TW201201802A - Substituted isoxazoline derivatives - Google Patents

Abstract

This invention recites substituted isoxazoline derivatives of Formula (1) or a veterinarily acceptable salt thereof, with parasiticidal activity, compositions thereof, and their use as a parasiticide in animals or birds where R1a, R1b, R1c, R2, R3, and n are as described herein.

Description

201201802 VI. INSTRUCTIONS: Cross-references to relevant applications. The US provisional application number 61/322,144 filed on April 8, 2010 and the US provisional application number 61/4 applied for on January 10, 2011 Priority of 31,107 [Technical Field to Be Invented by the Invention] The present invention relates to an isoxazoline derivative having parasiticidal activity. The compound of interest is the substituted isoxazoline 3-benzylacetamide, urethane and urea. The invention also relates to veterinary compositions and methods of use thereof. [Prior Art] There is a need for improved antiparasitic agents for use in animals and birds, and in particular, improved insecticides and acaricides are required. Furthermore, there is a need for improved topical and oral products that can be easily administered, which contain at least one species that can be used to effectively treat ectoparasites such as insects (eg, mites, mites and flies) and mites (eg, Anti-parasitic agents for mites and tick. These products are especially useful for the disposal of companion animals, livestock and poultry. Compounds currently used for the insecticidal and acaricidal treatment of companion animals, livestock and poultry do not always exhibit good activity, speed of action or duration of action. Most of the treatments contain dangerous chemicals that can have serious consequences, including eating and killing. It is generally recommended that the application of such agents limit the exposure of the agent. Pet items and labels have been used to overcome certain problems, but these methods are not resistant to chewing, feeding and subsequent toxicological effects on animals. Therefore, the current level of treatment of -5-201201802 is different, depending on toxicity, dosage method and efficacy. Currently, some agents are actually ineffective due to parasite resistance. The technical community has revealed that isoxazoline derivatives have insecticidal and acaricidal activity. For example, WO2005/085216, WO2007/1 058 1 4, WO2007/026965, WO2008/122375 and JP2008239611 describe 4-(5-substituted-5-substituted aryl-4,5-isoxazol-3-yl) Benzylamine and amine derivatives. Further, W02005/051932 lists specific 4,5-dihydroisoxazole benzamide derivatives, but does not disclose the compounds of the present invention. Although effective broad-spectrum anti-parasitic agents are available, there is still a need for safer, more convenient, and environmentally friendly products that overcome the threat of developing resistance. These references do not cite any examples of the isoxazoline-substituted oxazoles of the present invention, nor do they indicate that such compounds can be used against parasitic species in the range associated with companion animals, livestock, poultry, or against parasites in the range. Formal life cycle stage. The present invention overcomes or ameliorates one or more of the various disadvantages of the nature of the existing compounds. In particular, the present invention describes novel transoxazoline substituted aryl and heteroaryl carbazoles exhibiting such properties. SUMMARY OF THE INVENTION The present invention provides a compound of formula (1), or a veterinary acceptable salt thereof, as a parasiticidal agent, especially an ectoparasite, and thus, useful for preventing, treating, repelling and controlling animals. And avian mites and insect infections and invasions. In addition, the present invention contemplates the prevention and treatment of sputum infectious diseases,

S • 6- 201201802 For example, Lyme disease, canine and bovine anaplasmosis' canine ehrlichiosis, canine rickettsiosis, canine And canine and bovine babesiosis, epizootic bovine abortion, and theileriosis. Therefore, according to the present invention, a compound of the formula (1) is provided

Or a veterinary acceptable salt thereof, wherein

Rla, 1111> and 111<: are each independently selected from the group consisting of halogen, cyano, Ci-Cs alkyl, Ci. Q haloalkyl and Ci. Ce haloalkoxy, and each R1 may be the same or different from each other; R2 is hydrogen, halo, cyano, alkyl, haloalkyl or C^-Ce alkoxy, (: 丨-(: 6 haloalkoxy, C3-C6 cycloalkyl, wherein η is an integer 1, 2 or 3, and when η is 2 or 3, each R2 may be the same or different from each other; R3 is selected from C丨-C8 alkyl, C〇-C3 alkyl C3-C6 cycloalkyl, Ci· 201201802 c6 alkyl-OR4 or c!-C6 alkyl C(0)NRaRb, wherein the C丨-C8 alkyl group and the C^C3 alkyl group (:3.(6)cycloalkyl group are optionally at least one selected Substituted from the following groups: halo-cyano, hydroxy and S(0)pR4; R-based Ci.Ce or C1.C6 halogen;

Ra is hydrogen or Ci.c6; 1^ is hydrogen, c丨-C6 alkyl, C丨.c6 haloalkyl, c0.c4 alkyl c3-c6 cycloalkyl or ChG alkyl Het, wherein Het is a 5- or 6-membered monocyclic aromatic ring containing at least one hetero atom selected from N, 0 or S, and Het may be optionally substituted with at least one substituent selected from the group consisting of: a base 'cyano group, <: 丨-C6 alkyl group and C丨.C6_alkyl group; and P is an integer 〇, 1 or 2. In another aspect of the invention, when the integer η is 3, (R2)n is R2a, R2b and R2e. When the integer η is 2, the shell IJ (R2) n is R2a and R2b, R2a and R2° or R2b and R2c. When the integer n is 1, the shell U (R2)n is R2a, R2b or R2c. In another aspect of the invention, the compound of formula (1) comprises compounds of formula (1 A), (1 B), (1C) and (ID)

S -8- 201201802

Or a veterinary acceptable salt thereof. In another aspect of the invention, the compound of formula (1) comprises a compound of formula (1A). In still another aspect of the invention, the compound of the formula (1) comprises a compound of the formula (1B). In still another aspect of the invention, the compound of formula (1) comprises a compound of formula (1 C). In still another aspect of the invention, the compound of formula (1) comprises a compound of formula (i D). In another aspect of the invention, 'Rla, Rlb and R1. In another aspect of the present invention, each of Rla, Rlb and Ric is independently selected from the group consisting of fluorine, chlorine, and bromine, and is independently selected from the group consisting of halogen, cyano, C^Cs alkyl or Ci-Ce haloalkyl. Cyano, Ci.Cs alkyl and Ci_C6 haloalkyl. In still another aspect of the invention, Rla, Rlb& Rle are each independently selected from the group consisting of fluorine, chlorine, bromine, cyano, methyl, ethyl, -CF3 and -CH2CF3. In still another aspect of the invention, Rla ' Rib -9- 201201802 and Rle are each independently selected from the group consisting of fluorine, chlorine, bromine, and CF3. In still another aspect of the invention, 'Rla, Rlb and Ri. They are each independently selected from fluorine or chlorine. In still another aspect of the invention, Rla and Ri. Each is chlorine and Rlb is fluorine. In still another aspect of the invention, R 1 a, R 1 b and R 1 are used. Each is chlorine. In another aspect of the invention, R2a, R2b and R2. Each is independently hydrogen, halo, cyano, C丨.c6 alkyl, C丨-C6 haloalkyl or C3-C6 cycloalkyl. In still another aspect of the invention, R2a, R2b and R2c are each independently hydrogen, halo, cyano, methyl, ethyl, -CF3, -CH2CF3, cyclopropyl or cyclobutyl. In still another aspect of the invention, each of R2a, R2b and R2e is independently hydrogen, fluorine, chlorine, bromine, cyano, methyl or CF3. In still another aspect of the invention, R2a, R2b and R2<= are each independently fluorine, chlorine, bromine, methyl or CF3. In still another aspect of the invention, both R2a and R2b are hydrogen, and R2c is hydrogen, halo, cyano, methyl, ethyl, -CF3, -CH2CF3, cyclopropyl or cyclobutyl. In still another aspect of the invention, both R2a and R2b are hydrogen, and R2e is hydrogen, fluorine, chlorine, bromine, cyano, methyl or CF3. In still another aspect of the invention, both 1123 and R2b are hydrogen and R2e is fluorine, chlorine, bromine, methyl or CF3. In still another aspect of the invention, both R2a and R2b are hydrogen, and R2e is fluorine, chlorine or bromine. In still another aspect of the invention, both '1232 and R2b are hydrogen and R2c is fluorine. In still another aspect of the invention, both ' R2a and R2b are hydrogen and R2e is chlorine. In still another aspect of the invention, both R2a and R2b are hydrogen and R2. It is bromine. In still another aspect of the invention, the 'R3 is selected from the group consisting of Ci.C8 alkyl or CQ.C3 alkyl C3_c6 cycloalkyl; wherein (^-(^ alkyl and the C〇-C3 alkyl c3.

S -10- 201201802 c6 cycloalkyl is optionally substituted with at least one group selected from the group consisting of halo, hydroxy and S(0)pR4, wherein p is an integer of 0, 1 or 2 and R4 is methyl , ethyl or isopropyl. In still another aspect of the present invention, R3 is selected from the group consisting of C^C8 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, methylcyclopropyl, ethylcyclopropyl, methylcyclobutyl, and B. a cyclobutyl group and a methylcyclopentyl group; wherein the alkyl group, the cycloalkyl group and the alkylcycloalkyl group are optionally substituted with at least one group selected from the group consisting of halo, hydroxy, -SCH3 and -S (0) 2CH3. In still another aspect of the invention, R3 is selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, isobutyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl 'Cyclopentyl, methylcyclopropyl, ethylcyclopropyl, methylcyclobutyl, ethylcyclobutyl and methylcyclopentyl; wherein the alkyl, cycloalkyl and alkylcycloalkyl groups Optionally substituted with at least one group selected from the group consisting of halo, hydroxy, -sch3 and -s(o)2ch3. In still another aspect of the invention, R3 is selected from the group consisting of methyl, ethyl, propyl, butyl, isopropyl, isobutyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl , cyclopentyl, methylcyclopropyl, ethylcyclopropyl, methylcyclobutyl, ethylcyclobutyl and methylcyclopentyl; wherein the alkyl, cycloalkyl and alkylcycloalkyl groups Optionally substituted with at least one group selected from the group consisting of fluorine, chlorine, -SCH3 and -S(0)2CH3. In still another aspect of the invention, R3 is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl and methylcyclopropyl; wherein the alkyl, cycloalkyl And the alkylcycloalkyl group is optionally substituted with at least one group selected from the group consisting of fluorine, chlorine, -SCH3 and -S(0)2CH3. In still another aspect of the invention, R3 is selected from the group consisting of methyl, ethyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl and methylcyclopropyl. In still another aspect of the invention, R3 is Ct.Ce alkyl-OR4, wherein Ci-Cfi alkyl is methyl, ethyl or propyl, and R4 is methyl, ethyl, isopropyl or trifluoro methyl. In still another aspect of the invention, R3 is -CH2-0-CH3, -ch2-o-ch2ch3 or -ch2-o-cf3. In still another aspect of the invention, 113 is υ6 alkyl C(0)NRaRb, wherein the Ci-Ce alkyl is methyl or ethyl, the Ra is hydrogen, and the Rb is methyl, ethyl, trifluoromethyl. , methylcyclopropyl, -CH2-pyrazole, -CH2-carbazole, -CH2-imidazole, -CH2-thiazolyl, -CH2-isothiazolyl, -CH2-triazole, -CH2-tetrazole, -CH2·pyridine, -CH2-indole, and -CH2-pyrimidine. In still another aspect of the present invention, Rb is methyl, ethyl, methylcyclopropyl, _CH21&azole, -ch2-imidazole, -ch2-triazole, -ch2-tetrazole, -ch2-pyridine, -ch2-嗒哄 and - ch2-pyrimidine. In still another aspect of the invention, the integer P is 〇. In still another aspect of the invention, the integer p is 1. In still another aspect of the invention, the integer P is two. In another aspect of the invention, the compound of formula (1) comprises: N-{5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-di Hydroisoiso-3-yl]-2-fluorobenzyl}acetamidamine; 1^-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(three Fluoromethyl)-4,5-dihydroisoxazole_3_yl]benzyl b-2-methylpropionamide; N-{2-fluoro-5-[5-(3,4,5-three Chlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}cyclopropanecarbamide;

S -12- 201201802 N-{2-Fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3 _yl]benzyl}cyclobutanecarbamamine; N-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5 -dihydroisoxazol-3-yl]benzyl}propanamine; 2-cyclopropyl-N-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5 -(trifluoromethyl)-4,5-dihydroisoindolefoxa-3-yl]benzyl}acetamidamine; N-{2-fluoro-5-[5-(3,4,5-three Chlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}-3-methylbutane decylamine; 2-cyclopropyl-N-{ 5-[5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-fluorobenzyl} Acetamine; N-{5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl] 2-fluorobenzyl}acetamide; N-{5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroiso Oxazol-3-yl]-2-fluorobenzyl}cyclopropanecarbamide; N-{5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl -4,5-dihydroisoxazol-3-yl]-2-fluorobenzyl}-3,3-difluorocyclobutanecarbamamine N-{2-chloro-5-[5-(3 ,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroiso N-oxazol-3-yl]benzyl}acetamidamine; N-{2_chloro-5_[5-(3,4,5·trichlorophenyl)-5-(trifluoromethyl)-4,5 -dihydroisoxazole-3-yl]benzyl}cyclopropanecarbamide; N-{2-chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoro Methyl)-4,5-dihydroisoxazol-3-yl]benzyl}-2-methylpropanoxime; N-{2-chloro-5-[5-(3,5-dichloro- 4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}acetamidamine; -13- 201201802 N-(2-bromo-5 (5-(3,4,5-Trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzyl)acetamide, N-cyclopropane Methyl-N'-{2-fluoro-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazole-3 -yl]-benzyl}-propanediamine; and N-ethyl-N'-{2-fluoro-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoro Methyl-4,5-dihydro-isoxazol-3-yl]-benzyl}-propanediamine, or a veterinary acceptable salt thereof. In still another aspect of the invention, the compound of formula (1) comprises: N-{5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5- Dihydroisoxazol-3-yl]-2-fluorobenzyl}acetamidamine; N-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(three Fluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}-2-methylpropanamide; N-{2-fluoro-5-[5-(3,4,5- Trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}cyclopropanecarbamide; N-{2-fluoro-5-[5- (3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}cyclobutanecarbamamine; N-{2 -fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}propanamine 2-cyclopropyl-N-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole -3-yl]benzyl}acetamidamine; N-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5- Dihydroisoxazol-3-yl]benzyl}-3-methylbutane decylamine; N-{5-[5-(3,5-dichloro-4-fluorophenyl)-5-(three Fluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-fluorobenzyl}acetamide:

