Isoxazoline derivatives as anti-parasitic agents

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to azetidine-substituted isoxazoline derivatives of formula (1), where A represents phenyl, naphtyl or heteroaryl, where said heteroaryl represents 5-6-membered aromatic monocyclic ring and contains 1 N heteroatom; each of R1a, R1b and R1c independently represents hydrogen, halogen, cyano, nitro or C1-C6halogenalkyl; R2 represents halogen, cyano or nitro; R3 represents hydrogen, halogen, hydroxyl, cyano, N3 or -NHR4; R4 represents hydrogen, -C(O)R5, -C(S)R5, -C(O)NRaR5, -S(O)pRc, -S(O)2NRaR5 or -C(NR7)R5; R5 represents hydrogen, C1-C6alkyl, C2-C6alkenyl, C0-C6alkylC3-C6cycloalkyl, C0-C6alkylphenyl, C0-C6alkylheteroaryl, representing 5-6-membered aromatic monocyclic ring, containing from 1 to 3 heteroatoms, each of which is independently selected from N, O and S, or C0-C6alkylheterocycle, where said heterocycle represents 4-membered monocyclic ring, containing 1 heteroatom, selected from N, O and S; R6 represents C1-C6halogenalkyl; R7 represents cyano; Ra represents hydrogen, C1-C6alkyl or C0-C3alkylC3-C6cycloalkyl; Rb represents hydrogen, C1-C6alkyl or C3-C6cycloalkyl; Rc represents C1-C6alkyl, C1-C6halogenalkyl, C1-C6halogenalkylC3-C6cycloalkyl, C0-C3alkylC3-C6cycloalkyl or C0-C3alkylphenyl, each of which is possibly substituted with at least one substituent, selected from cyano or halogen, each of groups C1-C6alkyl or C0-C3alkylC3-C6cycloalkyl ad R5 can be possibly and independently substituted with at least one substituent, selected from cyano, halogen, hydroxyl, C1-C6alkoxy, C1-C6halogenalkoxy, C1-C6halogenalkyl, -S(O)pRc, -SH, -S(O)pNRaRb, -NRaC(O)Rb, -SC(O)Rc and -C(O)NRaRb; and where grouping C0-C6alkylheteroaryl or C1-C6alkylheterocycle as R5 can be possibly additionally substituted with at least one substituent, selected from halogen, oxo, hydroxyl, C1-C6alkyl and -SH; n represents integer number 0 or 1, and p represents integer number 0, 1 or 2 and its stereoisomers. Invention also relates to pharmaceutical or veterinary composition, possessing parasiticidal activity, containing therapeutic amount of formula (I) derivative and pharmaceutically or veterinarily acceptable excipient, diluents or carrier.

EFFECT: azetidine-substituted isoxazoline derivatives of formula (1), intended for manufacturing means for treatment or control of parasitic infection or invasion in animal.

20 cl, 5 tbl, 225 ex

 

Field of the INVENTION

This invention relates to a derivative of isoxazoline with parasiticidal activity. The considered compounds are derivatives of isoxazoline, substituted phenyl-azetidinone, naphthyl-azetidinone or heteroaryl-azetidinone. The invention also relates to compositions and methods for their use.

PRIOR art

There is a need for improved antiparasitic agents for use in mammals and, in particular, there is a need for improved insecticides and acaricides. In addition, there is a need for improved products for local and convenient oral administration, which contain one or more antiparasitic agents, and which can be used for effective destruction of ectoparasites, such as insects (e.g. fleas, lice and flies) and mites (for example acariform mites and the mites order). Such products are particularly useful for the treatment of companion animals such as cats, dogs, llamas and horses, and livestock, such as cattle, bison, pigs, sheep and goats.

Currently available compounds for protivobakteritsidny and protivobakteritsidny treatment of companion animals and livestock is not always, check�are good activity high speed action or a longer duration of action. Most of the tools for processing and contain hazardous chemicals that can have serious consequences, including death in case of accidental ingestion. Persons applying these agents, in General it is recommended to limit their use. To overcome some of the problems used lugs and collars for animals, but they are susceptible to chewing, and swallowing and may have a subsequent Toxicological effects on a mammal. Thus, the existing treatment provides varying degrees of success, which partly depend on toxicity, method of administration and efficiency. In addition, currently a number of agents actually becomes ineffective because of parasite resistance.

Derivatives isoxazoline in the prior art as having acaricidal and acaricidal activity. For example, in WO 2007/105814 (US 2009/0156643), WO 2008/122375 and WO 2009/035004 described certain alkylen-related amides. In addition, in WO 2007/075459 disclosed phenylisoxazole substituted 5-6-membered heterocycles. However, in none of these documents are examples of isoxazoline, substituted phenylacetylenes, and in the prior art does not indicate that such compounds would be useful against a broad spectrum�RA parasites regardless of the morphological stages of their life cycle in animals.

Despite the availability of effective antiparasitic agents of broad-spectrum, a need remains for a more secure, convenient, efficient and environmentally friendly product, which can overcome the threat of development of resistance.

The present invention overcomes one or more of the various disadvantages of existing connections or improve their properties. In particular, the present invention provides a new isoxazolyl, substituted phenyl-azetidine that demonstrates such properties.

A BRIEF SUMMARY of the INVENTION

In the present invention proposed a compound of formula (1) and formula (XX), their stereoisomers, their pharmaceutically or veterinary acceptable salts, which act as parasiticides, in particular, ectoparasiticide; and which therefore can be used for treatment of infections and infestations of mites and insects in animals. In addition, the invention encompasses the control and prevention of occurrence of endoparasites in animals. The present invention also covers the control and treatment of diseases tick-borne origin, for example, Lyme disease (Lyme, anaplasmosis dogs and cattle, ehrlichiosis dogs, ricketsiosis dogs, babesiosis of dogs and cu�Phnom cattle epizootic abortion in cattle and of theileriosis. Thus, according to the invention proposed compound of formula (1)

,

where

A represents phenyl, naphthyl or heteroaryl, where the specified heteroaryl contains from 1 to 4 heteroatoms, each independently selected from N, O and S;

each of R1a, R1band R1cindependently represents hydrogen, halogen, hydroxyl, cyano, nitro, C1-C6alkyl, C1-C6halogenated, C1-C6alkoxy, C0-C3alkyls3-C6cycloalkyl, C1-C6halogenoalkane, -C(O)NH2-SF5or-S(O)pR;

R2represents halogen, cyano, C1-C6alkyl, C1-C6halogenated, nitro, hydroxyl, -C(O)NRaRbWith2-C6of alkenyl, C2-C6alkenyl, -S(O)pR or-OR;

R3represents hydrogen, halogen, hydroxyl, cyano, C1-C6alkyl, C1-C6halogenated, S0-C3alkyls3-C6cycloalkyl, -C(O)NH2, nitro, -SC(O)R, -C(O)NRaRbWith0-C3NRaRb, -NRaNRbR4, -NRaORb, -ONRaRbN3, -NHR4, -Or, or-S(O)pR;

R4represents hydrogen, C1-C6alkyl, C0-� 6alkyls3-C6cycloalkyl, -C(O)R5, -C(S)R5, -C(O)NRaR5, -C(O)C(O)NRaR5, -S(O)pRc, -S(O)2NRaR5, -C(NR7)R5, -C(NR7)NRaR5With0-C6alkylphenyl, S0-C6alkylglycerol or C0-C6alkylglycerols;

R5represents hydrogen, C1-C6alkyl, C2-C6of alkenyl, C0-C6alkyls3-C6cycloalkyl, S0-C6alkylphenyl, S0-C6alkylglycerol or C0-C6alkylglycerols;

R6represents cyano, C1-C6alkyl, C1-C6halogenated, -C(O)NRaRbWith2-C6of alkenyl, C2-C6alkynyl, S2-C6halogenoalkanes or C2-C6halogenoalkanes;

R7represents hydrogen, C1-C6alkyl, hydroxyl, cyano, nitro, -S(O)pRcor C1-C6alkoxy;

R represents C1-C6alkyl or C3-C6cycloalkyl, each of which may substituted by at least one halogen;

Rarepresents hydrogen, C1-C6alkyl or C0-C3alkyls3-C6cycloalkyl; where the alkyl and alkylsilanes possibly substituted by cyano or at least one Deputy halog�n;

Rbrepresents hydrogen, C1-C6alkyl, C3-C6cycloalkyl, S0-C3alkylphenyl, S0-C3alkylglycerol or C0-C3alkylglycerols, each of which maybe substituted, where chemically possible, with at least one Deputy, selected from hydroxyl, cyano, halogen or-S(O)pR;

Rcrepresents C1-C6alkyl, C1-C6halogenated, C1-C6halogenates3-C6cycloalkyl, S0-C3alkyls3-C6cycloalkyl, S0-C3alkylphenyl, S0-C3alkylglycerol or C0-C3alkylglycerols, each of which may substituted by at least one substituent selected from cyano, halogen, hydroxyl, oxo, C1-C6alkoxy, C1-C6halogenoalkane, C1-C6halogenoalkane, -S(O)pR, -SH, -S(O)pNRaRb, -NRaRb, -NRaC(O)Rb, -SC(O)Rb, -SCN, or-C(O)NRaRb;

each group C1-C6alkyl or C0-C6alkyls3-C6cycloalkyl as R4and R5it may be possible and independently substituted by at least one substituent selected from cyano, halogen, hydroxyl, oxo, C1-C6alkoxy, C1-C6halogenatom�and, C1-C6halogenoalkane, -S(O)pRc, -SH, -S(O)pNRaRb, -NRaRb, -NRaC(O)Rb, -SC(O)Rc, -SCN, or-C(O)NRaRb; and

where grouping With0-C6alkylphenyl, S0-C6alkylglycerol or C0-C6alkylglycerols as R4and R5may be optionally substituted by at least one substituent selected from cyano, halogen, oxo, =S, =NR7, hydroxyl, C1-C6alkoxy, C1-C6alkyl, C1-C6halogenoalkane, -SH, -S(O)pR and C1-C6halogenoalkane;

n is an integer 0, 1 or 2, and when n represents 2, then R2may be the same or different; and

p is an integer 0, 1 or 2;

his stereoisomer and pharmaceutically or veterinary acceptable salts.

In another aspect of the invention, But represents a phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazolyl, imidazolyl pyrrolyl, furanyl, thiophenyl, triazolyl, tetrazolyl, thiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzothiophene, indole, benzimidazole, indazole, benzotriazole, thieno[2,3-C]pyridine, thieno[3,2-b]pyridine and benzo[1,2,5]thiadiazole. In another aspect of the invention, But represents a phenyl, naphthyl, Piri�inil, pyrimidinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isoxazolyl, benzofuranyl, benzothiophene, indole and benzo[1,2,5]thiadiazole. In another aspect of the invention, But represents a phenyl, naphthyl, pyridinyl, pyrazolyl, triazolyl, isoxazolyl, benzofuranyl and benzo[1,2,5]thiadiazole. In another aspect of the invention, But represents a phenyl, naphthyl, pyridinyl, pyrazolyl and benzo[1,2,5]thiadiazole. In another aspect of the invention, But represents a phenyl, pyridinyl, naphthyl or benzo[1,2,5]thiadiazole. In another aspect of the invention, But represents a phenyl or pyridinyl. In another aspect of the invention a represents phenyl. In another aspect of the invention, But represents pyridinyl. In another aspect of the invention a represents naphthyl. In still another aspect of the invention, But represents a benzo[1,2,5]thiadiazole.

Another aspect of the invention are compounds of formula(2), (3), (4), (5) and (6)

,,

,and

.

Yet another aspect of the invention comprise compounds of formulas (2A), (2b), (2c), (2d), (2e), (2f), (3A), (4A), (4b), (5A), (6A) and (6b)

,,

,,

, ,

,,

,,

or.

Yet another aspect of the invention are compounds of the formula (2A), (2b), (2C), (2d), (6A) and (6b)

,,

,,

and

Yet another aspect of the invention are compounds of the formula (2a)

.

Yet another aspect of the invention are compounds of the formula (2b)

.

Yet another aspect of the invention are compounds of the formula (2c)

.

Yet another aspect of the invention are compounds of formula (2d)

.

Yet another aspect of the invention are compounds of formula (6A)

.

Yet another aspect of the invention are compounds of formula (6b)

.

In another aspect of the invention, each of R1a, R1band R1cindependently selected from hydrogen, halogen, hydroxyl, cyano, C1-C6alkyl, C1-C6halogenoalkane, group0-C 3alkyls3-C6cycloalkyl, -S(O)pR and SF5. In still another aspect of the invention, each of R1a, R1band R1cindependently selected from hydrogen, halogen, hydroxyl, cyano, C1-C6halogenoalkane and group C0-C3alkyls3-C6cycloalkyl. In still another aspect of the invention, each of R1a, R1b, R1cindependently selected from hydrogen, halogen, hydroxyl, cyano and C1-C6halogenoalkane. In still another aspect of the invention, each of R1a, R1band R1cindependently selected from hydrogen, fluorine, chlorine, bromine, cyano and C1-C6halogenoalkane. In still another aspect of the invention, each of R1a, R1band R1cindependently selected from hydrogen, fluorine, chlorine, bromine and C1-C6halogenoalkane. In still another aspect of the invention, each of R1a, R1band R1cindependently selected from hydrogen, fluorine, chlorine, bromine and-CF3. In still another aspect of the invention, each of R1a, R1band R1cindependently selected from hydrogen, fluorine, chlorine and-CF3.

In still another aspect of the invention, the integer n in (R2)nrepresents 2. When the integer n represents 2, then R2may be the same or different. In still another aspect of the invention a� the number n (R 2)nis a 1. In still another aspect of the invention, the integer n in (R2)nis a 0.

In still another aspect of the invention, R2selected from halogen, cyano, C1-C6alkyl, C1-C6halogenoalkane, hydroxyl, -C(O)NRaRbWith2-C6alkenyl or-OR. In still another aspect of the invention, R2selected from halogen, cyano, C1-C6alkyl, C1-C6halogenoalkane, hydroxyl, -C(O)NRaRbor-OR. In still another aspect of the invention, R2selected from halogen, cyano, C1-C6alkyl, -C(O)NRaRbor hydroxyl. In still another aspect of the invention, R2selected from halogen, cyano, -C(O)NRaRbor hydroxyl. In still another aspect of the invention, R2selected from cyano, or-C(O)NRaRbor hydroxyl. In still another aspect of the invention, R2selected from cyano. In still another aspect of the invention, R2selected from-C(O)NRaRb.

In another aspect of the invention, R3represents hydrogen, halogen, hydroxyl, cyano, C1-C6alkyl, C1-C6halogenated, S0-C3alkyls3-C6cycloalkyl, -C(O)NH2, -SC(O)R, -C(O)NRaRbWith0-C3NRaR4, -NRaNRbR4, -NRsup> aORb, -ONRaRbN3, -NHR4, -Or, or-S(O)pR. In yet another aspect of the invention, R3represents hydrogen, halogen, hydroxyl, cyano, C1-C6alkyl, C1-C6halogenated, S0-C3alkyls3-C6cycloalkyl, -C(O)NH2, -C(O)NRaRbWith0-C3NRaR4, -NRaNRbR4, -NRaORb, -ONRaRbN3, -NHR4or-S(O)pR. In yet another aspect of the invention, R3represents hydrogen, halogen, hydroxyl, cyano, C1-C6alkyl, C1-C6halogenated, S0-C3alkyls3-C6cycloalkyl, -C(O)NH2, -C(O)NRaRbWith0-C3NRaR4, -NRaNRbR4, -NHR4N3or-S(O)pR. In yet another aspect of the invention, R3represents hydrogen, halogen, hydroxyl, cyano, C1-C6alkyl, C1-C6halogenated, S0-C3alkyls3-C6cycloalkyl, -C(O)NH2, -C(O)NRaRb, -NHR4N3or-S(O)pR. In yet another aspect of the invention, R3represents hydrogen, halogen, hydroxyl, cyano, C1-C6alkyl, C1-C6halogenated, S0-C3alkyls3-C6cycloalkyl, -C(O)NH2 or N3.

