 80% are 1, 6, 9 and 10.

[0473] The preferred embodiments of the present application are described above, but the present application is not limited to the above, and any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the scope of protection of the present application.

Claims

1. A compound represented by Formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: wherein, Ring A is selected from a 5-10 membered aryl group, said aryl group being optionally substituted with one or more R x substituents; R1, R2, R3are each independently selected from H, halogen or C1-C6haloalkyl; X is selected from -C(O)-, -S(O)2-; R5is selected from hydrogen, C1-C6alkyl, C1-C6alkoxy; R6is selected from C3-C8cycloalkyl, said C3-C8cycloalkyl being optionally substituted with halogen, C1-C6alkyl, C1-C6haloalkyl, CN; or, R5, R6together with the nitrogen atom to which they are attached form a 3-6 membered heterocyclic ring, said 3-6 membered heterocyclic ring being optionally substituted with halogen, C1-C6alkyl, C1-C6haloalkyl, CN; R x selected from H, C1-C6 alkyl; n is selected from an integer of 0, 1 or 2.

2. The compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the R1, R2, R3are each independently selected from H, F, Cl, CF3.

3. The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the ring A is selected from the following structures: wherein R x and n are as defined in claim 1.

4. The compound, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein ring A is selected from the following structures: * represents the connecting end with the X group in the general formula.

5. The compound according to any one of claims 1-4, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is selected from -C(O)-.

6. The compound according to any one of claims 1-5, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3are each independently selected from H, halogen, CF3.

7. The compound according to any one of claims 1-6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R5is selected from hydrogen; R6is selected from C3-C4cycloalkyl, said C3-C4cycloalkyl being substituted with one or more halogen, CF3, CN.

8. The compound according to any one of claims 1-6, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R5, R6together with the nitrogen atom to which they are attached form a four-membered heterocyclic ring, said four-membered heterocyclic ring being optionally substituted with one or more halogen, CF3.

9. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of any one of claims 1-8, wherein is selected from the following structures:

10. The compound, stereoisomer, or pharmaceutically acceptable salt thereof of any one of claims 1-9, wherein is selected from the following structures:

11. The compound, stereoisomer, or pharmaceutically acceptable salt thereof, of any one of claims 1-10, wherein, The compound has the following formula (II): wherein R1, R2, R3, R5and R6are as defined in any one of claims 1-10.

12. A compound, stereoisomer thereof, or pharmaceutically acceptable salt thereof, wherein, The compound is selected from:

13. A pharmaceutical composition comprising a compound according to any one of claims 1-12, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

14. Use of a compound according to any one of claims 1-12, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or of a composition according to claim 13, for the manufacture of a medicament for the control of harmful organisms.

15. The use according to claim 14, wherein the medicament is for the prevention or treatment of a parasitic infestation or infection in an animal.

16. The use according to claim 15, wherein the medicament is an antiparasitic, preferably an antiparasitic agent against invertebrate parasitic pests.

17. The use according to claim 15, wherein the parasites are invertebrate parasitic pests that are parasitic in or on animals; preferably arthropods; more preferably flies, mosquitoes, mites, lice, fleas, maggots, ticks, bed bugs or assassin bugs; further preferably mites, fleas, ticks or lice.

18. Use according to claim 15, wherein the animal is a mammal, an avian or a fish; preferably a canine, a feline, an equine, a poultry or a livestock; more preferably a dog, a cat, a chicken, a sheep, a cow or a pig.

19. Use according to any one of claims 14 to 18, wherein the medicament is applicable to the locus of the harmful organism or to a plant susceptible to attack by the harmful organism.

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