S -14- 201201802 N-{2-Chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3 _yl]benzyl}acetamide; N-{2-chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro Isoxazol-3-yl]benzyl}cyclopropanecarbamide; N-{2-chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl) -4,5-dihydroisoxazol-3-yl]benzyl}-2-methylpropanamine; N-{2-chloro-5-[5-(3,5-dichloro-4-fluoro Phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}acetamidamine; and N-(2-bromo-5-(5-(3, 4,5-Trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzyl)acetamide, or a veterinary acceptable salt thereof. In still another aspect of the invention, the compound of formula (1) comprises: N-{5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5- Dihydroisoxazol-3-yl]-2-fluorobenzyl}acetamidamine; N-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(three Fluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}-2-methylpropanamide; N-{2-fluoro-5-[5-(3,4,5- Trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}cyclopropanecarbamide; N-{2-fluoro-5-[5- (3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}cyclobutanecarbamamine; N-{2 -fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}propanamide ; N-{5-[5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2- Fluorobenzyl}acetamide; N-{2-chloro-5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5--15 - 201201802 Dihydroisoxazol-3-yl]benzyl}acetamidamine; and N-(2-bromo-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoro) Methyl)-4,5-dihydroiso Dfoxazol-3-yl)benzyl)acetamide, or a veterinary acceptable salt thereof. Another embodiment of the invention is a veterinary composition comprising a) a compound of formula (1), or a veterinary acceptable salt thereof, and (b) a veterinary acceptable excipient, diluent or carrier Agent. Preferably, the composition comprises a therapeutically effective amount of a compound of formula (1), or a veterinary acceptable salt thereof, and a veterinary acceptable excipient, diluent or carrier. The composition can comprise at least one additional veterinary agent. Preferred additional veterinary agents include endoparasites, endectocides, ectoparasites, insecticides, and insect repellents. Still another aspect of the invention is the use of a compound of formula (1) for the manufacture of a medicament. Still another aspect of the present invention is the use of the composition for treating a parasitic infection or invasion of an animal or a bird, comprising administering a therapeutically effective amount of a compound of the present invention or an animal or a bird thereof, or a bird thereof, or a bird thereof The step of veterinary acceptable salt. The compound of formula (1), or a veterinary acceptable salt thereof, or a composition thereof can be administered orally, topically or subcutaneously. More preferably, the compositions can be administered orally or topically. Still another aspect of the invention is the use of the composition for the treatment of a parasitic infection or invasion of an animal or bird comprising administering a therapeutically effective amount of a compound of the invention or a veterinarian thereof to an animal or bird in need of such treatment The step of accepting a salt in combination with at least one additional veterinary agent. The compound of formula (1), or a veterinary acceptable salt thereof, may be used alone or in combination with an additional veterinary agent.

S -16- 201201802 or its composition is administered orally, topically and subcutaneously. In particular, animal departments include companion animals and livestock. More specifically, companion animals include cats, dogs, and horses. More specifically, companion animals include dogs and cats. The most specific companion animal is a dog. Clear livestock include cattle, pigs, sheep, goats and bison; more specifically, livestock include cattle, pigs and sheep. Most specifically, livestock are cattle and sheep. To be clear, birds are poultry. More specifically, poultry include chickens, turkeys, ducks and geese, and the most clear poultry is turkey and chicken. The compounds of the invention, alone or in combination with additional veterinary agents, can be administered in the form of: (a) a single veterinary composition comprising a compound of the invention or a veterinary acceptable salt thereof, and optionally at least one as described herein. An additional veterinary agent and a veterinary acceptable excipient, diluent or carrier; or (b) two individual veterinary compositions comprising (i) a first composition comprising a compound of the invention or a veterinarian thereof An acceptable salt and veterinary acceptable excipient, diluent or carrier, and (second) second composition comprising at least one additional veterinary agent as described herein and a veterinary acceptable Forming agent, diluent or carrier. The veterinary composition can be administered simultaneously or sequentially and in any order. The WO patent publications and JP patent applications listed herein are hereby incorporated by reference. For the avoidance of doubt, it should be understood that throughout the application, all references to veterinary acceptable compounds and salts thereof include pharmaceutically acceptable compounds and salts thereof or agriculturally acceptable compounds and salts thereof. In addition, it should be understood that all references to veterinary activity in the entire application include pharmacy • 17- 201201802 Activity or pesticide activity. DEFINITIONS For the purposes of the present invention 'As described and claimed herein, the following terms and phrases are defined as follows: "Additional Veterinary Agent (etc.)" or "Veterinary Agent (etc.)" as used in the present invention unless otherwise Does not mean 'otherwise refers to other veterinary compounds or products' that provide a therapeutically effective amount of the agent, as described herein, can be used to treat parasitic infections or invasions of animals and birds. "Alkoxy" is used in the present invention. Unless otherwise stated, it is intended to mean an oxygen radical of another alkyl substituent. The alkyl moiety of the alkoxy group (ie, the 'alkyl radical') has the same definition as follows. Examples of non-limiting alkoxy groups include: - 〇ch3, -OCH2CH3 and the like. The halo moiety of the alkoxy group has the same definition as the following. Non-limiting examples of haloalkoxy groups include: -OCH2F, -OCHF2, -OCF3, -0CF2C13 and the like "Alkyl" When used in the present invention, unless otherwise stated, includes a saturated monovalent hydrocarbon alkyl group having the formula CnH2n + 1. The alkyl group may be a straight or branched chain and may be Substituted or substituted. For example, the term "CQ-C3 alkyl" or "C^-Cs alkyl" means a monovalent, straight or branched chain ester containing from 0 to 3 or from 1 to 8 carbon atoms. Family group. Non-exclusive examples of C^-Cs alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, t-butyl, t-butyl, n-propyl, n-butyl, isobutyl , second butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3·methylbutyl

S -18- 201201802 benzyl, neopentyl, 3,3-dimethylpropyl, 2-methylpentyl, 2,2-dimethylpentyl, hexyl, 3-ethylhexyl, heptyl, 4 - ethylheptyl, octyl and the like. An alkyl group co-presented with another term (eg, alkylcycloalkyl (ie, -ch 2 cyclopentyl (methylcyclopentyl)' -CH 2 cyclobutyl, -(CH 2 ) 2 cyclopropyl (ethyl) a cyclopropyl group and the like. The alkyl group, the cycloalkyl group and the alkylcycloalkyl group may be attached to a chemical atomic group by any carbon atom of the aliphatic chain. The alkyl group and the alkylcycloalkyl group may be optionally "Animal (etc.)" used in the present invention, unless otherwise stated, means an individual animal that is a member of a mammalian class. Non-exclusive examples of animals include companion animals and domestic animals. The invention of the invention " as used in the present invention, unless otherwise stated, means a compound of the formula (1), (ΙΑ), (IB), (1C) and (1D) or a veterinary acceptable salt thereof. "Cycloalkyl" as used in the present invention, unless otherwise stated, includes fully saturated or partially saturated carbocyclic alkyl groups, wherein the alkyl group is as defined above. Non-limiting examples of partially saturated cycloalkyl groups include : cyclopropene, cyclobutene, cycloheptene, cyclooctene, cycloheptane-1, 3-diene and the like. Preferred cycloalkyl is a 3- to 6-membered saturated monocyclic ring including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cycloalkyl group can be carbocyclic. Any carbon atom in the ring is attached to a chemical atomic group. The cycloalkyl group is optionally substituted with at least one substituent. "Poultry" as used in the present invention ' unless otherwise stated, means chicken, turkey, duck And goose 'especially chickens and turkeys, more particularly chickens. "Halogen" or "halo" used in the present invention, unless otherwise stated -19-201201802, means fluorine, chlorine, bromine or iodine Furthermore, when used in a combination of words such as "haloalkyl" or "haloalkoxy", the alkyl and alkoxy groups may be partially or completely substituted by a halogen atom, and the alkyl group and the alkoxy group may be used. Partially or completely substituted by a halogen atom, the halogen atoms may be the same or different, and the alkyl and alkoxy radicals have the same meaning as defined above and may be attached to the chemical atomic group by any carbon atom of the aliphatic chain. Examples of "haloalkyl" include F3c-, C1CH2-, cf3ch2-, and cf3cci2- and such The term "haloalkoxy" is as defined in the term "haloalkyl". Examples of "haloalkoxy" include cf3o-, CC13CH20-, hcf2ch2ch2o-, and CF3CH20-, CF2C1CH20- and "Het" or "heteroaryl" as used in the present invention, unless otherwise stated, means an aromatic monocyclic ring containing one or more heteroatoms independently selected from N, S or fluorene. The ring, preferably one to four nitrogen heteroatoms, and optionally one oxygen or sulfur heteroatom. Non-exclusive examples of monocyclic rings include pyrrolyl, pyrazolyl, oxazolyl, pyridyl, triazolyl, tetrazolyl, indolyl, pyrimidinyl and the like. Hetyl can be used in the ring. A carbon atom or a hetero atom is attached to a chemical atomic group. The Het is optionally substituted 〇 "insect (etc.)" when used in the present invention, unless otherwise stated, means a bite type, a chewing type or a bloodsucking type insect. Non-exclusive examples include biting flies (e.g., flies, horn flies, black flies, bovine flies, and horse flies), ticks, ticks, ticks, and the like. "Parasites (etc.)" as used in the present invention, unless otherwise stated, means endoparasites and ectoparasites. Endoparasites are life.

S -20- 201201802 Parasites in their hosts, including worms (eg, trematodes, barges, and nematodes) and protozoa. The ectoparasite is an organism of the phylum of the phylum of animals (nodules and insects) fed through the skin of the host or on the skin. Preferred branching animals are the order of the eye, such as ticks and mites. "Therapeutically effective amount" as used in the present invention, unless otherwise stated, means that the compound of the invention (i) treats or prevents a particular parasitic infection or invasion, (减弱) attenuates, ameliorates or eliminates a particular parasitic infection or One or more symptoms of invasion, or (Hi) prevention or delay in the onset of one or more symptoms of a particular parasitic infection or invasion described herein. "Treatment, treating, and the like when used in the present invention Unless otherwise stated, it is meant to reverse, alleviate or inhibit the parasitic infection, invasion or condition. When used in the present invention, these terms also encompass (depending on the condition of the animal) preventing or controlling the onset of a condition or condition or a condition associated with the condition or condition, including reducing the condition or condition prior to suffering from the infection or invasion. Or the severity of the symptoms associated with it. Thus, treatment can mean administration of a compound of the invention to an animal that is not at the time of administration and is suffering from infection or invasion. Disposal also covers the prevention of infection or invasion or recurrence of the syndrome associated with it, and the “control” is also the allegation (eg, killing, repelling, repelling, incapacity, stopping, eliminating, soothing, minimizing and eradicating) . "Veterinologically or pharmaceutically acceptable" as used in the present invention, unless otherwise stated, means that the substance or composition must be chemically and with the formulation, other components of the composition, and/or the animal to be treated. / or toxic compatible. -21-201201802 [Embodiment] The present invention provides a compound of formula (1), or a veterinary acceptable salt thereof, together with a veterinary composition, which can be used as an anti-parasitic agent for animals and birds, especially as an ectoparasite Compound of the agent. The compounds of the invention may also be synthesized by synthetic routes including methods well known in the chemical arts, especially as described herein. The starting materials are typically prepared from commercially available sources such as Aldrich Chemicals (Milwaukee, Wis.) or readily prepared by methods well known to those skilled in the art (e.g., as generally described in Louis F. Fieser and Mary Fieser, "Reagents For Organic Synthesis", 1; 19, Wiley, New York (1967, 1999 ed.) or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including the supplement (also via Beilstein online) Method in the library)). The compounds of the invention may exist as one or more stereoisomers. Various stereoisomers include mirror image isomers, non-image isomers, and atropisomers. Included within the scope of the invention are all stereoisomers, such as mirror image isomers and non-image isomers, all geometric isomers and tautomeric forms of the compounds of formula (I), including exhibiting more than one type of isomerization. a compound, and a mixture of one or more thereof. The compounds of the invention may exist in the form of a mixture of stereoisomers, individual stereoisomeric forms or optically active forms. For example, the two possible mirror image isomers of Formula 1 are described as Formula 1 al and Formula 1 bbl' includes the isoxazoline-to-palm center as indicated by an asterisk (*). Those skilled in the art will recognize that one of the stereoisomers may be more active and/or

S • 22- 201201802 exhibits an advantageous effect when enriched with respect to another stereoisomer or when separated from another stereoisomer. Techniques for the preparation/isolation of individual mirror image isomers include chiral synthesis starting from a suitable optically pure precursor, stereoselective synthesis starting from the original palm precursor, or using, for example, fractional crystallization or palm The racemate (or the racemate of the salt or derivative) is isolated by high pressure liquid chromatography (HPLC). See "Enantiomers, Racemates and Resolutions" by Wiley, NY, 1981 J. Jacques and A. Collet: and "Handbook of Chiral Chemicals" chapter 8, Eds D. Ager and M. D ekker, ISBN: 0-8 247- 1058-4. Geometric isomers can be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization. Or a racemate (or a racemate precursor) which may be an acid or a base such as tartaric acid or 1-benzene with a suitable optically active compound (for example, an alcohol ' or if the compound of formula (I) contains an acidic or basic atomic group' Glycolamine) reaction. The non-image-isomerized mixture formed can be separated by chromatography and/or fractional crystallization, and one or both of the non-image isomers can be converted to the corresponding pure mirror image isomers in a manner well known to those skilled in the art. .

23-201201802 For purposes of illustration, the following reaction schemes illustrate possible pathways for the synthesis of key intermediates and compounds of the invention. The individual reaction steps are described in more detail in the Examples section below. Those skilled in the art will recognize that other suitable starting materials, reagents, and synthetic routes can be used to synthesize the intermediates and the compounds of the present invention and their various derivatives. Further, many of the compounds prepared by the methods described below can be further modified according to the disclosure using conventional chemistry. Schemes 1 through 7 outline the general methods that can be used to prepare the compounds of the invention. However, it is to be understood that the invention as described in detail herein and as set forth in the appended claims In the following schemes and examples, the following catalyst/reactant systems include: N,N-dimethylformamide (DMF); N-bromo-succinimide (NBS); N-chloro-amber Amine (NCS); acetonitrile (CAN), ethyl acetate (EtoAc), tetrahydrofuran (THF); triphenylphosphine (PPh3); Des Martin Sodium Periodane (DMP); n-Butyllithium (n-BuLi); Methyl hydrazine (DMSO); triethylamine (TEA or NEt3); ethyl acetate (EtOAc); bis(triphenylphosphine)palladium chloride (Pd(PPh3)2Cl2), obtained from Strem; , N, N', N'-tetramethyl-hydrazine-(7-azabenzotriazol-1-yl)urea (HATU), available from Aldrich; bis(1,5-cyclooctadiene) Di-mu-methoxy indium (I) (Ir[C0D]) 2), available from Aldrich; 4,4,4,,4,,5,5,5,,5,-octamethyl [2, 2'-linked-1,3,2-oxo-boron] (B2pin2), available from Aldrich; 4,4'-di-t-butyl-2,2'-bi-pyrene ratio (dtbpy ) from Aldrich; N-hydroxybenzotriazole (H0BT) from Aldrich, di-t-butyl dicarbonate (B0C20) 'from Aldrich, 1-ethyl-3-(3-dimethylamine) Dipropyl) carbodiimide hydrochloride (EDC) from Aldrich, dimethyl acetamide DMA) 'trifluoroacetic acid (TFA) and diphenylphosphoryl azide (DPPA).