In still another aspect of the invention, R3represents hydrogen, halogen, hydroxyl, cyano, C1-C6alkyl, C1-C6halogenated or N3. In still another aspect of the invention, R3represents hydrogen, halogen, hydroxyl, cyano, C1-C6alkyl or N3. In still another aspect of the invention, R3represents hydrogen, halogen, hydroxyl, cyano or N3. In still another aspect of the invention, R3represents hydrogen, fluorine, chlorine, bromine, N3, hydroxyl or cyano. In still another aspect of the invention, R3represents hydrogen, fluorine, N3, hydroxyl or cyano. In still another aspect of the invention, R3represents hydrogen. In still another aspect of the invention, R3represents fluorine. In still another aspect of the invention, R3represents chlorine. In still another aspect of the invention, R3represents a hydroxyl. In still another aspect of the invention, R3represents cyano. In still another aspect of the invention, R3is an N3.

In another aspect of the invention, R4represents C1-C6alkyl, C0-C6alkyls3-C6cycloalkyl, -C(O)R5, -C(S)R5, -C(O)NRaR5/sup> , -C(O)C(O)NRaR5, -S(O)pRc, -S(O)2NRaR5, -C(NR7)R5, -C(NR7)NRaR5With0-C6alkylglycerol or C0-C6alkylglycerols; where each of the groups (C1-C6alkyl or C0-C6alkyls3-C6cycloalkyl as R4and R5it may be possible and independently substituted as disclosed herein, and where each of the substituents Ra, Rc, R4and R5it may be possible and independently substituted as disclosed in this description. In still another aspect of the invention, R4represents-C(O)R5, -C(O)NRaR5, -S(O)pRc, -C(S)R5, -S(O)2NRaR5, -C(NR7)R5or-C(NR7)NRaR5and where each of the substituents Ra, Rcand R5it may be possible and independently substituted as disclosed elsewhere herein.

In still another aspect of the invention, R4represents-C(O)R5or-C(O)NRaR5and where each of the substituents Raand R5it may be possible and independently substituted as disclosed elsewhere herein.

In still another aspect of the invention, when R4represents-C(O)R5then R5represents hydrogen, C1-C6alkyl, C0-C6and�of CILS 3-C6cycloalkyl, S0-C6alkylphenyl, S0-C6alkylglycerol or C0-C6alkylglycerols where the specified C1-C6alkyl or C0-C6alkyls3-C6cycloalkyl as R5it may be possible and independently substituted by at least one substituent selected from cyano, halogen, hydroxyl, oxo, C1-C6alkoxy, C1-C6halogenoalkane, C1-C6halogenoalkane, -S(O)pRc, -SH, -S(O)pNRaRb, -NRaRb, -NRaC(O)Rb, -SC(O)Rc, -SCN, or-C(O)NRaRbwhere a specified grouping With0-C6alkylphenyl, S0-C6alkylglycerol or C0-C6Alkylglucoside as R5may be optionally substituted by at least one substituent selected from cyano, halogen, hydroxyl, C1-C6alkoxy, C1-C6alkyl, C1-C6halogenoalkane, -SH, -S(O)pR and C1-C6halogenoalkane. The substituents Raand Rcalso possibly substituted by at least one substituent as defined in this specification.

In still another aspect of the invention, when R4represents-C(O)R5then R5represents hydrogen, C1-C6alkyl, C0-C6alkyls 3-C6cycloalkyl or C0-C6alkylglycerol, where the groups With0-C6alkyls3-C6cycloalkyl or C0-C6alkylglycerol possibly substituted as defined in this specification.

In still another aspect of the invention, when R4represents-C(O)R5then R5is methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -(CH2)2-cyclopropyl, -(CH2)2-cyclobutyl, -(CH2)2-cyclopentyl, pyrazolyl, -CH2-pyrazolyl, -(CH2)2-pyrazolyl, pyridinyl, -CH2-pyridinyl, -(CH2)2-pyridinyl, where alkyl (e.g. methyl, ethyl and propyl), cycloalkyl (such as cyclopropyl and cyclobutyl) or alkylsilanes (e.g.-CH2-cyclopropyl and -(CH2)2-cyclobutyl) may be possible and independently substituted as specified in this specification.

In still another aspect of the invention, when R4represents-C(O)R5then R5is methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopenta�, -(CH2)2-cyclopropyl, -(CH2)2-cyclobutyl, -(CH2)2-cyclopentyl, pyrazolyl, -CH2-pyrazolyl, -(CH2)2-pyrazolyl, pyridinyl, -CH2-pyridinyl, -(CH2)2-pyridinyl, where alkyl (e.g. methyl, ethyl and propyl), cycloalkyl (such as cyclopropyl and cyclobutyl) or alkylsilanes (e.g.-CH2-cyclopropyl and -(CH2)2-cyclobutyl) may be possible and independently substituted by at least one substituent selected from cyano, halogen, hydroxyl, oxo, methoxy, -CF3, ethoxy, -S(O)pR-SCH3, -SCH2CH3, -NH2, -NHCH3, -NHCH2CH3, -NH(CH2)2CH3groups-N-N, -N2the cyclopropyl, -N2cyclobutyl, -NRC(O)Rbor-C(O)NH2.

In still another aspect of the invention, when R4represents-C(O)R5then R5is methyl, ethyl, propyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, pyrazolyl, -CH2-pyrazolyl, pyridinyl, -CH2-pyridinyl, where alkyl (e.g. methyl, ethyl and isopropyl), cycloalkyl (such as cyclopropyl and cyclobutyl) or alkylsilanes (e.g.-CH2-cyclopropyl) may be possible and independently of zameshano at least one Deputy, selected from cyano, halogen, hydroxyl, oxo, -CF3, S(O)pR, methoxy, ethoxy, -SCH3, -NH2, -NHCH3, -NHCH2CH3groups-NH, -NH, -NHC(O)H or-C(O)NH2.

In still another aspect of the invention, when R4represents-C(O)R5then R5is methyl, ethyl, propyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, pyrazolyl, -CH2-pyrazolyl, pyridinyl, -CH2-pyridinyl, where alkyl (e.g. methyl, ethyl and isopropyl), cycloalkyl (such as cyclopropyl and cyclobutyl) or alkylsilanes (e.g.-CH2dihydro) may be possible and independently substituted by at least one substituent selected from cyano, halogen, hydroxyl, oxo, -CF3, methoxy, -SCH3, S(O)pR-NH2, -NHCH3, -NHCH2CH3groups-N, -NHC(O)H or-C(O)NH2.

In still another aspect of the invention, when R4represents-C(O)R5then R5is oxetan, Titan, azetidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, -CH2-oxetane, -CH2-Titan, -CH2-azetidin or-CH2-tetrahydrofuran, each of which may substituted as defined in this description. In another one�m another aspect of the invention, when R4represents-C(O)R5then R5is oxetan, Titan, azetidine, tetrahydrofuran, tetrahydrothiophene, -CH2-oxetane, -CH2-Titan or-CH2-azetidine, each of which may substituted as defined in this description. In still another aspect of the invention, when R4represents-C(O)R5then R5is oxetan, Titan, azetidin, -CH2-oxetane, -CH2-Titan or-CH2-azetidine, each of which may substituted as defined in this description. In still another aspect of the invention, when R4represents-C(O)R5then R5is oxetan, Titan or azetidine, each of which may substituted as defined in this description. In still another aspect of the invention, when R4represents-C(O)R5then R5represents-CH2-oxetane, -CH2-Titan or-CH2-azetidine, each of which may substituted as defined in this description. In still another aspect of the invention, when R4represents-C(O)R5then R5represents pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, pyridine, pyridazine, pyrazine or pyrimidine, each of which is feasible� substituted, as defined in this specification.

In still another aspect of the invention, when R4represents-C(O)R5then R5represents C1-C6alkyl, C3-C6the alkenyl or C0-C6alkyls3-C6cycloalkyl, where each of the C1-C6the alkyl group or C0-C6alkyls3-C6cycloalkyl possibly substituted by at least one substituent selected from cyano, halogen, hydroxyl, -S(O)pRc, C1-C6alkoxy, -S(O)pNRaRbor-SC(O)Rc; pyrazole, pyridine, oxazol, pyridazine, triazole, azetidin, Titan, where each heterocyclyl and heteroaryl group may optionally substituted by at least one Deputy, selected from fluorine, hydroxyl, methyl and oxo;

where R, Ra, Rband Rcare as defined elsewhere herein.

In still another aspect of the invention, when R4represents-C(O)NRaR5then Rarepresents hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -(CH2)2-cyclopropyl, -(CH2)2-cyclobutyl or -(CH2)2-cyclopentyl; where alkyl (for example methyl and propyl), cyclol�Il (such as cyclopropyl and cyclopentyl) or alkylsilanes (e.g.-CH 2-cyclopropyl, -CH2-cyclopentyl and -(CH2)2cyclobutyl) possibly substituted by cyano or at least one Deputy halogen; and R5is such as defined in this specification.

In still another aspect of the invention, when R4represents-C(O)NRaR5then Rarepresents hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl; where alkyl (for example methyl and propyl), cycloalkyl (such as cyclopropyl and cyclopentyl) or alkylsilanes (e.g.-CH2-cyclopropyl, and-CH2-cyclopentyl) possibly substituted by cyano or at least one Deputy halogen; and R5is such as defined in this specification.

In still another aspect of the invention, when R4represents-C(O)NRaR5then Rarepresents hydrogen or methyl, and R5selected from hydrogen, methyl, ethyl, propyl, cyclopropyl and group C0-C6alkylglycerols, where each alkyl group and alkylglycerol possibly substituted as disclosed elsewhere herein.

In still another aspect of the invention, when R4represents-S(O)pRc, the integer p is 2, and Rcso, how about�the determined in this description, then the specified substituent Rcpossibly substituted by at least one substituent as defined in this description. In still another aspect of the invention, when R4represents-S(O)pRc, the integer p is 2, Rcrepresents C1-C6alkyl, possibly substituted by at least one substituent as defined in this description. In still another aspect of the invention, when R4represents-S(O)pRc, the integer p is 2, then Rcrepresents C1-C6alkyl, possibly substituted by at least one substituent selected from cyano or halogen. In still another aspect of the invention, when R4represents-S(O)pRc, the integer p is 2, and Rcrepresents C1-C6alkyl. In still another aspect of the invention, when R4represents-S(O)pRc, the integer p is 2, and Rcis methyl, ethyl, propyl or isopropyl. In still another aspect of the invention, when R4represents-S(O)pRc, the integer p is 2, and Rcis methyl or ethyl.

In still another aspect of the invention, R6represents cyano, C1-C6alkyl, C1-C6halogenated or-C(O)NH2.In still another aspect of the invention, R 6represents cyano, C1-C6alkyl or C1-C6halogenated. In still another aspect of the invention, R6represents cyano, methyl, ethyl or C1-C6halogenated. In still another aspect of the invention, R6represents a cyano, methyl or C1-C6halogenated. In still another aspect of the invention, R6represents cyano or C1-C6halogenated. In still another aspect of the invention, R6represents C1-C6halogenated. In still another aspect of the invention, R6represents-CF3, -CHF2, -CH2F and-CF2Cl. In still another aspect of the invention, R6represents-CF3, -CHF2and-CH2F. In still another aspect of the invention, R6represents-CF3.

In still another aspect of the invention R is methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl or cyclopentyl. In still another aspect of the invention R is methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl.

In still another aspect of the invention, Rarepresents hydrogen, methyl, ethyl, propyl, isopropyl or isobutyl, and each alkyl group possibly substituted as defined in this description. In yet another drogomyrecka of the invention, R arepresents hydrogen, methyl, ethyl, propyl or isopropyl, and each alkyl group possibly substituted as defined in this description. In still another aspect of the invention, Rarepresents hydrogen, methyl or ethyl, wherein each alkyl possibly substituted as defined in this specification.

In still another aspect of the invention, Rarepresents hydrogen, methyl, ethyl, propyl, isopropyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, -CH2-or cyclopropyl-CH2-cyclobutyl, with each alkyl group, cycloalkyl and alkylsilanes possibly substituted as defined in this description. In still another aspect of the invention, Rarepresents hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, -CH2-or cyclopropyl-CH2-cyclobutyl, with each alkyl group, cycloalkyl and alkylsilanes possibly substituted as defined in this description. In still another aspect of the invention, Rarepresents hydrogen, methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, -CH2-or cyclopropyl-CH2-cyclobutyl, with each alkyl group, cycloalkyl and alkylsilanes possibly substituted as defined in this specification.

In another aspect of the invention, Rbis �Wallpaper of hydrogen, C1-C6alkyl, C3-C6cycloalkyl, S0-C3alkylphenyl or C0-C3alkylglycerol. In still another aspect of the invention, Rbrepresents hydrogen, C1-C6alkyl, C3-C6cycloalkyl or C0-C3alkylglycerol. In still another aspect of the invention, Rbrepresents hydrogen, C1-C6alkyl or C3-C6cycloalkyl. In still another aspect of the invention, Rbrepresents hydrogen, methyl, ethyl, isopropyl, propyl, isobutyl, cyclopropyl or cyclobutyl.

