Isoxazoline compound and application

Abstract

The invention provides an isoxazoline compound and application thereof, the isoxazoline compound has a structure as shown in a formula I. The isoxazoline compound can be used for preventing and treating parasitic infection and killing agricultural pests, has a good prevention and treatment effect, and shows good pharmacokinetic properties in a mouse body.

Description

Isoxazoline compound and application TECHNICAL FIELD

[0001] The present application belongs to the technical field of medical compounds, and particularly relates to an isoxazoline compound and application thereof. BACKGROUND

[0002] Animal ectoparasites have a great harm to the health of companion animals and the production performance of livestock and poultry, and effective control of animal ectoparasite infection has been the goal of the agricultural and veterinary departments (WOOD S D, KNAUER C S. Discovery of veterinary antiparasitic agents in the 21st century: a view from industry [J]. Int J Parasitol, 2010, 40(10): 1177-81.). Isoxazolines is a new type of pest control drug, which mainly acts on the γ-aminobutyric acid (GABA) gate chloride channel of invertebrates (MITA T, KIKUCHI T, MIZUKOSHI T, et al. Isoxazoline-substituted benzamide compound and noxious organism control agent [J]. WO Patent, 2005, 2005085216: A1. & OZOE Y, ASAHI M, OZOE F, et al. The antiparasitic isoxazoline A1443 is a potent blocker of insect ligand-gated chloride channels [J]. Biochemical and biophysical research communications, 2010, 391(1): 744-9.). Its action site is different from other insecticides acting on this ion channel (such as Dieldrin, Fipronil, etc.), which can overcome the resistance of existing insecticides. The International Insecticide Resistance Action Committee (IRAC) classifies it as Group 30 (IRAC Group 30). After the researchers of Japan Nissan Chemical Company and the United States DuPont Company developed the insecticidal active ingredient fluralaner (CASIDA JE. Golden age of RyR and GABA-R diamide and isoxazoline insecticides: common genesis, serendipity, surprises, selectivity, and safety [J]. Chemical research in toxicology, 2015, 28(4): 560-6.), Afolaner, Sarolaner and Lotilaner were developed in succession.Currently, the four isoxazoline drugs are used for pet deworming, and the annual global sales of this type of deworming drugs (including compound preparations) exceed 2 billion US dollars, which has become the main product for daily deworming of companion animals. Among the currently marketed lana drugs, three drugs have the same N-trifluoroethyl glycine amide tail chain, and the metabolic capacity of insects to this fragment is upgraded, which may produce multi-drug resistance to lana deworming drugs. Therefore, the development of a new generation of lana deworming drugs that are safer, more convenient, more effective and more environmentally friendly can overcome the common drug resistance problem of deworming drugs while providing pet owners with new drug options.

[0003] In addition, isoxazoline compounds act on GABA-gated chloride channels and have obvious killing effect on agricultural pests related to agriculture, and have wide application potential in pesticides. SUMMARY

[0004] The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the claims.

[0005] In view of the deficiencies of the prior art, the purpose of the present application is to provide an isoxazoline compound and its application.

[0006] To achieve this purpose, the present application adopts the following technical solutions:

[0007] On the one hand, the present application provides an isoxazoline compound, which has the structure shown in the following formula I:

[0008] Among them,

[0009] X is selected from -CH= or -N=;

[0010] Y is selected from -CH= or -N=;

[0011] Z is selected from The wavy line represents the connection site of the group;

[0012] R1is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, halogenated C1-C6alkyl, deuterated C1-C6alkyl, halogenated C2-C6alkenyl, halogenated C2-C6alkynyl, halogen, cyano, nitro, -C(O)NR a R b , -C(O)R a , -C(O)OR a , -OR a , -R a OR b , -OC(O)R a , -OC(O)OR a , -OC(O)NRa R b 、-NR a R b 、-SR a 、-S(O)R a 、-S(O)2R a or a 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms, wherein the 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms is optionally substituted by 1-3 R a replace;

[0013] R2 is selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C2-C6 alkenyl, halo-C2-C6 alkynyl;

[0014] R3 is selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, deuterated C1-C6 alkyl, halo-C2-C6 alkenyl, halo-C2-C6 alkynyl;

[0015] R4 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NR a R b 、-C(O)R a 、-C(O)OR a 、-OR a 、-R a OR b 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR a R b 、-NR a R b 、-SR a 、-S(O)R a 、-S(O)2R a or a 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms, wherein the 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms is optionally substituted by 1-3 R a replace;

[0016] R5 is selected from hydrogen, C1-C6 alkyl, 1-3 R a Substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, halogen, cyano, nitro, -C(O)NRa R b 、-C(O)R a 、-C(O)OR a 、-OR a 、-R a OR b 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR a R b 、-NR a R b 、-SR a 、-S(O)R a 、-S(O)2R a or a 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms, wherein the 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms is optionally substituted by 1-3 R a replace;

[0017] Or R4 and R5 together with the connected nitrogen atom form a 3-7 membered saturated or unsaturated ring, in which case the saturated or unsaturated ring can be optionally replaced by 1-8 R a replace;

[0018] R6 is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkyl;

[0019] R7 is selected from hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halo-C1-C6 alkyl, C1-C6 alkoxy, deuterated C1-C6 alkyl, halo-C2-C6 alkenyl, halo-C2-C6 alkynyl;

[0020] Each R a 、R b Each is independently selected from hydrogen, deuterium, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, halogenated C1-C6 alkyl, deuterated C1-C6 alkyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, halogen, cyano, nitro, amino, carboxyl, carbonyl, hydroxyl, hydroxyalkyl, alkoxy, halogenated alkoxy, deuterated alkoxy, C3-C6 cycloalkyl, halogenated C3-C6 cycloalkyl, C3-C6 cycloalkyl substituted with alkoxy, C3-C6 cycloalkyl substituted with 1-3 R c Substituted C3-C6 cycloalkyl, C3-C6 heterocyclic group, halogenated C3-C6 heterocyclic group, alkyl-substituted C3-C6 heteroaryl, -S(O)2R c 、-OR c OR d 、-R c OR d 、-C(O)Rc or -OC(O)R c each R c , R d are each independently selected from the group consisting of halogen, Ci-C6alkyl, haloCi-C6alkyl; and

[0021] m = 0, 1, 2, 3, 4 or 5;

[0022] n = 0, 1, 2, 3 or 4.

[0023] In some embodiments, the isoxazoline compound has the structure of Formula Ia:

[0024] Z, R1, R2, R3, R4, R5, m, n are as defined above.

[0025] In other embodiments, the isoxazoline compound has the structure of Formula Ib:

[0026] R1, R2, R3, m, n are as defined above;

[0027] R a is selected from cyano or trifluoromethyl.

[0028] In some embodiments, R1is selected from hydrogen, halogen, Ci-C6alkyl, Ci-C6alkoxy, haloCi-C6alkyl or haloCi-C6alkoxy.

[0029] In other embodiments, R1is selected from hydrogen, fluorine, chlorine, methyl, methoxy, trifluoromethyl or trifluoromethoxy.

[0030] In other embodiments, R2is selected from hydrogen, halogen, Ci-C6alkyl, haloCi-C6alkyl;

[0031] In other embodiments, R2is trifluoromethyl.

[0032] In other embodiments, R3is selected from hydrogen, halogen, Ci-C6alkyl, haloCi-C6alkyl.

[0033] In other embodiments, R3is methyl, chlorine or fluorine.

[0034] In other embodiments, R4is hydrogen.

[0035] In other embodiments, R5is selected from C1-C6alkyl, haloC1-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, cyano-substituted C3-C6cycloalkyl, alkoxy-substituted C3-C6cycloalkyl, haloC1-C6alkyl-substituted C3-C6cycloalkyl, or haloC1-C6alkyl-substituted C3-C6heterocyclyl.

[0036] In other embodiments, R5is selected from trifluoroethyl, cyclopropyl, In other embodiments, selected from

[0037] In other embodiments, R6is selected from hydrogen or C1-C6alkyl.

[0038] In other embodiments, R7is selected from hydrogen or C1-C6alkyl.

[0039] In other embodiments, the isoxazoline compound is any one of the following compounds:

[0040] In further preferred embodiments, the isoxazoline compound is any one of the following compounds:

[0041] In another aspect, the present application also provides a tautomer, enantiomer, diastereomer, entiomer, exiomer, or a pharmaceutically acceptable salt of the isoxazoline compound as described above.

[0042] In another aspect, the present application also provides a pharmaceutical composition comprising a therapeutically effective amount of the isoxazoline compound, a tautomer, enantiomer, diastereomer, entiomer, exiomer, or a pharmaceutically acceptable salt thereof as described above; and a pharmaceutically acceptable carrier or excipient.

[0043] In another aspect, the present application provides use of the isoxazoline compound or a tautomer, enantiomer, diastereomer, entiomer, exiomer, or a pharmaceutically acceptable salt thereof as described above or the pharmaceutical composition as described above in the control of infection by an ectoparasite in a human or animal.

[0044] In another aspect, the present application provides a pesticidal composition comprising an active ingredient which is an isoxazoline compound or a tautomer, enantiomer, diastereomer, meso form, racemate or pharmaceutically acceptable salt thereof as described above, and optionally at least one pesticidally acceptable carrier and / or adjuvant, and a pharmaceutically acceptable carrier or excipient.

[0045] In another aspect, the present application provides a pesticidal formulation made from an isoxazoline compound or a tautomer, enantiomer, diastereomer, meso form, racemate or pharmaceutically acceptable salt thereof as described above.

[0046] In another aspect, the present application also provides the use of an isoxazoline compound or a tautomer, enantiomer, diastereomer, meso form, racemate or pharmaceutically acceptable salt thereof as described above in the manufacture of a product for controlling agricultural pests.

[0047] In a further preferred embodiment, the use in the manufacture of a product for controlling agricultural pests as described above, the pest species is at least one of the group consisting of mites, Lepidoptera, Diptera, Thysanoptera, Hemiptera, Isoptera, Coleoptera pests.

[0048] The terms:

[0049] Unless otherwise indicated, the terms used in the specification and claims have the following meanings.

[0050] The term "isomers" includes enantiomeric, diastereomeric, and geometric (or conformational) isomers of the given structure. For example, the present application includes R and S configurations at each asymmetric center, Z and E double bond isomers, Z and E conformational isomers, single stereochemical isomers, and enantiomeric, diastereomeric, and geometric (or conformational) isomer mixtures.

[0051] The term "pharmaceutically acceptable salts" refers to, for example, acid addition salts and / or base salts. Suitable acid addition salts are formed from acids which form nontoxic salts, for example hydrochloride salts / chlorides. Suitable base salts are formed from bases which form nontoxic salts, for example calcium salts and sodium salts. Also semisalts can be formed, for example hemisulfates and hemicalcium salts.

[0052] The term "therapeutically effective amount" refers to an amount of a compound of the present application that (i) treats a particular disease, condition, or disorder; (ii) alleviates, relieves, or eliminates one or more symptoms of a particular disease, condition, or disorder; or (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder as described herein.

[0053] The term "pharmaceutically acceptable carrier or excipient" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.

[0054] The term "alkyl" refers to saturated aliphatic hydrocarbon groups, which are straight-chain or branched groups, preferably containing from 1 to 20 carbon atoms, more preferably alkyl groups containing from 1 to 12 carbon atoms, and even more preferably alkyl groups containing from 1 to 6 carbon atoms. Non-limiting examples of lower alkyl groups containing from 1 to 6 carbon atoms include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like.

[0055] The term "alkenyl" refers to aliphatic hydrocarbons having at least one carbon-carbon double bond, including straight-chain and branched groups. In some embodiments, alkenyl groups have 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, or 2 to 4 carbon atoms. For example, the term "C 2-6 The term "alkenyl" includes straight-chain or branched unsaturated groups (having at least one carbon-carbon double bond) of 2 to 6 carbon atoms, including, but not limited to, ethenyl, 1 -propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl- 1 -propenyl, 1 -butenyl, 2-butenyl, and the like.

[0056] The term "alkynyl" refers to aliphatic hydrocarbons having at least one carbon-carbon triple bond, including straight-chain and branched groups. In some embodiments, alkynyl groups have 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 3 to 6 carbon atoms. For example, the term "C 2-6 The term "alkynyl" includes straight-chain or branched unsaturated groups (having at least one carbon-carbon triple bond) of 2 to 6 carbon atoms.

[0057] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include methoxy, ethoxy, propyloxy, butyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy.

[0058] The term "cycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents, the cycloalkyl ring comprising 3 to 20 carbon atoms, preferably comprising 3 to 12 carbon atoms, more preferably comprising 3 to 6 carbon atoms (e.g., 3, 4, 5, or 6 carbon atoms), most preferably comprising 5 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocyclic, fused, and bridged cycloalkyl groups.

[0059] The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 members that shares one carbon atom (termed a spiro atom) between single rings, which can contain one or more double bonds, but each ring does not have a fully conjugated pi-electron system. Preferably 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9, or 10 members). Spirocycloalkyl groups are classified as mono-, bi-, or polycyclo, preferably mono- and bi-, more preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered mono- spirocycloalkyl groups, depending on the number of rings sharing a spiro atom between rings.

[0060] The term "fused cycloalkyl" refers to a polycyclic group of 5 to 20 members, each ring in the system sharing an adjacent pair of carbon atoms with other rings in the system, which can contain one or more double bonds, but each ring does not have a fully conjugated pi-electron system. Preferably 6 to 14 members, more preferably 7 to 10 members. Fused cycloalkyl groups are classified as bi-, tri-, tetra-, or polycyclic, preferably bi- or tri-, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups, depending on the number of rings comprising the ring system.

[0061] The term "bridged cycloalkyl" refers to a polycyclic group of 5 to 20 members, any two rings sharing two non-adjacent carbon atoms, which can contain one or more double bonds, but each ring does not have a fully conjugated pi-electron system. Preferably 6 to 14 members, more preferably 7 to 10 members. Bridged cycloalkyl groups are classified as bi-, tri-, tetra-, or polycyclic, preferably bi-, tri-, or tetra-, more preferably bi- or tri-, depending on the number of rings comprising the ring system.

[0062] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic ringed hydrocarbon substituent containing from 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen, or S(O)m, where m is an integer from 0 to 2, but excluding ring moieties of -O-O-, -O-S-, or -S-S-, the remainder of the ring atoms being carbon. Preferably, there are from 3 to 12 ring atoms, of which from 1 to 4 are heteroatoms; more preferably, there are from 3 to 8 ring atoms, of which from 1 to 3 are heteroatoms; most preferably, there are from 5 to 6 ring atoms, of which from 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like, preferably tetrahydropyranyl, piperidinyl, pyrrolidinyl. Polycyclic heterocyclyl groups include spiroheterocyclyl, fused heterocyclyl, and bridged heterocyclyl groups.

[0063] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members sharing one atom (referred to as a spiro atom) between single rings, one or more of which are heteroatoms selected from nitrogen, oxygen, or S(O)m, where m is an integer from 0 to 2, the remainder of the ring atoms being carbon. It can contain one or more double bonds, but each ring does not have a fully conjugated pi-electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings sharing a spiro atom between rings, spiroheterocyclyl groups are classified as mono-, bi-, or polyspiroheterocyclyl groups, preferably mono- and bi-spiroheterocyclyl groups, more preferably 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered monospiroheterocyclyl groups.

[0064] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system sharing an adjacent pair of atoms with other rings in the system, one or more of which can contain one or more double bonds, but each ring does not have a fully conjugated pi-electron system, one or more of which are heteroatoms selected from nitrogen, oxygen, or S(O)m, where m is an integer from 0 to 2, the remainder of the ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of rings, fused heterocyclyl groups are classified as bi-, tri-, tetra-, or polycyclic fused heterocyclyl groups, preferably bi- or tri-cyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bi-cyclic fused heterocyclyl groups.

[0065] The term "bridged heterocyclyl" refers to a 5- to 14-membered, polycyclic heterocyclic radical, sharing two non-adjacent ring atoms, which can contain one or more double bonds, but no ring has a fully conjugated pi-electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)m, where m is an integer from 0 to 2, and the remaining ring atoms are carbon. Preferably, 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of rings, it can be referred to as bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclyl, preferably bicyclic, tricyclic, or tetracyclic, more preferably bicyclic or tricyclic.

[0066] The heterocyclyl groups include heterocyclyl groups as described above (including monocyclic, spiro, fused, and bridged heterocyclyl) fused to an aryl, heteroaryl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heterocyclyl ring, non-limiting examples of which include:

[0067] The term "aryl" refers to a 6- to 14-membered, all-carbon monocyclic or fused polycyclic (that is, rings which share pairs of adjacent carbon atoms) ring systems having a completely conjugated pi-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl.

[0068] The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5- to 10-membered, containing 1 to 3 heteroatoms; more preferably 5- or 6-membered, containing 1 to 2 heteroatoms; preferred examples include imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl, and pyridazinyl.

[0069] The heteroaryl groups include heteroaryl groups as described above fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0070] The term "saturated or unsaturated ring" includes the foregoing aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups.

[0071] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group, wherein alkyl is as defined above.

[0072] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0073] The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0074] The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.

[0075] The term "deuteroalkoxy" refers to an alkoxy group substituted with one or more deuterium atoms, wherein alkoxy is as defined above.

[0076] The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.

[0077] The term "cycloalkyloxy" refers to an -O-cycloalkyl group, wherein cycloalkyl is as defined above.

[0078] The term "heterocyclylalkyl" refers to an alkyl group substituted with one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.

[0079] The term "arylalkyl" refers to an alkyl group substituted with one or more aryl groups, wherein aryl and alkyl are as defined above.

[0080] The term "hydroxy" refers to an -OH group.

[0081] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0082] The term "amino" refers to -NH2.

[0083] The term "cyano" refers to -CN.

[0084] The term "nitro" refers to -NO2.

[0085] The term "carboxy" refers to -C(O)OH.

[0086] The defined carbon number range of the groups described in the present application means that the number of carbon atoms of any integer within the defined range is included, for example, C1-C6 means that the number of carbon atoms of the group can be 1, 2, 3, 4, 5 or 6, C2-C6 means that the number of carbon atoms of the group can be 2, 3, 4, 5 or 6, and the defined carbon number range of other groups is similar.

[0087] Compared with the prior art, the present application has the following beneficial effects:

[0088] The compounds of the present application can be used to prevent and treat parasitic infections, have good prevention and treatment effects, and exhibit good pharmacokinetic properties in mice.

[0089] Other aspects can be apparent after reading and understanding the detailed description. DETAILED DESCRIPTION

[0090] The technical solutions of the present application are further illustrated below by means of specific embodiments. Those skilled in the art should understand that the embodiments are only used to help understand the present application and should not be regarded as specific limitations on the present application.

[0091] Some reaction reagents involved in the present application are abbreviated as follows: Some reaction reagents involved in the present application are abbreviated as follows:

[0092] DMF: N,N-dimethylformamide;

[0093] HATU: 2-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate;

[0094] DIPEA: N,N-diisopropylethylamine;

[0095] DCM: dichloromethane;

[0096] T4P: 1-butylphosphonic anhydride;

[0097] TFA: trifluoroacetic acid;

[0098] Pd(dppf)Cl2: [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium;

[0099] THF: tetrahydrofuran;

[0100] NCS: N-chlorosuccinimide.

[0101] Example 001 Preparation of 4-(5-(3,5-dichloro-4-fluorophenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((l- (trifluoromethyl)cyclopropyl)amino)ethyl)benzamide (1)

[0102] Step 1: Compound 1-1 (20.0 g, 114 mmol, 1 eq.) was dissolved in DMF (150 mL), HATU (52.1 g, 137 mmol, 1.2 eq.) and DIPEA (44.3 g, 343 mmol, 3 eq.) were added, stirred at 25 °C for 0.5 h, then compound 1-2 hydrochloride (20.3 g, 126 mmol, 1.1 eq.) was added, stirred at 25 °C for 12 h. The reaction was quenched with water (300 mL), extracted with ethyl acetate (200 mL x 3). The organic phase was washed with saturated brine (200 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude compound 1-3 (30.0 g, yield 93%).