S -24- 201201802 Flowchart 1

Rla, Rlb, Rle, R2 and η are as defined herein. In Scheme 1, the intermediate (1.2) compound can be prepared by reacting an intermediate (1.1) compound with a guanidine-hydroxyamine in the presence of a base such as sodium acetate in a solvent such as ethanol. The chlorination of the intermediate (1.2) compound can be carried out in a solvent such as DMF at a temperature between about and 50 ° C with hydrazine-chlorosuccinimide (NCS) to provide the intermediate (1.3). The intermediate (1.3) compound and the intermediate (1.4) compound are reacted in a base such as sodium hydrogencarbonate such as ethyl acetate, THF or DMF to give an intermediate (I.5) compound. Deprotection of the intermediate (1.5) compound can be carried out using standard conditions (e.g., using TFA in dichloromethane) to yield intermediate (1.6) compound -25 - 201201802. The compound of the formula (1) can be produced by reacting a compound of the intermediate (1.6) with mercapto chloride in the presence of a base such as triethylamine or pyridine in a solvent such as dichloromethane or DMF. The compound of formula (1) can also be obtained by the intermediate compound (1.6) with a carboxylic acid in a suitable peptide coupling agent such as EDC, dicyclohexylcarbodiimide (DCC), HBTU, HATU or N, N'- The reaction is carried out in the presence of isopropyl carbodiimide (DIC) to produce a compound of formula (1). Further, the compound of the formula (1) can also be produced by reacting a compound of the intermediate (1.6) with a carboxylic acid anhydride in an aprotic solvent such as THF, dichloromethane or DMF. Flowchart 2A/B ΠΜ 2A V 2 Sweeping or ΤΗΡ

Rla, Rlb and Rle are as defined herein. Scheme 2 depicts the synthesis of intermediate compound 1.4. The necessary organic borate can be prepared as boric acid from the literature method (Org. Lett. 2007, 9, 761-764).

S 201201802 Ester intermediate (2B.2) form or a boronic acid (2A.1) form such as 3,5-dichloroboric acid from Aldrich is commercially available from Aldrich. The intermediate 2Α.1 or 2Β.2 compound can be added to dioxane or THF and water, followed by 2-bromo-3,3,3-trifluoropropene' potassium carbonate and bis(triphenylphosphine)palladium chloride. An intermediate (1.4) compound is produced.

R2 and η are as defined above. The compound of formula (1.1) can be obtained by the method shown in Scheme 3. Intermediate (3.1) compounds are commercially available from commercial sources. The intermediate (3.1) compound is treated with NBS and a catalytic amount of benzamidine peroxide in a solvent such as CC14 to produce the intermediate (3.2) compound. Treatment of the intermediate (3.2) compound with sodium azide in a solvent such as DMSO produces an intermediate (3.3) compound. The intermediate (3.4) compound can be prepared by treating the intermediate (3.3) compound with triphenylphosphine and water in a solvent such as THF. Alternatively, the intermediate (3.4) compound can be prepared by reduction of the intermediate 0.3) compound with hydrogen in the presence of a catalyst such as palladium on carbon in a suitable solvent such as ethanol, -27-201201802. The intermediate (3.5) compound can be prepared by reacting a compound of the intermediate (3.4) with a Boc-anhydride in the presence of one or more equivalents of a base such as triethylamine in a suitable solvent such as dichloromethane. . The compound of the formula (1.1) can be used in the presence of carbon monoxide and sodium formate in a solvent system (such as DMF) at 80 ° C to 100 ° by using an intermediate (3.5) compound and a catalyst such as dichlorobis(triphenylphosphine)palladium in the presence of carbon monoxide and sodium formate. The reaction is carried out at an elevated temperature of C, as described in U.S. Patent Application Serial No. US 2004/0 1 3 827. The intermediate (3.5) compound can also be obtained by quenching with DMF after treating the intermediate (3.4) compound with two or more equivalents of alkyllithium. The reaction is carried out at a low temperature (-78 ° C) in a solvent such as THF. Flow chart 4

R2 and η are as defined above. The intermediate compound of formula (3.3) can also be prepared as shown in Scheme 4. Commercially available benzoates can be reacted with a hydride reducing agent such as lithium borohydride to produce a compound of formula (4.2). The compound of the formula (3-3) can be obtained by reacting a compound of the formula (4-2) with diphenyl azide or by a hydroxyl group to form a leaving group (for example, mesylate 'C1 or Br) and replacing it with sodium azide. preparation.

S -28- 201201802 Flowchart 5

R2 and η are as defined above. Compounds of formula (1.1) can also be prepared from commercially available (5.1) compounds as shown in Scheme 5. The compound of the formula (5-2) can be prepared by reacting (5.1) with hydrazine-bromosuccinimide (NBS) in the presence of a catalytic amount of benzamidine peroxide in an organic solvent such as chloroform or carbon tetrachloride. . The compound of the formula (5.3) can be obtained by treating (5.2) with a quantity of sodium azide in a solvent such as DM SO at a temperature not exceeding 50 °C. Compounds of formula (5.4) can be prepared by treatment with triphenylphosphine and water (5.3) in a solvent such as THF. Or a compound of the formula (5.4) can be produced by reducing a compound of the formula (5.3) with hydrogen in a solvent such as ethanol in the presence of a catalyst such as palladium on carbon. The compound of the formula (5 5) can be produced by treating (5.4) di-tert-butyl dicarbonate in the presence of a base (-29-201201802 such as triethylamine) in a solvent such as dichloromethane. The compound of the formula (5.6) can be produced by reacting (5.5) with a hydride reducing agent such as lithium borohydride in a double solvent system of THE and methanol. The compound of formula (1.1) can be obtained by (5.6) with Dess Martin Sauerane (1,1,1-triethoxymethoxy-1,1-dihydro-1,2-phenyliodonium (benziodoxol)-3 (lH)-ketone) is prepared by oxidation. Flow chart 6

R2 and η are as defined herein. Compounds of formula (3-5) can also be prepared from the corresponding commercially available nitriles, as described in Tetrahedron 59, 5417, (2003) and Biorganic and Medicinal Chemistry Letters, 18, 2362, (2 008), via single pot reduction - Prepared by a protection strategy. Flow chart 7

R2 and η are as defined herein. A compound of formula 6-1 can be substituted via an atom as shown in flow chart 7 (such as

Prepared by S-30-201201802 Fluoride (Tetrahedron Letters, 50(12), 1 286-1289, (2009)). Those skilled in the art will recognize that in certain instances, after introduction of a particular reagent as described in the schemes, it may be necessary to perform additional synthetic steps not described in detail to accomplish the synthesis of the compound of formula (1). Those skilled in the art will also recognize that the compounds of formula (1) and the intermediates described herein can be subjected to various electrophilic, nucleophilic, free radical, organometallic, oxidative, and reducing reactions to add substituents or to modify existing substituents. Veterinarily acceptable salts of the compounds of formula (1), (ΙΑ), (IB), (1C) or (1D) include the acid addition salts and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, hydrogen sulfate/sulfate, borate, camphorsulfonate, citrate, ethanedisulfonate Acid salt, ethanesulfonate, formate, fumarate, glucoheptonate, glutamate, glucuronate, hexafluorophosphate, hydroxybenzophenone, hydrochloric acid Salt/chloride 'hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, laurate, malate, maleate, malonate , mesylate, methyl sulfate, naphthoate, 2-naphthalene sulfonate, nicotinic acid salt, nitrate, orotate, oxalate, palmitate, hydroxynaphate, phosphoric acid Salt/hydrogen phosphate/dihydrogen phosphate, sugar acid salt, stearate, succinate, tartrate, tosylate and trifluoroacetate. Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine 'benzyl ethylenediamine, calcium, choline, diethylamine, glycolamine, glycine, lysine 'magnesium' meglumine, alcohol amine, potassium, sodium, Tromethamine and zinc salts. Veterinary addition compounds of the formula (1), (1A), (1B), (1C), (1D) can be prepared by conventional methods. For example, the free base solution can be treated with a suitable acid (either neat or in a suitable solvent), and the salt formed can be isolated by filtration or by evaporation of the solvent under reduced pressure. For comments on suitable salts, see "Handbook of Pharmaceutical" Salts: Properties, Selection, and Use" by Stahl and W ermu th (Wi 1 ey-V CH, Weinheim, Germany, 2 002) 化合物 The compounds of the invention may exist in both unfused and solvated forms. The term 'lysate' is used herein to describe a molecular complex comprising a compound of the invention and one or more veterinary acceptable solvent molecules (e.g., ethanol). The term 'hydrate' is used when the solvent is water. The veterinary acceptable solvent system of the present invention includes a solvent in which the crystallization solvent can be isotopically substituted, for example, D^O, d$- ing, de-DMSO. In the following and throughout the application, all references to compounds of formula (1), (ΙΑ), (1Β), (1C), (ID) include the faults of their salts, solvates and complexes and their salts. Compound. As stated previously, the invention encompasses all polymorphic forms of all of the compounds of formula (1), (1A), (1 B), (1 C), (1 D) as defined herein. The present invention encompasses all veterinary acceptable isotopically labeled compounds of formula (1) wherein one or more atoms are replaced by an atom having the same atomic order but an atomic mass or mass number different from the atomic mass or mass number generally found in nature. Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen such as 2H and 3H' carbons such as ^C, 13c and 14c, chlorine, such as 36C1, fluorine, such as 18f, iodine, such as 1231 and |251 'nitrogen,

S -32- 201201802 such as 13n and I5N ' oxygen, such as l5o, 17〇 and 18〇 and sulfur, such as 35s. It will be understood by those skilled in the art that the compounds of the present invention can be prepared by methods other than those described in the context of the present invention by adjusting the methods of the present invention and/or methods known in the art, such as the present invention. The industry of technology, or use standard textbooks such as "Comprehensive Organic Transformations-A Guide to Functional Group Transformations" ' RC Larock, Wiley-VCH (1 999 or newer). The compound of formula (i) may be used as an ectoparasite. Thus, another embodiment of the invention is a veterinary composition comprising a therapeutically effective amount of a compound of formula (1), or a veterinary acceptable salt thereof, and A veterinary acceptable excipient, diluent or carrier. The compounds of the invention, including the compositions and methods used therein, can also be used in the manufacture of a medicament for use in the therapeutic applications described herein. A typical formulation is prepared by mixing a compound of formula (1) with a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include, for example, sugars, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents , water and the like. The particular carrier, diluent or excipient used will depend on the mode and purpose of the compound of the invention. Solvents are generally selected based on solvents known to those skilled in the art to be safe for the animal to be administered. The formulation may also include one or more buffering agents, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opaque agents, glidants, processing aids. , Colorants, Sweeteners - 33 - 201201802 Agents, perfumes, flavorings, and other known additives to provide an elegant appearance (ie, a compound of the invention or a veterinary composition thereof) or to aid in the manufacture of a veterinary product (ie, a pharmaceutical). Formulations can be prepared using conventional dissolution and mixing methods. Such compositions and methods for their preparation can be found, for example, in 'Remington's Veterinary Sciences,, 19th Edition (Mack Publishing Company, 1995; and H. Lieberman, "Veterinary Dosage Forms: Tablets, Vol. 1" and L. Lachman, Marcel Dekker, NY, 1980 (ISBN 0-8247-69 1 8-X). For example, a monolithic drug substance (ie, a compound of the invention or a stabilized form of the compound (eg, having a cyclodextrin derivative or other known intermixing agent) The complex of the compound) is dissolved in a suitable solvent in the presence of one or more other excipients. The compounds of the invention are generally formulated in a veterinary dosage form to provide an easily controllable dosage form for administration. Formulated in a formulation suitable for the particular use envisioned, the host animal being treated, and the particular species of the bird and the associated parasite. Typically, it is administered with one or more veterinary acceptable excipients, diluents or carriers. The agent is administered in combination as a formulation. The terms "excipient", "diluent" or "carrier" are used herein to describe a compound or formula other than formula (1). In addition to any component other than the anti-parasitic agent, the choice of excipient, diluent or carrier depends to a considerable extent on factors such as the particular mode of administration, excipient, carrier or diluent to solubility and stability. The effects and the nature of the dosage form. The methods by which the compounds of the invention may be administered include oral, topical and subcutaneous administration. The present invention contemplates administration of the composition monthly.