Another aspect of the invention are compounds of formula (1), selected from the following compounds:

1-(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)Etalon;

the cyclopropyl(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)methanon;

3-fluoro-N-methyl-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-carboxamide;

N-ethyl-3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-carboxamide;

N-cyclopropyl-3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-carboxamide;

the cyclopropyl(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-ftores�tidin-1-yl)methanon;

1-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpropan-1-he;

3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-fluoro-N-methylaziridine-1-carboxamide;

3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-ethyl-3-torasemide-1-carboxamide;

N-cyclopropyl-3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-carboxamide;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)propane-1-he;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)butane-1-he;

2-cyclopropyl-1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)Etalon;

3-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3-oxopropanenitrile;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylthio)Etalon;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methoxyethanol;

cyclobutyl(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)methanon;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)Hairdryer�l)-3-torasemide-1-yl)-2-methylpropan-1-it;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he;

N-cyclopropyl-3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-carboxamide;

3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-fluoro-N-methylaziridine-1-carboxamide;

3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-ethyl-3-torasemide-1-carboxamide;

3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-carboxamide;

the cyclopropyl(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-hydroxyazetidine-1-yl)methanon;

cyclobutyl(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-hydroxyazetidine-1-yl)methanon;

3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-fluoro-N-methylaziridine-1-carboxamide;

3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-ethyl-3-torasemide-1-carboxamide;

N-cyclopropyl-3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-carboxamide;

3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-ethyl-3-hidroxi�lidin-1-carboxamide;

N-cyclopropyl-3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-hydroxyazetidine-1-carboxamide;

3-(4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-fluoro-N-methylaziridine-1-carboxamide;

3-(4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-ethyl-3-torasemide-1-carboxamide;

3-(4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-cyclopropyl-3-torasemide-1-carboxamide;

3-(4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-temporaril-3-hydroxyazetidine-1-carboxamide;

3-(4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-ethyl-3-hydroxyazetidine-1-carboxamide;

3-(4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-ethyl-3-torasemide-1-carboxamide;

3-(4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-cyclopropyl-3-torasemide-1-carboxamide;

3-(4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-fluoro-N-methylaziridine-1-carboxamide;

1-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)Etalon;

the cyclopropyl(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemid�n-1-yl)methanon;

2-cyclopropyl-1-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)Etalon;

3-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3-oxopropanenitrile;

1-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he;

1-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methoxyethanol;

1-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)propane-1-he;

1-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)butane-1-he;

5-[3,5-bis(trifluoromethyl)phenyl]-3-{4-[1-(cyclobutanecarbonyl)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-[3,5-bis(trifluoromethyl)phenyl]-3-{4-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-[3,5-bis(trifluoromethyl)phenyl]-3-[4-(3-fluoro-1-isobutyrylacetate-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-[4-(1-butyryl-3-torasemide-3-yl)phenyl]-5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-[3-chloro-5-(trifluoromethyl)phenyl]-3-[4-(3-fluoro-1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-[4-(1-acetyl-3-torasemide-3-yl)phenyl]-5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-di�hydrosocial;

3-[3-(4-{5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-torasemide-1-yl]-3-oxopropanenitrile;

1-[(3-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)carbonyl]cyclopropanol;

1-[(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)carbonyl]cyclopropanol;

3-{4-[3-fluoro-1-(methoxyacetyl)azetidin-3-yl]phenyl}-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-1-isobutyrylacetate-3-ol;

1 butyryl-3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)azetidin-3-ol;

5-[3,5-bis(trifluoromethyl)phenyl]-3-{4-[1-(cyclopropylethyl)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;

2-[3-(4-{5-[3,5-bis(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-torasemide-1-yl]-2-oxoethyl;

5-[3-chloro-5-(trifluoromethyl)phenyl]-3-(4-{3-fluoro-1-[(methylthio)acetyl]azetidin-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-[3-chloro-5-(trifluoromethyl)phenyl]-3-{4-[1-(cyclobutanecarbonyl)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-[3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-torasemide-1-yl]-3-oxopropanoic;

3-[3-(4-{5-[3,4-dichloro-5-(�reformer)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-torasemide-1-yl]-3-oxopropanoic;

1-[(3-fluoro-3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-yl)carbonyl]cyclopropanol;

5-(3,5-dichlorophenyl)-3-{4-[3-fluoro-1-(3-methylbutanoyl)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-(4-{3-fluoro-1-[(methylthio)acetyl]azetidin-3-yl}phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-1-Propionaldehyde-3-ol;

5-[3-chloro-5-(trifluoromethyl)phenyl]-3-{4-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-(3,5-dichloro-4-fluorophenyl)-3-{4-[3-fluoro-1-(1H-pyrazol-3-ylcarbonyl)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;

4-{2-[3-(4-{5-[3,5-bis(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-torasemide-1-yl]-2-oxoethyl}pyridine;

5-[3-chloro-5-(trifluoromethyl)phenyl]-3-{4-[1-(cyclopropylethyl)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-3-[4-(3-fluoro-1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-{4-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]phenyl}-5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-[4-(1-acetyl-3-torasemide-3-yl)phenyl]-5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-3-[4-(3-PIF�-1-isobutyrylacetate-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-[3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-torasemide-1-yl]-3-oxopropanenitrile;

4-[(3-fluoro-3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-yl)carbonyl]pyridine;

5-[3,5-bis(trifluoromethyl)phenyl]-3-[4-(3-fluoro-1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-{4-[1-(cyclopentanecarbonyl)-3-torasemide-3-yl]phenyl}-5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-3-(4-{3-fluoro-1-[(methylthio)acetyl]azetidin-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

1-(cyclopropanecarbonyl)-3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-3-ol;

(3-(2-bromo-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(cyclopropyl)methanon;

2-(1-(cyclopropanecarbonyl)-3-torasemide-3-yl)-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)benzonitrile;

5-(3-chloro-5-(trifluoromethyl)phenyl)-3-(4-(3-fluoro-1-(methyl-sulfonyl)-azetidin-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-(2-bromo-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-1-(cyclopropanecarbonyl)azetidin-3-carbonitril;

1-(cyclopropanecarbonyl)-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-3-carbonit�l;

1-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-methylpropan-1-he;

2-methyl-1-(3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)propane-1-he;

the cyclopropyl(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)methanon;

the cyclopropyl(3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)methanon;

1-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)Etalon;

1-(3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)Etalon;

1-isobutyryl-3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-3-ol;

3-{4-[3-fluoro-1-(3,3,3-triptocaine)azetidin-3-yl]phenyl}-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-{4-[1-(cyclopropylethyl)-3-torasemide-3-yl]phenyl}-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-[4-(1-butyryl-3-torasemide-3-yl)phenyl]-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-[4-(3-fluoro-1-isobutyrylacetate-3-yl)phenyl]-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-[4-(3-fluoro-1-Propionaldehyde-3-yl)phenyl]-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-[3-chloro-5-(trifluoromethyl)phenyl]-3-[4-(3-fluoro-1-isobutyrylacetate-3-yl)phenyl]-5-(trif�ormetal)-4,5-dihydroisoxazole;

2-[3-(4-{5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-torasemide-1-yl]-2-oxoethyl;

5-[3-chloro-5-(trifluoromethyl)phenyl]-3-{4-[1-(cyclopentanecarbonyl)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-[4-(1-butyryl-3-torasemide-3-yl)phenyl]-5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-(3,5-dichlorophenyl)-3-[4-(1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

1-[(3-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-yl)carbonyl]cyclopropanol;

5-(3,5-dichlorophenyl)-3-{4-[1-(methoxyacetyl)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-{4-[1-(cyclopropylethyl)azetidin-3-yl]phenyl}-5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-[4-(1-acetylisatin-3-yl)phenyl]-5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-3-[4-(1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-[4-(1-butyrylacetate-3-yl)phenyl]-5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-[4-(1-butyrylacetate-3-yl)phenyl]-5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

2-[3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)azetidin-1-yl]-2-oxoethyl;

1-{[3-(-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)azetidin-1-yl]carbonyl}cyclopropanol;

5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-3-(4-{1-[(methylthio)acetyl]-azetidin-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-[3-chloro-5-(trifluoromethyl)phenyl]-3-{4-[1-(cyclopropylethyl)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-[3-chloro-5-(trifluoromethyl)phenyl]-3-{4-[1-(methoxyacetyl)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-[3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)azetidin-1-yl]-3-oxopropanenitrile;

1-{[3-(4-{5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)azetidin-1-yl]carbonyl}cyclopropanol;

5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-3-{4-[1-(methoxyacetyl)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-[3-chloro-5-(trifluoromethyl)phenyl]-3-[4-(1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-[4-(1-butyrylacetate-3-yl)phenyl]-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-[3-chloro-5-(trifluoromethyl)phenyl]-3-[4-(1-isobutyrylacetate-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

1-[(3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-yl)carbonyl]cyclopropanol;

3-[4-(1-Propionaldehyde-3-yl)phenyl]-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-(4-{1-[(methylthio)acetyl]azetidin-3-yl}phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-{4-[1-(methoxyacetyl)azetidin-3-yl]phenyl}-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-{4-[1-(cyclopropylethyl)azetidin-3-yl]phenyl}-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-(3,5-dichloro-4-fluorophenyl)-3-(4-{1-[(methylthio)acetyl]azetidin-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-(3,5-dichloro-4-fluorophenyl)-3-{4-[1-(methoxyacetyl)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;

1-[(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-yl)carbonyl]cyclopropanol;

5-(3,5-dichloro-4-fluorophenyl)-3-[4-(1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-(3,5-dichloro-4-fluorophenyl)-3-[4-(1-isobutyrylacetate-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-(3,5-dichloro-4-fluorophenyl)-3-(4-{1-[(3,3-diversecity-1-yl)carbonyl]-3-torasemide-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-1-(3,3,3-triptocaine)azetidin-3-ol;

5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-3-{4-[3-fluoro-1-(3,3,3-Cryptor-propanol)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-(3,5-dichloro-4-fluorophenyl)-3-(4-{3-fluoro-1-[(4-methyl-1,3-oxazol-5-yl)carbonyl]azetidin-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

N-[2-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-2-oxoethyl]formamide;

4-[(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]f�nil}-3-torasemide-1-yl)carbonyl]pyridazin;

1-[2-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-2-oxoethyl]-1H-1,2,4-triazole;

5-(3,5-dichloro-4-fluorophenyl)-3-(4-{3-fluoro-1-[(methyl-sulfonyl)acetyl]-azetidin-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-(3,5-dichloro-4-fluorophenyl)-3-{4-[3-fluoro-1-(1H-pyrazol-1-ylacetic)-azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-(3,5-dichloro-4-fluorophenyl)-3-{4-[3-fluoro-1-(1,3-oxazol-5-ylcarbonyl)-azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-(3,5-dichloro-4-fluorophenyl)-3-{4-[1-(2,2-diperbadankan)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;

1-{[3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-torasemide-1-yl]carbonyl}azetidin-3-ol;

1-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl]phenyl}-3-torasemide-1-yl)-2-methyl-1-oxoprop-2-ol;

3-[4-(1-but-3-enoyl-3-torasemide-3-yl)phenyl]-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

2-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-N,N-dimethyl-2-oxetanemethanol;

5-(3,5-dichloro-4-fluorophenyl)-3-[4-(3-fluoro-1-{[(trifluoromethyl)thio]acetyl}-azetidin-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-(3,5-dichloro-4-fluorophenyl)-3-{4-[3-fluoro-1-(2-methoxypropanol)-azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole�l;

5-(3,5-dichloro-4-fluorophenyl)-3-(4-{1-[(2,2-diversicolor)carbonyl]-3-torasemide-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl]phenyl}-3-torasemide-1-yl)-2-methyl-3-oxoprop-1-ol;

(2S)-4-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-4-oxobutyl-2-ol;

4-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl]phenyl}-3-torasemide-1-yl)-4-oxobutyl-2-ol;

3-{4-[3-chloro-1-(temporarycareer)azetidin-3-yl]phenyl}-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-{4-[3-chloro-1-(cyclopropanecarbonyl)azetidin-3-yl]phenyl}-5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-(3-chlorophenyl)-3-{4-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-{4-[5-(3-chloro-4,5-differenl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-1-(cyclopropanecarbonyl)-azetidin-3-ol;

3-{4-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]phenyl}-5-[3,4-debtor-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

(2S)-1-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-1-oxoprop-2-ol;

(2R)-1-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-1-oxoprop-2-ol;

(2S)-4-(3{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-4-oxobutyl-2-ol;

5-(3,5-dichloro-4-fluorophenyl)-3-(4-{3-fluoro-1-[(methylsulfinyl)acetyl]-azetidin-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-{4-[3-azido-1-(cyclopropanecarbonyl)azetidin-3-yl]phenyl}-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-[4-(3-azido-1-Propionaldehyde-3-yl)phenyl]-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

8-[2-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-2-oxoethyl] attentioin;

5-(3-fluorophenyl)-3-[4-(3-fluoro-1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-(3-chlorophenyl)-3-[4-(3-fluoro-1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

5-(3,4-dichlorophenyl)-3-[4-(3-fluoro-1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-{4-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-5-[3-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole;

5-(3-chloro-5-fluorophenyl)-3-{4-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-{4-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]phenyl}-5-(3,4-differenl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he;

3-{4-[1-(azetidin-1-ylcarbonyl)-3-torasemide-3-yl]phenyl}-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-{4-[1-(azetidin-1-ylcarbonyl)-3-torasemide-3-yl]phenyl}-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

3-{4-[1-(azetidin-1-ylcarbonyl)-3-torasemide-3-yl]phenyl}-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

1-(cyclopropanecarbonyl)-3-{4-[(5R)-5-[3,4-dichloro-5-(trifluoromethyl)-phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-3-ol;

5-(3,5-dichloro-4-fluorophenyl)-3-[4-(3-fluoro-1-isobutyrylacetate-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;

{[2-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl]phenyl}-3-torasemide-1-yl)-2-oxoethyl]sulfonyl}acetonitrile;

1-(3-{4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-3-methanesulfonyl-propane-1-he;

1-(3-{4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-2-(2,2,2-Cryptor-econsultancy)-Etalon;

dimethylamide 2-(3-{4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-2-oxo-econsult acid;

2-benzolsulfonat-1-(3-{4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-Cryptor-methyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-Etalon;

1-(3-{4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-2-methanesulfonyl-propane-1-he;

(1-cyclopropanecarbonyl-3-{4-[5-(3,4-dichloro-5-trifluoromethyl-FeNi�)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-azetidin-3-yl)-amide cyclopropanecarbonyl acid;

(3-amino-3-{4-[5-(3,4-dichloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-azetidin-1-yl)-cyclopropyl-methanon;

3-fluoro-3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-carboxamide;

N-cyclopropyl-3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-carboxamide;

N-cyclopropyl-3-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-carboxamide;

3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-hydroxy-N-propylamide-1-carboxamide;

3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-hydroxy-N,N-dimethylamide-1-carboxamide;

N-ethyl-3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl]phenyl}azetidin-1-carboxamide;

3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl]phenyl}-N-methylaziridine-1-carboxamide;

3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-N-methylaziridine-1-carboxamide;

3-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-N-utilisation-1-carboxamide;

3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl]phenyl}-N-utilisation-1-carboxamide;

3-(4-{5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroiso�ol-3-yl}phenyl)-N-methylaziridine-1-carboxamide;

3-(4-{5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl}phenyl)-N-cyclopropylamines-1-carboxamide;

N-cyclopropyl-3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-carboxamide;

N-cyclopropyl-3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)azetidin-1-carboxamide;

3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-fluoro-N-(2,2,2-trifluoroethyl)azetidin-1-carboxamide;

3-fluoro-N,N-dimethyl-3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-carboxamide;

3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-fluoro-M,N-dimethylamide-1-carboxamide;

3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-fluoro-N-(3,3,3-cryptochromes)azetidin-1-carboxamide;

3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-fluoro-N-oxetan-3-ilization-1-carboxamide;

3 azido-N,N-dimethyl-3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-carboxamide;

2-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]-5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]benzonitrile;

2-(1-acetyl-3-torasemide-3-yl)-5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,-dihydroisoxazole-3-yl]benzonitrile;

5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]-2-[3-fluoro-1-(3,3,3-triptocaine)azetidin-3-yl]benzonitrile;

5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]-2-(3-fluoro-1-Propionaldehyde-3-yl)benzonitrile;

5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]-2-(3-fluoro-1-isobutyrylacetate-3-yl)benzonitrile;

5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]-2-(3-fluoro-1-glycolylated-3-yl)benzonitrile;

2-(1-butyryl-3-torasemide-3-yl)-5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]benzonitrile;

2-[1-(cyclobutanecarbonyl)-3-torasemide-3-yl]-5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]benzonitrile;

2-[1-(cyclopentanecarbonyl)-3-torasemide-3-yl]-5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]benzonitrile;

5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]-2-[3-fluoro-1-(methoxyacetyl)azetidin-3-yl]benzonitrile;

2-[1-(cyclopropylethyl)-3-torasemide-3-yl]-5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]benzonitrile;

5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]-2-(3-fluoro-1-pentanolide-3-yl)benzonitrile;

5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]-2-{3-fluoro-1-[(methylthio)acetyl]-azetidin-3-yl}Bentonit�l;

2-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]pyridine;

(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)(1-oxidation-3-yl)methanon;

(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)(1,1-deoxidation-3-yl)methanon;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpropan-1-thione;

(1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpiperidin)cyanamide;

(1-(3-fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-azetidin-1-yl)-2-methanesulfonyl-Etalon; and

1-(3-{4-[5-(3,4-dichloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-2-methanesulfonyl-atanan,

their stereoisomers, pharmaceutically or veterinary acceptable salts.