[0103] Step 2: Compound 1-3 (30.0 g, 106 mmol, 1 eq.) was dissolved in DCM (150 mL), hydrogen chloride solution in dioxane (4 M, 150 mL) was added, stirred at 25 °C for 3 h. After the reaction was completed, it was concentrated under reduced pressure, and slurry at room temperature with ethyl acetate (30 mL) to give compound 1-4 hydrochloride (18.0 g, yield 77%). 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.21 (s, 3H), 3.55 (s, 2H), 1.32-1.24 (m, 2H), 1.10-1.00 (m, 2H).

[0104] Step 3: Compound 1-5 (5.00 g, 28.1 mmol, 1 eq.) was dissolved in DMF (50 mL), HATU (12.8 g, 33.7 mmol, 1.2 eq.) and DIPEA (10.9 g, 84.1 mmol, 3 eq.) were added, stirred at 25 °C for 0.5 h, then compound 1-4 (7.36 g, 33.7 mmol, 1.2 eq.) was added, stirred at 25 °C for 0.5 h. The reaction was poured into water (50 mL), extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, the crude product was separated and purified by column chromatography (SiO2, ethyl acetate / n-hexane, 0~60%) to give compound 1-6 (4.20 g, yield: 78%). MS-ESI calculated for [M+H] + 343, found 343.

[0105] Step 4: Compound 1-6 (297 mg, 1.14 mmol, 1.3 eq.) and 1-7 (300 mg, 876 µmol, 1 eq.) were dissolved in acetonitrile (3 mL), K2CO3 (12.1 mg, 87.6 µmol, 0.1 eq.) was added, stirred at 95 °C for 16 h. The reaction was concentrated under reduced pressure, water (10 mL) was added, extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, the crude product was separated and purified by column chromatography (SiO2, ethyl acetate / n-hexane, 0~40%) to give compound 1-8 (140 mg, yield: 27%). MS-ESI calculated for [M+H] + 585, found 585.

[0106] Step 5: Tetrabutylammonium bromide (5.3 mg, 23.9 μmol, 0.1 eq.), NH2OH.HC1 (49.8 mg, 718 μmol, 3 eq.) and NaOH (38.2 mg, 957 μmol, 4 eq.) were dissolved in H2O (0.5 mL) and added to a solution of 1-8 (140 mg, 239 μmol, 1 eq.) and THF (2.0 mL) and stirred at 25 °C for 12 h. The reaction was quenched by the addition of NH4C1 (5 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was separated and purified by preparative high-performance liquid chromatography (column: Xtimate C18, 30*150 mm I.D., 5um; mobile phase: [0.1% formic acid in water - acetonitrile], gradient: (66%-86%, 10 min, 100%, 2 min, 66%, 3 min)) to give compound 1 (6.8 mg, yield: 5%). 1 H NMR (400 MHz, CDC13) δ 7.61 (d, J = 6.0 Hz, 2H), 7.58 - 7.46 (m, 3H), 6.77 (s, 1H), 6.64 (t, J = 4.8 Hz, 1H), 4.16 - 4.05 (m, 3H), 3.71 (d, J = 17.6 Hz, 1H), 2.50 (s, 3H), 1.43 - 1.36 (m, 2H), 1.22 - 1.14 (m, 2H). MS - ESI calculated [M+H] + 600, found 600.

[0107] Example 002 Preparation of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((3-(trifluoromethyl)oxetan-3- yl)amino)ethyl)benzamide (2)

[0108] Synthetic route of fragment 2-3:

[0109] Step 1 : To a solution of 1-1 (493 mg, 2.81 mmol, 1 eq.) and 2-1 (500 mg, 2.81 mmol, 1 eq.) in DCM (5 mL) was added T4P (3.04 g, 4.22 mmol, 50% in ethyl acetate, 1.5 eq.) and DIPEA (1.09 g, 8.45 mmol, 3 eq.) and stirred at 25 °C for 2 h. After completion of the reaction, water (50 mL) was added and extracted with ethyl acetate (50 x 3 mL). The organic phase was washed with saturated NaHC03(50 x 2 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude compound 2-2 (780 mg, yield 92%).

[0110] Step 2: To a solution of 2-2 (780 mg, 2.61 mmol, 1 eq.) in DCM (10 mL) was added TFA (298 mg, 2.61 mmol, 2 mL, 1 eq.) and stirred at 25 °C for 5 h. The reaction mixture was concentrated under reduced pressure to give the crude trifluoroacetate salt of compound 2-3 (800 mg, yield 97%).

[0111] Synthetic route of compound 2:

[0112] Step 1 : To a solution of compound 2-4 (5.00 g, 23.5 mmol, 1 eq.) in MeOH (30 mL) and DMF (30 mL) was added Pd(dppf)Cl2(344 mg, 469 pmol, 0.02 eq.) and triethylamine (7.12 g, 70.3 mmol, 3 eq.) and stirred at 80 °C under 15 psi CO atmosphere for 24 h. After completion of the reaction, it was concentrated under reduced pressure. The crude product was purified by column chromatography (Si02, ethyl acetate / n-hexane, 0-10%) to give compound 2-5 (4.2 g, yield: 93%). 1 H NMR (400 MHz, CDC13) δ 7.98 (d, J = 8.0 Hz, 1H), 7.85-7.77 (m, 2H), 3.94 (s, 3H), 2.69-2.48 (m, 6H).

[0113] Step 2: To a solution of 2-5 (4.00 g, 20.8 mmol, 1 eq.) and 2-6 (6.07 g, 24.9 mmol, 1.2 eq.) in toluene (50 mL) and trifluorotoluene (50 mL) was added Cs2CO3 (678 mg, 2.08 mmol, 0.1 eq.) and stirred at 110 °C for 12 h, then quenched by H2O (10 mL). The mixture was extracted with ethyl acetate (10 mL x 2), the organic phase was washed with saturated brine (15 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was isolated and purified by column chromatography (SiO2, ethyl acetate / n-hexane, 0~5%) to give compound 2-7 (4.00 g, yield: 46%). 1 H NMR (400 MHz, CDC13) δ 8.02-7.91 (m, 1H), 7.74-7.63 (m, 2H), 7.43-7.38 (m, 1H), 7.34 (t, J = 2.0 Hz, 1H), 7.17 (d, J = 1.6 Hz, 2H), 3.94 (s, 3H), 2.64 (s, 3H).

[0114] Step 3: To a solution of NH2OH.HC1 (486 mg, 6.99 mmol, 2 eq.) and tetrabutylammonium bromide (112 mg, 349 μmol, 0.1 eq.) in H2O (4 mL) was added NaOH (419 mg, 10.5 mmol, 3 eq.) and stirred at 25 °C for 0.5 h, then a solution of 2-7 (1.46 g, 3.49 mmol, 1 eq.) in THF (20 mL) was added and stirred at 25 °C for 3 h. After the reaction was completed, NH4C1 (5 mL) was added to quench the reaction, then H2O (20 mL) was added and the mixture was extracted with ethyl acetate (20 mL x 2), the organic phase was washed with saturated brine (25 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was isolated and purified by column chromatography (SiO2, ethyl acetate / n-hexane, 0~7%) to give compound 2-8 (1.01 g, yield: 66%). 1 H NMR (400 MHz, CDC13) δ 7.98 (d, J = 8.8 Hz, 1H), 7.59-7.49 (m, 4H), 7.45 (t, J = 1.6 Hz, 1H), 4.14-4.06 (m, 1H), 3.93 (s, 3H), 3.73 (d, J = 17.2 Hz, 1H), 2.65 (s, 3H).

[0115] Step 4: Compound 2-8 (297 mg, 1.14 mmol, 1.3 eq.) was dissolved in THF (3 mL) and H2O (1 mL), LiOH.H2O (291 mg, 6.94 mmol, 3 eq.) was added, stirred at 25 °C for 6 h. The reaction was adjusted to pH 5-7 with 1M HC1, extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude compound 2-9 (960 mg, yield: 99%). 1 H NMR (400 MHz, CDC13) δ 8.18 - 8.08 (m, 1H), 7.64 - 7.57 (m, 2H), 7.54 (d, J = 1.6 Hz, 2H), 7.46 (t, J = 1.6 Hz, 1H), 4.16 - 4.09 (m, 1H), 3.75 (d, J = 17.2 Hz, 1H), 2.71 (s, 3H).

[0116] Step 5: To a solution of 2-9 (60.0 mg, 143 pmol, 1 eq.) in DMF (1 mL) was added HATU (65.4 mg, 172 pmol, 1.2 eq.) and DIPEA (55.6 mg, 430 pmol, 3 eq.), stirred at 25 °C for 10 min. To the mixture was added 2-3 (70 mg, 224 pmol, 1.56 eq.), stirred at 25 °C for 10 min. Water (10 mL) was added, extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by preparative thin-layer chromatography (Si02, ethyl acetate) to give compound 2 (13.7 mg, yield: 16%). 1 H NMR (400 MHz, CDC13) δ 8.18 - 8.08 (m, 1H), 7.64 - 7.57 (m, 2H), 7.54 (d, J = 1.6 Hz, 2H), 7.46 (t, J = 1.6 Hz, 1H), 4.16 - 4.09 (m, 1H), 3.75 (d, J = 17.2 Hz, 1H), 2.71 (s, 3H). + 598, found 598.

[0117] Example 003 Preparation of N-(2-(3-fluoro-3-(fluoromethyl)azetidin-l-yl)-2-oxoethyl)-2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamide (3)

[0118] Step 1: Compound 1-1 (3.80 g, 21.7 mmol, 1.0 eq.), hydrochloride salt of compound 3-1 (4.67 g, 32.5 mmol, 1.5 eq.), T4P (23.4 g, 32.5 mmol, 50% solution in ethyl acetate, 1.5 eq.), DIEA (11.2 g, 86.8 mmol, 4 eq.) were dissolved in dichloromethane (30 mL) and reacted at 20 °C for 1 hour. Water (30 mL) was added to quench, extracted with ethyl acetate (30 mL x 2), the organic phase was combined and washed with saturated brine (20 mL x 2), and concentrated under reduced pressure to obtain crude compound 3-2 (5.40 g, yield 94%).

[0119] Step 2: Compound 3-2 (6.00 g, 22.7 mmol, 1.0 eq.) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (12.9 g, 114 mmol, 4.0 eq.) was added dropwise, and reacted at 40 °C for 16 hours. Concentrated under reduced pressure to obtain crude trifluoroacetate salt of compound 3-3 (6.31 g, yield 100%).

[0120] Step 3: 1-5 (2.50 g, 14.0 mmol, 1.0 eq.), 3-3 (5.85 g, 21.0 mmol, 1.5 eq.), DIEA (7.25 g, 56.1 mmol, 4.0 eq.), HATU (8.00 g, 21.0 mmol, 1.5 eq.) were dissolved in DMF (15 mL) and stirred at 20 °C for 1 hour. Water (10 mL) and ethyl acetate (10 mL) were added, the liquid was separated, the aqueous phase was extracted with ethyl acetate (20 mL x 3), the organic phase was combined and washed with saturated brine (20 mL x 2), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and the crude product was separated and purified by column chromatography (SiO2, ethyl acetate) to obtain compound 3-5 (3.00 g, yield: 66%). 1 H NMR (400 MHz, CDCl3) δ 7.92-7.72 (m, 2H), 7.61-7.39 (m, 1H), 6.77-6.47 (m, 1H), 4.79-4.56 (m, 2H), 4.49-4.08 (m, 6H), 2.63 (s, 3H), 2.53 (s, 3H).

[0121] Step 4: 3-5 (250 mg, 770 pmol, 1.0 eq.), 3-6 (320 mg, 1.16 mmol, 1.5 eq.), Cs2C03(25.0 mg, 77.1 pmol, 0.1 eq.) were added to toluene (3 mL) and trifluorotoluene (3 mL) and stirred at 115 °C for 16 h. The reaction was concentrated under reduced pressure, water (10 mL) was added and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and the crude product was isolated and purified by column chromatography (Si02, ethyl acetate / n-hexane, 0-35%) to give compound 3-7 (180 mg, yield: 40%). 1 H NMR (400 MHz, CDC13) δ 7.78 - 7.64 (m, 2H), 7.56 - 7.50 (m, 1H), 7.47 - 7.42 (m, 1H), 7.35 - 7.30 (m, 2H), 6.64 - 6.58 (m, 1H), 4.84 - 4.57 (m, 2H), 4.47 - 4.03 (m, 6H), 2.58 - 2.43 (m, 3H).

[0122] Step 5: Compound tetrabutylammonium bromide (9.9 mg, 30.8 pmol, 0.1 eq.), NaOH (49.3 mg, 1.23 mmol, 4 eq.) and NH2OH.HC1 (64.2 mg, 925 pmol, 3 eq.) were dissolved in H20 (0.5 mL) and stirred at 25 °C for 0.5 h, then added to a solution of 3-7 (180 mg, 308 pmol, 1 eq.) and THF (2.0 mL) and stirred at 25 °C for 0.5 h. The reaction was quenched by adding NH4C1 (5 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure and the crude product was purified by preparative thin layer chromatography (Si02, ethyl acetate) to give compound 3 (24.6 mg, yield 13%). 1 H NMR (400 MHz, CDC13) δ 7.67 (s, 2H), 7.58 - 7.47 (m, 3H), 6.62 (t, J = 4.4 Hz, 1H), 4.81 - 4.68 (m, 1H), 4.66 - 4.57 (m, 1H), 4.41 (d, J = 17.6 Hz, 2H), 4.26 (d, J = 18.0 Hz, 2H), 4.15 - 4.05 (m, 3H), 3.71 (d, J = 17.2 Hz, 1H), 2.51 (s, 3H). MS-ESI calc [M+H] + 598, found 598.

[0123] Example 004 Preparation of 2-methyl-N-(2-oxo-2-((1-(trifluoromethyl)cyclopropyl)amino)ethyl)-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamide (4)

[0124] Step 1: To a solution of 3-6 (105 mg, 379 pmol, 1.3 eq.) and 1-6 (100 mg, 292 pmol, 1 eq.) in acetonitrile (3 mL) was added K2CO3 (4.04 mg, 29.2 pmol, 0.1 eq.) and stirred at 95 °C for 16 h. After the reaction was completed, the mixture was concentrated under reduced pressure. Diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was isolated and purified by column chromatography (SiO2, ethyl acetate / n-hexane, 0-50%) to give compound 4-1 (110 mg, yield 62%). MS-ESI calculated [M+H] + 601, found 601.

[0125] Step 2: Tetrabutylammonium bromide (5.35 mg, 16.6 pmol, 0.1 eq.), NH2OH.HC1 (34.6 mg, 498 pmol, 3 eq.) and NaOH (26.5 mg, 664 pmol, 4 eq.) were dissolved in H2O (0.5 mL) and stirred at 25 °C for 0.5 h. To the mixture was added a solution of 4-1 (100 mg, 166 pmol, 1 eq.) in THF (2 mL) and stirred at 25 °C for 0.5 h. After the reaction was completed, quenched with NH4C1 (5 mL) and extracted with ethyl acetate (10 mL x 2), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was isolated and purified by preparative thin layer chromatography (SiO2, ethyl acetate) to give compound 4 (19.3 mg, yield: 19%). 1 H NMR (400 MHz, CDC13) δ 7.67 (s, 2H), 7.59 - 7.44 (m, 3H), 6.98 (s, 1H), 6.74 (t, J = 5.2 Hz, 1H), 4.23 - 3.98 (m, 3H), 3.71 (d, J = 17.2 Hz, 1H), 2.49 (s, 3H), 1.41 - 1.34 (m, 2H), 1.20 - 1.10 (m, 2H). MS-ESI calculated [M+H] + 616, found 616.

[0126] Example 005 Preparation of 4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)- 4,5-dihydroisoxazol-3-yl)-N-(2-(3-fluoro-3-(fluoromethyl)azetidin-l-yl)-2- oxoethyl)-2-methylbenzamide (5)

[0127] Step 1 : Compound 3-5 (250 mg, 770 pmol, 1.0 eq.), 1-7 (301 mg, 1.16 mmol, 1.5 eq.) and Cs2C03(25 mg, 77.1 pmol, 0.1 eq.) were added to toluene (3 mL) and trifluorotoluene (3 mL) and stirred at 115 °C for 16 h. The reaction was concentrated under reduced pressure, water (10 mL) was added and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was isolated and purified by column chromatography (Si02, ethyl acetate / n-hexane, 0-50%) to give compound 5-1 (200 mg, yield: 46%). 1 H NMR (400 MHz, CDC13) δ 7.74-7.64 (m, 2H), 7.56-7.50 (m, 1H), 7.45-7.39 (m, 1H), 7.28-7.23 (m, 2H), 6.70-6.51 (m, 1H), 4.82-4.53 (m, 2H), 4.50-4.01 (m, 6H), 2.52 (s, 3H).

[0128] Step 2: Compound NH2OH.HC1 (47.7 mg, 687 pmol, 3 eq.), NaOH (36.6 mg, 916 pmol, 4 eq.) and tetrabutylammonium bromide (7.4 mg, 22.9 pmol, 0.1 eq.) were dissolved in H20 (0.5 mL) and added to a solution of 3-7 (130 mg, 229 pmol, 1 eq.) in THF (2.0 mL) and stirred at 25 °C for 12 h. The reaction was quenched by the addition of NH4C1 (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was isolated and purified by preparative high-performance liquid chromatography (column: Xtimate C18, 30*150 mm I.D., 5um; mobile phase: [0.1% formic acid in water - acetonitrile], gradient: (62%-82%, 10 min, 100%, 2 min, 62%, 3 min)) to give compound 5 (13.7 mg, yield: 10%). 1H NMR (400 MHz, CDC13) δ 7.61 (d, J = 6.0 Hz, 2H), 7.56 (s, 1H), 7.52 (d, J = 2.4 Hz, 2H), 6.66 (t, J = 4.4 Hz, 1H), 4.81 - 4.68 (m, 1H), 4.67 - 4.58 (m, 1H), 4.42 (d, J = 17.6 Hz, 2H), 4.26 (d, J = 18.0 Hz, 2H), 4.14 - 4.02 (m, 3H), 3.71 (d, J = 17.2 Hz, 1H), 2.51 (s, 3H). MS - ESI calculated [M+H] + 582, found 582.

[0129] Example 006 Preparation of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-(2-(trifluoromethyl)azetidin-l- yl)ethyl)benzamide (6)

[0130] Step 1: To a solution of 2-9 (400 mg, 956 pmol, 1 eq.) and 6-1 (144 mg, 1.14 mmol, 1.2 eq.) in DMF (10 mL) was added HATU (436 mg, 1.14 mmol, 1.2 eq.) and DIPEA (370 mg, 2.86 mmol, 499 pL, 3 eq.), stirred at 20 °C for 2 h, the reaction was completed, added H2O (10 mL), extracted with ethyl acetate (10 mL x 2), the combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (Si02, ethyl acetate / n-hexane = 0~25%) to give 6-2 (450 mg, yield 96%). MS - ESI calculated [M+H] + 489, found 489.

[0131] Step 2: To a solution of 6-2 (450 mg, 919 pmol, 1 eq.) in THF (4 mL) and H2O (1 mL) was added LiOH.H2O (115 mg, 2.75 mmol, 3 eq.), stirred at 20 °C for 5 h. The THF was rotary evaporated, acidified with 1 N HC1 to pH about 4, then extracted with ethyl acetate (15 mL x 2), the combined organic phase was washed with saturated brine (15 mL), dried over magnesium sulfate, filtered, concentrated under reduced pressure to give compound 6-3 (400 mg, yield 91%). MS - ESI calculated [M+H] + 475, found 475.