S -34- 201201802 The compound of the formula (1) can be used in the form of a capsule, a drug, a lozenge, a powder, a buccal tablet, a chewable tablet, a multiple nanoparticle, a gel, a solid solution, a film, a spray or a liquid. Oral administration. This is a preferred method of administration and it is desirable to develop active compounds of formula (1) which are particularly suitable for such formulations. The formulations may be used as a dip in soft or hard capsules, and the formulation will generally comprise a carrier such as water, ethanol, polyethylene glycol, N-methylpyrrolidone, propylene glycol, methylcellulose or suitable Oil and one or more emulsifiers and/or suspending agents. Liquid forms include suspensions, solutions, syrups, feedings and elixirs. Liquid formulations can also be prepared by reconstitution as a solid (e.g., from a pocket). Oral feeding is generally prepared by dissolving or suspending the active ingredient in a suitable medium. This is a preferred method of administration and it is desirable to develop an active compound of formula (1) which is particularly suitable for such formulations. The oral formulation may comprise from about 0.5 mg/kg to about 50 mg/kg of the compound of formula (1), preferably from about 1 mg/kg to about 30 mg/kg of the compound of formula (1). The compound can be administered topically to the skin or mucosa, i.e., administered to the skin or transdermally. This is a preferred method of administration and it is desirable to develop a compound of formula (1) which is particularly suitable for such formulations (e.g., in liquid form). Typical formulations used for this purpose include topping, spotting, multi-focusing, stripe-on, combing (C〇mb-〇n), rolling on the surface, dipping, spraying, Mousse, shampoo, powder formulation 'gel, hydrogel, lotion, solution, cream, ointment, dusting, dressing, foam, film, skin dressing, sheet, implant, sponge ', fiber, bandages and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, liquid petroleum, ash oil, glycine, N-methylformamide, glycol monomethyl ether, polyethylene glycol, propylene glycol, and -35-201201802. By. Penetration enhancers can be incorporated, see, for example, J Pharm Sci, 8 8 (10), 955-958 by Finnin and Morgan (October 1999). Pour or pour the formulation by arbitrarily adding a volatile component such as propan-2-ol by dissolving the active ingredient in an acceptable liquid carrier such as diethylene glycol butyl ether, liquid paraffin or a non-volatile ester. Or prepared by glycol ether. Alternatively, the topping, spotting or spraying of the formulation can be prepared by encapsulation, leaving a residue of the active agent on the surface of the animal, which effect confirms that the compound of formula (1) has a longer persistence and is more durable, for example, It may have a higher water fastness. The topical formulations contemplated by the present invention may comprise from about 0.5 mg/kg to about 50 mg/kg of the compound of formula (1), preferably from about 1 mg/kg to about 10 mg/kg of the compound of formula (1). The compounds of the invention may also be via a support matrix such as a synthetic or natural resin, plastic, cloth, leather or other such polymer system in the shape of a collar or ear tag. The collar or ear tag can be coated, impregnated, layered in any manner to provide an acceptable amount of the compound of the invention itself, or a veterinary acceptable excipient, diluent or carrier. And optionally additional veterinary agents or veterinary acceptable salts thereof. The composition suitable for the application of the present invention can be prepared by a conventional mixing method. The volume of the applied composition is from about 0.5 mL/kg to 5 mL/kg and preferably from about 1 mL/kg to 3 mL/kg. An agent may be added to the formulation of the invention to improve the surface durability of the formulation to the animal to which the formulation is applied, e.g., to improve its durability on animal coatings. The means for attaching or arranging the formulation include the agents. Examples of such agents include acrylic copolymers, especially fluorinated acrylic copolymers. Particularly suitable reagents are registered trademarks

S-36-201201802 Reagent "Foraperle" (Redline Products Inc, Texas, USA) Specific topical formulations may include unsuitable additives to minimize oral exposure " Subcutaneous injectable formulations may be prepared as sterile In the form of a solution, it may contain other substances, such as a salt or glucose sufficient to make the solution isotonic with blood. Acceptable liquid carriers include vegetable oils such as sesame oil, glycerides such as triacetin, esters such as benzoates, isopropyl myristate and fatty acid derivatives of propylene glycol, together with organic solvents such as pyrrolidine-2 Ketones and glycerol formals, which are prepared by dissolving or suspending the compound of the invention, alone or in combination with an additional veterinary agent, in a liquid carrier such that the final formulation contains from about 0.01% to about 10% by weight of active ingredient. Devices suitable for subcutaneous administration include needle (including microneedle) syringes, needleless syringes, and infusion techniques. The subcutaneous formulation is typically an aqueous solution, which may contain excipients such as salts, sugars, and buffers (preferably at a pH of from 3 to 9), but may be more suitable for formulation into a sterile non-aqueous solution or for some applications. Wait with the appropriate adjuvant 'such as sterile, non-pyrogenic water, together with the dry powder form used. Subcutaneous formulations can be prepared under sterile conditions, for example by lyophilization, using standard veterinary techniques well known to those skilled in the art. The compound of formula (1) used to prepare the subcutaneous solution can be increased by appropriate formulation techniques such as incorporation of a solubility enhancing agent. Such formulations are prepared in a conventional manner in accordance with standard pharmaceutical or veterinary practice. Further, 'these formulations will vary depending on the weight of the active compound contained therein' depending on the species of host animal to be treated, the severity and type of infection or invasion, and the weight of the animal. As described herein, the compounds of the invention may be administered alone or in combination with at least one additional veterinary agent (including insecticides, acaricides, insect repellents, fungicides, nematicides, antiprotozoa, bactericides, and growth regulators). To form a more versatile veterinary facility. Accordingly, the invention also relates to a composition comprising an effective amount of a compound of formula (1) or a veterinary acceptable salt thereof, at least one additional veterinary agent, and further comprising one or more veterinary acceptable excipients, diluted Agent or carrier. The following additional veterinary agents can be used in conjunction with the compounds of the invention to illustrate possible combinations without any limitation. Non-limiting examples of additional veterinary agents include: amitraz, published W01998/24767 and WO2005/060749 listed as arylpyridinium, aminoacetonitrile, insect repellent (eg, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole) , octadepsipeptides, oxfendazole, oxibendazole, paraherquamide, parbendazole, piperazines, praziquantel, thiabendazole, tetramisole, triclabendazole, levamisole, pyrantel pamoate, oxantel, morantel, and the like), avermectin (eg, abamectin, doramectin, emamectin, Eprinomectin, ivermectin, moxidectin, selamectin and the like), DEET, demiditraz, diethylethylamine coumarin, fipronil, insect growth regulators (eg hydroprene, kinoprene, methoprene) And the like), metaflumizone, niclosamide, permethrin, pyrethrins, pyriproxyfen, spinosad and the like. In certain cases, the combination of a compound of formula (1) with an additional veterinary agent can produce greater than additive

The effect of S -38- 201201802. It is always desirable to reduce the amount of active ingredient released into the environment while also determining the effective control of pests. It may be desirable to administer the compound of the present invention alone or a veterinary acceptable salt thereof, or to use a composition comprising a veterinary acceptable excipient, diluent or carrier, for example, for the treatment of a particular parasitic infection or invasion, Or the status associated with it. Included within the scope of the invention are two or more veterinary compositions, at least one compound of formula (1) of the invention, and another additional veterinary agent, which can be readily combined in a kit suitable for co-administering the composition. The compounds of the invention, including the compositions and methods used therein, can also be used in the manufacture of a medicament for use in the therapeutic applications described herein. A compound of the present invention, or a veterinary acceptable salt thereof, and a composition comprising a therapeutically effective amount of a compound of formula (1) and a veterinary acceptable excipient, diluent or carrier can be used as an ectoparasite. To prevent and treat the infection or invasion exhibited by the ectoparasite in an animal or bird. The compounds of the invention have utility as ectoparasites, especially as acaricides and insecticides. It can be used, inter alia, in the fields of veterinary medicine, livestock breeding and maintaining public health: against mites and insects that are parasitic on vertebrates, especially warm-blooded vertebrates, including companion animals, livestock and birds. Insects and insect parasites include: niches (eg, Ixodes spp., Rhipicephalus spp. 'Boophilus spp.'), Ambryomma spp., Hyaloma spp ·), (Haemaphysalis spp., Dermacentor spp., 〇rnithodorus spp. and the like), pots (eg, Dermanyssus spp., Sarcoptes spp.) Insect worm (psor〇ptes spp.), food skin-39- 201201802 locust (Chorioptes spp.), hairy worm (Demodex spp.) and the like); chewing type and blood-sucking worms (eg, Damalinia spp) ·, Linognathus spp. and the like; 蚤 (eg, Siphonaptera spp., Ctenocephalides spp., and the like); and biting flies and ticks (eg, Tabanidae spp., Haematobia spp., Stomoxys spp., Dermatobia spp., S imul iidae spp., Ceratopogonidae spp_, Psychodidae spp. and the like. Compounds of the invention and compounds comprising the invention together with at least one other The composition of veterinary medicaments is particularly valuable in the control of ectoparasites, endoparasites and insects (injury companion animals, livestock and birds or expansion or as a carrier of disease. Treatment with a combination of a compound of formula (1) and an additional veterinary agent can be used. The ectoparasites, insects, and endoparasites include those described above, and include worms of the scallops (eg, trematodes, worms, and worms) and nematodes (eg, nematodes). A suitable composition of the compound of the invention or a compound of the invention and at least one additional veterinary agent optionally used may be administered directly to the animal or bird and/or by application to the local environment in which the animal or bird resides (such as litter, protection) Indirect administration of a substance and the like. Direct administration includes contacting a skin, fur or feather of a medicated animal or bird with the compound or feeding or injecting the compound into the animal or bird. (1) a compound, or a veterinary acceptable salt thereof, and a composition thereof with at least one additional veterinary agent (such as the present invention) ) Has to dispose of and controlling insects and parasites of various life cycle stages of price Zhi, such stage

S -40- 201201802 Includes eggs, nymphs, larvae, infancy and adulthood. The invention also relates to a method of administering a compound of the invention, alone or in combination with at least one additional veterinary agent, arbitrarily administered veterinary acceptable excipient, diluent or carrier, to healthy animals and birds. It includes application to the animal or bird to reduce or eliminate the possibility of parasitic infection or invasion by humans due to parasites of the animal or bird, and to improve the environment in which the animal, bird and human inhabit. The reactions listed below are typically carried out under argon or nitrogen positive pressure or using a drying tube at ambient temperature (unless otherwise stated) in an anhydrous solvent. The reaction flask is provided with a rubber separator to introduce the substrate and reagents via a syringe. The glassware is dried and/or dried by heating. Analytical thin layer chromatography (TLC) was performed using a glass backed silica gel 60 F 254 pre-coated analytical plate and eluted in a suitable solvent ratio (v/v). The reaction was detected by TLC or LCMS and the reaction was terminated by the consumption of the starting material. The development of the TLC plate was carried out by UV light (254 nm wavelength) or developed with a suitable TLC developing solvent and completed by heat activation. Rapid column chromatography (Still et al, J. Org. Chem. 43, 2923, (1 978) is performed using tannin (RediSep Rf) or various MPLC systems, such as Biotage or ISCO purification systems. Known methods of use and/or separation and purification techniques are employed to isolate the compounds of the invention, together with various intermediates associated therewith. Such techniques are well known to those of ordinary skill and may include, for example, all types of chromatography (high pressure liquid layer Analytical (HPLC), column chromatography using conventional adsorbents such as silica gel and thin layer chromatography (TLC), recrystallization and differential (ie liquid-liquid) extraction techniques. -41- 201201802 Compound structure in the following examples It is determined by one or more of the following methods: mass spectrometry and mass spectrometry. The mass spectrometry (CH NMR) spectroscopy is determined using a Bruker spectrometer operating at a field intensity of 400 megahertz (MHz). The chemical shift is determined by the distance from the internal tetramethyl group. The fraction of parts per million (PPM ' δ) of the downfieid of the methotrex standard. Mass spectrometry (MS) data was obtained by chemical free radicalization using an Agilent mass spectrometer. Method: Acquity UPLC, chromatography was performed on a Waters BEH C18 column (2·1χ50 mm, 1.7 μm) at 50 ° 。. Binary gradient of mobile phase acetonitrile (containing 1% trifluoroacetic acid) and water (5_100%) The following examples are intended to illustrate the specific embodiments of the present invention. However, it is understood that the specific embodiments of the invention are not limited to the specific details of the embodiments, EXAMPLES The following examples are provided to provide a more detailed description of the process conditions. However, it is to be understood that the invention as fully described herein and as set forth in the appended claims , 3-trichloro-5-(1,1,1-trifluoroprop-2-en-2-yl)benzene:

S

-42· 201201802 Add 2·bromo-3,3,3- to a mixture of 25.0 g (131 mmol) of 3,4,5-trichlorobenzeneboronic acid (2A.1) in 200 mL of THF and 100 mL of water Trifluoropropene, potassium carbonate and bis(triphenylphosphine)palladium 11 ' were stirred and stirred overnight under reflux. The reaction mixture was partitioned between water and ethyl acetate. &lt;RTI ID=0.0&gt;&gt;&gt;&gt; The crude material was adsorbed onto silica gel and purified by column chromatography < 〇 10% acetone / heptane, 120 g cerium oxide. A colorless oil (5.35 g) of 4 4 NMR (CDC13) 5 5·85 (1 Η), 6·07 (1 Η), 7.48 (2 Η). Preparation 2 1,3-Dichloro-2- gas-5-(1,1,1-dioxoprop-2-yes-2-yl)-

2-Bromo-3,3,3-trifluoropropene (2.65 g, 15.1 mmol) and 2-(3,5-dichloro-4-fluorophenyl)-4,4,5,5-tetramethyl Add a solution of -1,3,2-dioxaborolane (2A.1) (4.4 g, 15.1 mmol) in 1,4-dioxane (60 mL), Na2CO3 (4.02 g, 38 mmol ) and water (20 mL). Next, bis(triphenylphosphine)palladium chloride (220 mg, 0.3 mmol) was added and the reaction mixture was heated to 80 ° C for 18 hours. The reaction mixture was cooled, filtered and concentrated under reduced pressure to remove diane. The residue was diluted with EtOAc (EtOAc m. The crude material was purified on silica gel eluting with 1% heptane to give the crude oil of the intermediate - 43- £ 201201802 (1.8 g, 47%). 4 NMR (CDC13): δ 7.43 (2H), 6.07 (1H), 5.82 (1H). Preparation 3 (5-Bromo-2-fluorobenzyl)carbamic acid tert-butyl ester:

Add a di-t-butyl dicarbonate solution to a solution of 1-(5-bromo-2-fluorophenyl) hydrochloride (10 g, 41_6 mmol) in dichloromethane (100 mL). g, 41.6 mmol) followed by the addition of triethylamine (8.4 g, 83.2 mmol). The solution was stirred at 0 ° C for 30 minutes and then at room temperature for 2 hours. The reaction was washed with water (2×2 5 mL) and concentrated using rotary evaporation to yield crude crude oil. The product was purified on silica gel eluting with EtOAc EtOAc (12.51 g, 41.6 mmol, 99%) (4 NMR (CDC13) 5 ppm: 7.46 (1H), 7.40 (1H), 6.92 (1H), 4.90 (1H), 4.30 (1 Η), 1 · 48 (9 Η) Preparation Example 4 (2-Fluoro-5-methylbenzylidenebenzyl)carbamic acid terpene vinegar

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-44- 201201802 (5-Bromo-2-fluorobenzyl)carbamate (丨〇·2 g, 33·5 mmol) was dissolved in anhydrous THF (80 mL), and the solution was cooled in a dry ice acetone bath To -78 ° C. n-Butyllithium (n-BuLi) (44 mL, 1.6 M in hexanes, 70.3 mmol) was added dropwise via a funnel over 30 min while maintaining the reaction under nitrogen atmosphere. The solution was stirred for a further 10 minutes, then DMF (4.9 g, 68 mmol) was added and all added at once. The cold bath was removed and the reaction was allowed to equilibrate to room temperature over two hours. The reaction was cooled to 0.degree. C. and quenched with saturated aqueous ammonium chloride (50 mL). The layers were stirred together for 30 minutes and then allowed to separate. The organic phase was collected, dried over sodium sulfate and concentrated using EtOAc (EtOAc) EtOAc. The oil was subjected to flash column chromatography using a gradient of ethyl acetate in hexane to give the title compound as a viscous oil. (6.78 g, 80%) lH NMR (400 MHz 'CDC13) 5 ppm 1.48 (s, 9 H) 4.45 (d, J = 5.56 Hz, 2 H) 4.9 9 - 5.0 6 (br, 1 H) 7.1 7- 7.25(m, 1 H) 7.8 2 - 7.8 6 (m, 1 H) 7.92 (d, J = 5.05 Hz, 1 H) 9.97 (s, 1 H). Preparation 5 {2-Fluoro-5-[(E/Z)-(hydroxyimino)methyl]-benzyl}-carbamic acid tert-butyl ester:

-45- 201201802 Add a hydroxylamine hydrochloride (1.37) to a mixture of (2-fluoro-5-methylbenzylidenebenzyl)carbamic acid tert-butyl ester (1.0 g, 3·9 mmol) in ethanol (2 mL). g, 19.7 mmol) and sodium acetate (1.62 g, 19.7 mmol). The mixture was stirred at room temperature for four hours. The volatiles were removed by rotary evaporation at low pressure. Water (40 mL) was added to the flask to suspend the product. After the mixture was stirred for 30 minutes, a white solid was collected by suction, washed with water (2×20 mL), and dried to give the intermediate. 1H NMR (400 MHz, CDC13) 3 ppm 1.48 (s, 9 H) 4.40 (d, J = 5.05 Hz, 2 H) 4.9 3 - 5.0 2 (brs, 1 H) 7.04-7.09 (m, 1 H) 7.49 (br m, 1 H) 7.57 (dd, J = 7.20, 2.15 Hz, 1 H) 8.1 〇(s, 1 H). Preparation 6 {5-[5-(3,4,5-Trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-fluorobenzyl Tert-butyl carbamic acid:

To a solution of {2-fluoro-5-[(Ε/Ζ)-(hydroxyimino)methyl]benzyl}aminocarbamic acid terpene vinegar (Preparation 5, 250 mg, 0.826 mmols) in DMF (5 mL) N-chlorosuccinimide (115 mg, 0.858) was added to the solution and added in three equal portions over 30 minutes with about ten minutes between each addition. The reaction mixture was stirred for 12 hours under nitrogen. Add 1,2,3-trichloro-5-trifluoroprop-2-en-2-yl)benzene to the crude reaction mixture (Preparation Example 1,228 mg, 0.826)

S-46- 201201802 mmol) and solid sodium bicarbonate (300 mg). The mixture was stirred at room temperature for 24 hours. The reaction mixture was partitioned between water (10 mL) and EtOAc (40 mL). The organic phase was washed successively with water (3.times.5 mL), dried (Na.sub.2), and evaporated. The product was purified on EtOAc (EtOAc:EtOAc) m/z (CI) 443 [M + H] + (lost Boc group upon liberation). Preparation 7 1-{2-Fluoro-5-[5-(3,4,5-trichlorophenyl) -5-(Trifluoromethyl)- 4,5-dihydroisoxazol-3-yl]phenyl}methylamine hydrochloride:

For {5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-fluorobenzyl} -T-butyl carbamic acid (Preparation Example 6) TF A (3 mL) was added. The reaction was stirred overnight at room temperature. The volatiles were distilled off under reduced pressure. Several evaporation cycles were performed using acetonitrile (3 x 20 mL) to remove excess TFA. The crude residue was dissolved in EtOAc (40 mL)EtOAc. A white precipitate (HC1 salt) is formed. The mixture was subjected to impact resistance in a closed container for ninety minutes. The white solid was collected using suction filtration to give the title compound. m/z (CI) 443 [M + H]+. ( -47- 201201802 Preparation 8: 3·(2-Fluoro-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)·4,5-dihydroiso Ethyl oxazol-3-yl)benzylamino)_3-oxypropionic acid ethyl ester.

1-{2-Fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]phenyl }Methylamine hydrochloride (6 g, 13.6 mm 〇1) was dissolved in (6 〇 mL), placed under an inert atmosphere (N2) and cooled to hydrazine. (: The reaction mixture was treated with triethylamine (0.69 mL, 4.9 mmol) and ethylpropanedichloride (0.63 mL, 4.9 mm ο 1) dropwise. The reaction was warmed to room temperature and stirred for 1 hour. Purification by column chromatography, EtOAc (EtOAc)EtOAc (EtOAc (EtOAc) 8 2hs, 3.71 1 Hd, 4.10 1 Hd, 4.23 2Hq, 4.55 2Hd, 7.10-7.15 lHm, 7.45-7.52 lHm, 7.65-7.70 4Hm MH + 5 5 5. Preparation 9: 3-(2-Fluoro-5 -(5-(3,4,5-trichlorophenyl)-5.(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzylamino)-3-oxo Propionic acid. F39n

S-48- 201201802 l-{2-Fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoindole 哩- A slurry of 3-yl]phenyl}methanamine hydrochloride (4 g, 7.2 mmol) in EtOAc (EtOAc) The reaction mixture was concentrated to dryness <RTI ID=0.0> The organic extract was dried and concentrated to a white foam (3.7 g, 7.0 mmol, 97%) 4 NMR (CDC13) 3.39 2Hs, 3.70 1 Hd, 4.08 lHd, 4.54 2Hd 7.09-7.14 lHm, 7.38-7.41 lHm, 7.5 8-7.63 3Hm, 7.66-7.68 lHm. MH+ 527. Example 1 N-Ethyl-N'-{2-fluoro-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-iso Oxazol-3-yl]-benzyl}-propanediamine

Ethylamine (2.44 mm 〇l) was weighed into an 8 mL vial. Add 3-(2-fluoro-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzyl A solution of the aminoamino)-3-oxypropionic acid (〇·〇 82 mmol, 40 mg) in DMF 1 mL. Add ruthenium hexafluorophosphate-(7-azabenzotriazol-bu)-N,N,N',N'-tetramethylurea (0.09 mmol '34.2 mg) in DMF (1 mL) The solution was then added triethylamine (0.82 mmol '83 mg). The reaction mixture was shaken at room temperature for 72 hours. The reaction mixture was treated with MP-isocyanate resin (0.82 mmol, 560 mg, ~ 1.47 mmol/g) and MP-carbonic acid resin (0.82 mmol, 260 mg, ~3.14 mmol/g), -49-201201802 and shaken at room temperature 16 hours. The reaction was filtered and concentrated to give a crude material. The crude product was purified by preparative HPLC (Waters, Gemini NX C 1 8 2 1 x 1 00 mm 5 μιη, mobile phase A = 0.1% trifluoroacetic acid in H2O, mobile phase B = acetonitrile, linear gradient 30% in 8 minutes) B to 100%, held for 1 minute, 20 ml/min, spiked by mass collection) yielded the desired product 16.3 mg. 29% yield Μ H + [ 5 5 4]. Retention time 2 · 8 4 minutes (A gi 1 en t 1 200, column = Gemini NX C1 8 4.6x50 mm 3 μιη, mobile phase A = 0.1% trifluoroacetic acid in H20, mobile phase B = acetonitrile, at 5 Minute linear gradient 30% B to 100% for 1 minute, 1.5 ml/min). Example 2 N-cyclopropylmethyl-N'-{2-fluoro-5-[5-(3,4,5-trichloro-phenyl)- 5-trifluoromethyl-4,5-di Hydrogen-isoxazol-3-yl]-benzyl}-propanediamine

Cyclopropane methylamine (2.44 mmol) was weighed into an 8 mL vial ^ 3-(2-fluoro-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl) a solution of -4,5-dihydroisoxazol-3-yl)benzylamino)-3-oxypropanoic acid (0.082 mmol '40 mg) in DMF (1 mL) was added to the tube bottle. Add 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (0-09 mmol, 34.2 mg) in DMF (1 mL) The solution was then added triethylamine (0.82 mmol, 83 mg). The reaction mixture was shaken at room temperature for 72 hours. The reaction mixture was MP-isocyanate resin (0.82 mmol, 560 mg'~1.47)

Treatment with S 201201802 mmol/g) and hydrazine carbonate resin (0.82 mmol, 260 mg, ~3.14 mmol/g) and shaking at room temperature for 16 hours. The reaction was filtered and concentrated under reduced pressure to give a crude material. The crude product was purified by preparative HPLC (Waters, Gemini NX C18 21x100mm 5μιη, mobile phase A = 0.1% trifluoroacetic acid in H20, mobile phase B = acetonitrile, linear gradient 30% B to 100% in 8 minutes, keeping 1 Minutes, 20 ml/min, by spike of mass collection) yielded the desired product 23.4 mg. 40% yield, MH + [5 80]. The residence time is 3.09 minutes (Agilent 1200, column = Gemini NX (: 18 4.6 &gt;&lt; 5〇1111113卩111, mobile phase VIII = 0.1% trifluoroacetic acid in 1120, mobile phase B = acetonitrile, at 5 Minute linear gradient 30% B to 100% for 1 minute, 1.5 ml/min. Example 3: ^{5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl) ..-4,5-Dihydroisoxazol-3-yl]-2-fluorobenzyl}acetamidamine:

Method for the preparation of guanamine A to 2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole- A mixture of DMA (2 mL) of 3-yl]phenyl}methylamine hydrochloride (100 mg, 0.21 mmol) (Preparation 7) was added to a mixture of EtOAc (. 24 mg '0.3 1 mmol). The reaction was allowed to stir at room temperature for ten - 51 - 201201802 minutes, then water (25 mL) was added and the mixture was stirred at room temperature for one hour. The final product in the form of a white precipitate (95 mg, 94%) was collected by suction filtration. NMR (400 MHz, chloroform-d) d ppm 2.05 (s, 3 H) 3.69 (d, J = 17.18 Hz, 1 H) 4.09 (d, J = 17.18 Hz, 1 H) 4.50 (d, J = 6.06 Hz , 2 H) 5.90-6.00 (m, 1 H) 7.0 8 - 7 . 1 7 (m, 1 H) 7.6 2 - 7.7 0 (m , 4 H)m/z (CI) 483 [M + H]+ . Example 4: N-{2-Fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoindolizole-3 · benzyl]-2-methylpropanamide:

Method B for the preparation of decylamine for 1-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoindole Add isopropyl (36.4 mg, 0.28 mmol) to a solution of oxazol-3-yl]phenyl}methylamine hydrochloride (45 mg, 0.094 mmol) (Preparation 7) in DMA (2 mL) Propionic acid (12.5 mg, 0.14 mmol), EDC (23.4 mg, 0.12 mmol) and H0BT (1.2 mg, 0.009 mmol). The reaction was stirred at room temperature for 12 hours. The reaction mixture was partitioned between ethyl acetate (50 mL) and water (20 mL). The organic phase was washed with water (3 x 20 mL). The solvent was distilled to give the title compound (42 mg &lt;&lt;&gt;&gt;&lt;&gt;&gt;&gt;&gt;&gt;&lt;&gt;&gt;&gt; , J = 1 3.83, 6.85 Hz, 1 H) 3.68 (d, J = 17.18 Hz, 1 H) 4.08 (d, J = 17.18 Hz, 1 H) 4.51 (d, J = 6.06 Hz, 2 H) 5.89 ( Br.s·, 1 H)7.06-7.20(m, 1 H) 7.5 9 - 7.7 1 (m, 4 H) ; m/z (CI)5 1 1 [M + H]+. Example 5: N-{2-Fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoindole_3 _yl]benzyl}cyclopropanecarbamide:

From 1-(2-fluoro-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-

4.5-Dihydroisoxazol-3-yl)phenyl)methanamine (Preparation Example 7) was prepared by reaction with cyclopropylcarbonyl chloride according to Method A. 4 NMR (400 MHz, CDC13) 5 ppm 0.78-0.83 (m, 2 H) 1.00-1.04 (m, 2 H) 1.35-1.42 (m, 1 H) 3.69 (d, J = 17.43 Hz, 1 H) 4.08 (d, J = 17.18 Hz, 1 H) 4.53 (d, J = 6.32 Hz, 1 H) 6.05 (br.s., 1 H) 7.14 (t, J = 8.97 Hz, 1 H) 7.60-7.72 (m , 4 H) ; m/z (CI) 509 [M + H]+. Example 6: Ν·{2-Fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4.5-dihydroisoxazol-3-yl] Benzyl}cyclobutanecarbamide: -53- 201201802

From 1-(2-fluoro-5(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4.5-dihydroisoxazol-3-yl)phenyl Methylamine hydrochloride (Preparation Example 7) was prepared by reaction with cyclobutanecarbonyl chloride according to the method. 4 NMR (400 MHz, CDC13) 5 ppm 1.86-2.05 (m, 2 H) 2.1 3 - 2.2 4 (m, 2 H) 2.24 - 2.37 (m, 2 H) 2.97-3.09 (m, 1 H) 3.69 ( d, J=16.93 Hz, 1 H)4.09 (d, J=17.18 Hz, 1 H) 4.51 (d, J = 6.32 Hz, 2 H) 5.76 (br.s., 1 H) 7.9-7.17 (m, 1 H) 7.62-7.70 (m, 4 H) ; ) ; m/z (CI) 525 [M + H]+. Example 7: N-{2-Fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4.5-dihydroisoxazol-3-yl] Benzyl}propanamine:

From 1-(2-fluoro-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-s 4,5-dihydroisoxazol-3-yl Phenyl)methylamine hydrochloride was prepared by reaction with propional chloride according to Method A. 4 NMR (400 MHz, CDC13) 5 ppm 1.19 (t, J = 7.58 Hz, 3 H) 2.27 (q, J = 7.58 Hz, 2 H) 3.69 (d, J = 17.18 -54 - 201201802

Hz, 1 H)4.09 (d, J=17.18 Hz, 1 H) 4.51 (d, J = 6.32 Hz, 2 H) 5.87 (br.s., 1 H) 7.0 8 - 7.1 8 (m, 1 H) 7.6 1 - 7.7 2 (m, 4 H); m/z (CI) 497 [M + H]+. Example 8: 2-Cyclopropyl-N-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydrogen Isoxazol-3-yl]benzyl}acetamide:

From 1-(2-fluoro-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4.5-dihydroisoxazol-3-yl)phenyl Methylamine hydrochloride is prepared by reaction with 2-cyclopropylacetic acid according to Method B. 4 NMR (400 MHz, CDC13) 5 ppm-0.07-0.07 (m, 2 Η) 0.3 6 - 0.4 8 (m, 2 H) 0.76 (t, J = 7.71 Hz, 1 H) 1.98 (d, J = 7.33) Hz, 2 H) 3.45 (d, J = 17.18 Hz, 1 H) 3.85 (d, J = 17.1 Hz, 1 H) 4.3 1 (d, J = 6.06 Hz, 2 H) 6.11 (br.s., 1 H) 6.91 (t, J = 9.47 Hz, 1 H) 7.3 7 - 7.5 1 (m, 5 H) ; m/z (CI) 525 [M + H] + 〇 Example 9: N-{2- Fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4.5-dihydroisoindolizine-3-yl]benzyl}-3-methyl Butane amide: -55- 201201802