Another aspect of the invention are compounds of formula (1), which have been shown to have biological indicators in at least one bioassay ED with the value100, LD100, LD90and/or ED80no more than 1 μg/ml or 1 µg/fly, selected from Examples 1-60, 65-70, 72-77, 82, 84-85, 87, 89, 91, 95-101, 103-104, 106-107, 109-110, 113, 116-117, 119-121, 123-126, 128-133, 135-143, 145-146, 148, 152-155, 158, 160-165, 167-171, 173-176 187-188, 197-199 and 200-224, their stereoisomers, pharmaceutically or veterinary acceptable salts.

Another aspect of the invention are compounds of formula (1), which have been shown to have biological indicators in at least one bioassay ED with the value100, LD100, LD90and/or ED80not more than 0.3 μg/ml, or not more than 0.3 µg/fly, selected from Examples 1-17, 19-30, 32-54, 56-60, 65-70, 72-74, 76-77, 82, 84, 87, 95-99, 103-104, 117, 131, 133, 135-143, 145-146, 148, 152-155, 158, 160-161, 165, 167-171, 173-175, 187-188, 202-204, 206, 209-221 and 223, their stereoisomers, pharmaceutically or veterinary acceptable salts.

Another aspect of the invention are compounds of formula (1), which have been shown to have biological indicators in at least one bioassay ED with the value100, LD100, LD90and/or ED80not more than 0.1 μg/ml, or not more than 0.1 µg/fly, selected from Examples 1-17, 19-21, 24, 26-30, 32-34, 36-48, 50-54, 56-60, 65-70, 72-74, 76-77, 84, 87, 95-99, 103-104, 117, 131, 133, 135-137, 139-143, 145-146, 148, 152-155, 158, 160, 165, 168-171, 173-175, 188, 202, 206, 209-213, 215-221 and 223, their stereoisomers, pharmaceutically or veterinary acceptable salts.

Another aspect of the invention are compounds of formula (1), which have been shown to have biological indicators in at least one bioassay ED with the value100, LD100, LD90and/or ED80not more than 0.03 µg/ml selected from the Examples 1-17, 19-21, 26-28, 32-34, 36-38, 40-48, 50-54, 56, 59-60, 65-66, 68, 70, 72-74, 76 84, 95-99, 103, 131, 133, 135, 141-143, 145-146, 155, 158, 165, 168-169, 171, 173-175, 202, 206, 209-210, 212-213, 215-216, 218-219 and 221, their stereoisomers, pharmaceutically or veterinary acceptable salts.

Another aspect of the invention are compounds of formula (1), which have been shown to have biological indicators in at least one bioassay ED with the value100, LD100, LD90and/or ED80not more than 0.01 μg/ml or more than 0.01 µg/fly, selected from Examples 1, 5, 10-12, 16, 19-21, 26-28, 33-34, 38, 40, 47, 50, 52, 54, 60, 84, 95, 99, 146, 168-169, 173-175, 202 and 221, their stereoisomers, pharmaceutically or veterinary acceptable salts.

Another aspect of the invention are compounds of formula (1), which have been shown to have biological indicators in at least one bioassay ED with the value100, LD100, LD90and/or ED800.003 µg/ml, selected from Examples 11, 19, 40, 169, 175, their stereoisomers, pharmaceutically or veterinary acceptable salts.

Another aspect of the invention are compounds of formula (1), selected from the following compounds:

5-(3,5-dichloro-4-fluorophenyl)-3-(4-{3-fluoro-1-[(methyl-sulfonyl)acetyl]-azetidin-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

1-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl]phenyl}-3-torasemide-1-yl)-2-methyl-1-oxoprop-2-ol;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl-3-torasemide-1-yl)-3,3,3-cryptochrome-1-it;

5-(3,5-dichloro-4-fluorophenyl)-3-[4-(3-fluoro-1-isobutyrylacetate-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole; and

(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)(1,1-deoxidation-3-yl)methanon,

their stereoisomers, pharmaceutically or veterinary acceptable salts.

Another aspect of the invention are compounds of formula (1), selected from the following compounds:

2,2-dichloro-1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)Etalon;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-2-fluoro-2-methylpropan-1-he;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-3-(methylthio)propane-1-he

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-3-(methyl-sulfonyl)propane-1-he;

(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)(tietan-3-yl)methanon;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroiso-xazal-3-yl)phenyl)-3-torasemide-1-yl)-3,3,3-Cryptor-2-methylpropan-1-he;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-2-methyl-2-(methyl-sulfonyl)-propane-1-he;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifter�ethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)propane-1-he;

(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)(1-(methyl-sulfonyl)-cyclopropyl)methanon;

5-(3,5-dichloro-4-fluorophenyl)-3-(4-(3-fluoro-1-(1,1,1,3,3,3-hexaferrite-2-yl)azetidin-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-3,3-ditropan-1-he;

2-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-N-methyl-2-oxetanemethanol;

2-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-N-isopropyl-2-oxetanemethanol;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-2-(3-hydroxyazetidine-1-yl)Etalon;

1-(3-(4-(5-(3,5-dichloro-4-hydroxyphenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpropan-1-he;

(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)(tietan-2-yl)methanon;

N-(1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-2-methyl-1-oxoprop-2-yl)acetamide;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-2-mercapto-2-methylpropan-1-he;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(triptime�yl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-3,3,3-Cryptor-2-hydroxy-2-methylpropan-1-it;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroiso-xazal-3-yl)phenyl)-3-torasemide-1-yl)-3-hydroxy-2,2-DIMETHYLPROPANE-1-he;

3-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-2,2-dimethyl-3-oxopropanenitrile;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-3,3-ditropan-1-he;

8-(1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-2-methyl-1-oxoprop-2-yl)-atantic;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-2-methyl-2-(methylthio)propane-1-he;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-2-methyl-2-(methyl-sulfonyl)-propane-1-he;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-2-methyl-1-oxoprop-2-sulfonamide;

1-(1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-2-methyl-1-oxoprop-2-yl)urea;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylsulfinyl)Etalon;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)Etalon;

1-(3-(4-(5-(3,5-dichloro-4-ft�henyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-2-(1H-pyrazol-1-yl)Etalon;

1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-2-hydroxy-2-methylpropan-1-he;

(3-{4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-tietan-3-yl-methanon;

(E)-N-(1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpiperidin)-cyanamide;

1-(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)azetidin-1-yl)-2-methylpropan-1-he;

3,3,3-Cryptor-1-(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)propane-1-he;

1-(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)azetidin-1-yl)-2-(methylthio)Etalon;

1-(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)azetidin-1-yl)-2-(methylsulfinyl)Etalon;

1-(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)azetidin-1-yl)-2-(methyl-sulfonyl)Etalon;

1-(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)azetidin-1-yl)-2-(1H-pyrazol-1-yl)Etalon;

1-(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)azetidin-1-yl)-2-hydroxy-2-methylpropan-1-he;

(3-fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-azetidin-1-yl)-tietan-3-yl-methanon;

(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)azetidin-1-yl)(1-oxidation-3-yl)methanon;

(1,1-deoxidation-3-yl)(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)methanon;

(E)-N-(1-(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-methylpiperidin)cyanamide;

1-(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpropan-1-he;

the cyclopropyl(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)methanon;

1-(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-di-hydrosocial-3-yl)phenyl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he;

1-(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylthio)Etalon;

1-(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylsulfinyl)-Etalon;

1-(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)-Etalon;

1-(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(1H-pyrazol-1-yl)Etalon;

1-(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)�enyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-hydroxy-2-methylpropan-1-it;

(3-{4-[5-(3,4-dichloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-tietan-3-yl-methanon;

(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(1-oxidation-3-yl)methanon;

(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(1,1-deoxidation-3-yl)methanon;

(E)-N-(1-(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpiperidin)-cyanamide;

1-(3-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpropan-1-he;

(3-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)(temporaril)methanon;

1-(3-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-di-hydrosocial-3-yl)phenyl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he;

1-(3-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylthio)Etalon;

1-(3-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-di-hydrosocial-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylsulfinyl)Etalon;

1-(3-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)-Etalon;

1-(3-(4-(5-(4-CL�R-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(1H-pyrazol-1-yl)Etalon;

1-(3-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-hydroxy-2-methylpropan-1-he;

(3-{4-[5-(3-chloro-4-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-tietan-3-yl-methanon;

(3-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)(1-oxidation-3-yl)methanon;

(3-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)(1,1-deoxidation-3-yl)methanon;

(E)-N-(1-(3-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpiperidin)-cyanamide;

1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-methylpropan-1-he;

the cyclopropyl(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)methanon;

3,3,3-Cryptor-1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)-phenyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)propane-1-he;

1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-(methylthio)Etalon;

1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-(methylsulfinyl)Etalon;

1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-�hydrosocial-3-yl)phenyl)azetidin-1-yl)-2-(methyl-sulfonyl)Etalon;

1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-(1H-pyrazol-1-yl)Etalon;

1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-hydroxy-2-methylpropan-1-he;

(3-fluoro-3-{4-[5-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-4,5-dihydro-izocsazol-3-yl]-phenyl}-azetidin-1-yl)-tietan-3-yl-methanon;

(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydro-izocsazol-3-yl)phenyl)azetidin-1-yl)(1-oxidation-3-yl)methanon;

(1,1-deoxidation-3-yl)(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3-(trifter-methyl)phenyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)methanon;

(E)-N-(1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-methylpiperidin)cyanamide;

1-(3-(4-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpropan-1-he;

the cyclopropyl(3-(4-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)methanon;

1-(3-(4-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-di-hydrosocial-3-yl)phenyl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he;

1-(3-(4-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylthio)Etalon;

1-(3-(4-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifter�ethyl)-4,5-di-hydrosocial-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylsulfinyl)Etalon;

1-(3-(4-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-di-hydrosocial-3-yl)phenyl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)Etalon;

1-(3-(4-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-di-hydrosocial-3-yl)phenyl)-3-torasemide-1-yl)-2-(1H-pyrazol-1-yl)Etalon;

1-(3-(4-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-di-hydrosocial-3-yl)phenyl)-3-torasemide-1-yl)-2-hydroxy-2-methylpropan-1-he;

(3-{4-[5-(3,4-debtor-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-tietan-3-yl-methanon;

(3-(4-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-di-hydrosocial-3-yl)phenyl)-3-torasemide-1-yl)(1-oxidation-3-yl)methanon;

(3-(4-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(1,1-deoxidation-3-yl)methanon;

(E)-N-(1-(3-(4-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpiperidin)-cyanamide;

1-(3-(4-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpropan-1-he;

(3-(4-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(cyclopropyl)methanon;

1-(3-(4-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he;

1-(3-(4-(5-(3-chloro-4-torfin�l)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylthio)Etalon;

1-(3-(4-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylsulfinyl)Etalon;

1-(3-(4-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)Etalon;

1-(3-(4-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(1H-pyrazol-1-yl)Etalon;

1-(3-(4-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-hydroxy-2-methylpropan-1-he;

(3-{4-[5-(3-Chloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-tietan-3-yl-methanon;

(3-(4-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(1-oxidation-3-yl)methanon;

(3-(4-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(1,1-deoxidation-3-yl)methanon;

(E)-N-(1-(3-(4-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpiperidin)cyanamide;

1-(3-(4-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpropan-1-he;

(3-(4-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(cyclopropyl)methanon;

1-(3-(4-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he;

1-(3-(4-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylthio)Etalon;

1-(3-(4-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylsulfinyl)Etalon;

1-(3-(4-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)Etalon;

1-(3-(4-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(1H-pyrazol-1-yl)Etalon;

1-(3-(4-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-hydroxy-2-methylpropan-1-he;

(3-{4-[5-(3-chloro-5-fluorophenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-tietan-3-yl-methanon;

(3-(4-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(1-oxidation-3-yl)methanon;

(3-(4-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(1,1-deoxidation-3-yl)methanon;

(E)-N-(1-(3-(4-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpiperidin)cyanamide;

1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydro-izocsazol-3-yl)phenyl)azetidin-1-yl)-2-methylpropan-1-he;

the cyclopropyl(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)methanon;

3,3,3-t�iftar-1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)propane-1-he;

1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydro-izocsazol-3-yl)phenyl)azetidin-1-yl)-2-(methylthio)Etalon;

1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydro-izocsazol-3-yl)phenyl)azetidin-1-yl)-2-(methylsulfinyl)Etalon;

1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydro-izocsazol-3-yl)phenyl)azetidin-1-yl)-2-(methyl-sulfonyl)Etalon;

1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydro-izocsazol-3-yl)phenyl)azetidin-1-yl)-2-(1H-pyrazol-1-yl)Etalon;

1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydro-izocsazol-3-yl)phenyl)azetidin-1-yl)-2-hydroxy-2-methylpropan-1-he;

(3-fluoro-3-{4-[5-trifluoromethyl-5-(3,4,5-tryptophanyl)-4,5-dihydro-izocsazol-3-yl]-phenyl}-azetidin-1-yl)-tietan-3-yl-methanon;

(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydro-izocsazol-3-yl)phenyl)azetidin-1-yl)(1-oxidation-3-yl)methanon;

(1,1-deoxidation-3-yl)(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)methanon;

(E)-N-(1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-methylpiperidin)cyanamide;

2-(1-(cyclopropanecarbonyl)-3-torasemide-3-yl)-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)benzonitrile; and

the cyclopropyl(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-hydroxy�slidin-1-yl)methanon,

their stereoisomers, pharmaceutically or veterinary acceptable salts.