[0132] Step 3: To a solution of 6-3 (50.0 mg, 105 pmol, 1 eq.) in DMF (2 mL) was added HATU (48.0 mg, 126 pmol, 1.2 eq.) and DIPEA (40.7 mg, 315 pmol, 3 eq.). Stirring at 25 °C for 10 min. The hydrochloride salt of 6-4 (20.3 mg, 126 pmol, 1.2 eq.) was added to the mixture, stirring at 25 °C for 10 min. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (SiO2, ethyl acetate) to give compound 6 (5.6 mg, yield: 9%). 1 H NMR (400 MHz, CDC13) δ 7.56 (s, 1H), 7.53 (d, J = 5.2 Hz, 4H), 7.45 (t, J = 1.6 Hz, 1H), 6.67-6.55 (m, 1H), 5.01-4.70 (m, 1H), 4.44-4.15 (m, 3H), 4.11 (d, J = 17.6 Hz, 1H), 4.05-3.85 (m, 1H), 3.72 (d, J = 17.2 Hz, 1H), 2.82-2.62 (m, 1H), 2.52 (s, 3H), 2.50-2.43 (m, 1H). MS-ESI calc [M+H] + 582, found 582.

[0133] Example 007 Preparation of 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((1- (trifluoromethyl)cyclopropyl)amino)ethyl)benzamide (7)

[0134] Step 1 : To a solution of 7-1 (315 mg, 1.13 mmol, 1.3 eq.) and 1-6 (300 mg, 876 μmol, 1 eq.) in toluene (5 mL) and trifluorotoluene (5 mL) was added Cs2C03(57.1 mg, 175 μmol, 0.2 eq.) and stirred at 110 °C for 12 h. The mixture was concentrated under reduced pressure, diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic phase was concentrated under reduced pressure, dissolved in toluene (5 mL) and added with sulfurous chloride (312 mg, 2.62 mmol, 3 eq.) and stirred at 70 °C for 4 h. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the crude. The crude was isolated and purified by column chromatography (S1O2, ethyl acetate / n-hexane, 0-40%) to give compound 7-2 (170 mg, yield 32%). MS-ESI calc. for [M+H] + 601, found 601.

[0135] Step 2: Compound tetrabutylammonium bromide (5.3 mg, 28.2 μmol, 0.1 eq.), NH2OH.HC1 (58.9 mg, 848 μmol, 3 eq.) and NaOH (45.2 mg, 1.13 mmol, 4 eq.) were dissolved in H20 (0.5 mL) and stirred at 25 °C for 0.5 h. A solution of 7-2 (170 mg, 282 μmol, 1 eq.) in THF (2.0 mL) was added and stirred at 25 °C for 0.5 h. The reaction was quenched with NH4C1 (5 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by preparative thin layer chromatography (S1O2, ethyl acetate) gave 7 (19.0 mg, yield: 11%). 1 H NMR (400 MHz, CDC13) δ 7.85 (s, 1H), 7.78 (s, 1H), 7.72 (s, 1H), 7.61-7.47 (m, 3H), 7.00 (s, 1H), 6.76 (t, J = 5.2 Hz, 1H), 4.22-4.05 (m, 3H), 3.75 (d, J = 17.6 Hz, 1H), 2.50 (s, 3H), 1.42-1.30 (m, 2H), 1.22-1.06 (m, 2H). MS-ESI calc. for [M+H] + 616, found 616.

[0136] Example 008 and Example 009 Preparation of (S)-4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((1- (trifluoromethyl)cyclopropyl)amino)ethyl)benzamide (8) and (R)-4-(5-(3-chloro-5- (trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(2- oxo-2-((1-(trifluoromethyl)cyclopropyl)amino)ethyl)benzamide (9)

[0137] Step 1: Compound 7 (500 mg) was purified by supercritical fluid chromatography (column: ChiralCel OJ, 250 x 50 mm I.D., 10 μm; mobile phase: [A is CO2 and B is Methanol (0.1% NH3H2O)], gradient: (B 20%) to give compound 8 (41.6 mg, yield: 8%). 1 H NMR (400 MHz, CDC13) δ 7.85 (s, 1H), 7.78 (s, 1H), 7.72 (s, 1H), 7.60-7.46 (m, 3H), 6.92 (s, 1H), 6.71 (t, J = 5.2 Hz, 1H), 4.23-4.04 (m, 3H), 3.75 (d, J = 17.2 Hz, 1H), 2.50 (s, 3H), 1.42-1.34 (m, 2H), 1.24-1.06 (m, 2H). MS-ESI calculated [M+H] + 616, found 616. Compound 9 (37.0 mg, yield: 7%). 1 H NMR (400 MHz, CDC13) δ 7.85 (s, 1H), 7.78 (s, 1H), 7.72 (s, 1H), 7.60-7.46 (m, 3H), 6.92 (s, 1H), 6.71 (t, J = 5.2 Hz, 1H), 4.23-4.04 (m, 3H), 3.75 (d, J = 17.2 Hz, 1H), 2.50 (s, 3H), 1.42-1.34 (m, 2H), 1.24-1.06 (m, 2H). MS-ESI calculated [M+H] + 616, found 616.

[0138] Example 010 Preparation of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((1-(trifluoromethyl)cyclopropyl)amino)ethyl)benzamide (10)

[0139] Step 1: To a solution of 2-9 (50.0 mg, 119 μmol, 1 eq.) in DMF (1 mL) was added HATU (54.5 mg, 143 μmol, 1.2 eq.) and DIPEA (46.3 mg, 358 μmol, 3 eq.). After stirring at 25 °C for 10 min, the hydrochloride salt of 1-4 (26.1 mg, 143 μmol, 1.2 eq.) was added and stirred at 25 °C for 10 min. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (SiO2, ethyl acetate) to give compound 10 (27.3 mg, yield 39%). 1 H NMR (400 MHz, CDC13) δ 7.63 - 7.47 (m, 5H), 7.46 (t, J = 1.6 Hz, 1H), 6.81 (s, 1H), 6.65 (t, J = 5.2 Hz, 1H), 4.18 - 4.03 (m, 3H), 3.72 (d, J = 17.6 Hz, 1H), 2.50 (s, 3H), 1.43 - 1.33 (m, 2H), 1.22 - 1.13 (m, 2H). MS - ESI calculated [M+H] + 582, found 582.

[0140] Example 011 and Example 012 Preparation of (S)-4-(5-(3,5-dichlorophenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((1- (trifluoromethyl)cyclopropyl)amino)ethyl)benzamide (11) and (R)-4-(5-(3,5- dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo- 2-((1-(trifluoromethyl)cyclopropyl)amino)ethyl)benzamide (12)

[0141] Step 1: Compound 10 (300 mg) was purified by supercritical fluid chromatography (column: ChiralCel OJ, 250 x 50 mm id, 10 μm; mobile phase: [A for CO2 and B for Methanol], gradient: (B 20%)) to give compound 11 (14.9 mg, yield: 5%). 1H NMR (400 MHz, CDC13) δ 7.59 - 7.42 (m, 6 H), 6.85 (s, 1 H), 6.85 (t, J = 5.2 Hz, 1 H), 4.19 - 3.95 (m, 3 H), 3.72 (d, J = 17.6 Hz, 1 H), 2.50 (s, 3 H), 1.41 - 1.32 (m, 2 H), 1.22 - 1.12 (m, 2 H). MS-ESI calculated [M+H] + 582, found 582.

[0142] Compound 12 (31.6 mg, yield: 11%). 1 H NMR (400 MHz, CDC13) δ 7.59 - 7.42 (m, 6 H), 6.85 (s, 1 H), 6.85 (t, J = 5.2 Hz, 1 H), 4.19 - 3.95 (m, 3 H), 3.72 (d, J = 17.6 Hz, 1 H), 2.50 (s, 3 H), 1.41 - 1.32 (m, 2 H), 1.22 - 1.12 (m, 2 H). MS-ESI calculated [M+H] + 582, found 582.

[0143] Example 013 Preparation of 4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(3-fluoro-3-(fluoromethyl)azetidin- 1-yl)-2-oxoethyl)-2-methylbenzamide (13)

[0144] Step 1: 3-5 (250 mg, 770 μmol, 1.0 eq.), 7-1 (320 mg, 1.16 mmol, 1.5 eq.) and Cs2CO3 (25 mg, 77.1 μmol, 0.1 eq.) were added to toluene (3 mL) and trifluorotoluene (3 mL) and stirred at 115 °C for 16 h. The reaction was concentrated under reduced pressure, water (5 mL) was added and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with water (5 mL) and saturated brine (5 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was isolated and purified by column chromatography (SiO2, ethyl acetate / n-hexane, 0~50%) to give compound 13-1 (150 mg, yield: 33%). 1 H NMR (400 MHz, CDC13) δ 7.59 - 7.42 (m, 6 H), 6.85 (s, 1 H), 6.85 (t, J = 5.2 Hz, 1 H), 4.19 - 3.95 (m, 3 H), 3.72 (d, J = 17.6 Hz, 1 H), 2.50 (s, 3 H), 1.41 - 1.32 (m, 2 H), 1.22 - 1.12 (m, 2 H). MS-ESI calculated [M+H]

[0145] Step 2: NH2OH.HC1 (53.6 mg, 772 μmol, 3 eq.), NaOH (41.1 mg, 1.02 mmol, 4 eq.) and tetrabutylammonium bromide (8.3 mg, 25.7 μmol, 0.1 eq.) were dissolved in H20 (0.5 mL) and stirred at 25 °C for 0.5 h, then added to a solution of 13-1 (150 mg, 257 μmol, 1 eq.) in THF (2.0 mL) and stirred at 25 °C for 0.5 h. The reaction was quenched by adding NH4C1 (5 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (2 x 10 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (Si02, ethyl acetate) to give compound 13 (26.3 mg) in 17% yield.1H NMR (400 MHz, CDC13) δ = 7.91-7.66 (m, 3H), 7.64-7.46 (m, 3H), 6.62 (t, J = 4.4 Hz, 1H), 4.80-4.57 (m, 2H), 4.41 (d, J = 17.6 Hz, 2H), 4.26 (d, J = 18.0 Hz, 2H), 4.16 (d, J = 17.6 Hz, 1H), 4.10 (t, J = 3.6 Hz, 2H), 3.75 (d, J = 17.6 Hz, 1H), 2.51 (s, 3H). MS-ESI calcd [M+H] + 598, found 598.

[0146] Example 014 Preparation of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-N-(2-(3-hydroxy-3-(trifluoromethyl)azetidin-l-yl)-2- oxoethyl)-2-methylbenzamide (14)

[0147] Step 1: To a solution of the hydrochloride salt of 14-1 (500 mg, 2.81 mmol, 1 eq.) and 1-1 (493 mg, 2.81 mmol, 1 eq.) in DCM (3 mL) was added DIPEA (1.09 g, 8.44 mmol, 3 eq.) and T4P (3.04 g, 4.22 mmol, 50% in ethyl acetate, 1.5 eq.). Stirred at 25 °C for 2 h. Diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with NaHC03(20 mL x 2), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give crude compound 14-2 (600 mg, yield 71%). 1H NMR (400 MHz, CDC13) δ 5.24 (s, 1H), 4.43 (d, J = 10.0 Hz, 1H), 4.34 (d, J = 11.2 Hz, 1H), 4.22 (d, J = 10.4 Hz, 1H), 4.08 (d, J = 11.6 Hz, 1H), 3.95-3.66 (m, 3H), 1.47 (s, 9H).

[0148] Step 2: To a solution of 14-2 (605 mg, 2.02 mmol, 1 eq.) in DCM (5 mL) was added TFA (1 mL). Stirring at 25 °C for 3 h. After the reaction was completed, the crude compound 14-3 trifluoroacetate salt (600 mg, yield 94%) was obtained by concentration under reduced pressure.

[0149] Step 3: To a solution of 2-9 (60.0 mg, 143 μmol, 1 eq.) in DMF (1 mL) was added HATU (65.4 mg, 172 μmol, 1.2 eq.) and DIPEA (55.6 mg, 430 μmol, 3 eq.). Stirring at 25 °C for 0.5 h. After the addition of 14-3 trifluoroacetate salt (60.0 mg, 192 μmol, 1.34 eq.), stirring at 25 °C for 0.5 h. Dilution with water (20 mL) and extraction with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by preparative thin layer chromatography (Si02, ethyl acetate) to give 14 (13.4 mg, yield: 20%). 1 H NMR (400 MHz, CDC13) δ 7.59-7.48 (m, 5H), 7.45 (t, J = 1.6 Hz, 1H), 6.67 (t, J = 4.8 Hz, 1H), 4.48 (d, J = 10.0 Hz, 1H), 4.35 (d, J = 11.2 Hz, 1H), 4.31-4.04 (m, 5H), 4.03-3.91 (m, 1H), 3.73 (d, J = 17.6 Hz, 1H), 2.49 (s, 3H). MS-ESI calculated [M+H] + 598, found 598.

[0150] Preparation of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(3-((2,2,2-trifluoroethyl)amino)oxetan-3-yl)methyl)benzamide (15)

[0151] Step 1: To a solution of 15-1 (500 mg, 2.47 mmol, 1 eq.) in THF (40 mL) was added trifluoroethyl trifluoromethanesulfonate (860 mg, 3.70 mmol, 1.5 eq.) and triethylamine (500 mg, 4.94 mmol, 687 μL, 2 eq.) and reacted at 70 °C for 12 h. After completion of the reaction, the crude compound 15-2 (700 mg, yield 99%) was obtained by concentration under reduced pressure.

[0152] Step 2: To a solution of 15-2 (178 mg, 626 μmol, 1 eq.) in DCM (10 mL) was added TFA (3 mL) and stirred at 25 °C for 12 h. The reaction was concentrated under reduced pressure to give the trifluoroacetic acid salt of crude compound 15-3 (150 mg, yield 80%). 1 H NMR (400 MHz, DMSO-d6) δ 7.79 (s, 3H), 4.4-4.5 (m, 2H), 4.36 (d, J = 7.2 Hz, 2H), 3.3-3.4 (m, 2H), 3.25 (d, J = 4.8 Hz, 2H).

[0153] Step 3: To a solution of 2-9 (35.0 mg, 83.6 μmol, 1 eq.) and 15-3 (49.9 mg, 167 μmol, 2 eq.) in DMF (2 mL) was added HATU (47.7 mg, 125 μmol, 1.5 eq.) and DIPEA (32.4 mg, 251 μmol, 43.7 μL, 3 eq.). It was stirred at 25 °C for 12 h. It was quenched with H2O (3 mL), extracted with ethyl acetate (5 mL x 2), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, the obtained crude was purified by preparative thin layer chromatography (SiO2, ethyl acetate) to give 15 (27.0 mg, yield 55%). 1 H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 6.0 Hz, 4H), 7.45 (t, J = 2.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 6.15 (t, J = 5.2 Hz, 1H), 4.60 - 4.47 (m, 4H), 4.10 (d, J = 17.2 Hz, 1H), 3.89 (d, J = 5.6 Hz, 2H), 3.72 (d, J = 17.6 Hz, 1H), 3.43 - 3.24 (m, 2H), 2.48 (s, 3H), 2.09 - 1.93 (m, 1H). MS-ESI calculated [M+H] + 584, found 584.

[0154] Example 016 Preparation of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-(2-(trifluoromethyl)pyrrolidin-1- yl)ethyl)benzamide (16)

[0155] Step 1: To a solution of 6-3 (50.0 mg, 105 μmol, 1 eq.) in DMF (2 mL) was added HATU (48.0 mg, 126 μmol, 1.2 eq.) and DIPEA (40.7 mg, 315 μmol, 3 eq.). Stirring at 25 °C for 10 min, to the mixture was added hydrochloride salt of 16-1 (21.9 mg, 125 μmol, 1.18 eq.) and stirred at 25 °C for 10 min. Quenching with water (10 mL) and extraction with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (SiO2, ethyl acetate) to give 16 (34.5 mg, 54% yield). 1 H NMR (400 MHz, CDC13) δ 7.57 - 7.50 (m, 5H), 7.45 (t, J = 1.6 Hz, 1H), 6.87 - 6.72 (m, 1H), 4.90 - 4.74 (m, 1H), 4.50 - 4.33 (m, 1H), 4.25 - 4.15 (m, 1H), 4.11 (d, J = 17.6 Hz, 1H), 3.72 (d, J = 17.2 Hz, 1H), 3.69 - 3.52 (m, 2H), 2.53 (s, 3H), 2.29 - 2.02 (m, 4H). MS-ESI calculated [M+H] + 596, found 596.

[0156] Example 017 Preparation of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-2-methyl-N-(1-((2,2,2-trifluoroethyl)amino)cyclopropyl)methyl)benzamide (17)

[0157] Step 1: To a solution of 17-1 (500 mg, 2.68 mmol, 1 eq.) in THF (10 mL) was added trifluoroethyl trifluoromethanesulfonate (934 mg, 4.02 mmol, 1.5 eq.) and triethylamine (543 mg, 5.37 mmol, 746 μL, 2 eq.) and stirred at 70 °C for 12 h. The reaction was concentrated under reduced pressure to give compound 17-2 (700 mg, 97% yield) as a crude compound.

[0158] Step 2: To a solution of 17-2 (250 mg, 931 pmol, 1 eq.) in dioxane (5 mL) was added hydrogen chloride in dioxane (4 M, 5 mL) and stirred at 25 °C for 16 h. The reaction was concentrated under reduced pressure and the resulting crude was slurry with ethyl acetate (15 mL) to give the hydrochloride salt of compound 17-3 (176 mg, yield 92%). 1 H NMR (400 MHz, DMSO-d6) d 8.13 (s, 3H), 3.50 - 3.31 (m, 2H), 2.90 - 2.81 (m, 2H), 0.75 - 0.65 (m, 4H).

[0159] Step 3: To a solution of 2-9 (35 mg, 83.6 pmol, 1 eq.) and 17-3 (34.2 mg, 167 pmol, 2 eq.) in DMF (2 mL) was added HATU (47.7 mg, 125 pmol, 1.5 eq.) and DIPEA (32.4 mg, 251 pmol, 43.7 pL, 3 eq.) respectively and stirred at 25 °C for 1 h, quenched with H2O (3 mL), extracted with ethyl acetate (5 mL x 2), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude was purified by preparative thin layer chromatography (SiO2, n- heptane / ethyl acetate, 1 : 1) to give compound 17 (25.0 mg, yield 52%). 1 H NMR (400 MHz, CDCl3) d 7.58 - 7.51 (m, 4H), 7.51 - 7.41 (m, 2H), 6.14 (s, 1H), 4.11 (d, J = 17.6 Hz, 1H), 3.72 (d, J = 17.2 Hz, 1H), 3.45 (d, J = 5.6 Hz, 2H), 3.41 - 3.28 (m, 2H), 2.51 (s, 3H), 1.63 (s, 1H), 0.80 - 0.74 (m, 2H), 0.72 - 0.66 (m, 2H). MS-ESI calculated [M+H] + 568, found 568.

[0160] Example 018 Preparation of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((1-(trifluoromethyl)cyclopropyl)methyl) amino)ethyl)benzamide (18)

[0161] Step 1: Compound 1-1 (500 mg, 2.85 mmol, 1 eq.) and hydrochloride salt of compound 18-1 (601 mg, 3.43 mmol, 1.2 eq.) were dissolved in DMF (8 mL), HATU (1.63 g, 4.28 mmol, 1.5 eq.) and DIPEA (1.11 g, 8.56 mmol, 3 eq.) were added, the reaction was stirred at 25 °C for 12 h. The reaction was quenched by water (30 mL), extracted with ethyl acetate (10 mL x 2), the organic phase was combined and washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude compound 18-2 (800 mg, yield 95%).