From (2-fluoro-5-(5-(3,4,5-trichlorophenyl)_5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)phenyl) Methylamine was prepared by reaction with 3-methylbutyric acid according to Method B. 4\1^11(4〇〇]\^2,€〇〇:130卩0111〇.83-0.91(m, 8 Η)1.01 -1.1 4(m, 1 Η)1.95 - 2.1 3(m, 4 H) 3.59 (d, J = 17.43 Hz, 1 H) 3.99 (d, J = 17.18 Hz, 1 H) 4.42 (d, J = 6.32 Hz, 2 H) 5.79 (br.s., 1 H) 6.9 7 - 7 . 1 1 (m, 1 H) 7.4 8 - 7.6 5 (ms 4 H) ; m/z (CI) 527 [M + H]+. Preparation 10: 5-(5-(3,5- Dibutyl 4-fluoro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-fluorobenzylaminocarboxylic acid tert-butyl ester:

T-butyl {2-fluoro-5-[(E/Z)-(hydroxyimino)methyl]benzyl}carbamic acid (Preparation Example 5, 250 mg '0.826 mmols) in DMF (5 mL) The solution was added with N-chloro-sodium iodide (ll5 mg, 0.858) and added in three equal portions over 30 minutes with approximately ten minutes between each addition. Reaction mixture in nitrogen atmosphere

Stir for 12 hours in S -56- 201201802. Add 1,3-dichloro-2-fluoro-5-(1,1,1-trifluoroprop-2-en-2-yl)benzene to the crude reaction mixture (Preparation Example 2, 214 mg, 0.826 mmol) And solid sodium bicarbonate (300 mg). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was partitioned between water (10 mL) andEtOAc. The organic phase was washed successively with water (3.times.5 mL), dried (sodium sulfate), and evaporated to dryness. The product was purified on EtOAc (EtOAc:EtOAc) m/z (CI) 425 [M + H] + (lost Boc group upon liberation) 4 NMR (400 MHz, chloroform - d) d ppm 1.48 (s, 9 H) 3.69 (d, J = 17.43 Hz , 1 H) 4. 〇 8 (d, J = 17.18 Hz, 1 H) 4.39 (d, J = 6.06 Hz, 2 H) 4.99 (br.s., 1 H) 7.12 (t, J = 9.09 Hz, 1 H) 7.55 - 7.69 (m, 4 H) 〇 Preparation 11 (5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5- Dihydroisoxazol-3-yl)-2-fluorophenyl)methylamine:

5-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-fluorobenzyl TCA (2 mL) was added to a solution of the third butyl carbamate (Preparation Example 1 〇, 910 mg, 1.73 mmols) in dichloromethane (10 mL). The reaction was stirred overnight at room temperature. The volatiles were distilled off under reduced pressure. Residual substances -57- 201201802 Ingested in ethyl acetate (60 ml). The organic phase was washed with saturated aqueous sodium bicarbonate (2×2 5 mL). The combined aqueous wash was back extracted with ethyl acetate (2 χ 2 〇 ml). All organic extracts were combined and dried over sodium sulfate. The solvent is distilled off under reduced pressure to give the product as a solid glass which is dried in vacuo. (736 mg '99%) m/z (CI) 425 [M + H]+. Example 10: 2 -Cyclopropyl-N-{5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoindole Zyrid-3-yl]-2-fluorobenzyl}acetamidamine:

Method C for the preparation of decylamine (5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3 a solution of 2-difluorophenyl)methylamine (48 mg, 0.118 mmol, Preparation 11) in DMF (2 mL). 0.542 mmol), H0BT (1.2 mg ' 0.009 mmol) and HBTU (41.1 mg, 0 · 1 1 〇mm ο 1) ° The reaction was stirred at room temperature for 12 hours. The reaction was filtered through a syringe filter. The filtrate was subjected to reverse phase HPLC to give the final product (12 mg &apos; 20%) as amorphous glass. Retention time = 3.33 min; and m/z (CI) 5 08.2 [M + H]+. Example 11: N-{5-[5-(3,5-Dichloro-4-fluorophenyl)-5-(difluoromethyl)-

S -58- 201201802 4,5-Dihydroisoxazole-3-yl]-2-fluorobenzyl}acetamide:

From (5-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-fluoro Phenyl)methylamine was reacted with ethyl chloroacetate according to Method A. NMR (400 MHz, CDC13) 5 ppm 2.05 (s, 3 H) 3.69 (d, J = 17.43 Hz, 1 H) 4.09 (d, J = 17.18 Hz, 1 H) 4.51 (d, J = 6.06 Hz, 2 H) 5.92 (br.s., 1 H) 7.14 (t, J = 8.97 Hz, 1 H) 7.60 (d, J = 6.06 Hz, 2 H) 7.63 - 7.72 (m, 2 H) ; ) ; m/ z(CI) 467 [M + H]+. Example 12 N-{5-[5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]- 2_fluorobenzyl}cyclopropanecarbamide:

From (5-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-fluoro Phenyl)methylamine was prepared by reaction with cyclopropanecarboxylic acid in the presence of HBTU, HOBT and Hunig base according to Method C. Analytical -59- 201201802 HPLC Column = Waters X-Terra 3.5 μηι 4.6 x 50mm, mobile phase Α = 0·1% trifluoroacetic acid in H20, mobile phase B = acetonitrile, 50% B to 100% in 5 minutes B, keep 1 minute, 2 ml / min. Residence time: 3.94 minutes, m/z (CI) 493 · 9 [Μ + Η] + » Example 13::^-{5-[5-(3,5-dichloro-4-fluorophenyl)- 5-(Trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-fluorobenzyl}-3,3-difluorocyclobutanecarbamide CI corpse

From (5-(5-(3,5-Dichloro-4-fluorophenyl)·5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-fluoro Phenyl)methylamine was reacted according to Method C in the presence of 3,3-difluorocyclobutylene-formic acid in the presence of HBTU, hydrazine and Hunig base. Analytical HPLC column = Waters X-Terra 3.5μπι 4.6x50mm, mobile phase Α = 0·1% trifluoroacetic acid in HzO, mobile phase B = acetonitrile, 5 0% B to 100% B in 5 minutes, keep 1 Minutes, 2 ml / min. Residence time: 4.16 minutes, m/z (CI) 543.9 [M + H]+. Preparation 12: Methyl 5-bromo-2-chlorobenzoate:

S -60- 201201802

To a suspension of 2-chloro-5-bromobenzoic acid (10 g, 42 mmol) in dichloromethane (50 ml) was added EtOAc &lt The reaction mixture was stirred at room temperature for 12 hours under a nitrogen atmosphere. All volatiles were removed by distillation at low pressure. The product (viscous oil) was dissolved in dichloromethane (50 mL) and MeOH (5 mL) was then evaporated. The solution was stirred at 0 ° C for ten minutes and at room temperature for one hour. The volatiles were removed by low pressure distillation to yield 5-bromo-2-chlorobenzoic acid methyl acetate (10.5 g, 99%). 4 NMR (400 MHz, CDC13) 6 ppm 3.96 (s, 3 H) 7.35 (d, J = 8.59 Hz, 1 H) 7.56 (dd, J = 8.59, 2.27 Hz, 1 H ) 7.9 9 (d, J = 2.5 3 H z,1 H). Preparation 13 (5-bromo-2-chlorophenyl)methanol:

Sodium borohydride (3.18 g, 84 mmol) was added to a solution of 5-bromo-2-chlorobenzoic acid in acetonitrile (Preparation 12, 10.5 g, 42 mmol) in THF (50 mL). MeOH (7 mL) was added dropwise. The reaction was stirred at room temperature for one hour. An additional amount of sodium borohydride (0.5 g) was added and the mixture was stirred at room temperature for an additional hour. The reaction mixture was poured into ethyl acetate (125 mL) and stirred for 20 min. Add water (50 mL) and add it slowly at the beginning. After 201201802, add it all at once. The layers were stirred vigorously for fifteen minutes. The organic phase was collected, dried over sodium sulfate and evaporated 4 NMR (400 MHz, CDC13) 5 ppm 4.77 (s, 2 H) 7.23 (d, J = 8.34 Hz, 1 H) 7.37 (dd, J = 8.34, 2.53 Hz, 1 H) 7.68 (d, J = 2.53) Hz, 1 H). Preparation 14 5-bromo-2-chlorobenzyl methanesulfonate:

A solution of 5-bromo-2-chlorophenyl)methanol (Preparation 13, 7.85 g, 35.4 mmol) in dichloromethane (50 mL) was cooled to 0 &lt;0&gt; Then triethylamine (3.64 g, 36 mmol) was added. The solution was stirred at 〇 ° C for two hours and then at room temperature for three hours. Dichloromethane (50 mL) was added and the reaction mixture was washed with water. The organic phase was dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; 5 ppm 3.09(s, 3 H)5.32(s, 2 H)7.32(d, J = 8.59 Hz, 0 H) 7.48(d, J = 2.27 Hz, 0 H)7_66(d, J = 2.27 Hz, 1 H) » Preparation Example I5 2-(Azidomethyl)-4_bromo-1-chlorobenzene: s -62- 201201802

Sodium azide (1.75 g, 25.6 mmol) was added to a DMS 0 (30 mL) solution of methicillin 5-dihydro-2-glycolic acid (Preparation 14, 7.68 g, 25.6 mmol). The reaction was stirred overnight at room temperature. Water (120 mL) was added to the reaction mixture. The product was extracted with EtOAc (2×1 mL). The combined extracts were then washed with water (6 x 50 mL). The organic phase is dried over sodium sulfate, and the solvent is distilled at low pressure and below 40 ° C (bath temperature) to afford the product as a glassy solid of 2-(azidomethyl)-4-bromo-1-chlorobenzene ( 5.78 g, 25.6 mmol). 4 NMR (400 MHz &gt; CDC13) 6 ppm 4.48-4.53 (m, 1 H) 7.2 5 - 7.3 4 (m, 1 H) 7.43 (dd, J = 8.59, 2.27 Hz, 1 H) 7.58 (d, J = 2.27 Hz, 2 H) o Preparation 16 1-(5-Bromo-2-chlorophenyl)methanamine hydrochloride:

Cl NH3+C|· Addition of triphenylphosphine to a solution of 2-(azidomethyl)-4-bromo-1-chlorobenzene (Preparation 15) which has been cooled to 〇 ° C in THF (70 mL) Water (6 mL). The reaction was stirred at 〇 ° C for one hour and then at room temperature for thirty-six hours. The volatiles were removed by rotary evaporation at low pressure. The white residue was dissolved in EtOAc (EtOAc) (EtOAc) A mixture of 4NHC1 (6 mL) of dioxane solution was added and stirred at 〇 ° C for two hours, and the product was precipitated as hydrochloride. The white precipitate was collected by suction <RTI ID=0.0></RTI></RTI> to <RTI ID=0.0></RTI> <RTI ID=0.0> 400 MHz ' DMS Ο - d 6) δ ppm 4.1 2 (s, 2 Η) 7 · 5 1 ( d, J = 8 · 5 9 Η z, 1 Η) 7.63 (dd, J = 8.59, 2.53 Hz, 1 H) 7.89 (d, 1 = 2.21 Hz, 1 H) 8.61 (br.s., 3 H). Preparation 17 (5-Bromo-2-chlorobenzyl)carbamic acid tert-butyl ester:

Add Boc anhydride to 1-(5-bromo-2-chlorophenyl)methanamine hydrochloride (Preparation 16, 4.78 g, 18.6 mmol) in dichloromethane (70 mL) cooled to EtOAc. 4.06 g, 18.6 mmol) and triethylamine (4.14 g, 41 mmol). The reaction was stirred at room temperature for twenty-four hours. The mixture was diluted with dichloromethane (40 mL) and washed with water (3×25 mL). The organic phase was dried over sodium sulfate and the solvent was distilled off at low pressure. The crude liquid was purified on silica gel afforded (5-bromo-2-chlorobenzyl) carbamic acid tributyl ester (5.9 g, 17.5 mmol). NMR (400 MHz &gt; CDC13) 6 ppm 1.49 (s, 9 H) 4.3 4 - 4.4 5 (m, 2 H) 5.00 (br.s., 1 H) 7.24 (d, J = 8.34 Hz, 1 H) 7.35 (dd, 1 H) 7.53 (d, J = 2.53 Hz, 1 H). s -64- 201201802 Preparation Example 18 (2-Chloro-5-methylbenzylidenebenzyl) carbamic acid tert-butyl ester:

(5-Bromo-2-chlorobenzyl)carbamic acid tert-butyl ester (Preparation Example 17, 3.5 g, 1 0.9 mmol) was dissolved in anhydrous THF (5OmL). The solution was cooled to -78 ° C under a nitrogen atmosphere. Then, n-BuLi (1.6. N hexane solution 15 mL, 2.2 eq.) was added dropwise via a funnel over 15 minutes. The reaction was stirred at -78 Torr for a further ten minutes in a nitrogen atmosphere, followed by a single serving (aliquot). DMF (2.41 g, 33 mmols) was added. The cold bath was removed and the reaction was allowed to warm to room temperature over two hours. The reaction was cooled to 〇 ° C then EtOAc (EtOAc) (EtOAc) Dry over sodium sulfate and concentrate to a viscous oil. The crude oil was dissolved in CH2C12 (30 mL) and applied to &lt;RTI ID=0.0&gt;&gt; Leaching gave the pure product (2-chloro-5-methylpyridyl octyl) amino carboxylic acid terpene vinegar (1.25 g, 42%) as a thick oil. 1H NMR (400 MHz ' CDC 13 ) Ppm 1.49 (s, 9 H) 4.50 (d, J = 6.06 Hz, 2 H) 5.10 (br.s., 1 H) 7.55 (d, J = 8.08 Hz, 1 H) 7.76 (dd, J = 8.08, 2.02 Hz, 1 H) 7.91 (d, J = 2.02 Hz, 1 H) 10. 〇l(s, 1 H) -65- 201201802 Preparation 19 {2-Chloro-5-[(E/Z)- (hydroxyimine) methyl]benzylaminocarboxylic acid tert-butyl ester:

Hydroxylamine hydrochloride (0.95 g, 13.8) was added to a solution of (2-chloro-5-methylindenyl)-carbamic acid tert-butyl ester (Preparation 18, 1.25 g, 4.6 mmol) in EtOAc (20 mL) Methyl) and sodium acetate (1·8 g, 23 mmol). The mixture was stirred at room temperature for 4 hours. The volatiles were removed by distillation at low pressure. The residue was partitioned between water (50 mL) and EtOAc (EtOAc) The organic phase was dried (sodium sulphate) and concentrated to give &lt;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot; ). Preparation 20 {2-Chloro-5-[(E/Z)-chloro(hydroxyimino)methyl]benzyl}-aminocarboxylic acid tert-butyl ester:

S

201201802 Pair of {2-chloro-5-[(E/Z)-(hydroxyimino)methyl]benzyl}-carbamic acid tert-butyl ester (Preparation Example 19, 1.12 g, 3.9 mmol) in DMF (40) The solution in mL) was added N-chlorosuccinimide (0.525 g, 3.93 mmol). The solution was stirred at room temperature for 12 hours. The crude reaction mixture containing (3-chloro-5-[(E/Z)-(hydroxyimino)methyl]benzyl}aminocarbamic acid tert-butyl ester was used directly in the next step. Preparation 21: 2- Chloro-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzylaminocarboxylic acid Butyl ester

TMF of {2-chloro-5-[(E/Z)-chloro(hydroxyimino)-methylbenzyl]-carbamic acid tert-butyl ester (Preparation 20, 692 mg, 2.1 mmols). mL) 1,2,3-trichloro-5-(1,1,1-trifluoroprop-2-en-2-yl)benzene (Preparation 1, 580 mg, 2.1 mmols) and solid hydrogen carbonate Sodium (1000 mg). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was partitioned between water (10 mL) and EtOAc (40 mL). The organic phase was washed successively with water (3.times.5 mL), dried (sodium sulfate), and evaporated to dryness. The product was purified on EtOAc (EtOAc:EtOAc) m/z (CI) 459 [M + H] + (the Boc group is lost upon liberation). 4 NMR -67- 201201802 (400 MHz, chloroform-d) d ppm 1.48 (s, 9 H) 3.69 (d, J = 17.18 Hz, 1 H) 4.08 (d, J = 17.18 Hz, 1 H) 4.44 (d , J = 6.06 Hz, 2 H) 5.02-5.12 (m, 1 H) 7.44 (d, J = 8.34 Hz, 1 H) 7.5 3 - 7.68 (m, 4 H). Preparation 22 l-{2-Chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoindole-3- Phenyl]phenyl}methylamine:

For {2-chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl} TCA (2 mL) was added as a solution of EtOAc (EtOAc m. The solution was stirred overnight at room temperature. The volatiles are removed by distillation at low pressure. The residual material was taken up in ethyl acetate (60 ml). The organic phase was washed with saturated aqueous sodium bicarbonate (2×25 mL). All organic extracts were combined and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure to give the product (595 mg, 79%). 4 NMR (400 MHz » CDC13) 6 ppm 3.68 -3.74 (m, 1 H) 4.02 (s, 2 H) 4.11 (d, J = 1 7.1 8 Hz, 1 H) 7.45 (d, J = 8.34 Hz, 1 H) 7.55 (dd, J — 8.34, 2.02 Hz, 1 H) 7 · 6 6 (s, 2 H) 7 · 7 5 (d, J = 2.02 Hz, 1 H) ; m/z (CI) 45 9 [M + H]+. S -68- 201201802 Example 14: N-{2-Aromatic 5-[5-(3,4,5-dichlorophenyl)-5-(dimethylmethyl)-4,5-dihydroiso Oxazol-3-yl]benzyl}acetamide:

1-{2-Chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzene To a stirred mixture of pyridine (Preparation 22, 50 mg, 0.11 mmol) The reaction was stirred at room temperature for ten minutes. Water (12 mL) was added to precipitate the product. The white precipitate was collected using suction filtration. Wash with water (6 x 10 mL) and air dry overnight. Obtained N-{2-chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethylhydrazine, 5-dihydroisoindole-3- Benzyl acetamide (40 mg, 73%) 4 NMR (400 MHz &gt; CDC13) 5 ppm 2.06 (s, 3 H) 3.69 (d, J = 17.18 Hz, 1 H) 4.09 (d, J=17.1 8 Hz, 1 H)4.55 (d, J = 6.32 Hz, 2 H) 5.99 (br.s., 1 H) 7.46 (d, J = 8.34 Hz, 1 H) 7.62 (dd, J = 8.34 , 2.02 Hz, 1 H) 7.66 (s, 3 H) ; m/z (CI) 5 0 1 [ M + H ] + » Example 15: N-{2-chloro-5-[5-(3, 4,5-Trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}cyclopropanecarbamide: -69- 201201802

From 1-{2-chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4.5-dihydroisoxazol-3-yl]phenyl Methylamine (Preparation Example 22) was obtained by reacting Method A with cyclopropanecarbonyl chloride. 1H NMR (400 MHz ' CDC13) S ppm 0.78 -0.8 3 (m, 2 H) 0.99 - 1.03 (m, 2 H) 1 . 3 7 - 1.45 (m , 1 H) 3.69 (d, 17.43 Hz, 1 H ) 4.08 (d, J = 17.43 Hz, 1 H) 4.57 (d, J = 6.32 Hz, 2 H) 6.12 - 6.1 8 (m, 1 H) 7.46 (ds J = 8.34 Hz, 1 H) 7.60 - 7.67 ( m, 4 H) ; m/z ( CI) 5 2 7 [ M + H ] +. Example 16: N-{2-Chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4.5-dihydroisoxazol-3-yl] Benzyl}-2-methylpropanamide:

From 1-{2-chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl] Phenyl}methylamine (Preparation Example 22) was obtained by reacting Method A with isobutylphosphonium chloride. 4 NMR (4 00 MHz, CDC13) 5 ppm 1.20 (dd, J = 6.82, 2.27 Hz, 6 H) 2.43 (s, 1 H) 3.71 (s, 1 H) 4.08 (d, -70- 201201802 J=17.18 Hz, 1 H) 4.54 (d, J = 6.06 Hz, 2 H) 5.9 6 - 6.02 (m, 1 H) 7.45 (d, J = 8.34 Hz, 1 H) 7.59-7.67 (m, 4 H) ; m /z(CI) 529 [M + H] + o Example 17: N-{2-chloro-5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl) Base)-4,5-dihydroisozozolyl]benzyl}acetamide:

From (2-chloro-5-(5-(3,5-dichloro_4.fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroiso Dfoxazol-3-yl)benzene Methylamine is prepared by a similar reaction with ethyl hydrazine chloride according to the method. 1H NMR (400 MHz, CDC13) 5 ppm 2.06 (s, 3 H) 3.66-3.72 (m, 1 H) 4.09 (d, J = 17.18 Hz, 1 H) 4.55 (d, J-6.32 Hz, 2 H) 5.95-6.02(m, 1 H)7.46(d, J = 8.34 Hz, 1 H) 7.58-7.64(m,3 H)7.65-7.67(m,1 H) ; m/z(CI)48 5 [M + H]+. Preparation 23: Methyl 4-bromo-3-(bromomethyl)benzoate:

Br Br -71- 201201802 Add NBS (4.8 g, 44 mmol) and a catalytic amount of benzoquinone to a solution of methyl 4-bromo-3-methylbenzoate (10 g, 43.6 mmol) in CC14 (30 mL) . The reaction was heated under reflux for 18 hours. The mixture was cooled to room temperature and diluted with CH2C12 (50 mL). The organic phase was washed with water (3 x 20 mL) and concentrated using a rotary evaporator under low pressure. The residual material was dissolved in hexane and applied to a 120 g silica gel column. The product was eluted with a gradient of ethyl acetate in hexane to yield ethyl 4-bromo-3-(bromomethyl)benzoate (7·73 g, 57%). 4 NMR (400 MHz &gt; CDC13) 5 ppm 3.95 (s, 3 H) 4.64 (s, 2 H) 7.68 (d, J = 8.34 Hz, 1 H) 7.83 (dd, J = 8.34, 2.02 Hz, 1 H ) 8.14 (d, J = 2.02 Hz, 1 H). Preparation 24 Methyl 3-(azidomethyl)-4-bromobenzoate:

To a solution of methyl 4-bromo-3-(bromomethyl)benzoate (Preparation 23, 7.73 g, 25 mmol) in EtOAc (40 mL) The mixture was stirred at room temperature for four hours. The mixture was cooled in an ice bath and water (250 mL) was added to the mixture. After the mixture was stirred at 0 ° C for one hour, a white precipitate appeared. The collected white solid was filtered with suction and washed with water to give &lt;RTI ID=0.0&gt;&gt;

S-72- 201201802 Preparation 25 3-(Aminomethyl)-4-bromobenzoic acid methyl ester:

To a solution of methyl 3-(azidomethyl)-4-bromobenzoate (Preparation 24, 6.77 g, 25 mmol) in EtOAc (EtOAc) 25.1 mmol). The mixture was stirred overnight at room temperature. The mixture was acidified by the addition of 1 N HCl (aq) (40 mL). Add EtOAc (100 mL) and water (60 mL). The layers are stirred vigorously together. The aqueous phase was taken and washed again EtOAc (2×40 mL). The aqueous phase was then neutralized with saturated aqueous sodium bicarbonate (40 mL). The product amine was extracted with dichloromethane (3 x 40 mL). The combined extracts were dried over sodium sulfate and evaporated to dryness crystals eluted NMR (400 MHz, CDC13) 5 ppm 3.94 (s, 3 H) 3.99 (s, 2 H) 7.65 (d, J = 8.34 Hz, 1 H) 7.79 (d, J = 2.27 Hz, 1 H) 8.09 (d , J = 2.02 Hz, 1 H). Preparation 26 Methyl 4-bromo-3-((t-butoxycarbonyl)methyl)benzoate:

Boc anhydride (3.92 g, added to a solution of 3-(aminomethyl)-4-bromobenzoate (Preparation 25, 4.38 g, 201201802 18 mmol) in CH2C12 (25 mL) cooled to 0 °C 18 mmol) followed by a Hunig test (2.58 g, 20 mmol). The reaction was stirred at 0 ° C for one hour' and then stirred at room temperature for five hours. The volume was reduced to approximately 10 mL by distillation at low pressure. The residual liquid was applied to a silica gel (80 g) and the oxime was eluted with 25% EtOAc in hexanes to yield methyl 4-bromo-3-((t-butoxycarbonyl)methyl)benzoate (5.28) g » 85%) ^ NMR (400 MHz &gt; CDC13) 6 ppm 1.49 (s, 9 H) 3.93 (s, 3 H) 4.43 (d, 2 H) 5.01-5.15 (m, 1 H) 7.64 (d, J = 8.34 Hz, 1 H) 7.80 (d, J = 2.02 Hz, 1 H) 8.03 (s, 1 H). Preparation 27 T-butyl 2-bromo-5-(hydroxymethyl)benzylcarbamic acid:

Adding hydroboration to a solution of 4-bromo-3-((t-butoxycarbonyl)methyl)-benzoic acid tert-butyl ester (Preparation 26, 5.28 g, 15.3 mmol) in THF (50 mL) Sodium (579 mg, 15.3 mmol). Me 〇H (10 mL) was added dropwise to the mixture by stirring the funnel over twenty minutes. The reaction was warmed to 45 ° C and stirred for one hour. A second equivalent of sodium borohydride (5 7 9 mg '1 5.3 mmol) was added and stirring was continued for 4 hours for 4 hours. The reaction was cooled until 〇 C ' was slowly quenched with a saturated aqueous solution of ammonium chloride. Add Et〇Ac (60 mL) and water (5 〇 mL). The layers - stirred vigorously for fifteen minutes. The organic phase was collected and dried under sodium sulfate to produce a solvent (4 74 g, 98%) 2-

S-74- 201201802 Tert-butyl bromide-5-(hydroxymethyl)benzylamine hydrazide. A NMR (400 MHz « CDC13) 6 ppm 1.48 (s, 9 H) 4.3 7 - 4.4 3 (m, 2H) 4.66 - 4.69 (m, 2 H) 5.01-5.09 (m, 1 H) 7. 16 - 7 2 0 (m, 1H) 7.38- 7.40 (m, 1H) 7.55 (d, J = 8.〇8 Hz, 1H). Preparation 28 2 -Bromo-5-methylindenylbenzylcarbamic acid tert-butyl ester:

Distillation of three portions of 2-bromo-5-hydroxymethyl)benzyl-carbamic acid tert-butyl ester (Preparation 27, 4.73 g, 15 mmol) in CH.sub.2 C. 50 mL) solution was added to Dess Martin Sodium Periodane (6.7 g, 15 mmol). The reaction mixture was warmed to room temperature over two hours. The solvent was distilled off at a low pressure. The residue was dissolved in CH.sub.2Cl.sub.sub.sub.sub.sub. The organic phase was dried (sodium sulfate) and distilled under reduced pressure to reduce volume. The crude material was purified on EtOAc (EtOAc:EtOAc) 4 NMR (400 MHz, CDCl3) 3 ppm 1.49 (s, 9H) 4.48 (d, J = 6.32 Hz, 2H) 5.05-5.16 (m, 1 H) 7.65-7.70 (m, 1 H) 7.7 3 - 7.7 8 (m, 1 H) 7.88 (d, J = 2.02 Hz, 1 H) 10.01 (s, 1 H). Preparation 29 2-Bromo-5-((transmethylimido)methyl)benzylaminocarbamic acid tert-butyl ester -75- 201201802

Hydroxylamine hydrochloride (260 mg, 3.8 mmol) was added to a solution of 2-bromo-5-carbamidobenzylaminocarbamic acid tert-butyl ester (Preparation 28, 1.15 g, 3.7 mmol) in EtOAc (20 mL) And sodium acetate (5 equivalents). The mixture was stirred at room temperature for 4 hours. The volatiles were distilled off under reduced pressure. The residue was partitioned between water (50 mL) and EtOAc (EtOAc) The organic phase was dried (Na2SO4) and concentrated to give 2-bromo-5 <RTI ID=0.0>((</RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; Preparation 3 0 2 ·Bromo-5-(chloro(hydroxyimino)methyl)benzyl-carbamic acid tert-butyl ester:

Br Add a solution of 5-((hydroxyimino)methyl)benzylcarbamate (Preparation 29, 1.18 g, 3.6 mmol) in DMF (40 mL) EtOAc (EtOAc) , 3.6 mmol). The solution was stirred at room temperature for 12 hours. The crude reaction mixture containing 2-bromo-5-(chloro(hydroxyimino)methyl)benzyl-carbamic acid tert-butyl ester was used directly in the next step.