Another aspect of the invention are compounds of formula (1), selected from the following compounds:

1-(3-(5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-methylpropan-1-he;

the cyclopropyl(3-(5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)methanon;

1-(3-(5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he;

1-(3-(5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methylthio)Etalon;

1-(3-(5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroiso-xazal-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methylsulfinyl)Etalon;

1-(3-(5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroiso-xazal-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)Etalon;

1-(3-(5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroiso-xazal-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(1H-pyrazol-1-yl)Etalon;

1-(3-(5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroiso-xazal-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-hydroxy-2-methylpropan-1-he;

(3-{5-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-pyridin-2-yl}-3-fluoro-azetidin-1-yl)-tietan-3-yl-methanon;

(3-(5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroiso-xazal-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(1-oxidation-3-yl)methanon;

(3-(5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(1,1-deoxidation-3-yl)methanon;

(E)-N-(1-(3-(5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-methylpiperidin)cyanamide;

1-(3-fluoro-3-(5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)pyridin-2-yl)azetidin-1-yl)-2-methylpropan-1-he;

the cyclopropyl(3-fluoro-3-(5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)methanon;

3,3,3-Cryptor-1-(3-fluoro-3-(5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)propane-1-he;

1-(3-fluoro-3-(5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(methylthio)Etalon;

1-(3-fluoro-3-(5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(methylsulfinyl)Etalon;

1-(3-fluoro-3-(5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(methyl-sulfonyl)Etalon;

1-(3-fluoro-3-(5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(1H-pyrazol-1-yl)Etalon;

1-(3-fluoro-3-(5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)pyridin-2-yl)azetidin-1-yl)-2-hydroxy-2-methylpropan-1-he;

(3-fluoro-3-{5-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydr�-isoxazol-3-yl]-pyridin-2-yl}-azetidin-1-yl)-tietan-3-yl-methanon;

(3-fluoro-3-(5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroiso-xazal-3-yl)pyridin-2-yl)azetidin-1-yl)(1-oxidation-3-yl)methanon;

(1,1-deoxidation-3-yl)(3-fluoro-3-(5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)methanon;

(E)-N-(1-(3-fluoro-3-(5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-di-hydrosocial-3-yl)pyridin-2-yl)azetidin-1-yl)-2-methylpiperidin)-cyanamide;

1-(3-(5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-di-hydrosocial-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-methylpropan-1-he;

the cyclopropyl(3-(5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)methanon;

1-(3-(5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-di-hydrosocial-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he;

1-(3-(5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-di-hydrosocial-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methylthio)Etalon;

1-(3-(5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-di-hydrosocial-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methylsulfinyl)-Etalon;

1-(3-(5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-di-hydrosocial-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)-Etalon;

1-(3-(5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemid�n-1-yl)-2-(1H-pyrazol-1-yl)Etalon;

1-(3-(5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-hydroxy-2-methylpropan-1-he;

(3-{5-[5-(3,4-dichloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-pyridin-2-yl}-3-fluoro-azetidin-1-yl)-tietan-3-yl-methanon;

(3-(5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(1-oxidation-3-yl)methanon;

(3-(5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-di-hydrosocial-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(1,1-deoxidation-3-yl)methanon;

(E)-N-(1-(3-(5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-methylpiperidin)cyanamide;

1-(3-(5-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-di-hydrosocial-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-methylpropan-1-he;

(3-(5-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(cyclopropyl)methanon;

1-(3-(5-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-di-hydrosocial-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he;

1-(3-(5-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methylthio)-Etalon;

1-(3-(5-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)Piri�in-2-yl)-3-torasemide-1-yl)-2-(methylsulfinyl)Etalon;

1-(3-(5-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)Etalon;

1-(3-(5-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(1H-pyrazol-1-yl)Etalon;

1-(3-(5-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-hydroxy-2-methylpropan-1-he;

(3-{5-[5-(4-Chloro-3-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-pyridin-2-yl}-3-fluoro-azetidin-1-yl)-tietan-3-yl-methanon;

(3-(5-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(1-oxidation-3-yl)methanon;

(3-(5-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydro-izocsazol-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(1,1-deoxidation-3-yl)methanon;

(E)-N-(1-(3-(5-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-methylpiperidin)cyanamide;

1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-methylpropan-1-he;

the cyclopropyl(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)methanon;

3,3,3-Cryptor-1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)-phenyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azet�DIN-1-yl)propane-1-he;

1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(methylthio)Etalon;

1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(methylsulfinyl)-Etalon;

1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(methyl-sulfonyl)-Etalon;

1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-di-hydrosocial-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(1H-pyrazol-1-yl)Etalon;

1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-di-hydrosocial-3-yl)pyridin-2-yl)azetidin-1-yl)-2-hydroxy-2-methylpropan-1-he;

(3-fluoro-3-{5-[5-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-4,5-dihydro-izocsazol-3-yl]-pyridin-2-yl}-azetidin-1-yl)-tietan-3-yl-methanon;

(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydro-izocsazol-3-yl)pyridin-2-yl)azetidin-1-yl)(1-oxidation-3-yl)methanon;

(1,1-deoxidation-3-yl)(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)methanon;

(E)-N-(1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-methylpiperidin)-cyanamide;

1-(3-(5-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-methylpropan-1-he;

cyclo�ropel(3-(5-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)methanon;

1-(3-(5-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he;

1-(3-(5-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methylthio)-Etalon;

1-(3-(5-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methylsulfinyl)Etalon;

1-(3-(5-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)Etalon;

1-(3-(5-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(1H-pyrazol-1-yl)Etalon;

1-(3-(5-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-hydroxy-2-methylpropan-1-he;

(3-{5-[5-(3,4-debtor-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-pyridin-2-yl}-3-fluoro-azetidin-1-yl)-tietan-3-yl-methanon;

(3-(5-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(1-oxidation-3-yl)methanon;

(3-(5-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(1,1-deoxidation-3-yl)methanon;

(E)-N-(1-(3-(5-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihyd�isoxazol-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-methylpiperidin)cyanamide;

1-(3-(5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-methylpropan-1-he;

(3-(5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(cyclopropyl)methanon;

1-(3-(5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he;

1-(3-(5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methylthio)Etalon;

1-(3-(5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methylsulfinyl)Etalon;

1-(3-(5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)Etalon;

1-(3-(5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(1H-pyrazol-1-yl)Etalon;

1-(3-(5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-hydroxy-2-methylpropan-1-he;

(3-{5-[5-(3-Chloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-pyridin-2-yl}-3-fluoro-azetidin-1-yl)-tietan-3-yl-methanon;

(3-(5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(1-oxidation-3-yl)methanon;

(3-(5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2 -�)-3-torasemide-1-yl)(1,1-deoxidation-3-yl)methanon;

(E)-N-(1-(3-(5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-methylpiperidin)cyanamide;

1-(3-(5-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-methylpropan-1-he;

(3-(5-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(cyclopropyl)methanon;

1-(3-(5-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he;

1-(3-(5-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methylthio)Etalon;

1-(3-(5-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methylsulfinyl)Etalon;

1-(3-(5-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)Etalon;

1-(3-(5-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(1H-pyrazol-1-yl)Etalon;

1-(3-(5-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-hydroxy-2-methylpropan-1-he;

(3-{5-[5-(3-Chloro-5-fluorophenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-pyridin-2-yl}-3-fluoro-azetidin-1-yl)-tietan-3-yl-methanon;

(3-(5-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)Piri�in-2-yl)-3-torasemide-1-yl)(1-oxidation-3-yl)methanon;

(3-(5-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(1,1-deoxidation-3-yl)methanon;

(E)-N-(1-(3-(5-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-methylpiperidin)cyanamide;

1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-methylpropan-1-he;

the cyclopropyl(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)methanon;

3,3,3-Cryptor-1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)propane-1-he;

1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)phenyl)-1,2-diazetidine-1-yl)-2-(methylthio)Etalon;

1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydro-izocsazol-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(methylsulfinyl)Etalon;

1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydro-izocsazol-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(methyl-sulfonyl)Etalon;

1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydro-izocsazol-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(1H-pyrazol-1-yl)Etalon;

1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydro-izocsazol-3-yl)pyridin-2-yl)azetidin-1-yl)-2-hydroxy-2-methylpropan-1-he;

(3-fluoro-3-{5-[5-trifluoromethyl-5-(3,4,5-tryptophanyl)-4,5-dihydro-isoxazol�-3-yl]-pyridin-2-yl}-azetidin-1-yl)-tietan-3-yl-methanon;

(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydro-izocsazol-3-yl)pyridin-2-yl)azetidin-1-yl)(1-oxidation-3-yl)methanon;

(1,1-deoxidation-3-yl)(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)methanon; and

(E)-N-(1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-methylpiperidin)cyanamide,

their stereoisomers, pharmaceutically or veterinary acceptable salts.

Another aspect of the invention is a compound of formula (XX)

.

Yet another aspect of the invention is a composition that contains (a) a compound of formula (XX), its stereoisomers or veterinary or pharmaceutically acceptable salt, and (b) a veterinary or pharmaceutically acceptable excipient, diluent, or carrier. The variables R1a, R1b, R1c, R2, R4, R6and n are as defined elsewhere herein. Preferably, the composition comprises a therapeutically effective amount of a compound of formula (XX), its stereoisomers or veterinary or pharmaceutically acceptable salts and veterinary or pharmaceutically acceptable excipient, diluent, or carrier.

Another aspect of the invention is a veterinary or pharmaceutical composition, which has a population�t (a), the compound of formula (1) or formula (XX), its stereoisomers, or a veterinary or pharmaceutically acceptable salt and (b) a veterinary or pharmaceutically acceptable excipient, diluent, or carrier. Preferably, the composition comprises a therapeutically effective amount of a compound of formula (1) or formula (XX), its stereoisomers or veterinary or pharmaceutically acceptable salts and his veterinary or pharmaceutically acceptable excipient, diluent, or carrier.

The composition may contain at least one additional veterinary agent. Preferred additional veterinary agents include endoparasiticides, endectocides, ectoparasiticide, insecticide and anthelmintic agents.

Yet another aspect of the invention is the use of a compound of formula (1) or formula (XX) for the manufacture of medicines.

Yet another aspect of the invention is a method of treating a parasitic infection or infestation in an animal that includes the step of introducing a specified animal in need of such treatment, a therapeutically effective amount of the compounds of the present invention, its stereoisomers, or a veterinary or pharmaceutically acceptable salt. Compounds of formula (1) and formula (XX), their stereoisomers, veterinary or pharmaceutically acceptable salts, or their compositions can be �conducted orally topically, intramuscularly, subcutaneously and via intraperitoneal injection. Preferably the animal is a mammal. More preferably, the mammal is an animal companion or livestock. Preferably the animal is a companion animal is a dog, cat or horse. Preferably, livestock is a member of the bovine, porcine or subfamily sheep. Preferably the animal is a bird. More preferably, the bird is a poultry. Preferably the animal is a fish. The compound of the present invention and the composition thereof can be administered to an animal orally, topically and by intramuscular, intraperitoneal and subcutaneous injection. Preferably the compounds of the present invention and their compositions can be administered to an animal orally or topically.

Yet another aspect of the invention is a method of treating a parasitic infection or infestation in an animal that includes the step of introducing a specified animal in need of such treatment, a therapeutically effective amount of a compound of formula (1) or formula (XX), its stereoisomers or veterinary or pharmaceutically acceptable salt in combination with at least one additional veterinary Agay�Tom. Compounds of formula (1) or formula (XX), their stereoisomers, veterinary or pharmaceutically acceptable salts themselves, with an additional veterinary agent or composition can be administered to an animal orally, topically or by injection (intramuscular, intraperitoneal or subcutaneous). Preferred additional veterinary agents include endoparasiticides, endectocides, ectoparasiticide, insecticide and anthelmintic agents.

Compounds of the present invention by themselves or in combination with an additional veterinary agent may be introduced in the form of (a) a single veterinary composition which contains the compound of the present invention, its stereoisomer, veterinary or pharmaceutically acceptable salt and possibly at least one additional veterinary agent, as disclosed herein, and veterinary or pharmaceutically acceptable excipient, diluent, or carrier; or (b) two separate veterinary compositions containing (1) a first composition containing a compound of the present invention, its stereoisomer, veterinary or pharmaceutically acceptable salt and a veterinary or pharmaceutically acceptable excipient, diluent or carrier, and (2) a second composition containing at least one additional veterinary Agay�t, as disclosed in the present description, and veterinary or pharmaceutically acceptable excipient, diluent, or carrier. Veterinary or pharmaceutical compositions can be administered simultaneously or sequentially and in any order.

Another aspect of the invention are compositions containing a compound of the formula (1), its stereoisomer, pharmaceutical or veterinary salt, possibly at least one additional veterinary agent, which are useful for the control and elimination of parasites in animals.

Everything mentioned in this description, patent publications, patents and priority documents incorporated by reference in their entirety.

DEFINITION

For the purposes of this invention as it is disclosed in this specification and claimed, the following terms and phrases are defined as follows.

The term "additional(e) veterinary(e) agent(s)" as used in this description, unless otherwise indicated, refers to other veterinary or pharmaceutical compounds or products that provide a therapeutically effective amount of these agents, which are useful for the treatment of a parasitic infection in an animal, as disclosed elsewhere herein.

The term "alkoxy", as used herein, unless otherwise indicated, refers to oxygen, water�Noah group, having an additional alkyl substituent. The alkyl portion (i.e., alkyl group) alkoxy group has the same definition as below. Non-limiting examples include: -och3, -Och2CH3and such.

The term "alkyl", as used herein, unless otherwise indicated, refers to saturated monovalent hydrocarbon alkane radicals of the General formula CnH2n+1. Alkane radical may be straight or branched and can be unsubstituted or substituted. For example, the term "(C1-C6)alkyl" refers to monovalent straight or branched aliphatic group containing from 1 to 6 carbon atoms. Non-limiting examples of (C1-C6)alkyl groups include, without limiting them, methyl, ethyl, propyl, isopropyl, sec-butyl, tert-butyl, n-propyl, n-butyl, ISO-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, 3,3-dimethylpropyl, 2-methylpentyl, hexyl and the like. The alkyl group can be attached to a chemical group through any one of the carbon atoms of the aliphatic chain. Alkyl group, possibly substituted as disclosed elsewhere herein.

The term "alkenyl" as used herein, unless otherwise indicated, refers to a straight or razvetvlenno�th aliphatic hydrocarbon chain, having from 2 to 6 carbon atoms and containing at least one carbon-carbon double bond (e.g.-C=C - or-C=CH2). Non-limiting examples alkenyl include: ethenyl, 1-propenyl, 2-propenyl, Isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-pentenyl and the like.

The term "alkynyl" as used in this description, unless otherwise specified, refers to a straight or branched aliphatic hydrocarbon chain having from 2 to 6 carbon atoms and containing at least one carbon-carbon triple bond (for example-C≡C - or-C≡CH). Non-limiting examples of alkynyl include: ethinyl, 2-PROPYNYL, 1-methyl-2-PROPYNYL, 2-butynyl, 3-butynyl, 2-methyl-3-butynyl and the like.

The term "animal" as used in this description, unless otherwise specified, refers to an individual animal that is a mammal, bird or fish. Specifically, the term "mammal" refers to a vertebral animal that is a person or not a person is a member of the taxonomic class Mammalia. Non-limiting examples of mammalian, non-human, include companion animals and livestock. Non-limiting examples of animal-companion include a dog, a cat, a llama, a goat and a horse. Preferred animal companion TPU� dog, the cat and the horse. More preferred is a dog. Equally preferred is a cat or a horse. Non-limiting examples of representatives of livestock include pigs, camels, rabbits, goat, sheep, deer, elk, representatives of the bovine (cattle and Buffalo. A preferred representative of livestock is cattle. Equally preferred is a pig. Specifically, the term "poultry" refers to a vertebral animal of the taxonomic class Aves. Birds are feathered, winged, bipedal, endothermic and oviparous. Non-limiting examples of birds include poultry (e.g. chicken, Turkey, duck and goose), all members of which are referred to here as a bird. Specifically, the fish belongs to the taxonomic class Chondrichthyes (cartilaginous fish like sharks and diamond rays) and Osteichthyes (bony fishes), representatives of which live in water have gills or slime-covered skin for breathing, fins, and may have scales. Non-limiting examples of fish include shark, salmon, rainbow trout, whitefish, Atlantic catfish, tilapia, sea bass, tuna, halibut, white-winged halibut, flounder, sole, striped bass, eel, yellowtail, grouper and the like.

The term "compounds of the present invention", as used in Yes�dimensional description, unless otherwise indicated, refers to the compound of formula (1) or formula (XX), its stereoisomers, and veterinary or pharmaceutically acceptable salts.

The term "cycloalkyl", as used herein, unless otherwise indicated, includes a fully saturated or partially saturated carbocyclic alkyl group. Non-limiting examples of partially saturated cycloalkyl include cyclopropene, cyclobutene, cycloheptene, cyclooctene, cyclohepta-1,3-diene and the like. Preferred cycloalkyl represent a 3-6-membered saturated monocyclic ring, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Cycloalkyl group can be attached to a chemical group via any one carbon atom within a carbocyclic ring. Cycloalkyl group possibly substituted by at least one Deputy. In addition, when used in such compound words as alkylsilanes mentioned alkyl and cycloalkyl groups have the same meaning as defined herein, and may be attached to a chemical group via any one carbon atom of the aliphatic chain. Examples of the group "alkylsilanes" include methylcyclopropane (-CH2-cyclopropane), ethylcyclopropane (-CH2CH2-cycloprop�n), methylcyclobutane (-CH2-CYCLOBUTANE), ethylcyclopentane (-CH2CH2-CYCLOBUTANE), methylcyclohexane (-CH2-cyclohexane) and the like. Cycloalkyl possibly substituted as disclosed elsewhere herein.