[0162] Step 2: Compound 18-2 (800 mg, 2.70 mmol, 1 eq.) was dissolved in hydrogen chloride in dioxane solution (4 M, 10 mL), the reaction was stirred at 25 °C for 2 h. The reaction was concentrated under reduced pressure to give the crude compound 18-3 hydrochloride salt (600 mg, yield 95%).

[0163] Step 3: Compound 2-9 (50 mg, 0.120 mmol, 1 eq.) and compound 18-3 hydrochloride salt (41.7 mg, 0.179 mmol, 1.5 eq.) were dissolved in DMF (2 mL), HATU (68.2 mg, 0.179 mmol, 1.5 eq.) and DIPEA (46.4 mg, 0.359 mmol, 3 eq.) were added, the reaction was stirred at 25 °C for 2 h. The reaction was quenched by water (10 mL), extracted with ethyl acetate (5 mL x 3), the organic phase was combined and washed with saturated brine (5 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by preparative thin layer chromatography (SiO2, ethyl acetate) to give compound 18 (48.7 mg, yield 68%). 1 H NMR (400 MHz, CDC13) δ 7.56 - 7.40 (m, 6 H), 6.72 (t, J = 4.8 Hz, 1 H), 6.55 (t, J = 5.2 Hz, 1 H), 4.17 - 4.03 (m, 3 H), 3.70 (d, J = 17.2 Hz, 1 H), 3.52 (d, J = 6.0 Hz, 2 H), 2.47 (s, 3 H), 1.05 - 0.98 (m, 2 H), 0.85 - 0.75 (s, 2 H). MS-ESI calc [M+H] + 596, found 596.

[0164] Example 019 Preparation of 4-(5-(3,5-dichloro-2-fluorophenyl)-5-(trifluoromethyl)- 4,5-dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((1-(trifluoromethyl)cyclopropyl) amino)ethyl)benzamide (19)

[0165] Step 1: Compound 19-1 (1.00 g, 4.10 mmol, 1 eq.) and 1-(trifluoromethyl)vinyl boronic acid hexanol ester (1.10 g, 4.92 mmol, 1.2 eq.) were dissolved in dioxane (10 mL) and water (2 mL), Pd(dppf)Cl2(300.0 mg, 0.410 mmol, 0.1 eq.) and K2CO3(1.70 g, 12.3 mmol, 3 eq.) were added, the reaction was stirred at 100 °C under nitrogen protection for 12 h. The reaction was concentrated under reduced pressure to get the crude product, which was purified by column chromatography (SiO2, n-heptane) to give compound 19-2 (700 mg, yield 66%). 1 H NMR (400 MHz, CDCl3) d 7.46 (d, J = 6.0 Hz, 1H), 7.27-7.21 (m, 1H), 6.27 (s, 1H), 5.83 (s, 1H).

[0166] Step 2: Compound 19-3 (149 mg, 0.772 mmol, 1 eq.) was dissolved in DMF (5 mL), NCS (155 mg, 1.16 mmol, 1.5 eq.) was added, the reaction was stirred at 25 °C for 2 h. Then compound 19-2 (200 mg, 0.772 mmol, 1 eq.) and triethylamine (234 mg, 2.32 mmol, 3 eq.) were dissolved in DMF (2 mL) and added dropwise to the above reaction solution, the reaction was continued to stir at 25 °C for 12 h. The reaction was quenched by adding water (10 mL), extracted with ethyl acetate (5 mL x 3), the organic phase was combined, washed with saturated brine (5 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (SiO2, n-heptane: ethyl acetate, 10:1) to give compound 19-4 (100 mg, yield 29%). 1 H NMR (400 MHz, CDCl3) d 7.97 (d, J = 8.6 Hz, 1H), 7.74 (dd, J = 6.0, 2.8 Hz, 1H), 7.59-7.54 (m, 2H), 7.52 (dd, J = 6.0, 2.8 Hz, 1H), 4.18 (dd, J = 18.0, 2.2 Hz, 1H), 3.92 (s, 3H), 3.86 (dd, J = 18.0, 1.2 Hz, 1H), 2.64 (s, 3H).

[0167] Step 3: Compound 19-4 (100 mg, 0.222 mmol, 1 eq.) was dissolved in tetrahydrofuran (1.5 mL), methanol (1 mL) and water (0.5 mL), lithium hydroxide monohydrate (28.0 mg, 0.666 mmol, 3 eq.) was added, and the reaction was stirred at 25 °C for 12 h. The reaction was adjusted to pH about 3 with hydrochloric acid (1 M), extracted with ethyl acetate (5 mL x 2), the organic phase was combined, washed with saturated brine (5 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting compound 19-5 (50 mg, yield 52%) was concentrated.

[0168] Step 4: Compound 19-5 (50 mg, 0.115 mmol, 1 eq.) and hydrochloride salt of 1-4 (50.1 mg, 0.229 mmol, 2 eq.) were dissolved in DMF (2 mL), HATU (131 mg, 0.344 mmol, 3 eq.) and DIPEA (44.4 mg, 0.344 mmol, 3 eq.) were added, and the reaction was stirred at 25 °C for 2 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (5 mL x 3), the organic phase was combined, washed with saturated brine (5 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude was purified by preparative thin layer chromatography (SiO2, ethyl acetate) to give compound 19 (30 mg, yield 44%). 1 H NMR (400 MHz, CDCl3) d 7.75-7.71 (m, 1H), 7.56-7.46 (m, 4H), 7.12 (s, 1H), 6.80 (t, J = 5.2 Hz, 1H), 4.20-4.11 (m, 3H), 3.84 (d, J = 16.6 Hz, 1H), 2.47 (s, 3H), 1.37-1.32 (m, 2H), 1.17-1.10 (m, 2H). MS-ESI calculated [M+H] + 600, found 600.

[0169] Example 020 Preparation of 2-methyl-N-(2-oxo-2-((1-(trifluoromethyl)cyclopropyl)amino)ethyl)-4-(5-(2,3,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamide (20)

[0170] Step 1 : Compound 20-1 (1.20 g, 4.61 mmol, 1 eq.) and 1-(trifluoromethyl)vinyl boronic acid hexanol ester (1.23 g, 5.53 mmol, 1.2 eq.) were dissolved in dioxane (20 mL) and water (4 mL), Pd(dppf)Cl2(337.3 mg, 0.461 mmol, 0.1 eq.) and K2CO3(1.91 g, 13.8 mmol, 3 eq.) were added, the reaction was stirred at 100 °C for 12 h under nitrogen protection. The reaction was concentrated under reduced pressure to give a crude product, which was purified by column chromatography (SiO2, n-heptane) to give compound 20-2 (800 mg, yield 63%). 1 H NMR (400 MHz, CDC13) δ 7.54 (d, J = 2.4 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 6.26 (d, J = 1.6 Hz, 1H), 5.69 (d, J = 1.6 Hz, 1H).

[0171] Step 2: Compound 19-3 (140.3 mg, 0.726 mmol, 1 eq.) was dissolved in DMF (5 mL), NCS (145.4 mg, 1.09 mmol, 1.5 eq.) was added, and the reaction was stirred at 25 °C for 2 h. After the reaction was completed, compound 20-2 (200 mg, 0.726 mmol, 1 eq.) and triethylamine (220 mg, 2.18 mmol, 3 eq.) were dissolved in DMF (2 mL) and added dropwise to the above reaction solution, and the reaction was continued to be stirred at 25 °C for 12 h. The reaction was quenched by adding water (10 mL), extracted with ethyl acetate (5 mL x 3), the organic phase was combined, washed with saturated brine (5 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (SiO2, n-heptane: ethyl acetate, 10: 1) to give compound 20-3 (50 mg, yield 15%). 1 H NMR (400 MHz, CDC13) δ 7.54 (d, J = 2.4 Hz, 1H), 7.24 (d, J = 2.4 Hz, 1H), 6.26 (d, J = 1.6 Hz, 1H), 5.69 (d, J = 1.6 Hz, 1H).

[0172] Step 3: Compound 20-3 (50 mg, 0.107 mmol, 1 eq.) was dissolved in tetrahydrofuran (1.5 mL), methanol (1 mL) and water (0.5 mL), lithium hydroxide monohydrate (13.5 mg, 0.321 mmol, 3 eq.) was added, the reaction was stirred at 25 °C for 12 h. The reaction was adjusted to pH about 3 with hydrochloric acid (1 M), extracted with ethyl acetate (5 mL x 2), the organic phase was combined, washed with saturated brine (5 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude compound 20-4 (30 mg, yield 62%) was used directly for the next step.

[0173] Step 4: Compound 20-4 (30 mg, 66.3 µmol, 1 eq.) and hydrochloride salt of 1-4 (29.0 mg, 0.133 mmol, 2 eq.) were dissolved in DMF (2 mL), HATU (75.6 mg, 0.199 mmol, 3 eq.) and DIPEA (25.7 mg, 0.199 mmol, 3 eq.) were added, the reaction was stirred at 25 °C for 2 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (5 mL x 3), the organic phase was combined, washed with saturated brine (5 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude compound 20 (3 mg, yield 7%) was purified by preparative thin layer chromatography (SiO2, ethyl acetate). 1 HNMR (400 MHz, CDCl3) δ 7.91 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 7.58-7.53 (m, 2H), 7.50-7.47 (m, 1H), 6.65 (s, 1H), 6.59-6.53 (m, 1H), 4.24-4.17 (m, 1H), 4.13-4.02 (m, 3H), 2.50 (s, 3H), 1.37 (s, 2H), 1.18-1.14 (m, 2H). MS-ESI calculated [M+H] + 616, found 616.

[0174] Example 02 Preparation of N-(2-(3-cyano-3-fluoroazetidin-1-yl)-2-oxoethyl)-4-(5-(3,5- dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide (21)

[0175] Step 1: Compound 1-1 (230 mg, 1.32 mmol, 1 eq.) and oxalate salt of 21-1 (250 mg, 1.32 mmol, 1 eq.) were dissolved in DCM (3 mL), DIPEA (510 mg, 3.95 mmol, 3 eq.) and T4P (1.42 g, 1.972 mmol, 50% solution in ethyl acetate, 1.5 eq.) were added, the reaction was stirred at 25 °C for 2 hours. The reaction was quenched by adding water (10 mL), extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated NaHC03(10 mL x 2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude compound 21-2 (300 mg, yield 89%).

[0176] Step 2: Compound 21-2 (300 mg, 1.166 mmol, 1 eq.) was dissolved in DCM (5 mL), TFA (1 mL) was added, the reaction was stirred at 25 °C for 2 hours. The reaction was concentrated under reduced pressure to give the crude trifluoroacetate salt of compound 21-3 (120 mg, yield 37%).

[0177] Step 3: Compound 2-9 (50 mg, 0.120 mmol, 1 eq.) and trifluoroacetate salt of 21-3 (48.5 mg, 0.179 mmol, 1.5 eq.) were dissolved in DMF (2 mL), HATU (68.2 mg, 0.180 mmol, 1.5 eq.) and DIPEA (61.8 mg, 0.478 mmol, 4 eq.) were added, the reaction was stirred at 25 °C for 12 hours. The reaction was quenched by adding water (5 mL), extracted with ethyl acetate (5 mL x 2), the combined organic phase was washed with saturated brine (5 mL x 3), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by preparative thin layer chromatography (Si02, ethyl acetate) to give compound 21 (14 mg, yield 15%). 1 H NMR (400 MHz, CDC13) δ 7.58 - 7.41 (m, 6 H), 6.67 (t, J = 4.4 Hz, 1 H), 4.89 - 4.77 (m, 1 H), 4.74 - 4.58 (m, 2 H), 4.55 - 4.43 (m, 1 H), 4.15 - 4.03 (m, 3 H), 3.75 - 3.67 (m, 1 H), 2.49 (s, 3 H). MS - ESI calculated [M+H] + 557, found 557.

[0178] Example 022 Preparation of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-N-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)-2- methylbenzamide (22)

[0179] Step 1: Compound 6-3 (50.0 mg, 105 μmol, 1.0 eq.), hydrochloride salt of compound 22-1 (27.3 mg, 210 μmol, 1.5 eq.), HATU (60.0 mg, 158 μmol, 1.5 eq.), DIPEA (54.4 mg, 421 μmol, 4.0 eq.) were dissolved in DMF (2 mL) and stirred at 20 °C for 1 h. Water (2 mL) was added, and the mixture was partitioned between ethyl acetate (2 mL) and water (2 mL). The aqueous phase was extracted with ethyl acetate (1 mL x 2), and the combined organic phase was washed with water (1 mL x 3), then saturated brine (1 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by preparative thin-layer chromatography (SiO2, n-heptane: ethyl acetate = 1:1) to give compound 22 (25 mg, 43% yield). 1 H NMR (400 MHz, CDC13) δ 7.59 - 7.37 (m, 6H), 6.60 (t, J = 4.4 Hz, 1H), 4.64 - 4.40 (m, 4H), 4.21 - 4.00 (m, 3H), 3.72 (d, J = 17.2 Hz, 1H), 2.51 (s, 3H). MS-ESI calcd [M+H] + 550, found 550.

[0180] Example 022 Preparation of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-N-(2-(3,3-difluoroazetidin-1-yl)-2-oxoethyl)-2- methylbenzamide (22)

[0181] Step 1: Compound 22-1 (50.0 mg, 105 pmol, 1.0 eq.), hydrochloride salt of compound 23-1 (34.0 mg, 210 pmol, 1.5 eq.), HATU (60.0 mg, 158 pmol, 1.5 eq.), DIPEA (54.4 mg, 421 pmol, 4.0 eq.) were dissolved in DMF (2 mL) and reacted at 20 °C for 1 h. Water (2 mL) was added, and the mixture was partitioned between ethyl acetate (2 mL) and water (2 mL). The aqueous phase was extracted with ethyl acetate (1 mL x 2), and the combined organic phase was washed with water (1 mL) and saturated brine (1 mL). The resulting crude product was purified by preparative thin-layer chromatography (SiO2, n-heptane: ethyl acetate = 1: 1) to give compound 23 (25 mg, 41% yield). 1 H NMR (400 MHz, CDC13) δ 7.61 - 7.40 (m, 6H), 6.62 (t, J = 4.4 Hz, 1H), 4.51 - 4.34 (m, 1H), 4.33 - 4.24 (m, 2H), 4.20 - 4.02 (m, 4H), 3.72 (d, J = 17.2 Hz, 1H), 3.52 - 3.25 (m, 1H), 2.51 (s, 3H). MS-ESI calc [M+H] + 582, found 582.

[0182] Example 024 Preparation of N-(2-((l-cyanocyclopropyl)amino)-2-oxoethyl)-4-(5-(3,5- dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzamide (24)

[0183] Step 1: Compound 1-1 (400 mg, 2.28 mmol, 1.0 eq.), hydrochloride salt of compound 24-1 (271 mg, 2.28 mmol, 1.0 eq.), HATU (1.04 g, 2.74 mmol, 1.2 eq.), DIPEA (1.88 g, 6.85 mmol, 3.0 eq.) were dissolved in DMF (9.8 mL) and reacted at 20 °C for 1 h. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 2). The organic phase was washed with saturated brine (15 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give compound 24-2 (520 mg, 95% yield).

[0184] Step 2: Compound 24-2 (520 mg, 2.17 mmol, 1.0 eq.) was dissolved in 1,4-dioxane (5 mL) solution, hydrogen chloride solution in 1,4-dioxane (4 M, 5 mL) was added dropwise, and the reaction was stirred at 20 °C for 12 h. The crude compound 24-3 hydrochloride salt (350 mg, yield 92%) was obtained by concentration under reduced pressure.

[0185] Step 3: Compound 2-9 (100 mg, 239 μmol, 1.0 eq.), compound 24-3 hydrochloride salt (66.6 mg, 478 μmol, 2.0 eq.), HATU (136 mg, 359 μmol, 1.5 eq.), DIPEA (124 mg, 956 μmol, 4.0 eq.) were dissolved in DMF (2 mL), and the reaction was stirred at 20 °C for 1 h. Water (10 mL) and ethyl acetate (10 mL) were added, and the organic phase was extracted with ethyl acetate (10 mL x 2). The organic phase was washed with water (10 mL) and then saturated brine (5 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by preparative high performance liquid chromatography (column: X-Bridge C18, 50 x 4.6 mm I.D., 3.5 μm; mobile phase: [0.1% formic acid in water-acetonitrile]; gradient: 20%-95%, 3 min) to give compound 24 (10 mg, yield 8%). 1 H NMR (400 MHz, CDC13) δ 7.61 - 7.43 (m, 6 H), 6.76 (t, J = 4.8 Hz, 1 H), 4.73 (br, s, 1 H), 4.15 - 4.11 (m, 3 H), 3.73 (d, J = 17.2 Hz, 1 H), 2.52 (s, 3 H), 1.73 - 1.47 (m, 2 H), 1.36 - 1.30 (m, 2 H). MS-ESI calcd [M+H] + 539, found 539.

[0186] Example 025 Preparation of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-N-(2-(3-fluoro-3-(trifluoromethyl)azetidin-l-yl)-2- oxoethyl)-2-methylbenzamide (25)

[0187] Step 1: Compound 1-1 (500 mg, 2.85 mmol, 1.0 eq.), hydrochloride salt of compound 25-1 (769 mg, 4.28 mmol, 1.5 eq.), HATU (1.63 g, 4.28 mmol, 1.5 eq.), DIPEA (1.48 g, 11.4 mmol, 4.0 eq.) were dissolved in DMF (5 mL) and reacted at 20 °C for 1 h. Water (10 mL) and ethyl acetate (10 mL) were added and extracted with ethyl acetate (10 mL x 2). The organic phase was combined and washed with water (10 mL), then saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound 25-2 (856 mg, yield 100%). 1 H NMR (400 MHz, CDC13) δ 4.59 - 4.23 (m, 4H), 3.85 - 3.78 (m, 2H), 1.47 (s, 9H).

[0188] Step 2: Compound 25-2 (856 mg, 2.85 mmol, 1.0 eq.) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (1.30 g, 11.4 mmol, 4.0 eq.) was added dropwise, and reacted at 20 °C for 16 h. Concentration under reduced pressure obtained the crude trifluoroacetate salt of compound 25-3 (895 mg, yield 100%).

[0189] Step 3: Compound 2-9 (50.0 mg, 120 pmol, 1.0 eq.), trifluoroacetate salt of compound 25-3 (56.3 mg, 179 pmol, 1.5 eq.), HATU (68.2 mg, 179 pmol, 1.5 eq.), DIPEA (61.8 mg, 478 pmol, 4.0 eq.) were dissolved in DMF (2 mL) and reacted at 20 °C for 1 h. Water (1 mL) and ethyl acetate (1 mL) were added and extracted with ethyl acetate (1 mL x 2). The organic phase was combined and washed with water (1 mL), then saturated brine (1 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude was purified by preparative thin layer chromatography (Si02, n-heptane: ethyl acetate = 3: 1) to obtain compound 25 (20 mg, yield 28%). 1 H NMR (400 MHz, CDC13) δ 7.62 - 7.36 (m, 6H), 6.57 (t, J = 4.4 Hz, 1H), 4.73 - 4.33 (m, 4H), 4.22 - 4.01 (m, 3H), 3.72 (d, J = 17.2 Hz, 1H), 2.51 (s, 3H). MS - ESI calculated [M+H] + 600, found 600.