S-76- 201201802 Preparation 31 2_Bromo-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)·4,5·dihydroisoxazole-3- Tert-butyl benzylaminocarbamate:

Add a solution of 2-bromo-5-(chloro(hydroxyimino)-methyl)benzylcarbamate (Preparation 26' 700 mg' 1.9 mmol) (20 mL) to d 1,2,3 -Trichloro-dipropion-2-ylidene-2-yl)benzene (Preparation Example 1, 530 mg, 1,92 mmol) and sodium hydrogencarbonate (1 g). The mixture was stirred at room temperature for 12 hours. The reaction mixture was partitioned between water (1 mL) and ethyl acetate (120 mL). The organic phase was dried over sodium sulfate and the solvent was evaporated. The residual oil was purified on silica gel using EtOAc / hexanes as mobile phase to yield 2-bromo-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4. 5-Dihydroisoindolin-3-yl)benzyl-aminocarbamic acid terpene vinegar (854 mg, 60%). Preparation 32 (2-bromo-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzene Methylamine:

Br C: • 77- 201201802 p- 2-Bromo-5-(5-(3,4,5·trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3 TPA (2 mL) was added as a solution of benzyl benzyl carbamic acid in the title compound (m.p. The solution was stirred overnight at room temperature. The volatiles were removed by distillation at low pressure. The residual material was taken up in ethyl acetate (60 ml). The organic phase was washed with a saturated aqueous solution of sodium bicarbonate (2×25 ml). The combined aqueous wash was extracted with ethyl acetate (2 x 20 mL). All organic extracts were combined and dried over sodium sulfate. The solvent was removed by distillation under reduced pressure to provide the product (2-bromo-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro Isoxazol-3-yl)phenyl)methanamine (6 77 mg, 1.4 mm ο 1). m / z (C I) 5 0 3 [ M + Η ] +. Example 18: Ν-(2-bromo-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3- Base) benzyl) acetamamine:

(2-Bromo-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisooxazol-3-yl)phenyl To a stirred mixture of methylamine (Preparation 32, 70 mg, 0.14 mmol) and EtOAc (EtOAc) The reaction was stirred at room temperature for ten minutes. Water (12 mL) was added to precipitate the product. The white precipitate was collected using suction filtration. With water

S-78- 201201802 Wash (6x10 mL), then air dry overnight. The product N-(2-bromo-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl) was obtained. Benzyl)acetamide (55 mg, 73%) as a white solid. 4 NMR (400 MHz, CDC13) δ ppm 2.06 (s, 3 H) 3.66-3.74 (m, J = 17.18 Hz, 1 H) 4.09 (d, J = 17.18 Hz, 1 H) 4.54 (d, J = 6.32 Hz, 2 H) 5.98-6.05 (m, 1 H) 7.51-7.56 (m, 1 H) 7.62-7.67 (m, 4 H); m/z (CI) 545 [M + H] + Biological analysis The biological activity of the compounds of the present invention was tested against the hard larvae, soft mites, horn flies and mites using the following test methods. Rhipicephalus sanguineus whole organism contact analysis The compound of formula (1) is dissolved in isopropanol (IP A), and an aliquot is added to the vial placed on the drum for at least 2 hours to evaporate the IPA. . IPA was used alone as a negative control group, and fipronU was used as a positive control group. Use a swab to add 50 to 200 aphid larvae to the vial and close the vial. At about 24 and 48 hours, the vial was tested and recorded as active on the ground. Check the bottle showing the condition of the tick and/or the fall of the ground at about 48 hours. The endpoint data can be recorded as an effective dose of 〇〇% (ED1()()) and/or a lethal dose of 〇〇1% (LD1QQ) in pg/cm2. Examples 1 and 2 demonstrate that EDl °G is 1 〇.〇 Hg/cm2. Examples 3-9, 11 and 14-18 demonstrate ED1()()S1.0 pg/cm2, and wherein Examples 5-7 and 11 demonstrate ED1() (^0.1 pg/cm2 ° -79- 201201802 soft 蜱(Ornithidorus turicata) blood feeding analysis The compound of formula (1) is dissolved in dimethyl hydrazine (DMS hydrazine), and aliquots are added in divided portions to citrated bovine blood in a membrane-coated petri dish. The culture dish is placed on the heating bracket. About 5 spiders are placed on the membrane, capped and kept for feeding. The rear hatch is taken out and placed in a petri dish containing sand. At about 24, 48 and End-point data can be recorded as ED1()() and/or LD1()() in units of pg/mL for 72 hours of observation. The positive control group is fipronil. And DMSO was used as a negative control group. In this analysis, Examples 3 and 11 exhibited ED 10051 Mg/cm2. Haematobia irritans feeding analysis formula (1) compound dissolved in DMSO, divided into equal parts Add to the citrated bovine blood in a culture dish. Place about ten horn flies in each dish and cover. Treated blood The hornfly is maintained on the cell. The hornfly maintains about 80 °F at a minimum relative humidity of about 50%. The flies fall and the mortality rate are observed at about 2 and 24 hours. The endpoint data is recorded as a lethal dose of 90% (LD9Q). Unit pg/mL. In this analysis, Example 3 exhibited an LD9G of 10 pg/mL. In this analysis, Examples 6, 8, 9 and 1 1 showed an LD9Q of 3 pg/mL. Furthermore, in this analysis, implementation Examples 4, 5, 7, 17, and 18 show LD9() at 1 pg/mL. Cats (Ctenocephalides felis) membrane feeding analysis - adult

S -80- 201201802

The compound of the formula (1) was dissolved in DMS hydrazine, and an aliquot was added in portions to the citrated bovine blood in a petri dish which was pre-warmed to a temperature of 37 °C. A feeding tube containing about 30 to 35 sputum was placed on the culture dish. Cats are fed for about 2 hours. At about 2 and 24 hours, the cat was observed to fall to the ground and/or died. The endpoint data was recorded as an effective dose of 80% (ED8Q) in units of fig/mL. In this analysis, Examples 6, 7 and 18 exhibited an ED8() of 10 pg/mL. Furthermore, in this analysis, 'Examples 3, 5, 12 and 13 show ED8Q of 3 pg/mL -81-

Claims (1)

201201802 VII. Patent application scope: 1. A compound of formula (1) Or a veterinary acceptable salt thereof, wherein Rla, Rib and Rle are each independently selected from the group consisting of halogen, sulfhydryl, C丨_C8, Ke-C6_hospital and Ci_C6 halogen oxy* and each R1 R1 is the same or different: R2 is hydrogen, halo, cyano, C丨-C6 alkyl, C丨_C6 haloalkyl or alkoxy, haloalkoxy, C3-C6 cycloalkyl, wherein n Is an integer of 1, 2 or 3, and when η is 2 or 3, each R2 may be the same or different from each other; R3 is selected from C丨-C8 alkyl, C〇-C3 alkyl C3-C6 cycloalkyl , Ch C6 alkyl-OR4 or C丨-C6 alkyl C(0)NRaRb, wherein the C丨-&lt;:8 alkyl group and the C〇-C3 yard-based C3-C6 ring system are optionally subjected to at least Substituted by a group selected from the group consisting of halo, cyano, hydroxy and S(0)pR4; R4 C丨-C6 alkyl or C丨-C6 haloalkyl; S-82- 201201802 Ra is hydrogen Or a ChQ alkyl group; Rb is hydrogen, Ci.Cs alkyl, ChCi; haloalkyl, C〇_C4_hospital C3. C6 cycloalkyl or Ci.Cs alkyl Het, wherein the Het system contains at least one a 5- or 6-membered monocyclic aromatic ring selected from the group consisting of a hetero atom of ruthenium, osmium or S, and the Het may optionally be subjected to at least one substituent selected from the group consisting of Substituted: halo, cyano, Ci.Cfi alkyl and υ6-alkyl; and the oxime is an integer 〇, 1 or 2. 2. The compound of claim 1, wherein: Rla, Rlb and R1. Each of which is independently selected from the group consisting of halogen, cyano, Cl.C8 alkyl and ChQ haloalkyl, or one of Rla, ruler 115 or Rle is S02CF3 〇3. The compound of claim 2 has Formula (1 a), (IB), (1C) or (1D) -83- £ 201201802 Or a veterinaryly acceptable salt thereof, wherein Rla, Rlb and Rle are each independently selected from the group consisting of halogen, cyano, Ci.Cs alkyl and ChCe haloalkyl, or one of Rla'Rlb or Rle is S02CF3: R2a, R2b and R2e are each independently hydrogen, halo, cyano, C丨-C6 alkyl, ChQ haloalkyl or C3_C6 cycloalkyl. 4. The compound of claim 3, which has the formula (1D): S -84 - 201201802 Or a veterinary acceptable salt thereof, wherein Rla, Rlb &amp; Rle are each independently selected from the group consisting of halogen, cyano, alkyl and haloalkyl, or one of Rla, 11115 or 111 &lt;: - S02CF3: and R2e It is hydrogen, halo, cyano, methyl, ethyl, -cf3, -CH2CF3, cyclopropyl or cyclobutyl. 5. The compound of claim 4, wherein: Rla, Rlb and R]M are each independently selected from the group consisting of fluorine, chlorine, bromine, cyano, methyl, ethyl, -CF3 and -CH2CF3; and R2e It is hydrogen, fluorine, chlorine, bromine, cyano, methyl or CF3. 6. The compound of claim 5, wherein Rla, Rlb and Rle are each independently selected from the group consisting of fluorine, chlorine, bromine and CF3; and R2e is fluorine, chlorine, bromine, methyl or CF3. 7. The compound of claim 6, wherein: R3 is selected from the group consisting of Us alkyl or CQ.C3 alkyl C3.C6 cycloalkyl; wherein (^.(^ alkyl and the C. C3 alkane) The C3.C6 cycloalkyl group is optionally substituted by -85-201201802 with one group selected from the group consisting of halo, hydroxy and S(0)pR4, wherein P is an integer of 0, 1 or 2 and R4 Methyl, ethyl or isopropyl. 8. A compound according to claim 7 wherein: R3 is selected from the group consisting of alkyl, cyclopropyl, cyclobutyl, cyclopentyl, methylcyclopropyl, Ethyl cyclopropyl, methylcyclobutyl, ethylcyclobutyl and methylcyclopentyl; wherein the Ci.C8 alkyl group and the cycloalkyl or alkylcycloalkyl group are optionally at least one selected from the group consisting of Substituted by the following groups: halo, hydroxy, -SCH3 and -s(o)2ch3. 9. The compound of claim 1 is selected from the group consisting of: N-{5-[5-(3, 4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-fluorobenzyl}acetamide; N-{2-fluoro -5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}-2-methyl Propylamine; 1^-{2-fluoro-5-[5-(3,4,5 -trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}cyclopropanecarbamide; N-{2-fluoro-5-[5 -(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazolyl]benzyl}cyclobutanecarbamide; N-{2-fluoro 5-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}propanamine; -cyclopropyl-N-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3 -yl]benzyl}acetamide; N-{2-fluoro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro Isoxazol-3-yl]benzylbu 3_methylbutane decylamine: 2-cyclopropyl-N_{5-[5-(3,5-dichloro-4-fluorophenyl)-5- (Trifluoromethyl)-S-86- 201201802 4.5-Dihydroisoxazol-3-yl]-2-fluorobenzyl}acetamidamine; Ν·{5-[5-(3,5-dichloro 4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-fluorobenzyl}acetamidamine; Ν-{5-[5- (3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2-fluorobenzyl}cyclopropanecarbamide Ν-{5-[5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]-2- fluorine }}-3,3-difluorocyclobutanecarbamamine-{2-chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4 ,5-dihydroisoxazol-3-yl]benzyl}acetamidamine; Ν-{2-chloro-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoro Methyl)-4,5-dihydroisoxazol-3-yl]benzyl}cyclopropanecarbamide; Ν-{2-chloro-5-[5-(3,4,5-trichlorophenyl) -5-(Trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}-2-methylpropanamide; Ν-{2-chloro-5-[5-( 3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl]benzyl}acetamidamine; Ν-(2-bromo) - 5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzyl)acetamide, hydrazine -cyclopropylmethyl-Ν'-{2-fluoro-5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoindole Zyridin-3-yl]-benzylpropanylamine; and Ν-ethyl-Ν'-{2-fluoro-5-[5-(3,4,5-trichloro-phenyl)-5- Trifluoromethyl-4.5-dihydro-isoxazol-3-yl]-benzyl}-propanediamine; or a veterinary acceptable salt thereof. A veterinary composition comprising a therapeutically effective amount of a compound of formula (1) -87-201201802 Or a veterinary acceptable salt thereof, wherein Rla, Rlb and Rle are each independently selected from the group consisting of halogen, cyano, C^Ce alkyl, haloalkyl and Ci-Q haloalkoxy, and each R1 may be the same as each other Or different; R2 is hydrogen, halo, cyano, c丨_C6 alkyl, C丨-C6 haloalkyl or C^Ce alkoxy, CUC6 haloalkoxy, C3.C6 cycloalkyl, Wherein η is an integer of 1, 2 or 3, and when η is 2 or 3, each R2 may be the same or different from each other; R3 is selected from C丨-C8 alkyl, C0-C3 alkyl (: 3-( : 6 cycloalkyl, C, -C6 alkyl-OR4 or C丨.C6 alkyl C(0)NRaRb, wherein the C丨-C8 alkyl group and the CQ_C3 alkyl C3.C6 cycloalkyl group are optionally subjected to Substituted by at least one group selected from the group consisting of halo, cyano, hydroxy and S(0)pR4; C, C6 alkyl or haloalkyl; Ra is hydrogen or (^. Rb is hydrogen, Ci.C6 alkyl, Ci-C^haloalkyl, C〇-C4 alkyl c3·C6 cycloalkyl or ChCs alkyl Het, wherein the Het system contains at least one S-88 - 201201802 5- or 6-membered monocyclic aromatic rings selected from heteroatoms of N, hydrazine or S, and the Het may optionally be subjected to at least one substituent selected from the group consisting of Substituted: _ group, cyano group, ChCe alkyl group and Cl-C6_alkyl group; and P is an integer of 0, 1 or 2. 1 1 . The veterinary composition of claim 10, further comprising A veterinary acceptable excipient, diluent or carrier. 12. The veterinary composition of claim 11 further comprising at least one additional veterinary agent. A composition of 丨1 or 1 2 for use in the treatment of parasites of animals or birds. 1 4 . The composition of claim 13 wherein the animal is accompanied by an animal or domestic animal, the bird is a poultry And the parasite is an ectoparasite. 1 5 · The use of a compound as claimed in claim 1 is for the manufacture of medicine. S -89- 201201802 Four designated representatives: (1) Representative of the case Pictured: None (2) Simple description of the symbol of the representative circle: No 201201802 V. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: S -4-