The term "halogen" or "halogen", as used herein, unless otherwise indicated, refers to fluorine, chlorine, bromine and iodine. Further, when used in compound words such as "halogenated", "halogenoalkane", "halogenoalkanes" or "halogenoalkanes" mentioned alkyl, alkoxy, alkenyl and alkynyl can be partly or completely replaced by halogen atoms that can be the same or different, and the alkyl, alkoxy, alkenyl and Alchemilla grouping has the same meaning as above, and can be attached to a chemical group via any one carbon atom of the aliphatic chain. Examples of "halogenoalkane" include F3C-, ClCH2-, CF3CH2- and CF3CCl2- and the like. The term "halogenoalkane" is defined analogously to the term "halogenated". Examples of "halogenoalkane" include CF3O-, CCl3CH2O-, HCF2CH2CH2O - and CF3CH2O - and the like. The term "halogenoalkane" is defined analogously to the term "halogenated", except that the aliphatic chain contains less�th least one carbon-carbon double bond. Examples of "halogenoalkane" include CF3C=C-, CCl3C=C-, HCF2C=C - CF3C=CC, and the like. The term "halogenoalkane" is defined analogously to the term "halogenated", except that the aliphatic chain contains at least one carbon-carbon triple bond. Examples of "halogenoalkane" include CF3C≡C-, CCl3C≡C-, HCF2C≡C -, and CF3C(HS -, and the like.

The term "heterocycle", as used herein, unless otherwise indicated, refers to partially saturated or saturated 3-6-membered monocyclic ring, containing one or more heteroatoms, each independently selected from N, O or S, preferably from one to four heteroatoms. Non-limiting examples of heterocycle include oxiranyl, Taranis, aziridinyl, oxetanyl, titanyl, azetidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, piperidinyl, piperazinyl, tetrahydropyranyl, 2H-asirin, 2,3-dihydro-azet, 3,4-dihydro-2H-pyrrole and the like Heterocyclic group may be attached to a chemical group via any one carbon atom or a heteroatom (e.g. N, O and S) within the monocyclic ring. Heterocycles may substituted as disclosed elsewhere herein.

The term "heteroaryl" or "Het", as used�tsya in this description, unless otherwise specified, refers to a 5-6 membered aromatic monocyclic ring or an 8-10-membered condensed aromatic ring, where the specified monocyclic and condensed ring group contains one or more heteroatoms, each independently selected from N, O or S, preferably from one to four heteroatoms. Non-limiting examples of monocyclic heteroaryl include pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiazolyl, isoxazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and the like. Non-limiting examples of condensed heteroaryl include benzofuranyl, benzothiophene, indole, benzimidazole, indazole, benzotriazole, thieno[2,3-C]pyridine, thieno[3,2-b]pyridine, benzo[1,2,5]thiadiazole and the like. Heteroaryl group may be attached to a chemical group through any one of the carbon atoms or heteroatoms (e.g. N, O and S) within a monocyclic or condensed ring. Heteroaryl possibly substituted as disclosed elsewhere herein.

The term "possibly substituted" is used herein interchangeably with the phrase "substituted or unsubstituted". Unless otherwise indicated, possibly substituted group may have� Deputy for each eligible position of the group, and each substitution is independent of the others. Possibly substituted, the group may also have substituents. Thus, the phrase "possibly substituted by at least one Deputy" means that the number of substituents may range from zero up to the number of available positions for substitution.

The term "parasite(s)", as used herein, unless otherwise indicated, refers to the endoparasites and ectoparasites. Endoparasites are parasites that live within the body of his master, and include helminths (e.g. trematodes, cestodes and nematodes and protozoa. Ectoparasites are organisms that belong to the type of Arthropoda (e.g., spiders, insects and crustaceans (e.g. copepods - sea louse), which eat through the skin or on the skin of the host. Preferred arachnids are members of the mites (Acarina), for example parasitemia and acrimonie mites. Preferred insects are gall midges, fleas, gnats, stinging flies (gigalo autumn, gigalo small cow, padolina fly, horsefly, and the like) and lice. Preferably the compounds of the present invention can be used to kill parasites, i.e. treat parasitic infections or infestations.

The term "therapeutically effective�guidance number", as used in this description, unless otherwise specified, refers to the amount of the compounds of the present invention that (1) treats the particular parasitic infection or infestation, (2) relaxes, reduces the intensity of or eliminate one or more symptoms of the particular parasitic infection or infestation, or (3) prevents or delays the onset of one or more specific symptoms described in this description of parasitic infections or infestations.

The term "treating", "treat" and the like, as used herein, unless otherwise indicated, refers to reversing, reduction or inhibition of parasitic infection, infestation, or condition. As they are used herein, these terms also encompass, depending on the condition of the mammal, the prevention of the onset of the disorder or condition or symptoms associated with the disorder or condition, including reducing the severity of the disorder or condition, or symptoms, assotsiirovannyh with him, before the defeat of the specified infection or infestation. Thus, treatment can refer to the introduction of the compounds of the present invention to a mammal, which at the time of introduction is not affected by infection or infestation. Treatment also includes prevention of relapse of infection, or infestation, and�and symptoms, associated with them, as well as references to "control" (for example, to kill, to scare away, to expel, to give incompetent, discourage, eliminate, reduce, minimize and destroy).

The term "veterinary acceptable", as used herein, unless otherwise indicated, indicates that the substance or composition must be compatible chemically and/or toxicologically with the other ingredients contained in the preparation, compositions, and/or mammals, of which they treat. The term "pharmaceutically acceptable has the same meaning given to the term "veterinary" is acceptable.

The symbol ""as used in this description, unless otherwise specified, refers to the attachment point.

DETAILED description of the INVENTION

In the present invention proposed a compound of formula (1), their stereoisomers, as well as veterinary compositions that are useful as antiparasitic agents for animals and birds, in particular, compounds that act as an ectoparasiticide. In addition, in the present invention proposed a compound of formula (XX), their stereoisomers, as well as veterinary compositions that are useful as antiparasitic agents for animals and birds, in particular, compounds that act as an ectoparasiticide.

Compounds of the present invention can be synthesized by synthesis routes that include processes analogous to the methods well known in the field of chemistry, particularly in light of the descriptions contained therein. The starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wis.), either can be easily obtained by methods well known to specialists in this field (for example obtained by methods in General are 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, Ed. ed. Springer-Verlag, Berlin, including supplements (also available via an electronic database Beilstein)).

Compounds of the present invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, the diastereomers and atropoisomeric. The person skilled in the art it is obvious that one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to other stereoisomer(s) or when separated from the other stereoisomer(s). In addition, the specialist knows how to separate, enrich, and/or to selectively receive the stereoisomers. Compounds according to the invention can be presented in the form of a mixture of stereoisomers, individual stereoisomers �in optically active form. For example, two possible enantiomer of formula 1 are depicted as formula 1A and formula Ib, including isoxazoline chiral center identified with an asterisk (*). Molecular image below, follow the standard notations to reflect stereochemistry.

For illustrative purposes, the reaction schemes depicted below show possible ways of synthesis of key intermediates and compounds of the present invention. For a more detailed description of individual reaction steps, see the Examples below. For the person skilled in the art it is clear that for the synthesis of intermediates and compounds of the present invention and their various derivatives can be used other suitable starting materials, reagents and the synthesis pathway. Further, many of the compounds obtained by the methods described below can be further modified in the light of this description, using traditional chemistry. Scheme 1-17 represent General procedures appropriate to obtain the compounds of the present invention. It should be understood, however, that the invention, as it is fully disclosed in this description and as shown in the claims, should not be limited to the details of the following schemes or way� receipt.

The following Schemes and Examples, include the following catalysts/reagents: N,N-dimethylformamide (DMF); N-N-dimethyl sulfoxide (DMSO); N-chloro-succinimide (NCS), N-bromo-succinimide (NBS); ethanol (EtOH); methanol (MeOH); tetrahydrofuran (THF); triethylamine (TEA); acetonitrile (CH3CN, ACN); n-BuOH (n-butanol); lithium hydroxide (LiOH); hydrazine (H2Needed to harm2); potassium bicarbonate (JISC3); potassium carbonate (K2CO3); diethyl ether (Et2O); sodium carbonate (Na2CO3); hydroxylamine (NH2OH); sulphuric acid (H2SO4); ammonium chloride (NH4Cl); dichloro methane (CH2Cl2); hydrochloric acid (HCl); trifluoroacetic acid (TFA); methyl tert-butyl ether (MTBE); potassium acetate (Coac); isopropyl alcohol (IPA), n-butyllithium (n-BuLi); triethylamine (Et3N); ethyl acetate (EtOAc); sodium acetate (NaOAc); chloride bis(triphenylphosphine)palladium II (PdCl2(PPh3)2) from Strem; hexaphosphate N,N,N',N'-tetramethyl-O-(7-asobancaria-1-yl)Urania (HATU); the hydrate of 1-hydroxybenzotriazole (HOBt); di-tert-butyl-dicarbonate (Boc2O); carbonyldiimidazole (CDI); the trioxide diethylaminoethyl (DAST); 2,2'-azobis(2-methylcrotonate) (AIBN); fluoride of tetrabutylammonium (TBAF); TRIFLUORIDE bis(2-methoxyethyl)aminocore (BAST); tert-butyl carbonate (Boc); a pyridine serratrice (PySO3); triphenylphosphine palladium (Pd(PPh3)4); 4-dimethylaminopyridine (DMAP); hexamethyldisilane�ID (KHMDS); (2,2,6,6-tetramethylpiperidine-1-yl)oxyl (TEMPO); and diisobutylaluminum (DIBAL-H).

Scheme 1

R2and n are as defined elsewhere herein.

Phenylaziridine can be obtained as shown in Scheme 1. As a result of the introduction of the BOC-protection in hydrochloride hydroxyazetidine followed by oxidation of the hydroxyl group get kitasamycin 2. He may be subjected to kondensierten with bromosilane through education aryl Grignard reagent (Grignard) and subsequent condensation with the ketone with the receipt of cellpenetrating 3. Replacement of the bromine silane was carried out by treatment with potassium bromide in acetic acid to give the desired brompheniramine 4. Fluoridation of hydroxyazetidine 4 may be performed by processing BAST with getting 5.

Scheme 1.5

R1a, R1band R1care as defined elsewhere herein.

Ailelerini (8) can be obtained according to the Scheme 1.5. Required organoborate can be obtained in the form of intermediates-borate esters (1.5 B2) by literature methods (Org. Lett. 2007, 9, 761-764) or purchased as Baranovich acid (1.A), such as 3,5-daliborova acid from Aldrich. Intermediate 1.A or 1.5 B2 can be add�hree-to-dioxane or THF and water, followed by the addition of 2-bromo-3,3,3-triptocaine, potassium carbonate and chloride bis(triphenylphosphine)palladium II with the preparation of the intermediates (8).

Scheme 2

R1a, R1b, R1c, R2and n are as defined elsewhere herein.

Scheme 2 shows the receiving isoxazolines from the approach formulated above or arrangerede. From brompheniramine 5 in the reaction of exchange of the halogen-metal with subsequent quenching by DMF get arylamidase 6, which can also be obtained in other ways (Schemes 3 and 4). The aldehyde is subjected to condensation with hydroxylamine to obtain the oxime 7. From the oxime by a two-stage process carried out in one reaction vessel, can be obtained isoxazoline ring. As a result of processing of the oxime N-chlorosuccinimide get chlorosis, which undergoes [3+2] cyclization with arylolefins 8 with obtaining isoxazoline 9. These stages can also be carried out in separate reactions. Removing the First protective group on azetidine can be achieved by treatment with trifluoroacetic acid.

Figure 3

R1a, R1b, R1c, R2and n are as defined elsewhere herein. Alternative synthesis of BOC-protected azetidine shown in Scheme 3. As a result of interaction titilate�Ala 4-bromobenzaldehyde 10 Mg or with metal iPrMgCl with subsequent treatment of the CeCl 3get the ORGANOMETALLIC reagent, which is added to the N-protected 3-azetidinone. As a result of condensation with hydroxylamine, chlorination and cyclization as described in Scheme 2, get isoxazolin 13. The fluorination of the hydroxyl group can be accomplished through interaction with Xtaflor-E.

Scheme 4

R2and t are as defined elsewhere herein.

Alternative phenylaziridine can be obtained from bromilow esters or polarimeter, as shown in Scheme 4. As a result, aryl ester case lithium get arylmethyl 15, which can be protected in the form of silane. The formation of aryl Grignard with magnesium or by the reaction of the exchange of the halogen-metal receive aryl anion, which can condense with T-protected azetidinone 2 with obtaining arylacetamide 17. Removing protection from alcohol and oxidation provide formultimedia 19, which may undergo condensation with hydroxylamine to obtain the oxime 12.

Scheme 5

R1a, R1band R1care as defined elsewhere herein.

Similarly, compounds in which the Central phenyl ring substituted condensed�Rovaniemi aryl or heteroaryl groups, can be obtained as shown in Scheme 5 for afternova series. Target naphthylacetamide can be obtained from 1-bromo-4-methylnaphthalene as shown in Scheme 5. The reaction of the exchange of the halogen-metal or the formation of the Grignard reagent from bromonaphthalene get 20 nattily anion, which can condense with ketoamide 2 with obtaining naphthylacetamide 21. The fluorination of the resulting alcohol can be achieved by the processing of BAST, or DAST Xtafluor-E with obtaining foreseeing 22. As a result of bromination of the methyl group, followed by hydroxylation and oxidation get the target aldehyde 24, which may be subjected to formation of oxime, chlorination and cyclization as described in Scheme 2 to obtain isoxazolines 25.

Scheme 6

R1a, R1band Rcare as defined elsewhere herein.

Compounds in which the Central phenyl ring of the substituted heteroaryl groups, can be obtained as shown in Scheme 6 for peredelnogo series. Education diethylacetal can be carried out using ethylformate. As a result of processing of yodellin 27 n-BuLi receive ORGANOMETALLIC reagent, which is added to the N-protected 3-azetidinone 28. As a result of condensation obtained for�usciranno" aldehyde with hydroxylamine followed by chlorination and cyclization get isoxazolin 31. Benzhydrylidene protective group can be removed by hydrogenation or treatment with claritinclaritin with getting hydroxyazetidine 32, or alternatively, hydroxyazetidine 31 may be fluorinated by treatment with XtaFluor-E followed a similar release with obtaining foreseeing 33.

Scheme 7

R1a, R1band R1care as defined elsewhere herein.

Deputy on azetidinone the ring may be eliminated as shown in Scheme 7. As a result catalyzed by palladium/zinc reaction cross-combination of localdevice 34 with N-protected iodisation 35 get phenylaziridine 36. This aldehyde may be subjected to kondensierten with hydroxylamine, chlorination and cyclization as described in Scheme 2, to obtain hydrido connection 38.

Scheme 8

R1a, R1band R1care as defined elsewhere herein.