[0190] Example 026 Preparation of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-N-(2-(3-fluoro-3-(fluoromethyl)azetidin-l-yl)-2- oxoethyl)-2-methylbenzamide (26)

[0191] Step 1: Compound 2-9 (50.0 mg, 120 pmol, 1.0 eq.), trifluoroacetate salt of compound 3-3 (49.9 mg, 179 pmol, 1.5 eq.), HATU (68.2 mg, 179 pmol, 1.5 eq.), DIPEA (61.8 mg, 478 pmol, 4.0 eq.) were dissolved in DMF (2 mL) and reacted at 20 °C for 1 h. Water (1 mL) and ethyl acetate (1 mL) were added and extracted with ethyl acetate (1 mL x 2). The organic phase was combined, washed with water (1 mL), then saturated brine (1 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude was purified by preparative thin layer chromatography (SiO2, n-heptane: ethyl acetate = 3: 1) to give compound 26 (20 mg, yield 30%). 1 H NMR (400 MHz, CDC13) δ 7.74 - 7.37 (m, 6H), 6.63 (t, J = 4.0 Hz, 1H), 4.79 - 4.54 (m, 2H), 4.46 - 4.21 (m, 4H), 4.10-4.08 (m, 3H), 3.72 (d, J = 17.2 Hz, 1H), 2.51 (s, 3H). MS-ESI calculated [M+H] + 564, found 564.

[0192] Example 027 Preparation of 4-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((l-(trifluoromethyl)cyclopropyl)amino) ethyl)benzamide (27)

[0193] Step 1: 27-1 (1.00 g, 4.78 mmol, 1.0 eq.), potassium carbonate (1.98 g, 14.3 mmol, 3.0 eq.), 1-(trifluoromethyl)vinyl boronic acid hexanol ester (1.17 g, 5.25 mmol, 1.1 eq.), Pd(dppf)Cl2 (349 mg, 477 μmol, 0.1 eq.) were added into 1,4-dioxane (10 mL) and water (2 mL), stirred at 90 °C for 16 h. Filtered, the solvent was evaporated, water (10 mL) and ethyl acetate (10 mL) were added, extracted with ethyl acetate (10 mL x 2). The organic phase was combined, washed with water (10 mL), then saturated brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated and purified by column chromatography (SiO2, ethyl acetate / n-hexane, 0~1%) to give compound 27-2 (540 mg, yield 50%). 1 H NMR (400 MHz, CDC13) δ 7.27 (s, 1H), 7.20 - 7.04 (m, 2H), 6.07 (s, 1H), 5.85 (s, 1H).

[0194] Step 2: 19-3 (200 mg, 1.04 mmol, 1.0 eq.), NCS (138 mg, 1.04 mmol, 1.0 eq.) were dissolved in DMF (5 mL), stirred at 20 °C for 1 h, then 27-2 (279 mg, 1.24 mmol, 1.2 eq.), triethylamine (126 mg, 1.24 mmol, 1.2 eq.) were added, stirred at 20 °C for 15 h. Water (5 mL) and ethyl acetate (5 mL) were added, extracted with ethyl acetate (5 mL x 2). The organic phase was combined, washed with water (5 mL), then saturated brine (5 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated and purified by column chromatography (SiO2, ethyl acetate / n-hexane, 0~20%) to give compound 27-3 (90 mg, yield 21%). 1 H NMR (400 MHz, CDC13) δ 8.03 - 7.93 (m, 1H), 7.58 - 7.54 (m, 2H), 7.43 (s, 1H), 7.28 - 7.25 (m, 1H), 7.23 - 7.14 (m, 1H), 4.12 (d, J = 17.1 Hz, 1H), 3.94 (s, 3H), 3.73 (d, J = 17.6 Hz, 1H), 2.65 (s, 3H).

[0195] Step 3: Compound 27-3 (90 mg, 216 μmol, 1.0 eq.), NaOH (22 mg, 541 μmol, 2.5 eq.) were dissolved in tetrahydrofuran (2 mL) and water (2 mL), stirred at 20 °C for 16 hours. Water (5 mL) and methyl tert-butyl ether (5 mL) were added, separated, the aqueous phase was extracted with ethyl acetate (5 mL), the aqueous phase was adjusted to pH 3-4 with 1 M aqueous hydrochloric acid solution, extracted with ethyl acetate (5 mL x 3), the organic phase was combined, washed with saturated brine (5 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound 27-4 (40 mg, yield 46%).

[0196] Step 4: Compound 27-4 (35.0 mg, 87.1 μmol, 1.0 eq.), compound 1-4 (28.6 mg, 131 μmol, 1.5 eq.), HATU (49.7 mg, 131 μmol, 1.5 eq.), DIPEA (45.0 mg, 348 μmol, 4.0 eq.) were dissolved in DMF (2 mL), reacted at 20 °C for 1 hour. Water (1 mL) and ethyl acetate (1 mL) were added, extracted with ethyl acetate (1 mL x 2). The organic phase was combined, washed with water (1 mL), then saturated brine (1 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (SiO2, n-heptane: ethyl acetate = 1:3) to obtain compound 27 (30 mg, yield 61%). 1 H NMR (400 MHz, CDC13) δ 7.60 - 7.35 (m, 4H), 7.22 - 7.10 (m, 2H), 7.28 - 7.25 (m, 1H), 6.83 (t, J = 5.2 Hz, 1H), 4.20 - 4.02 (m, 3H), 3.72 (d, J = 17.2 Hz, 1H), 2.49 (s, 3H), 1.44 - 1.29 (m, 2H), 1.21 - 1.11 (m, 2H). MS-ESI calculated [M+H] + 566, found 566.

[0197] Example 028 Preparation of 4-(5-(3,4-dichloro-5-fluorophenyl)-5-(trifluoromethyl)- 4,5-dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((1-(trifluoromethyl)cyclopropyl) amino)ethyl)benzamide (28)

[0198] Step 1: 28-1 (1.00 g, 4.10 mmol, 1.0 eq.), potassium carbonate (1.70 g, 12.3 mmol, 3.0 eq.), 1-(trifluoromethyl)vinyl boronic acid hexanol ester (1.00 g, 4.51 mmol, 1.1 eq.), Pd(dppf)Cl2 (300 mg, 410 μmol, 0.1 eq.) were added into 1,4-dioxane (10 mL) and water (2 mL), stirred at 90 °C for 16 hours. Filtered, the solvent was evaporated, water (10 mL) and ethyl acetate (10 mL) were added, extracted with ethyl acetate (10 mL x 2). The organic phase was combined, washed with water (10 mL), then saturated brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated and purified by column chromatography (SiO2, ethyl acetate / n-hexane, 0~1%) to give compound 28-2 (580 mg, yield 55%). 1 HNMR (400 MHz, CDC13) δ 7.40 (s, 1H), 7.22 (d, J = 9.2 Hz, 1H), 6.09 (s, 1H), 5.87 (s, 1H).

[0199] Step 2: 19-3 (200 mg, 1.04 mmol, 1.0 eq.), NCS (138 mg, 1.04 mmol, 1.0 eq.) were dissolved in DMF (5 mL), stirred for 1 hour under nitrogen protection, then 28-2 (322 mg, 1.24 mmol, 1.2 eq.), triethylamine (126 mg, 1.24 mmol, 1.2 eq.) were added, stirred at 20 °C for 15 hours. Water (5 mL) and ethyl acetate (5 mL) were added, extracted with ethyl acetate (5 mL x 2). The organic phase was combined, washed with water (5 mL), then saturated brine (5 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was isolated and purified by column chromatography (SiO2, ethyl acetate / n-hexane, 0~20%) to give compound 28-3 (100 mg, yield 21%). 1 H NMR (400 MHz, CDC13) δ 7.98 (d, J = 8.8 Hz, 1H), 7.57 (s, 2H), 7.43 (s, 1H), 7.21-7.15 (m, 1H), 4.12 (d, J = 17.2 Hz, 1H), 3.94 (s, 3H), 3.73 (d, J = 17.6 Hz, 1H), 2.65 (s, 3H).

[0200] Step 3: Compound 28-3 (100 mg, 222 pmol, 1.0 eq.), NaOH (22 mg, 555 pmol, 2.5 eq.) were dissolved in THF (2 mL) and water (2 mL), stirred at 60 °C for 16 h. THF was removed, added water (5 mL) and ethyl acetate (5 mL), separated, the aqueous phase was extracted with ethyl acetate (5 mL), the organic phase was adjusted to pH 3-4 with 1 M aqueous HCl solution, then dried, the aqueous phase was adjusted to pH 3-4 with 1 M aqueous HCl solution, extracted with ethyl acetate (5 mL x 3), the organic phase was combined, washed with saturated brine (5 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound 28-4 (90 mg, yield 93%).

[0201] Step 4: Compound 28-4 (40.0 mg, 91.7 pmol, 1.0 eq.), hydrochloride of compound 1-4 (30.1 mg, 138 pmol, 1.5 eq.), HATU (52.3 mg, 138 pmol, 1.5 eq.), DIPEA (47.4 mg, 367 pmol, 4.0 eq.) were dissolved in DMF (2 mL), reacted at 20 °C for 1 h. Added water (1 mL) and ethyl acetate (1 mL), extracted with ethyl acetate (1 mL x 2). The organic phase was combined, washed with water (1 mL), then saturated brine (1 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (SiO2, n-heptane: ethyl acetate = 1:3) to obtain compound 28 (20 mg, yield 36%). 1 H NMR (400 MHz, CDC13) d 7.61 - 7.37 (m, 5H), 6.97 (s, 1H), 6.74 (t, J = 5.2 Hz, 1H), 4.22 - 3.99 (m, 3H), 3.71 (d, J = 17.2 Hz, 1H), 2.49 (s, 3H), 1.46 - 1.31 (m, 2H), 1.21 - 1.11 (m, 2H)). MS-ESI calcd [M+H] + 600, found 600.

[0202] Example 029 Preparation of 4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((1- (trifluoromethyl)cyclopropyl)amino)ethyl)benzamide (29)

[0203] Step 1: Compound 29-1 (10.0 g, 38.5 mmol, 1 eq.) was dissolved in methanol (100 mL), then Pd / C (1.00 g, 10% purity) was added, and hydrogen was replaced three times. It was stirred at 20 °C for 16 hours under the atmosphere of hydrogen balloon. Filtration and concentration under reduced pressure gave the crude product, which was purified by column chromatography (ethyl acetate / n-hexane = 0~12%) to give 29-2 (6.05 g, yield 68%). 1 HNMR (400MHz, CDC13) δ 6.96 (s, 1H), 6.93 (s, 1H).

[0204] Step 2: Compound 29-2 (3.00 g, 13.0 mmol, 1.0 eq.) was dissolved in 20% dilute sulfuric acid (10 mL) and acetonitrile (10 mL), and an aqueous solution of sodium nitrite (1.35 g, 1 mL, 19.6 mmol, 1.5 eq.) was added dropwise at 0~10 °C under ice water bath. After addition, it was stirred for 0.5 hours, and a solution of cuprous bromide (5.61 g, 39.1 mmol, 3.0 eq.) in 20% dilute sulfuric acid (5 mL) was added dropwise at 0~10 °C. After the gas was released and the heat was released, it was naturally raised to 20 °C under nitrogen atmosphere and stirred for 15.5 hours. It was extracted with ethyl acetate (10 mL x 3), and the organic phase was combined, washed with water (10 mL), then saturated brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (ethyl acetate / n-hexane = 0~1%) to give 29-3 (1.95 g, yield 51%). 1 H NMR (400MHz, CDC13) δ 7.85-7.84 (d, J = 2.0 Hz, 1H), 7.78-7.77 (d, J = 2.0 Hz, 1H).

[0205] Step 3: Compound 29-3 (1.00 g, 3.40 mmol, 1.0 eq.), potassium carbonate (1.41 g, 10.2 mmol, 3.0 eq.), 1-(trifluoromethyl)vinyl boronic acid hexanol ester (831 mg, 3.74 mmol, 1.1 eq.), Pd(dppf)Cl2 (249 mg, 340 μmol, 0.1 eq.) were added to dioxane (10 mL) and water (2 mL), and stirred at 90 °C for 16 hours. Filtration, the filter cake was washed with ethyl acetate (10 mL x 2), and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by column chromatography (ethyl acetate / n-hexane = 0~1%) to give compound 29-4 (800 mg, yield 76%). 1 H NMR (400MHz, CDC13) δ 7.77 (s, 1H), 7.71 (s, 1H), 6.15 (d, J = 0.8 Hz, 1H), 5.92-5.84 (m, 1H).

[0206] Step 4: Compound 19-3 (200 mg, 1.04 mmol, 1.0 eq.), NCS (138 mg, 1.04 mmol, 1.0 eq.) were dissolved in DMF (5 mL) and stirred for 1 hour under nitrogen protection, then 29-4 (320 mg, 1.04 mmol, 1.0 eq.) and triethylamine (126 mg, 1.24 mmol, 1.2 eq.) were added and stirred at 20 °C for 1 hour. Water (5 mL) and ethyl acetate (5 mL) were added and extracted with ethyl acetate (5 mL x 2). The organic phase was combined and washed with water (5 mL), then saturated brine (5 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was separated and purified by column chromatography (ethyl acetate / n-hexane = 0-5%) to obtain compound 29-5 (190 mg, yield 37%). 1 H NMR (400 MHz, CDC13) δ 8.05-7.92 (m, 2H), 7.87 (s, 1H), 7.65-7.42 (m, 2H), 4.17 (d, J = 17.2 Hz, 1H), 3.94 (s, 3H), 3.74 (d, J = 17.2 Hz, 1H), 2.65 (s, 3H).

[0207] Step 5: 29-5 (90 mg, 180 μmol, 1.0 eq.) and NaOH (22 mg, 540 μmol, 3.0 eq.) were dissolved in tetrahydrofuran (2 mL) and water (2 mL) and stirred at 55 °C for 16 hours. The aqueous phase was adjusted to pH 3-4 with 1 N aqueous hydrochloric acid solution, extracted with ethyl acetate (5 mL x 2), and the organic phase was combined and washed with saturated brine (5 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain compound 29-6 (80.0 mg, crude).

[0208] Step 6: Compound 29-6 (80.0 mg, 165 μmol, 1.0 eq.), hydrochloride of compound 1-4 (54.0 mg, 247 μmol, 1.5 eq.), HATU (93.8 mg, 247 μmol, 1.5 eq.) and DIPEA (85.1 mg, 658 μmol, 4.0 eq.) were dissolved in DMF (2 mL) and reacted at 20 °C for 1 hour. Water (1 mL) and ethyl acetate (1 mL) were added and extracted with ethyl acetate (1 mL x 2). The organic phase was combined and washed with water (1 mL), then saturated brine (1 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (n-hexane: ethyl acetate = 1:3) to obtain compound 29 (50.0 mg, yield 47%). 1H NMR (400 MHz, CDC13) δ 7.97 (d, J = 1.6 Hz, 1H), 7.86 (s, 1H), 7.61 - 7.44 (m, 3H), 7.26 (s, 1H), 6.90 (t, J = 5.2 Hz, 1H), 4.23 - 4.10 (m, 3H), 3.73 (d, J = 17.2 Hz, 1H), 2.48 (s, 3H), 1.43 - 1.31 (m, 2H), 1.18 - 1.04 (m, 2H). MS - ESI calculated [M+H] + 650, found 650.

[0209] Example 030 Preparation of 4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)- 4,5-dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((1-(trifluoromethyl)cyclopropyl)amino) ethyl)benzamide (30)

[0210] Step 1: 30-1 (2.50 g, 8.53 mmol, 1.0 eq.), potassium carbonate (3.54 g, 25.6 mmol, 3.0 eq.), 1-(trifluoromethyl)vinyl boronic acid hexanol ester (2.27 g, 10.2 mmol, 1.2 eq.), Pd(dppf)Cl2 (624 mg, 853 μιηοΐ, 0.1 eq.) were added into dioxane (40 mL) and water (10 mL), stirred at 90 °C for 12 h. The reaction solution was concentrated under reduced pressure. The crude product was purified by column chromatography (n-heptane, 100%) to give compound 30-2 (2.00 g, yield 76%). 1 H NMR (400 MHz, CDC13) δ 7.93 (s, 1H), 7.90 (s, 2H), 6.19 (s, 1H), 5.94 (d, J = 1.2 Hz, 1H).

[0211] Step 2: Compound 19-3 (200 mg, 1.04 mmol, 1.0 eq.), NCS (138 mg, 1.04 mmol, 1.0 eq.) were dissolved in DMF (5 mL), stirred under nitrogen protection for 1 h, then 30-2 (383 mg, 1.24 mmol, 1.2 eq.), triethylamine (126 mg, 1.24 mmol, 1.2 eq.) were added, stirred at 20 °C for 1 h. Water (5 mL) and ethyl acetate (5 mL) were added, extracted with ethyl acetate (5 mL x 2). The organic phase was combined, washed with water (5 mL), then saturated brine (5 mL), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate / n-heptane = 0~5%) to give compound 30-3 (270 mg, yield 52%).1 H NMR (400 MHz, CDC13) δ 8.11 (s, 2H), 8.02-7.93 (m, 2H), 7.58 (m, 2H), 4.24 (d, J = 17.1 Hz, 1H), 3.94 (s, 3H), 3.78 (d, J = 17.1 Hz, 1H), 2.66 (s, 3H).

[0212] Step 3: Compound 30-3 (90 mg, 180 pmol, 1.0 eq.), NaOH (22 mg, 540 pmol, 3.0 eq.) were dissolved in tetrahydrofuran (2 mL) and water (2 mL), stirred at 20 °C for 16 hours. The aqueous phase was adjusted to pH 3-4 with 1 N aqueous hydrochloric acid solution, extracted with ethyl acetate (5 mL x 2), the organic phase was combined, washed with saturated brine (5 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound 30-4 (80.0 mg, crude).

[0213] Step 4: Compound 30-4 (80.0 mg, 165 pmol, 1.0 eq.), hydrochloride salt of compound 1-4 (54.1 mg, 247 pmol, 1.5 eq.), HATU (94.0 mg, 247 pmol, 1.5 eq.), DIPEA (85.2 mg, 659 pmol, 4.0 eq.) were dissolved in DMF (2 mL), and reacted at 20 °C for 1 hour. Water (1 mL) and ethyl acetate (1 mL) were added, and extracted with ethyl acetate (1 mL x 2). The organic phase was combined, washed with water (1 mL), and then saturated brine (1 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (n-heptane: ethyl acetate = 1:3) to obtain compound 30 (30.0 mg, yield 47%). 1 H NMR (400 MHz, CDC13) δ 8.11 (s, 2H), 8.02-7.93 (m, 2H), 7.58 (m, 2H), 4.24 (d, J = 17.1 Hz, 1H), 3.94 (s, 3H), 3.78 (d, J = 17.1 Hz, 1H), 2.66 (s, 3H). + 650, found 650.

[0214] Example 031 Preparation of 4-(5-(3-fluoro-5-(trifluoromethyl)phenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((1- (trifluoromethyl)cyclopropyl)amino)ethyl)benzamide (31)

[0215] Step 1: 31-1 (2.00 g, 8.23 mmol, 1.0 eq.), potassium carbonate (3.41 g, 24.7 mmol, 3.0 eq.), 1-(trifluoromethyl)vinyl boronic acid hexanol ester (2.19 g, 9.88 mmol, 1.2 eq.), Pd(dppf)Cl2 (602 mg, 823 μmol, 0.1 eq.) were added into dioxane (10 mL) and water (2 mL), stirred at 90 °C for 16 hours. The reaction solution was concentrated under reduced pressure, the crude product was separated and purified by column chromatography (n-heptane, 100%) to obtain compound 31-2 (2.00 g, yield 94%). 1 H NMR (400 MHz, CDC13) δ 7.52 (s, 1H), 7.38 (d, J = 8.8 Hz, 2H), 6.12 (d, J = 1.2 Hz, 1H), 5.90 (d, J = 1.6 Hz, 1H).

[0216] Step 2: Compound 19-3 (200 mg, 1.04 mmol, 1.0 eq.), NCS (138 mg, 1.04 mmol, 1.0 eq.) were dissolved in DMF (5 mL), stirred under nitrogen protection for 1 hour, then 31-2 (320 mg, 1.24 mmol, 1.2 eq.), triethylamine (126 mg, 1.24 mmol, 1.2 eq.) were added, stirred at 20 °C for 1 hour. Water (5 mL) and ethyl acetate (5 mL) were added, extracted with ethyl acetate (5 mL x 2). The organic phase was combined, washed with water (5 mL), then saturated brine (5 mL), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure. The crude product was separated and purified by column chromatography (ethyl acetate / n-heptane = 0~5%) to obtain compound 31-3 (200 mg, yield 43%). 1 H NMR (400 MHz, CDC13) δ 7.52 (s, 1H), 7.38 (d, J = 8.8 Hz, 2H), 6.12 (d, J = 1.2 Hz, 1H), 5.90 (d, J = 1.6 Hz, 1H).

[0217] Step 3: Compound 31-3 (90 mg, 180 pmol, 1.0 eq.), NaOH (22 mg, 540 pmol, 3.0 eq.) were dissolved in tetrahydrofuran (2 mL) and water (2 mL), stirred at 20 °C for 16 hours. The aqueous phase was adjusted to pH 3-4 with 1 N aqueous hydrochloric acid solution, extracted with ethyl acetate (5 mL x 2), the combined organic phase was washed with saturated brine (5 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give compound 31-4 (80.0 mg, crude).

[0218] Step 4: Compound 31-4 (80.0 mg, 184 pmol, 1.0 eq.), hydrochloride of compound 1-4 (60.3 mg, 276 pmol, 1.5 eq.), HATU (105 mg, 276 pmol, 1.5 eq.), DIPEA (95.0 mg, 735 pmol, 4.0 eq.) were dissolved in DMF (2 mL), reacted at 20 °C for 1 hour. Water (1 mL) and ethyl acetate (1 mL) were added, extracted with ethyl acetate (1 mL x 2). The combined organic phase was washed with water (1 mL), then saturated brine (1 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude obtained was purified by preparative thin layer chromatography (n-heptane: ethyl acetate = 1:3) to give compound 31 (30.0 mg, yield 50%). 1 H NMR (400 MHz, CDC13) δ 7.69 (s, 1H), 7.62-7.40 (m, 5H), 7.07 (s, 1H), 6.79 (t, J = 5.2 Hz, 1H), 4.26-4.06 (m, 3H), 3.75 (d, J = 17.2 Hz, 1H), 2.49 (s, 3H), 1.45-1.31 (m, 2H), 1.21-1.07 (m, 2H). MS-ESI calc [M+H] + 600, found 600.

[0219] Example 032 Preparation of 4-(5-(3-chloro-5-methylphenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((1-(trifluoromethyl)cyclopropyl)amino) ethyl)benzamide (32)

[0220] Step 1 : Compound 32-1 (1.85 g, 9.00 mmol, 1 eq.) and 1-(trifluoromethyl)vinyl boronic acid hexanol ester (2.00 g, 9.00 mmol, 1 eq.) were dissolved in dioxane (40 mL) and water (10 mL), Pd(dppf)Cl2(659 mg, 0.900 mmol, 0.1 eq.) and potassium carbonate (3.74 g, 27.0 mmol, 3 eq.) were added, the reaction was stirred at 90 °C under nitrogen protection for 12 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (n-heptane) to obtain compound 32-2 (1.00 g, yield 50%). 1 H NMR (400 MHz, CDC13) δ 7.26 (s, 1H), 7.21 (s, 1H), 7.15 (s, 1H), 5.99 (q, J = 1.2 Hz, 1H), 5.78 (q, J = 1.2 Hz, 1H), 2.37 (s, 3H).

[0221] Step 2: Compound 19-3 (140 mg, 0.726 mmol, 1 eq.) was dissolved in DMF (5 mL), NCS (145 mg, 1.09 mmol, 1.5 eq.) was added, and the reaction was stirred at 25 °C for 2 hours. Then compound 32-2 (160 mg, 0.726 mmol, 1 eq.) and triethylamine (220 mg, 2.18 mmol, 3 eq.) were dissolved in DMF (2 mL) and added dropwise to the above reaction solution, and the reaction was continued to stir at 25 °C for 12 hours. The reaction was quenched by adding water (10 mL), extracted with ethyl acetate (5 mL x 3), the organic phase was combined, washed with saturated brine (5 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by column chromatography (n-heptane: ethyl acetate = 9: 1) to obtain compound 32-3 (200 mg, yield 67%). 1 H NMR (400 MHz, CDC13) δ 7.26 (s, 1H), 7.21 (s, 1H), 7.15 (s, 1H), 5.99 (q, J = 1.2 Hz, 1H), 5.78 (q, J = 1.2 Hz, 1H), 2.37 (s, 3H).

[0222] Step 3: Compound 32-3 (200 mg, 0.486 mmol, 1 eq.) was dissolved in tetrahydrofuran (1.5 mL), methanol (1 mL) and water (0.5 mL), lithium hydroxide monohydrate (61.1 mg, 1.46 mmol, 3 eq.) was added, the reaction was stirred at 25 °C for 12 h. The reaction was adjusted to pH about 3 with hydrochloric acid (1 M), extracted with ethyl acetate (5 mL x 2), the organic phase was combined, washed with saturated brine (5 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting compound 32-4 (50 mg, yield 26%) was obtained after concentration.

[0223] Step 4: Compound 32-4 (50 mg, 0.126 mmol, 1 eq.) and hydrochloride salt of 1-4 (41.2 mg, 0.189 mmol, 1.5 eq.) were dissolved in DMF (2 mL), HATU (71.7 mg, 0.189 mmol, 1.5 eq.) and DIPEA (48.7 mg, 0.377 mmol, 3 eq.) were added, the reaction was stirred at 25 °C for 2 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (5 mL x 3), the organic phase was combined, washed with saturated brine (5 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude was purified by preparative thin layer chromatography (ethyl acetate) to give compound 32 (58.8 mg, yield 83%). 1 H NMR (400 MHz, CDCl3) δ 7.55-7.43 (m, 4H), 7.40 (s, 1H), 7.31 (s, 1H), 7.23 (s, 1H), 7.02 (t, J = 4.8 Hz, 1H), 4.16-4.11 (m, 2H), 4.07 (d, J = 17.2 Hz, 1H), 3.73 (d, J = 17.2 Hz, 1H), 2.45 (s, 3H), 2.39 (s, 3H), 1.35-1.28 (m, 2H), 1.11 (s, 2H). MS-ESI calculated [M+H] + 562, found 562.

[0224] Example 033 Preparation of 4-(5-(3-chloro-5-methoxyphenyl)-5-(trifluoromethyl)- 4,5-dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((1-(trifluoromethyl)cyclopropyl) amino)ethyl)benzamide (33)

[0225] Step 1: Compound 33-1 (1.00 g, 4.52 mmol, 1.0 eq.), potassium carbonate (1.87 g, 13.5 mmol, 3.0 eq.), 1-(trifluoromethyl)vinyl boronic acid hexanol ester (1.10 mg, 4.97 mmol, 1.1 eq.), Pd(dppf)Cl2(330 mg, 452 μmol, 0.1 eq.) were added into dioxane (10 mL) and water (2 mL), stirred at 90 °C for 16 hours. Filtered, the filter cake was washed with ethyl acetate (10 mL x 2), the filtrate was concentrated under reduced pressure. The crude product was separated and purified by column chromatography (n-Heptane, 100%) to give compound 33-2 (860 mg, yield 80%). 1 H NMR (400 MHz, CDCl3) δ 7.11-7.02 (m, 1H), 6.99-6.92 (m, 1H), 6.92-6.85 (m, 1H), 6.01 (d, J = 1.2 Hz, 1H), 5.81 (d, J = 1.6 Hz, 1H), 3.84 (s, 3H).

[0226] Step 2: Compound 19-3 (200 mg, 1.04 mmol, 1.0 eq.), NCS (166 mg, 1.24 mmol, 1.2 eq.) were dissolved in DMF (5 mL), stirred under nitrogen protection for 1 hour, then 33-2 (245 mg, 1.04 mmol, 1.0 eq.) was added, triethylamine (126 mg, 1.24 mmol, 1.2 eq.), stirred at 20 °C for 1 hour. Water (5 mL) and ethyl acetate (5 mL) were added, extracted with ethyl acetate (5 mL x 2). The organic phase was combined, washed with water (5 mL), then saturated brine (5 mL), dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure. The crude product was separated and purified by column chromatography (ethyl acetate / n-Heptane = 0~5%) to give compound 33-3 (240 mg, yield 54%). 1 H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.4 Hz, 1H), 7.65-7.47 (m, 2H), 7.18 (s, 1H), 7.10 (s, 1H), 6.96 (t, J = 2.0 Hz, 1H), 4.09 (d, J = 17.2 Hz, 1H), 3.97-3.84 (m, 6H), 3.75 (d, J = 17.2 Hz, 1H), 2.64 (s, 3H).

[0227] Step 3: Compound 33-3 (240 mg, 561 μmol, 1.0 eq.), NaOH (67.3 mg, 1.68 mmol, 3.0 eq.) were dissolved in tetrahydrofuran (5 mL) and water (5 mL), stirred at 20 °C for 6 hours. The reaction solution was concentrated under reduced pressure, the aqueous phase was adjusted to pH 3 with 1N aqueous hydrochloric acid solution, extracted with ethyl acetate (5 mL x 2), the combined organic phase was washed with saturated brine (5 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain compound 33-4 (190 mg, crude).

[0228] Step 4: Compound 33-4 (100 mg, 242 μmol, 1.0 eq.), hydrochloride of compound 1-4 (79.2 mg, 363 μmol, 1.5 eq.), HATU (138 mg, 363 μmol, 1.5 eq.), DIPEA (125 mg, 967 μmol, 4.0 eq.) were dissolved in DMF (2 mL), reacted at 20 °C for 1 hour. Water (1 mL) and ethyl acetate (1 mL) were added, extracted with ethyl acetate (1 mL x 2). The combined organic phase was washed with water (1 mL), then saturated brine (1 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by preparative thin layer chromatography (n-heptane: ethyl acetate = 1:3) to obtain compound 33 (40.0 mg, yield 29%). 1 H NMR (400 MHz, CDC13) δ 7.59 - 7.45 (m, 3H), 7.33 (s, 1H), 7.18 (s, 1H), 7.10 (s, 1H), 6.96 (t, J = 2.0 Hz, 1H), 6.92 (t, J = 5.2 Hz, 1H), 4.16 (d, J = 5.2 Hz, 2H), 4.08 (d, J = 17.2 Hz, 1H), 3.86 (s, 3H), 3.74 (d, J = 17.2 Hz, 1H), 2.48 (s, 3H), 1.40 - 1.31 (m, 2H), 1.18 - 1.09 (m, 2H). MS-ESI calculated [M+H] + 578, found 578.

[0229] Example 034 Preparation of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-N,2-dimethyl-N-(2-oxo-2-((1-(trifluoromethyl)cyclopropyl) amino)ethyl)benzamide (34)

[0230] Step 1: Compound 34-1 (1.00 g, 5.28 mmol, 1 eq.) was dissolved in DMF (10 mL), HATU (2.41 g, 6.34 mmol, 1.2 eq.) and DIPEA (2.05 g, 15.8 mmol, 3 eq.) were added, stirred at 25 °C for 0.5 h, then compound 1-2 hydrochloride (939 mg, 5.81 mmol, 1.1 eq.) was added, stirred at 25 °C for 0.5 h. The reaction was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine (30 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give compound 34-2 (1.56 g, crude).

[0231] Step 2: Compound 34-2 (1.56 g, 5.26 mmol, 1 eq.) was dissolved in DCM (8 mL), hydrogen chloride solution in dioxane (4 M, 8 mL) was added, stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was slurried with ethyl acetate (10 mL) to give compound 34-3 hydrochloride (950 mg, yield 77%). 1 H NMR (400 MHz, DMSO-d6) δ 9.45 (s, 1H), 9.07 (s, 2H), 3.71 (s, 2H), 2.53 (s, 3H), 1.32-1.25 (m, 2H), 1.13-0.96 (m, 2H).

[0232] Step 3: Compound 2-9 (70 mg, 167 μmol, 1 eq.) was dissolved in DMF (1 mL), HATU (76 mg, 200 μmol, 1.2 eq.) and DIPEA (64 mg, 502 μmol, 3 eq.) were added, stirred at 25 °C for 0.5 h, then compound 34-3 hydrochloride (43 mg, 184 μmol, 1.1 eq.) was added, stirred at 25 °C for 0.5 h. The reaction was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (SiO2, ethyl acetate) to give compound 34 (40.3 mg, yield 40%). 1H NMR (400 MHz, CDC13) δ 7.61 - 7.51 (m, 4H), 7.45 (t, J = 1.6 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.01 (s, 1H), 4.21 - 4.04 (m, 3H), 3.72 (d, J = 17.6 Hz, 1H), 2.95 (s, 3H), 2.37 (s, 3H), 1.41 - 1.34 (m, 2H), 1.22 - 1.14 (m, 2H). MS - ESI calculated [M+H] + 596, found 596.

[0233] Example 035 Preparation of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-2-methyl-N-((R)-1-oxo-1-((1-(trifluoromethyl)cyclopropyl) amino)propan-2-yl)benzamide (35)

[0234] Step 1: To a solution of 35-1 (1.00 g, 5.28 mmol, 1 eq.) in DMF (10 mL) was added HATU (2.41 g, 6.34 mmol, 1.2 eq.) and DIPEA (2.04 g, 15.8 mmol, 3 eq.). After stirring at 25 °C for 0.5 h, the hydrochloride salt of 1-2 (939 mg, 5.81 mmol, 1.1 eq.) was added to the mixture and stirred at 25 °C for 0.5 h. The reaction was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give compound 35-2 (2.0 g, crude).

[0235] Step 2: Compound 35-2 (2.00 g, 6.75 mmol, 1 eq.) was dissolved in DCM (10 mL), and hydrogen chloride solution in dioxane (4 M, 10 mL) was added, and stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was slurry in ethyl acetate (10 mL) to give the hydrochloride salt of compound 35-3 (950 mg, yield 60%). 1 H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.29 (s, 3H), 3.80 (q, J = 7.2 Hz, 1H), 1.35 (d, J = 7.2 Hz, 3H), 1.32 - 1.22 (m, 2H), 1.14 - 0.97 (m, 2H).

[0236] Step 3: Compound 2-9 (70 mg, 167 μmol, 1 eq.) was dissolved in DMF (1 mL), HATU (76 mg, 200 μmol, 1.2 eq.) and DIPEA (64 mg, 502 μmol, 3 eq.) were added, stirred at 25 °C for 0.5 h, then hydrochloride salt of compound 35-3 (42 mg, 184 μmol, 1.1 eq.) was added, stirred at 25 °C for 0.5 h. The reaction was poured into water (5 mL) and extracted with ethyl acetate (5 mL x 3). The organic phase was washed with saturated brine (5 mL x 2), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (SiO2, n-heptane / ethyl acetate = 1:1) to give compound 35 (41.8 mg, yield 41%). 1 H NMR (400 MHz, CDC13) δ 7.59 - 7.50 (m, 4H), 7.49 - 7.38 (m, 2H), 7.10 (s, 1H), 6.48 (dd, J = 3.2, 7.2 Hz, 1H), 4.68 (t, J = 7.2 Hz, 1H), 4.11 (dd, J = 1.2, 17.2 Hz, 1H), 3.72 (d, J = 17.6 Hz, 1H), 2.47 (s, 3H), 1.50 (d, J = 7.2 Hz, 3H), 1.39 - 1.31 (m, 2H), 1.14 (s, 2H). MS-ESI calc [M+H] + 569, found 596.

[0237] Example 036 Preparation of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-2-methyl-N-((S)-1-oxo-1-((1-(trifluoromethyl)cyclopropyl) amino)propan-2-yl)benzamide (36)

[0238] Step 1: Compound 36-1 (1.00 g, 5.28 mmol, 1 eq.) was dissolved in DMF (10 mL), HATU (2.41 g, 6.34 mmol, 1.2 eq.) and DIPEA (2.04 g, 15.8 mmol, 3 eq.) were added, stirred at 25 °C for 0.5 h, then hydrochloride salt of compound 1-2 (939 mg, 5.81 mmol, 1.1 eq.) was added, stirred at 25 °C for 0.5 h. The reaction was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give compound 36-2 (1.70 g, crude).

[0239] Step 2: Compound 36-2 (1.70 g, 5.73 mmol, 1 eq.) was dissolved in DCM (10 mL), hydrogen chloride solution in dioxane (4 M, 10 mL) was added, and the mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was slurried with ethyl acetate (10 mL) to give the hydrochloride salt of compound 36-3 (830 mg, yield 62%). 1 H NMR (400 MHz, DMSO-d6) δ 9.35 (s, 1H), 8.42 - 7.94 (m, 3H), 3.79 (d, J = 6.8 Hz, 1H), 1.34 (d, J = 6.8 Hz, 3H), 1.32 - 1.23 (m, 2H), 1.13 - 0.97 (m, 2H).

[0240] Step 3: Compound 2-9 (70 mg, 167 μmol, 1 eq.) was dissolved in DMF (1 mL), HATU (76.3 mg, 200 μmol, 1.2 eq.) and DIPEA (64 mg, 502 μmol, 3 eq.) were added, and the mixture was stirred at 25 °C for 0.5 h, then compound 36-3 (42 mg, 184 μmol, 1.1 eq.) was added, and the mixture was stirred at 25 °C for 0.5 h. The reaction was poured into water (5 mL) and extracted with ethyl acetate (5 mL x 3). The organic phase was washed with saturated brine (5 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (SiO2, n-heptane / ethyl acetate = 1:1) to give compound 36 (33.4 mg, yield 33%). 1 H NMR (400 MHz, CDCl3) δ 7.58 - 7.48 (m, 4H), 7.47 - 7.37 (m, 2H), 7.22 (s, 1H), 6.57 (t, J = 6.8 Hz, 1H), 4.70 (q, J = 7.2 Hz, 1H), 4.11 (dd, J = 1.6, 17.2 Hz, 1H), 3.72 (d, J = 17.6 Hz, 1H), 2.46 (s, 3H), 1.50 (d, J = 7.2 Hz, 3H), 1.38 - 1.31 (m, 2H), 1.13 (s, 2H). MS - ESI calculated [M+H] + 596, found 596.

[0241] Example 037 Preparation of 4-(5-(3-chloro-5-(trifluoromethoxy)phenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl-N-(2-oxo-2-((1- (trifluoromethyl)cyclopropyl)amino)ethyl)benzamide (37)

[0242] Step 1 : Compound 37-1 (2.00 g, 7.26 mmol, 1 eq.) and 1-(trifluoromethyl)vinyl boronic acid hexanol ester (1.93 g, 8.71 mmol, 1.2 eq.) were dissolved in dioxane (10 mL) and H20 (2 mL), Pd(dppf)Cl2(531 mg, 726 μmol, 0.1 eq.) and K2C03(3.01 g, 21.7 mmol, 3 eq.) were added, stirred at 95 °C for 16 h. The reaction was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (Si02, n-heptane) to give compound 37-3 (1.56 g, yield 73%). 1 HNMR (400 MHz, CDC13) δ 7.41 (s, 1H), 7.30 (s, 1H), 7.23 (s, 1H), 6.10 (s, 1H), 5.87 (d, J = 1.6 Hz, 1H).