The introduction of the nitrile as axial Deputy of foreseeing can be accomplished as shown in Scheme 8. The formation of the acetal of aldehyde 39 may be sushestvenno using ethylformate. Aryl fluoride may then be replaced by the anion of 1-benzhydrylamine-3-carbonitrile with getting phenylaziridine 42. As a result of CH�Tiya protection benzhydryl group followed by re-introduction of protection by Boe anhydride to get N-BOC-phenylaziridine 44. This "masked" aldehyde may be subjected to kondensierten with hydroxylamine, chlorination and cyclization as shown in Scheme 2, to obtain isoxazolines 46. By removal of the BOC-protecting group and acylation of the obtained amine get isoxazoline 48. The bromine atom on the phenyl ring may be removed by treatment with zinc Rail (Reike) in acetic acid with obtaining isoxazolines 49.

Scheme 9

R1a, R1band R1care as defined elsewhere herein.

The bromine atom on the phenyl ring may also be removed at earlier stages in the sequence in order to obtain a "stencil" for the parallel synthesis of amides, amines, ureas and the like.

Scheme 10

R1a, R1b, R1cand R5are as defined elsewhere herein.

The nature of the substituent R2can be changed either by selecting the source material, or the mutual transformation of the substituents on the aryl ring as shown in Scheme 10. Jadefire 52 can be obtained by processing aminoether 51 sodium nitrite and potassium iodide. Restoration of the ester to the alcohol with the help of hydride diisobutylaluminum followed by oxidation with �via TEMPO get italicised 54. This aldehyde may be subjected to kondensierten with hydroxylamine, chlorination and cyclization as shown in Scheme 2, to obtain isoxazoline 56. Selective manner with iodine leads to the formation of the Grignard reagent using iPrMgCl and obtained ORGANOMETALLIC compound is added to the N-protected azetidinone with getting phenylaziridine 57. Fluoridation of azetidine can be implemented using Xtafluro-E. By removing benzhydryl protective group using chloroethylphosphonic and acylation of the obtained amine with acid chlorides or anhydrides (or through a combination with the desired organic acids) are phenylacetamide 60. At this point, the bromine atom of the phenyl ring may undergo mutual conversion to other functional groups (i.e. nitrile, as shown) through metal-catalyzed cross-combinations. Alternative, 58 can be converted to the nitrile by palladium reaction cross-combination with the subsequent protection of benzhydrol and acylation with the formation of the final products 61.

Scheme 11

R1a, R1b, R1c, R2and n are as defined elsewhere herein.

taxes, in which azetidinone the ring is in the meta-position relative�structure to isoxazoline, can be obtained from 3-bromobenzaldehyde derivatives as shown in Scheme 11. As a result of processing of pomalidomide 62 i-PrMgCl receive ORGANOMETALLIC reagent, which is added to the N-protected azetidine with getting hydroxyazetidine 63. This "masked" aldehyde can undergo condensation with hydroxylamine, chlorination and cyclization as shown in Scheme 2, to obtain isoxazoline 65 resulting from the removal of protection by using chloroethylphosphonic or fluorination with subsequent removal of the protection get the desired amines (66 and 67), which can be further functionalized to target amides, urea, amines and sulfonamides are described below.

Scheme 12

R1a, R1b, R1c, R2, R3and n are as defined elsewhere herein.

Removal of the BOC-protective group on azetidine in the schemes above (for example in the structures of 9, 25, 38, 50) can be effected by treatment with HCl in methanol or trifluoroacetic acid in dichloromethane.

Scheme 13

R1a, R1b, R1c, R2, R3, R5and n are as defined elsewhere herein.

Amide analogues azetidinone rings can be obtained as shown in Scheme 13. Acylation azetidinone ring� can be achieved by interaction of azetidine 70 with the acid chloride in a mixture of pyridine/DMA or by condensation with a carboxylic acid using a condensing agent, such as HATU or HOBt

Scheme 14

R1a, R1b, R1c, R2, R3, R5and n are as defined elsewhere herein.

Sulfonamide analogs azetidinone rings can be obtained as shown in Scheme 14. As a result of the interaction of azetidine 70 with sulphonylchloride in the presence of triethylamine to obtain the desired sulfonamide.

Scheme 15

R1a, R1b, R1c, R2, R3, R4and n are as defined elsewhere herein.

Compounds in which R4is an alkyl or substituted alkyl, can be obtained from azetidine 70 via standard chemistry alkylation or by reductive amination with the corresponding aldehydes as shown in Scheme 15.

Scheme 16

R1a, R1b, R1c, R2, R3, Ra, R5and n are as defined elsewhere herein.

Urea analogs can be obtained as shown in Scheme 16. As a result of the interaction of azetidine 70 with the isocyanate or pre-educated carbamoylation in the presence of a tertiary amine base get urea.

Scheme 17

Tioned 76 m�can be obtained by treatment of amide 71 reagent of Lawesson (Lawesson's) in toluene boiling with reflux. To thioamide 76 in a solvent such as CH2Cl2can be added metalcraft education thioimidate intermediate compounds in the form of a solution. Then directly to thioimidate solution can be added cyanamide and a base Hunya (Hunig's) in THF with getting cyanamide 77.

For the person skilled in the art it is obvious that in some cases, after the introduction of the reagent, as shown in the diagrams, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of compounds of formula (1) or formula (XX).

The present invention includes all veterinary acceptable isotopically labeled compounds of formula (1) and formula (XX), where one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.

Examples of isotopes suitable for inclusion in compounds of the present invention include isotopes of hydrogen, such as2H and3H, carbon, such as11C,13C and14C, chlorine, such as36Cl, fluorine, such as18F, iodine, such as123I and125I, nitrogen, such as13N and15N, oxygen, such as15Oh,17O and18�, and sulfur, such as35S.

For the person skilled in the art it is obvious that the compounds of the present invention can be obtained in ways different from the ways disclosed in this description, included in this description by reference, by adapting the methods disclosed herein, and/or adaptation of methods known in the art, for example as disclosed in this description of the prior art, either through the use of standardized guidelines, such as "Comprehensive Organic Transformations - A Guide to Functional Group Transformations", RC Larock, Wiley-VCH (1999 or later editions).

Compounds of formula (1) and formula (XX) are useful as agents against ectoparasites and endoparasites, therefore, another embodiment of the present invention is a veterinary or pharmaceutical composition containing a therapeutically effective amount of a compound of formula (1) or formula (XX), its stereoisomers, and veterinary or pharmaceutically acceptable excipient, diluent or carrier. Compounds of the present invention (including the compositions and methods used) can also be used in the manufacture of a medicine for disclosed in this description therapeutic applications.

A typical composition is prepared by mixing a compound of formula (1) or formula (XX) with a carrier, diluent or �excipients. Suitable carriers, diluents and excipients well known to specialists in this field and include substances such as hydrocarbons, waxes, water soluble and/or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water and the like. Specific carrier, diluent or excipient will depend on the means and purposes for which used the compound of the present invention. Solvents are generally selected based on solvents that are experts in this field recognized as safe when administered to animals. The compositions can also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspendida agents, preservatives, antioxidants, cloud emulsions, sliding substances, substances that facilitate the processing, dyes, podslastiteli, flavors, corrigentov and other known additives to provide an elegant appearance of the drug (namely, the compounds of the present invention or veterinary composition) or to facilitate the production of a veterinary or pharmaceutical products (i.e. medicines).

The composition can be obtained by conventional procedures of dissolution and�of asiania. Such compositions and methods for their preparation may be found, for example, in 'Remington's Veterinary Sciences', 19th Edition (Mack Publishing Company, 1995; and " Veterinary Dosage Forms: Tablets, Vol.1", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., 1980 (ISBN 0-8247-6918-X). For example, the mass of medicinal substance (i.e., compound of the present invention or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent)) is dissolved in a suitable solvent in the presence of one or more other excipients. Compounds of the present invention is usually prepared in the veterinary or pharmaceutical dosage forms with obtaining easily controlled dosage forms for administration. Compounds of the present invention can also be mixed with feed for the animal.

The compounds can be administered alone or in compositions, suitable for a particular designated use, a particular type of pet, the treated and the parasite involved. In General, they are administered as a composition in combination with one or more of a veterinary or pharmaceutically acceptable salts, excipients, diluents or carriers. The term "excipient", "diluent" or "carrier" is used herein to describe any ingredient other than the compound of formula (1) or formula (XX or any additional antiparasitic agent. The choice of excipient, diluent or carrier, to a large extent depend on factors such as the specific route of administration, the effect of excipient, carrier or diluent on solubility and stability, the nature of the dosage form and species of animal.

The methods by which the compounds of the present invention can be administered include oral, local and injectable (subcutaneous, intraperitoneal and intramuscular) administration. The preferred method of administration of a compound of formula (1) or formula (XX) is an oral solid dosage form or oral liquid dosage form. Equally preferred is topical administration.

Compounds of formula (1) or formula (XX) can be introduced by perarolo by capsule, bolus, tablet, powders, lozenges, chewable tablets, multi - and nanoparticles, gels, solids solution, films, sprays, liquid form, or mixed with food/feed. Oral administration is the preferred route of administration, and therefore it is desirable to create an active compound of the formula (1) or formula (XX), which are particularly suitable for such compositions. Such compositions can be used as fillers in soft or hard capsules, t�blackah or chewing the pellets, and usually contain a carrier, for example water, ethanol, polyethylene glycol, N-methylpyrrolidone, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspendida agents. Liquid formulations include suspensions, solutions, syrups, jellies and potions. Liquid compositions can also be prepared by dissolving solid substances, for example, from a sachet. Oral jelly usually obtained by dissolving or suspending the active ingredient in a suitable environment. For livestock and fish can be obtained from mixtures of food. Oral compositions may contain from about 0.5 mg/kg to 50 mg/kg of a compound of formula (1) or formula (XX) and preferably from about 1 mg/kg to 30 mg/kg of a compound of formula (1) or formula (XX). Depending on the type of the host treated and the parasite against which the treatment can be carried out to adjust the dose.

The compounds can be administered topically to the skin or mucosa, that is dermaline or transdermal. This is the preferred method of administration, and therefore it is desirable to create an active compound of the formula (1) or formula (XX), which are particularly suitable for such compositions, for example liquid forms. Typical compositions for this purpose include damage done by pouring (pour-on), through the point�tion application (spot-on), by multi-application (multi-spot-on), in the form of strips (stripe-on), in the form of combs (comb-on), in the form of rolls (roll-on), impregnating, spray, musicomania compositions, shampoo, powder compositions, gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, substrates, implants, sponges, fibres, bandages and microemulsions. Can also be used liposomes. Conventional carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, N-methylformamide, glycolmonomethyl esters, polyethylene glycol, propylene glycol, and the like. Can be included penetration enhancers - see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999). Applied by pouring or by spot application of the composition can be obtained by dissolving active ingredients in a suitable liquid medium such as bucindolol, liquid paraffin or non-volatile ester, possibly with the addition of a volatile component, such as propane-2-ol or a glycol ester. Alternative applied by pouring, by the point of application or spray compositions may be obtained by encapsulation, to leave a residue of active agent on the surface of the animal, this effect may ensure that the compounds of formula (1) or forms�crystals (XX) will have increased persistence of action and greater duration of action, for example, they can be faster in the water. Local compositions described in this description of the combination may contain from about 0.5 mg/kg to 50 mg/kg of a compound of formula (1) and preferably from about 1 mg/kg to 10 mg/kg of a compound of formula (1) or formula (XX). Compositions suitable for point of application of the invention, may be obtained by mixing traditional. Quantity of coating composition can range from about 0.5 ml/kg to 5 ml/kg and preferably from about 1 ml/kg to 3 ml/kg. similarly, the dose may be adjusted.

Compounds of the present invention can also be administered topically through the matrix-substrate, such as synthetic or natural resins, plastics, fabric, leather, or other such polymer systems in the form of an ear tag or a tag on the collar. Specified ear tag or tag on the collar may be coated, impregnated, sandwiched in any manner so as to provide veterinary or pharmaceutically acceptable amount of the compounds of the present invention by itself or with a veterinary or pharmaceutically acceptable excipient, diluent or carrier and a possible additional veterinary agent, or veterinary or pharmaceutically acceptable salt.

The compositions of the present invention mo�ut to be added to the agents to improve the persistence of such compositions on the surface of the animal, to which they are applied, for example, to improve their persistence in the animal blanket. Especially it is preferable to incorporate such agents in the composition, which is applied by pouring or by spot application. Examples of such agents include acrylic copolyme and in particular fluorinated acrylic copolymers. Particularly appropriate reagent is a reagent with the trademark "Foraperle" (Redline Products Inc, Texas, USA). Some local compositions can include neharika additives to minimise oral exposure.

Injectable compositions can be obtained in the form of a sterile solution which may contain other substances such as salt or glucose, in an amount 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 benzyl benzoate, isopropyl myristate and fatty acid derivatives of propylene glycol and organic solvents, such as pyrrolidin-2-he and clearinterval. The compositions have a dissolution or suspendirovanie compounds of the present invention by itself or with an additional veterinary agent in the liquid carrier so that the final composition contains from about 0.01 to 50% by weight active ingredient�s, preferably from about 0.01% to about 10% by weight of active ingredients.

Suitable devices for injection include needle (including microhole) injectors, needleless injectors and infusion techniques. Compositions for subcutaneous administration are typically aqueous solutions which may contain excipients, such as salts, carbohydrates and sautereau agents (preferably to a pH from 3 to 9), but for a number of applications, they are more expedient manner can be prepared as a sterile non-aqueous solution or in the form of a dry powder for use in combination with an acceptable carrier, such as sterile apyrogenic water. Preparation of compositions for subcutaneous injection in a sterile environment, for example by lyophilization, can easily be accomplished using standard veterinary techniques, well known to specialists in this field. The solubility of a compound of formula (1) or formula (XX) used in the preparation of solutions for subcutaneous administration, may be increased through the application of appropriate techniques for the manufacture of drugs, such as the inclusion of agents which increase the solubility.

Such compositions are the traditional way in accordance with standard medical or veterinary practice. In addition to t�, these compositions will vary depending on the weight of the contained active compounds, depending on the animal species the host being treated, the severity and type of infection or infestation and body weight of the animal.

Fish compounds of the present invention can be prepared in the form of compositions for oral administration by mixing with feed. For example, the compounds of the present invention can be prepared in the form of feed product (e.g. pellets), which can easily be distributed fish in the form of a feed agent. Further, the compounds of the present invention can be administered topically by immersing fish in an aqueous environment containing at least one compound of the present invention. For example, fish may be transferred into the tank for treatment or forced to move from one charge to the custody of another. Compounds of the present invention can also be introduced directly into the water that contains fish. The compound of the present invention can be presented in any water-dispersible compositions so that, when introduced into water, the compound is dissolved with the formation of a solution. Alternatively, compounds of the present invention can be administered by injection. Preferred injectable ways to treat fish are�I intraperitoneal or intramuscular. Injectable compositions include any liquid suspension, such as oils, aqueous solutions or emulsions of oil and water. Compounds of the present invention may also be administered in conjunction with additional agents, antigens, advantage, carriers, diluents or nutrients.

Compounds of formula (1) and formula (XX) are also active against all or individual stages of development of insects, parasitic on animal showing normal sensitivity, as well as against those who demonstrate a resistance to widely used parasiticides.

As herein disclosed, the compounds of the present invention can be administered by themselves or in combination with at least one additional veterinary agent, including insecticides, acaricides, de-worming drugs, fungicides, nematicide, Antiprotozoal agents, bactericides and plant growth regulators, with the formation of multi-component agent, giving a wider range of veterinary suitability. Thus, the present invention also relates to compositions containing an effective amount of a compound of formula (1), its stereoisomer, and an effective amount of at least one additional veterinary agent, and may further contain one or more veterina�but or pharmaceutically acceptable excipients, diluents or carriers.