[0243] Step 2: Compound 19-3 (302 mg, 1.56 mmol, 1 eq.) and NCS (208 mg, 1.56 mmol, 1 eq.) were dissolved in DMF (5 mL), stirred at 25 °C for 2 h. 37-2 (500 mg, 1.72 mmol, 1.1 eq.) and triethylamine (189 mg, 1.87 mmol, 1.2 eq.) were added, stirred at 25 °C for 2 h. The reaction was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (Si02, ethyl acetate / n-heptane, 0-6%) to give compound 37-3 (170 mg, yield 22%). 1 HNMR (400 MHz, CDC13) δ 7.98 (d, J = 8.8 Hz, 1H), 7.62-7.53 (m, 3H), 7.42 (s, 1H), 7.34 (d, J = 0.8 Hz, 1H), 4.14 (d, J = 17.2 Hz, 1H), 3.93 (s, 3H), 3.74 (d, J = 17.2 Hz, 1H), 2.65 (s, 3H).

[0244] Step 3: Compound 37-3 (170 mg, 352 μmol, 1 eq.) was dissolved in THF (2 mL) and H20 (0.5 mL), LiOH.H20 (44 mg, 1.05 mmol, 3 eq.) was added, stirred at 25 °C for 16 h. The reaction mixture was adjusted to pH 5-7 with 1 N HC1, extracted with ethyl acetate (10 mL x 2), the organic phase was washed with brine (10 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give compound 37-4 (160 mg, crude).

[0245] Step 4: Compound 37-4 (100 mg, 213 μmol, 1 eq.) was dissolved in DMF (1 mL), HATU (98 mg, 257 μmol, 1.20 eq.) and DIPEA (83 mg, 642 μmol, 3.00 eq.) were added, stirred at 25 °C for 0.5 h, then compound 1-4 (51 mg, 233 μmol, 1.09 eq.) was added, stirred at 25 °C for 0.5 h. The reaction was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was separated and purified by preparative high performance liquid chromatography (column: Xtimate C18, 30*150mm I.D., 5um; mobile phase: A for H2O (0.1% TFA) and B for CH3CN], gradient: (63%-83%, 10 min, 100%, 2 min, 63%, 3 min)) to give compound 37 (37.24 mg, yield 27%). 1 H NMR (400 MHz, CDC13) δ 7.63 - 7.46 (m, 4H), 7.41 (s, 1H), 7.34 (s, 1H), 7.18 (s, 1H), 6.86 (t, J = 5.2 Hz, 1H), 4.21 - 4.04 (m, 3H), 3.73 (d, J = 17.6 Hz, 1H), 2.49 (s, 3H), 1.42 - 1.32 (m, 2H), 1.21 - 1.09 (m, 2H). MS-ESI calculated [M+H] + 632, found 632.

[0246] Example 038 Preparation of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-N-(2-oxo-2-((1-(trifluoromethyl)cyclopropyl)amino)ethyl)benzamide (38)

[0247] Step 1: Compound 38-1 (5.00 g, 28.1 mmol, 1 eq.) and 2-6 (7.00 g, 28.8 mmol, 1 eq.) were dissolved in trifluorotoluene (50 mL) and toluene (50 mL), cesium carbonate (914 mg, 2.81 mmol, 0.1 eq.) was added, and the reaction was stirred at 110 °C for 12 h. The reaction was quenched with water (50 mL), extracted with ethyl acetate (50 mL x 2), the organic phase was combined, washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude was purified by column chromatography (n-Heptane: ethyl acetate = 20: 1) to give compound 38-2 (6.00 g, yield 53%). 1 H NMR (400 MHz, CDC13) δ 8.12 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 1.2 Hz, 1H), 7.33 (t, J = 1.6 Hz, 1H), 7.16 (d, J = 1.6 Hz, 2H), 3.96 (s, 3H).

[0248] Step 2: Sodium hydroxide (1.20 g, 29.8 mmol, 4 eq.), NH2OH.HC1 (3.10 g, 22.3 mmol, 3 eq.) and tetrabutylammonium bromide (1.16 g, 0.744 mmol, 0.1 eq.) were dissolved in water (50 mL), and the reaction was stirred at 0 °C for 0.5 h. Compound 38-2 (3.00 g, 7.44 mmol, 1 eq.) was then dissolved in toluene (50 mL) and added dropwise to the above reaction solution, and the reaction was stirred at 25 °C for 12 h. The reaction was quenched by adding saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phase was combined, washed with saturated brine (50 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude was purified by column chromatography (n-Heptane: ethyl acetate = 9: 1) to give compound 38-3 (200 mg, yield 6%). 1 H NMR (400 MHz, CDC13) δ 8.12 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 1.2 Hz, 1H), 7.33 (t, J = 1.6 Hz, 1H), 7.16 (d, J = 1.6 Hz, 2H), 3.96 (s, 3H).

[0249] Step 3: Compound 38-3 (200 mg, 0.478 mmol, 1 eq.) was dissolved in tetrahydrofuran (1.5 mL), methanol (1 mL) and water (0.5 mL), lithium hydroxide monohydrate (60.2 mg, 1.44 mmol, 3 eq.) was added, the reaction was stirred at 25 °C for 6 h. The reaction was adjusted to pH about 3 with 1 N hydrochloric acid, extracted with ethyl acetate (10 mL x 2), the organic phase was combined, washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting compound 38-4 (190 mg, crude) was concentrated.

[0250] Step 4: Compound 38-4 (200 mg, 0.495 mmol, 1 eq.) and hydrochloride salt of compound 1-4 (162 mg, 0.742 mmol, 1.5 eq.) were dissolved in DMF (3 mL), HATU (282 mg, 0.742 mmol, 1.5 eq.) and DIPEA (192 mg, 1.49 mmol, 3 eq.) were added, the reaction was stirred at 25 °C for 2 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude was purified by preparative thin layer chromatography (ethyl acetate) to give compound 38 (37.5 mg, yield 13%). 1 HNMR (400 MHz, CDC13) δ 7.88 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.67 - 7.61 (m, 2H), 7.52 (d, J = 1.6 Hz, 2H), 7.44 (t, J = 1.6 Hz, 1H), 4.19 (d, J = 4.8 Hz, 2H), 4.11 (d, J = 17.2 Hz, 1H), 3.73 (d, J = 17.2 Hz, 1H), 1.37 - 1.31 (m, 2H), 1.16 - 1.10 (m, 2H). MS - ESI calculated [M+H] + 568, found 568.

[0251] Example 39 (Comparative Example 1) Preparation of N-(2-(cyclopropylamino)-2- oxoethyl)-4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2- methylbenzamide

[0252] Step 1: Compound 1-1 (2.00 g, 11.4 mmol, 1.0 eq.) was dissolved in dichloromethane (50 mL), then compound 39-1 (978 mg, 17.1 mmol, 1.5 eq.), T4P (12.3 g, 17.1 mmol, 50% ethyl acetate solution, 1.5 eq.) and DIPEA (5.90 g, 45.7 mmol, 4.0 eq.) were added, stirred at 25 °C for 1 h. Water (5 mL) and ethyl acetate (5 mL) were added, the liquid was separated, the aqueous phase was extracted with ethyl acetate (5 mL x 2). The organic phase was combined, washed with water (5 mL x 3), then saturated brine (5 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound 39-2 (1.72 g, yield 70%).

[0253] Step 2: Compound 39-2 (1.70 g, 7.93 mmol, 1.0 eq.) was dissolved in DCM (2 mL), hydrogen chloride solution in dioxane (4 M, 10 mL) was added, and stirred at 25 °C for 16 h. After the reaction was completed, methyl tert-butyl ether (5 mL) was added, stirred for 1 h, and filtered to obtain the hydrochloride salt of compound 39-3 (920 mg, yield 85%).

[0254] Step 3: Compound 2-9 (70.0 mg, 167 μmol, 1.0 eq.) and the hydrochloride salt of compound 39-3 (37.8 mg, 251 μmol, 1.5 eq.), HATU (95.5 mg, 251 μmol, 1.5 eq.), DIPEA (86.5 mg, 670 μmol, 4.0 eq.) were dissolved in DMF (2 mL), and reacted at 20 °C for 1 h. Water (1 mL) and ethyl acetate (1 mL) were added, the liquid was separated, the aqueous phase was extracted with ethyl acetate (1 mL x 2), the organic phase was combined, washed with water (1 mL), then saturated brine (1 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (n-heptane: ethyl acetate = 1:20) to obtain compound 39 (35 mg, yield 41%). 1 H NMR (400 MHz, DMSO-d6) δ 8.49 (t, J = 6.0 Hz, 1H), 8.02 (d, J = 4.0 Hz, 1H), 7.83 (t, J = 1.6 Hz, 1H), 7.67-7.57 (m, 4H), 7.48 (d, J = 8.4 Hz, 1H), 4.50-4.23 (m, 2H), 3.78 (d, J = 6.0 Hz, 2H), 2.70-2.60 (m, 1H), 2.40 (s, 3H), 0.71-0.56 (m, 2H), 0.48-0.37 (m, 2H). MS-ESI calculated value [M+H] +514, found 514.

[0255] Example 040 Preparation of 2-chloro-N-(2-(cyclopropylamino)-2-oxoethyl)-4-(5-(3,5- dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-6-methylbenzamide (40)

[0256] Step 1 : Compound 40-1 (4.00 g, 15.2 mmol, 1 eq.) and potassium isopropenyltrifluoroborate (2.46 g, 16.6 mmol, 1.1 eq.) were dissolved in dioxane (20 mL) and H2O (10 mL), K2CO3 (6.28 g, 45.4 mmol, 2.99 eq.) and Pd(dppf)Cl2 (1.11 g, 1.52 mmol, 0.1 eq.) were added, stirred at 60 °C for 20 h. The reaction solution was concentrated under reduced pressure, ethyl acetate (20 mL) was added, filtered, the organic phase was washed with saturated brine (10 mL x 1), dried over magnesium sulfate, filtered, and rotary evaporated. The crude product was separated and purified by column chromatography (SiO2, ethyl acetate / n-hexane, 1-3%) to give 40-2 (2.7 g, yield 79%).

[0257] Step 2: Compound 40-2 (2.70 g, 12.0 mmol, 1 eq.) was dissolved in THF (20 mL) and H2O (10 mL), potassium osmate (374 mg, 1.20 mmol, 0.1 eq.) and sodium periodate (5.91 g, 27.6 mmol, 2.30 eq.) were added, stirred at 20 °C for 20 h. Aqueous sodium thiosulfate (20 mL) was added, separated, the aqueous phase was extracted with ethyl acetate (10 mL x 2), the combined organic phase was washed with water (10 mL x 2), then saturated brine (10 mL x 2), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by column chromatography (ethyl acetate / n-hexane, 1-3%) to give 40-3 (1.05 g, yield 39%).

[0258] Step 3: Compound 40-3 (1.05 g, 4.63 mmol, 1 eq.) and 2-6 (1.69 g, 6.95 mmol, 1.5 eq.) were dissolved in toluene (10 mL), Cs2CO3 (302 mg, 927 μmol, 0.2 eq.) was added, stirred at 110 °C for 16 h. The reaction solution was concentrated under reduced pressure, ethyl acetate (15 mL) was added, filtered, and concentrated under reduced pressure. The crude product was separated and purified by column chromatography (SiO2, ethyl acetate / n-hexane, 1-3%) to give 40-4 (1.45 g, yield 69%).

[0259] Step 4: Dissolve NH2OH HCI (558 mg, 8.03 mmol, 2.50 eq.), tetrabutylammonium bromide (103 mg, 320 μmol, 0.1 eq.) and NaOH (385 mg, 9.63 mmol, 3.0 eq.) in H2O (2 mL), add a solution of 40-4 (1.45 g, 3.21 mmol, 1 eq.) in THF (10 mL), stir at 20 °C for 15.5 h. After the reaction is completed, quench the reaction with NH4CI (20 mL), extract with ethyl acetate (25 mL x 2), combine the organic phase, wash with saturated brine (25 mL x 2), dry over magnesium sulfate, filter, and concentrate under reduced pressure. Purify the crude product by column chromatography (ethyl acetate / n-hexane, 2-5%) to give 40-5 (1.35 g, yield 90%).

[0260] Step 5: Dissolve compound 40-5 (200 mg, 429 μmol, 1 eq.) in THF (2 mL) and H2O (2 mL), add LiOH H2O (36 mg, 858 μmol, 2.00 eq.), stir at 70 °C for 16 h. Concentrate the reaction under reduced pressure, adjust the pH of the aqueous phase to 3-4 with 1 mol / L aqueous hydrochloric acid solution, extract with ethyl acetate (10 mL x 2), wash the organic phase with saturated brine (10 mL x 2), dry over magnesium sulfate, filter, and concentrate under reduced pressure to give 40-6 (190 mg, yield 98%). MS-ESI calc. for [M+H] + 452, found 452.

[0261] Step 6: Dissolve compound 40-6 (85 mg, 188 μmol, 1 eq.) in DMF (1 mL), add HATU (107 mg, 281 μmol, 1.5 eq.) and DIPEA (97 mg, 751 μmol, 4.0 eq.), stir at 25 °C for 0.5 h, then add hydrochloride salt of compound 39-3 (43 mg, 286 μmol, 1.52 eq.), stir at 20 °C for 1 h. Quench the reaction with water (10 mL), extract with ethyl acetate (10 mL x 2), combine the organic phase, wash the organic phase with water (10 mL x 2), then wash with saturated brine (10 mL x 2), dry over magnesium sulfate, filter, and concentrate under reduced pressure. Purify the crude product by preparative thin layer chromatography (SiO2, n-hexane / ethyl acetate = 1:6) to give 40 (15 mg, yield: 15%). 1H NMR (400 MHz, DMSO-d6) δ 8.76 (t, J = 5.9 Hz, 1H), 7.99 (d, J = 3.9 Hz, 1H), 7.83 (t, J = 1.8 Hz, 1H), 7.65 - 7.54 (m, 4H), 4.47 - 4.29 (m, 2H), 3.81 (d, J = 5.9 Hz, 2H), 2.75 - 2.57 (m, 1H), 2.37 (s, 3H), 0.69 - 0.57 (m, 2H), 0.50 - 0.33 (m, 2H). MS - ESI calculated [M+H] + 548, found 548.

[0262] Example 041 Preparation of N-(2-(cyclopropylamino)-2-oxoethyl)-4-(5-(3,5- dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-5-fluoro-2- methylbenzamide (41)

[0263] Step 1 : Compound 41-1 (1.00 g, 4.05 mmol, 1 eq.) and potassium isopropenyl trifluoroborate (660 mg, 4.46 mmol, 1.10 eq.) were dissolved in dioxane (10 mL) and H2O (5 mL), K2CO3 (1.68 g, 12.2 mmol, 3.00 eq.) and Pd(dppf)Cl2 (296 mg, 405 μmol, 0.1 eq.) were added, stirred at 80 °C for 20 h. The reaction solution was concentrated under reduced pressure, ethyl acetate (20 mL) was added, filtered, the organic phase was washed with saturated brine (10 mL x 1), dried over magnesium sulfate, filtered, and rotary evaporated. The crude product was separated and purified by column chromatography (SiO2, ethyl acetate / n-hexane, 1-5%) to give 41-2 (0.7 g, yield 83%).

[0264] Step 2: Compound 41-2 (700 mg, 3.36 mmol, 1 eq.) was dissolved in THF (7 mL) and H2O (7 mL), potassium osmate (105 mg, 337 μmol, 0.1 eq.) and sodium periodate (1.65 g, 7.71 mmol, 2.30 eq.) were added, stirred at 20 °C for 20 h. Aqueous sodium thiosulfate (20 mL) was added, separated, the aqueous phase was extracted with ethyl acetate (10 mL x 2), the combined organic phase was washed with water (10 mL x 2), then saturated brine (10 mL x 2), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by column chromatography (ethyl acetate / n-hexane, 3-5%) to give 41-3 (0.4 g, yield 57%).

[0265] Step 3: Compound 41-3 (300 mg, 1.43 mmol, 1 eq.) and 2-6 (522 mg, 2.15 mmol, 1.5 eq.) were dissolved in toluene (20 mL), Cs2CO3(465 mg, 1.43 mmol, 1.0 eq.) was added, and the mixture was stirred at 110 °C for 16 h. The reaction solution was concentrated under reduced pressure, ethyl acetate (35 mL) was added, and the mixture was washed with saturated brine (15 mL x 2), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, ethyl acetate / n-hexane, 0-3%) to give 41-4 (195 mg, 31% yield).

[0266] Step 4: NH2OH HCI (88 mg, 1.27 mmol, 2.50 eq.), tetrabutylammonium bromide (17 mg, 52.7 μmol, 0.1 eq.), and NaOH (61 mg, 1.53 mmol, 3.0 eq.) were dissolved in H2O (1 mL), and a solution of 41-4 (220 mg, 506 μmol, 1 eq.) in THF (5 mL) was added. The mixture was stirred at 20 °C for 15.5 h. After the reaction was completed, NH4CI (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (25 mL x 2). The combined organic phase was washed with saturated brine (25 mL x 2), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate / n-hexane, 2-10%) to give 41-5 (185 mg, 81% yield).

[0267] Step 5: Compound 41-5 (200 mg, 444 μmol, 1 eq.) was dissolved in THF (5 mL) and H2O (5 mL), and LiOH HCI (53 mg, 1.33 mmol, 3.00 eq.) was added. The mixture was stirred at 20 °C for 16 h. The reaction solution was concentrated under reduced pressure, and the aqueous phase was adjusted to pH 3-4 with 1 mol / L aqueous HCI solution. The mixture was extracted with ethyl acetate (10 mL x 2), and the organic phase was washed with saturated brine (10 mL x 2), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give 41-6 (180 mg, 93% yield).

[0268] Step 6: Compound 41-6 (70 mg, 160 μmol, 1 eq.) was dissolved in DMF (1 mL), HATU (92 mg, 242 μmol, 1.5 eq.) and DIPEA (83 mg, 642 μmol, 4.0 eq.) were added, followed by the hydrochloride salt of compound 39-3 (36 mg, 239 μmol, 1.5 eq.), and stirred at 20 °C for 1 h. The reaction was quenched by water (10 mL), extracted with ethyl acetate (10 mL x 2), the organic phase was combined, washed with water (10 mL x 2), then saturated brine (10 mL x 2), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (SiO2, n-heptane / ethyl acetate = 1:4) to give compound 41 (5 mg, yield 6%). 1 H NMR (400 MHz, CD3OD) δ 7.72 (d, J = 7.1 Hz, 1H), 7.67-7.56 (m, 3H), 7.38 (d, J = 11.0 Hz, 1H), 4.44-4.24 (m, 1H), 4.13-3.91 (m, 3H), 2.82-2.60 (m, 1H), 2.44 (s, 3H), 0.85-0.65 (m, 2H), 0.60-0.47 (m, 2H). MS-ESI calculated [M+H] + 532, found 532.

[0269] Example 042 Preparation of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-5-fluoro-2-methyl-N-(2-oxo-2-(2,2,2-trifluoroethyl)amino)ethyl)benzamide benzamide (42)

[0270] Step 1: Compound 41-6 (70 mg, 160 μmol, 1 eq.) was dissolved in DMF (1 mL), HATU (92 mg, 242 μmol, 1.5 eq.) and DIPEA (83 mg, 642 μmol, 4.0 eq.) were added, followed by the hydrochloride salt of compound 42-1 (46 mg, 239 μmol, 1.5 eq.), and stirred at 20 °C for 1 h. The reaction was quenched by water (10 mL), extracted with ethyl acetate (10 mL x 2), the organic phase was combined, washed with water (10 mL x 2), then saturated brine (10 mL x 2), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin layer chromatography (SiO2, n-heptane / ethyl acetate = 1:2) to give 42 (40 mg, yield 43%). 1H NMR (400 MHz, CDC13) δ 7.79 (d, J = 7.1 Hz, 1H), 7.59 - 7.37 (m, 3H), 7.24 (d, J = 10.8 Hz, 1H), 7.06 - 6.70 (m, 2H), 4.34 - 4.11 (m, 3H), 4.02 - 3.90 (m, 2H), 3.79 (d, J = 17.4 Hz, 1H), 2.44 (s, 3H). MS - ESI calculated [M+H] + 574, found 574.

[0271] Example 4 Preparation of N-(2-(cyclopropylamino)-2-oxoethyl)-4-(5-(3,5- dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3-fluoro-2- methylbenzamide (4)

[0272] Step 1 : Compound 4-1 (1.00 g, 4.05 mmol, 1 eq.) and potassium isopropenyl trifluoroborate (899 mg, 6.08 mmol, 1.5 eq.) were dissolved in dioxane (10 mL) and H20 (2 mL), K2C03(1.68 g, 12.2 mmol, 3.00 eq.) and Pd(dppf)Cl2(296 mg, 405 μmol, 0.1 eq.) were added and stirred at 90 °C for 2 h. The reaction was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with saturated brine (2 x 50 mL), dried over anhydrous MgS04, filtered and concentrated under reduced pressure. The crude product was isolated and purified by column chromatography (Si02, ethyl acetate / n-hexane, 0-4%) to give 4-2 (758 mg, yield 90%).

[0273] Step 2: Compound 4-2 (750 mg, 3.60 mmol, 1 eq.) was dissolved in THF (20 mL) and H20 (5 mL), potassium osmate (112 mg, 360 μmol, 0.1 eq.) and sodium periodate (2.31 g, 10.8 mmol, 3.0 eq.) were added and stirred at 25 °C for 16 h. The reaction was quenched by adding aqueous sodium thiosulfate solution (20 mL) and then water (30 mL) was added and extracted with ethyl acetate (30 x 3), the organic phase was combined, washed with brine (30 mL), dried over magnesium sulfate and concentrated under reduced pressure. The crude product was isolated and purified by column chromatography (ethyl acetate / n-hexane, 0-5%) to give 4-3 (608 mg, yield 80%).

[0274] Step 3: Compound 43-3 (600 mg, 2.85 mmol, 1 eq.) and 2-6 (833 mg, 3.43 mmol, 1.2 eq.) were dissolved in toluene (20 mL), Cs2CO3(558 mg, 1.71 mmol, 0.6 eq.) was added, and stirring was performed at 110 °C for 16 h. The reaction was poured into water (10 mL) and extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated brine (20 mL x 2), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was isolated and purified by column chromatography (SiO2, ethyl acetate / n-hexane, 0-6%) to give 43-4 (200 mg, yield 16%).

[0275] Step 4: NH2OH HCI (96 mg, 1.38 mmol, 3.0 eq.), tetrabutylammonium bromide (15 mg, 46.5 μmol, 0.1 eq.) and NaOH (74 mg, 1.85 mmol, 4.0 eq.) were dissolved in H2O (2 mL) and stirred at 0 °C for 10 min. A solution of 43-4 (200 mg, 460 μmol, 1 eq.) in THF (0.5 mL) was added and stirred at 25 °C for 20 min. The reaction was quenched by adding saturated ammonium chloride solution (10 mL), poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude product was isolated and purified by column chromatography (ethyl acetate / n-hexane, 0-6%) to give 43-5 (70 mg, yield 34%).

[0276] Step 5: Compound 43-5 (70 mg, 155 μmol, 1 eq.) was dissolved in THF (1 mL), methanol (0.5 mL) and H2O (0.5 mL), and LiOH HCI (20 mg, 477 μmol, 3.07 eq.) was added. The mixture was stirred at 25 °C for 16 h. The reaction mixture was adjusted to pH 5-7 with 1 N HCI and extracted with ethyl acetate (10 mL x 2). The organic phase was washed with brine (10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to give the crude product 43-6 (70 mg).

[0277] Step 6: Compound 43-6 (35 mg, 80.2 pmol, 1 eq.) was dissolved in DMF (1 mL), HATU (37 mg, 97.3 pmol, 1.21 eq.) and DIPEA (32 mg, 248 pmol, 3.09 eq.) were added, then hydrochloride salt of compound 39-3 (15 mg, 99.6 pmol, 1.24 eq.) was added, and stirred at 95 °C for 16 h. The reaction was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (SiO2, n-heptane / ethyl acetate = 1:2) to give 43 (10 mg, yield 23%). 1 H NMR (400 MHz, DMSO-d6) d 8.61 (t, J = 6.0 Hz, 1H), 8.05 (d, J = 3.9 Hz, 1H), 7.82 (t, J = 2.0 Hz, 1H), 7.70 - 7.62 (m, 3H), 7.31 (d, J = 8.1 Hz, 1H), 4.40 - 4.32 (m, 1H), 4.32 - 4.24 (m, 1H), 3.79 (d, J = 6.1 Hz, 2H), 2.71 - 2.60 (m, 1H), 2.31 (d, J = 2.4 Hz, 3H), 0.69 - 0.58 (m, 2H), 0.48 - 0.36 (m, 2H). MS-ESI calculated [M+H] + 532, found 532.

[0278] Example 044 Preparation of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-3-fluoro-2-methyl-N-(2-oxo-2-(2,2,2-trifluoroethyl)amino) ethyl)benzamide (44)

[0279] Step 1: Compound 43-6 (35 mg, 80.2 pmol, 1 eq.) was dissolved in DMF (1 mL), HATU (37 mg, 97.3 pmol, 1.21 eq.) and DIPEA (32 mg, 248 pmol, 3.09 eq.) were added, then hydrochloride salt of compound 42-1 (19 mg, 98.7 pmol, 1.23 eq.) was added, and stirred at 25 °C for 0.5 h. The reaction was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (SiO2, n-heptane / ethyl acetate = 1:2) to give 44 (9.83 mg, yield 21%). 1H NMR (400 MHz, DMSO-d6) δ 8.75 (t, J = 6.0 Hz, 1H), 8.66 (t, J = 6.2 Hz, 1H), 7.82 (t, J = 1.8 Hz, 1H), 7.72 - 7.59 (m, 3H), 7.33 (d, J = 8.1 Hz, 1H), 4.43 - 4.22 (m, 2H), 4.04 - 3.87 (m, 4H), 2.31 (d, J = 2.4 Hz, 3H). MS - ESI calculated [M+H] + 574, found 574.

[0280] Biological test evaluation

[0281] Example 1 Test of killing efficacy on mites in an in vitro model

[0282] Mite collection: Use a cotton swab or small forceps to gently dip live mites in the cage box, 17-26 live mites per group.

[0283] Drug treatment and detection method: 100 μL of drug solution of different concentrations (3% DMSO solution + 97% water to obtain a target final concentration of 30 μM of drug solution) is added to each group of 24-well plates to ensure that the drug is in full contact with the mites. After incubation at room temperature for 5 min, the mites are removed from each plate to another dry 24-well plate, sealed at the top, and dried for about 1 h, the mite activity is observed, and the number of dead mites / total mites is recorded. Then the 24-well plate containing the mites is cultured in a room temperature and high humidity environment, 1 h, 2 h, 4 h, 6 h, 8 h, 22 h, 24 h (time points after drug addition), the number of dead mites / total mites is counted, and the mite mortality rate is calculated, and the 24 h after drug addition is the end point.

[0284] At the corresponding time point, the mite mortality rate is greater than or equal to 90% is marked as “+++”; the mite mortality rate is less than 90% and greater than or equal to 50% is marked as “++”, and the mite mortality rate is less than 50% is marked as “+”. The experimental results are as shown in Table 1.

[0285] Table 1

[0286] Example 2 Test of killing efficacy on fruit flies in an in vitro model

[0287] 1. Drug preparation: The test sample is prepared into a 30 uM / mL, 100 uM / mL solution with 3% DMSO + 97% water solvent.

[0288] 2. Experimental animals: > 50 fruit flies are used per group.

[0289] 3, Method of administration and statistics of test results: Put a piece of filter paper in a fruit fly tube, drop 200 μL of 5% glucose solution containing 30 uM or 100 uM of the test substance or solvent control on the filter paper, and transfer the fruit flies cultured to 7 days old into the fruit fly tube containing the test substance or solvent control. Record the number of dead fruit flies at the time point after administration, and draw the survival curve. The experimental results are shown in Table 2.

[0290] Table 2

[0291] Test Example 3: Test of killing effect on agricultural pests.

[0292] Solution preparation: Weigh 2 mg of the test compound, dissolve it in 200 μL of acetone, and dilute the sample to the desired concentration with 0.1% Tween 80 aqueous solution to prepare the test solution.

[0293] 1, Test of Plutella xylostella: Prepare the test sample into a solution with a final concentration of 0.0156 mg / L, 0.125 mg / L, and 1 mg / L. Cut fresh and clean rape leaves into small pieces of 3 cm x 3 cm. Immerse the leaves in the solution of different concentrations for 10 seconds, and then dry them naturally. Put the treated leaves into a culture dish lined with wet filter paper, and introduce 20 3rd instar larvae of Plutella xylostella. Place the culture dish in a constant temperature room, and check the mortality rate after 72 hours.

[0294] 2, Test of aphids: Prepare the test sample into a solution with a final concentration of 2 mg / L, 10 mg / L, and 50 mg / L. Immerse fresh cotton leaves of the same size in the solution of different concentrations for 10 seconds, and then dry them. Place the leaves with the back facing up on a culture plate, introduce 100 wingless adult aphids, seal with a paper strip, and place in a constant temperature room. Check the mortality rate after 72 hours.

[0295] 3, Test of mites: Prepare the test sample into a solution with a final concentration of 0.02 mg / L, 0.2 mg / L, and 2 mg / L. Put the filter paper treated with the test agent in a culture dish, and introduce about 30 mites in the center of each culture dish. After 30 minutes, put 0.05 g of mite feed in the center of the culture dish, and place the culture dish in a constant temperature room. Check the mortality rate after 72 hours.

[0296] 4, Test of borer: Prepare the test sample into a solution with a final concentration of 0.125 mg / L, 0.5 mg / L, and 2 mg / L. Cut fresh leaves, immerse them in the solution of different concentrations for 10 seconds, and then dry them. Put the treated leaves in a culture dish, introduce 30 borer larvae, and place in a constant temperature room. Check the mortality rate after 72 hours. The experimental results are shown in Table 3.

[0297] Table 3

[0298] Experimental Example 4 Pharmacokinetic evaluation in mice

[0299] 1. Preparation of drug: 5% DMSO + 10% 15-hydroxypolyoxyl stearate (BASF) + 85% saline (the final concentration of drug solution for IV group was 1.2 mg / mL; the final concentration of drug solution for PO group was 3 mg / mL).

[0300] 2. Experimental animals: 3 mice (ICR mice, SPF level) were used in each group.

[0301] 3. Administration method: The mice were weighed before administration, and the administration amount was calculated according to the body weight. The administration was performed by intravenous injection or oral gavage.

[0302] 4. Blood sampling: 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h after administration. The blood was collected from the cheek, and about 0.05 mL of sample was collected for each sample, and was anticoagulated with EDTA-2K, and was placed on wet ice after collection.

[0303] 5. Sample processing: After the blood sample was collected, it was placed on ice, and was centrifuged to separate the plasma within 1 hour (centrifugation condition: 6000 g, 3 minutes, 2-8°C). The plasma sample was stored in a -80°C refrigerator when stored before analysis.

[0304] 6. Data processing: The pharmacokinetic parameters were calculated by using Phoenix WinNonlin 8.2.0 from the blood concentration data at different time points. The experimental results are shown in Table 4 below.

[0305] Table 4

[0306] The results show that the compound of the present application exhibits good pharmacokinetic properties in mice.

[0307] The applicant declares that the isoxazoline compound and the application thereof of the present application are illustrated by the above examples, but the present application is not limited to the above examples, i.e. it does not mean that the present application must rely on the above examples to be implemented. It should be understood by those skilled in the art that any improvement of the present application, equivalent replacement of each raw material of the product of the present application, addition of auxiliary ingredients, selection of specific methods, etc. fall within the protection scope and disclosure scope of the present application.

Claims

1. An isoxazoline compound having the structure of Formula I: ###0001### Formula I wherein X is selected from -CH= or -N=; Y is selected from -CH= or -N=; Z is selected from the wavy line represents the point of attachment of the group; R1is selected from hydrogen, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, haloCi-C6alkyl, deuterated Ci-C6alkyl, haloC2-C6alkenyl, haloC2-C6alkynyl, halogen, cyano, nitro, -C(O)NR a R b , -C(O)R a , -C(O)OR a , -OR a , -R a OR b , -OC(O)R a , -OC(O)OR a , -OC(O)NR a R b , -NR a R b , -SR a , -S(O)R a , -S(O)2R a or a 3-10 membered saturated or non-saturated ring containing 0-3 heteroatoms optionally substituted with 1-3 R a ; R2is selected from hydrogen, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, haloC1-C6alkyl, deuterated C1-C6alkyl, haloC2-C6alkenyl, haloC2-C6alkynyl; R3is selected from hydrogen, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, haloC1-C6alkyl, deuterated C1-C6alkyl, haloC2-C6alkenyl, haloC2-C6alkynyl; R4is selected from hydrogen, Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, haloCi-C6alkyl, deuterated Ci-C6alkyl, haloC2-C6alkenyl, haloC2-C6alkynyl, halogen, cyano, nitro, -C(O)NR a R b , -C(O)R a , -C(O)OR a , -OR a , -R a OR b , -OC(O)R a , -OC(O)OR a , -OC(O)NR a R b , -NR a R b , -SR a , -S(O)R a , -S(O)2R a or a 3-10 membered saturated or non-saturated ring containing 0-3 heteroatoms, which 3-10 membered saturated or non-saturated ring containing 0-3 heteroatoms is optionally substituted with 1-3 R a ; R5is selected from hydrogen, Ci-C6alkyl, Ci-C6alkyl substituted with 1-3 R a substituted Ci-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, haloCi-C6alkyl, deuterium substituted Ci-C6alkyl, haloC2-C6alkenyl, haloC2-C6alkynyl, halogen, cyano, nitro, -C(O)NR a R b , -C(O)R a , -C(O)OR a , -OR a , -R a OR b , -OC(O)R a , -OC(O)OR a , -OC(O)NR a R b , -NR a R b , -SR a , -S(O)R a , -S(O)2R a or a 3-10 member saturated or non-saturated ring containing 0-3 heteroatoms, which 3-10 member saturated or non-saturated ring optionally substituted with 1-3 R a ; or R4and R5together with the nitrogen atom to which they are attached form a 3- to 7-membered saturated or unsaturated ring, which saturated or unsaturated ring is optionally substituted with 1-8 R a substituents; R6is selected from hydrogen, C1-C6alkyl, C2-C6alkenyl, haloC1-C6alkyl, C1-C6alkoxy, deuterated C1-C6alkyl; R7is selected from hydrogen, halogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, haloC1-C6alkyl, C1-C6alkoxy, deuterated C1-C6alkyl, haloC2-C6alkenyl, haloC2-C6alkynyl; each R a , R b is independently selected from hydrogen, deuterium, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, haloC1-C6alkyl, deuterated C1-C6alkyl, haloC2-C6alkenyl, haloC2-C6alkynyl, halogen, cyano, nitro, amino, carboxyl, carbonyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, C3-C6cycloalkyl, haloC3-C6cycloalkyl, alkoxy-substituted C3-C6cycloalkyl, C3-C6heterocyclyl, haloC3-C6heterocyclyl, alkyl-substituted C3-C6heteroaryl, -S(O)2R c , -OR c , -OR c , -OR d , -R c , -OR d , -C(O)R c , or -OC(O)R c , each R c , R d is independently selected from halogen, C1-C6alkyl, haloC1-C6alkyl; and m = 0, 1, 2, 3, 4, or 5; n = 0, 1, 2, 3, or 4.

2. The isoxazoline compound according to claim 1, wherein the isoxazoline compound has the structure of formula la: Z, R1, R2, R3, R4, R5, m, n are defined as in claim 1.

3. The isoxazoline compound according to claim 1 or 2, wherein the isoxazoline compound has the structure of formula lb: R1, R2, R3, m, n are defined as in claim 1; R a selected from cyano or trifluoromethyl.

4. The compound according to claim 1 of formula I, wherein R1is selected from hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy, haloC1-C6alkyl, or haloC1-C6alkoxy.

5. The compound according to claim 1 of formula I, wherein R1is selected from hydrogen, fluorine, chlorine, methyl, methoxy, trifluoromethyl, or trifluoromethoxy.

6. The compound according to claim 1 of formula I, wherein R2is selected from hydrogen, halogen, C1-C6alkyl, haloC1-C6alkyl.

7. The compound according to claim 1 of formula I, wherein R2is trifluoromethyl.

8. The compound according to claim 1 of formula I, wherein R3is selected from hydrogen, halogen, C1-C6alkyl, haloC1-C6alkyl.

9. The compound according to claim 1 of formula I, wherein R3is methyl, chlorine, or fluorine.

10. The compound according to claim 1 of formula I, wherein R4is hydrogen.

11. A compound of formula I according to claim 1, wherein R5 is selected from Ci-C6alkyl, haloCi-C6alkyl, C3-C6cycloalkyl, haloC3-C6cycloalkyl, cyano-substituted C3-C6cycloalkyl, alkoxy-substituted C3-C6cycloalkyl, haloCi-C6alkyl-substituted C3-C6cycloalkyl or haloCi-C6alkyl-substituted C3-C6heterocyclyl.

12. A compound of formula I according to claim 1, wherein R5 is selected from trifluoroethyl, cyclopropyl, 13. A compound of formula I according to claim 1, wherein is selected from 14. The compound according to claim 1 of formula I, wherein R6is selected from hydrogen or C1-C6alkyl.

15. The compound according to claim 1 of formula I, wherein R7is selected from hydrogen or C1-C6alkyl.

16. An isoxazoline compound selected from any one of the following compounds:

17. The isoxazoline compound according to claim 16, selected from any one of the following compounds:

18. A tautomer, enantiomer, diastereomer, entgegen, or pharmaceutically acceptable salt of the isoxazoline compound according to any one of claims 1-17.

19. A pharmaceutical composition, wherein, a therapeutically effective amount of an isoxazoline compound, a tautomer, enantiomer, diastereomer, entgegen, or pharmaceutically acceptable salt thereof, according to any one of claims 1-17; and a pharmaceutically acceptable carrier or excipient.

20. Use of an isoxazoline compound of any one of claims 1-17 or a tautomer, enantiomer, diastereomer, meso, racemic or a pharmaceutically acceptable salt thereof of claim 18 or a pharmaceutical composition of claim 19 for the control of ectoparasite infections in humans or animals.

21. A pesticidal composition comprising an active ingredient which is an isoxazoline compound of any one of claims 1-17 or a tautomer, enantiomer, diastereomer, meso, racemic or a pharmaceutically acceptable salt thereof of claim 18, and a pharmaceutically acceptable carrier or excipient, optionally together with at least one further pesticidally acceptable carrier and / or adjuvant.

22. A pesticidal formulation made from an isoxazoline compound of any one of claims 1-17 or a tautomer, enantiomer, diastereomer, meso, racemic or a pharmaceutically acceptable salt thereof of claim 18.

23. Use of an isoxazoline compound of any one of claims 1-17 or a tautomer, enantiomer, diastereomer, meso, racemic or a pharmaceutically acceptable salt thereof of claim 18 for the manufacture of a product for the control of agricultural pests.

24. Use according to claim 23 for the control of agricultural pests, the pest species being at least one of the group consisting of mites, Lepidoptera, Diptera, Thysanoptera, Hemiptera, Isoptera, Coleoptera pests.

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