Following next is a list of additional veterinary agents, together with which can be used compounds of the present invention, is intended to illustrate the possible combinations but does not impose any restrictions. Non-limiting examples of additional veterinary agents include: amitraz, aripirazole, as described in the publications WO 1998/24767 and WO 2005/060749, aminoacetonitrile, anthelmintic agents (such as albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, octapeptide, oxfendazole, oxibendazole, paraphernalia (2-dioxaborinane, Mercantil), parbendazole, piperazines, praziquantel, thiabendazole, tetramisole, triclabendazole, levamisole, Pyrantel, pamoate, oxantel, morantel and the like), indoxacarb and its derivatives, avermectins (such as abamectin, doramectin, emamectin,: eprinomectin, ivermectin, moxidectin, selamectin and the like), milbemycin, milbemycin oxime, DEET (N,N'-diethyl-3-methylbenzamide), demetres, diethylcarbamazine, fipronil, growth regulators insect (e.g. hydroprene, CANopen, methoprene, pyriproxyfen, and the like), metaflumizone, niclosamide, permethrin, pyrethrins, spinosad and formamidine (e.g. demedeiros, amitraz and the like). In certain instances, combinations of a compound of formula (1) or f�of rmula (XX) with an additional(and) veterinary(and) agent(s) that might result in a more than additive effect. A reduced amount of active ingredients released into the environment while maintaining effective control of insects is always desirable.

It may be desirable to administer the compound of the present invention, its stereoisomers alone or in a composition containing a veterinary acceptable excipient, diluent or carrier, for example, for the purpose of treating a particular parasitic infection or infestation, or an associated state. In the framework of the present invention, two or more veterinary compositions, at least one of which contains a compound of the formula (1) or formula (XX) in accordance with the invention, and other, additional veterinary agent, can conveniently be combined in the form of a kit suitable for co-administration of the compositions.

Compounds of the present invention (including the compositions and their methods) can also be used in the manufacture of the medicinal product described herein for therapeutic applications.

Compounds of the present invention, their stereoisomers, and compositions containing a therapeutically effective amount of a compound of formula (1) or formula (XX) and a veterinary acceptable excipient, diluent or carrier, are useful as parasiticides (against endo - and ecto-parasites) for �of ONTRAS and treatment of infections or infestations, due to the specified parasite in the animal. Compounds of the present invention find use as an ectoparasiticide, in particular as an acaricide and insecticide. They may, in particular, to be used in the field of veterinary medicine, cattle breeding, fish farming and the maintenance of public health: against mites and insects that are parasitic on vertebrates, particularly warm-blooded vertebrate animals, including companion animals, livestock and birds. Compounds of the present invention are also parasiticides for cold-blooded fish. Some non-limiting examples of mites and insects-parasites include: ticks (e.g. Ixodes spp., Rhipicephalus spp. Boophilus spp., Amblyomma spp. Hyalomma spp. Haemaphysalis spp. Dermacentor spp. Ornithodorus spp.and the like); clamp (for example, Dermanyssus spp., Sarcoptes spp., Psoroptes spp. Chorioptes spp., Demodex spp.and the like); chewing and sucking lice (e.g., Damalinia spp., Linognathus spp.and the like); fleas (e.g. Siphonaptera spp. Ctenocephalides spp.and the like); and stinging flies and mosquitoes (e.g., Tabanidae spp. Haematobia spp. StomoKcus spp. Dermatobia spp., Simuliidae spp., Ceratopogonidae spp., Psychodidae spp. and the like). In another example, the ectoparasites of copepod crustaceans of the order, the more Concertino genera Lepeophtheirus (especially salmon louse, Lepeoptheirus salmonis) and/or Caligus (e.g. S. elongates, C. rogercreysii, S. teres, S. Flexispina and then�the like), especially sea lice, can be treated with a compound of the present invention. Compounds according to the invention can also be used for the destruction of endoparasites, such as heart worms, roundworms, hookworms, whipworms and tapeworms.

Compounds of the present invention and compositions containing compounds of the present invention in combination with at least one other veterinary agent, are of particular importance in the control of ectoparasites, endoparasites and insects that are harmful to the animal, or spread of animal disease or act as vectors. Ectoparasites, insects, and endoparasites, which can be addressed through a combination of a compound of formula (1) or formula (XX) and additional veterinary agent, include those disclosed earlier in this description, including helminth type platyhelminthes (e.g. trematodes, eucestoda and cestode) and nemathelminthes (e.g. nematodes).

Any of the compounds of the present invention or a suitable combination of the compounds of the present invention and possibly at least one additional veterinary agent may be administered directly to an animal and/or indirectly by entering it in a local environment in which the animal is located. Direct introduction includes to�timing with the skin, language or feathers from the subject (animal or bird with the compound(s), or the feeding of compound animal or a bird or connection introduction by injection.

Compounds of formula (1) or formula (XX), their stereoisomers and the combination with at least one additional veterinary agent, as disclosed herein, are essential for the treatment and control of different stages of the life cycle of insects and parasites including egg, nymph, larva, juvenile and adult stage.

The present invention also relates to a method of introducing the compounds of the present invention by itself or in combination with at least one additional veterinary agent, and possibly veterinary or pharmaceutically acceptable excipient, diluent or carrier animal with good health comprising the application of a specified animal to reduce or eliminate the possibility of parasitic infection or infestation of parasites that are carried by the animal, and to improve the surrounding conditions in which live animal and man.

Interaction disclosed below, in General carried out under positive pressure of argon or nitrogen or with a drying tube, at ambient temperature (unless otherwise stated) in anhydrous solvents, and the reaction flasks were plugged with rubber�th tube for the introduction of substrates and reagents via syringe. Glassware was subjected to drying in the furnace and/or dry heat. Analytical thin-layer chromatography (TLC) was carried out using plates pre-coated with amorphous silica gel 60 F 254, and suirable relevant ratios of solvent (about./vol.). Response was assessed using TLC or LC-MS and was completed upon consumption of the starting materials. Visualization of TLC plates was performed using UV light (wavelength 254 nm) or by using the appropriate TLC visualizing solvent and activated by heating. Flash column chromatography (Still et al., J. Org. Chem. 43, 2923, (1978)) was performed using silica gel (RediSep Rf) or different jhud systems, such as the purification system biotage AB or ISCO.

For isolation of the compounds of the present invention, and various related intermediates can be used traditional methods and/or techniques of separation and purification known to the person skilled in the art. Such techniques are well known to specialists in this field and may include, for example, all types of chromatography (liquid chromatography high pressure (ghvd), column chromatography using common adsorbents such as silica gel, and thin layer chromatography (TLC), recrystallization, and differential techniques (i.e., liquid - liquid) extrac�AI.

Structures of compounds in the examples below were confirmed by one or more of the following methods: spectroscopy proton magnetic resonance and mass spectroscopy. Spectra proton magnetic resonance (1H NMR) were determined using the Bruker spectrometer working at a wavelength of 400 megahertz (MHz). Chemical shifts are given in ppm (MD, δ) down from internal tetramethylsilane standard. The data of mass spectra (MS) were obtained using Agilent mass spectrometer with chemical ionization at atmospheric pressure. Method: Acquity HPLC with chromatography performed on a column (Waters VEINS C18 (2.1 x 50 mm, 1.7 μm) at 50°C. the Mobile phase was a binary gradient of acetonitrile (containing 0.1% trifluoroacetic acid) and water (5-00%).

Embodiments of the present invention is illustrated by the following Examples. However, it should be understood that embodiments of the invention are not limited to specific details of these Examples, as other variations known or obvious to the person skilled in the art in light of the present description of the invention.

EXAMPLES

Also a specialist in this field will understand that to attach substituents or modify existing substituents of a compound of formula (1) or formula (XX) and intermediate compounds disclosed in this description�research Institute, can be subjected to various electrophilic, nucleophilic, radical, ORGANOMETALLIC reaction, oxidation reaction and the reduction reaction.

The following examples provide a more detailed description of the process conditions. It should be understood, however, that the invention, as it is fully disclosed in this description and as shown in the claims, should not be limited to the details of the following schemes or ways to get.

Preparatory example 1: tert-Butyl-3-hydroxyazetidine-1-carboxylate

To a stirred cold (0°C) solution of hydrochloride of 3-hydroxyazetidine (75 g, of 0.68 mol) in ethanol (1300 ml) was added triethylamine (208 g/280 ml of 2.05 mol), and then Vos2(164 g, 0.75 mole). The resulting solution was stirred at ambient temperature for 16 hours. GC (gas chromatography)/MS (mass spectrometric) analysis of the reaction mixture showed that the reaction was completed. Volatiles were removed in vacuo, and the residue was diluted with EtOAc (1300 ml) and washed with 10% citric acid (700 ml), water (700 ml) and brine (700 ml). The organic phase was dried over sodium sulfate, filtered and concentrated to give the desired product (100,8 g, 85% yield).1H NMR (CDCl3) δ 4.6 (m, 1H), 4.2 (m, 2H), 3.8 (m, 2H), 1.4 (s, 9H).

Preparatory example 2: tert-Butyl-3-oxoa�lidin-1-carboxylate

In a three-neck flask with a volume of 5 l equipped with a stirrer driven, thermocouple, addition funnel and a device for supplying nitrogen, downloaded Roux-SO3(277 g, 1.74 mol) and DMSO (900 ml) and cooled to 10°C in an ice bath. Was added TEA (177 g/244 ml, 1.74 mol). Slowly through the dropping funnel at 10°C was added a solution of tert-butyl-3-hydroxyazetidine-1-carboxylate (Preparation example 1, to 100.8 g, of 0.58 mol) in DMSO (500 ml). The reaction mixture was stirred at ambient temperature overnight. GC/MS analysis of the reaction mixture showed that the reaction was completed. The reaction mixture was quenched with brine (1 l). The solid phase was filtered, and the aqueous was extracted with ethyl acetate (3×1 l). The combined organic phases were washed with saturated aqueous NaHCO3(1.5 l), brine (1.5 l), dried over sodium sulfate, filtered and concentrated to give the desired product (94 g, 95% yield).1H NMR (CDCl3) δ 4.6 (s, 4H), 1.4 (s, 9H).

Preparatory example 3: tert-Butyl-3-hydroxy-3-(4-(trimethylsilyl)phenyl)azetidin-1-carboxylate

In a three-neck flask of 2 l equipped with a stirrer driven, thermocouple, addition funnel and a device for supplying nitrogen, loaded (4-bromophenyl)trimethylsilane (80,4 g, 0.35 mole), THF (600 ml), Mg (8.5 g) and I2(catalytic amount). Suspension Ki�atili to reflux at 68°C for 1.5 hours until complete disappearance of the magnesium. The solution was cooled to 0°C in an ice bath. Then slowly through the dropping funnel was added a solution of tert-butyl-3-oxoazetidin-1-carboxylate (Preparation example 2, 30 g, 0.17 mole) in THF (200 ml). The solution was stirred at 0°C for 3 hours. Analysis by LC/MS indicated the formation of desired product. The reaction mixture was quenched with brine at 0°C. the Aqueous layer was extracted with EtOAc (2×800 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated to give the desired product (47,4 g, 84% yield).1H NMR (CDCl3) δ 7.3 (d, 2H), 7.2 (d, 2H), 4.0 (d, 2H), 3.9 (d, 2H), 2.9 (s, 1H), 1.2 (s, 9H), 0.0 (s, 9H).

Preparatory example 4: tert-Butyl-3-(4-bromophenyl)-3-hydroxyazetidine-1-carboxylate

A mixture of tert-butyl-3-hydroxy-3-(4-(trimethylsilyl)phenyl)azetidin-1-carboxylate (Preparation example 3, 45 g, 0.14 mol) and KBr (25 g, 0.21 mole) in acetic acid (1 l) and MeOH (100 ml) was heated at 60°C for 20 minutes. Then to the reaction mixture were added N-chlorosuccinimide (22,4 g, 0.17 mole) and stirred at 60°C for 2 hours. Analysis by LC/MS showed that the reaction was completed (only pic of the product). After cooling to ambient temperature the mixture was poured into a mixture of ice-water (1 l). The mixture was extracted with CHCl3(2×800 ml). The combined organic phases were washed with 3M NaOH (2×600 ml), water (600 ml), dried� sodium sulfate, was filtered and concentrated. The crude product was washed with ether to give the desired product (35 g, 76% yield).1H NMR (CDCl3) δ 7.5 (d, 2H), 7.4 (d, 2H), 4.2 (s, 4H), 3.4 (s, 1H), 1.4 (s, 9H).

Preparatory example 5: tert-Butyl-3-(4-bromophenyl)-3-torasemide-1-carboxylate

tert-Butyl-3-(4-bromophenyl)-3-hydroxyazetidine-1-carboxylate (Preparation example 4, 25 g, 0,076 mol) in CH2Cl2(500 ml) was cooled to -78°C. To this suspension slowly via the dropping funnel was added BAST (20.2 g, 0.09 mole). The temperature of the reaction mixture slowly increased from -78°C to ambient temperature. The mixture was stirred at ambient temperature overnight. Analysis by LC/MS showed that the reaction was completed. The reaction mixture was quenched with a saturated aqueous solution of NaHCO3(500 ml) and 1M NaOH (500 ml). The aqueous layer was extracted with CH2Cl2(2×800 ml). The combined organic phases were washed with aqueous citric acid (2×700 ml), dried over Na2SO4, filtered and concentrated to give the desired product as a yellow-brown solid (24.4 g, 97% yield).1H NMR (CDCl3) δ 7.5 (d, 2H), 7.3 (d, 2H), 4.4 (m, 2H), 4.2 (m, 2H), 1.4 (s, 9H).

Preparatory example 6: tert-Butyl-3-fluoro-3-(4-formylphenyl)azetidin-1-carboxylate

To a solution of tert-Buti�-3-(4-bromophenyl)-3-torasemide-1-carboxylate (Preparation example 5, 1.0 g, 3 mmol) in THF (10 ml) at -78(C was slowly added n-BuLi (2.1 ml of a 1.6 M solution in hexano). The reaction mixture was stirred at -78(C for 15 minutes, then was added DMF (0.5 ml, 6 mmol). The reaction mixture was allowed to warm to room temperature and stir for another 1 hour. Was added saturated aqueous NH4Cl (10 ml) and the aqueous phase was extracted with ether (2(10 ml). The combined organic phases were dried (Na2SO4) and concentrated under vacuum. The crude product was subjected to chromatography on silica (12g column) using a gradient of 0-30% EtOAc/hexane for the run time of 12 minutes. The yield 460 mg). LC/MS: retention time is 3,004 minutes; MS: calculated for (C15H18FNO3) 279,127 found for 180.2 M-SU.1H NMR (CDCl3) δ 10.0 (s, 1H), 8.0 (d, 2H), 7.7 (d, 2H), 4.5 (m, 2H), 4.2 (m, 2H), 1.6 (s, 9H).

Preparatory example 7: tert-Butyl-3-fluoro-3-(4-((hydroxyimino)methyl)phenyl)azetidin-1-carboxylate

To a solution of tert-butyl-3-fluoro-3-(4-formylphenyl)azetidin-1-carboxylate (Preparation example 6, 460 mg, of 1.65 mmol) in ethanol (30 ml) was added NH2OH·HCl (127 mg, 1.8 mmol) and water (2.5 ml). The solution was heated to 50°C for 1 hour and then was allowed to stir at room temperature for 2 hours. To remove ethanol reactant was concentrated under vacuum.To the residue was added water (5 ml) and was extracted with EtOAc (2×10 ml). The combined organic phases were dried (Na2SO4) and concentrated under vacuum to give the intermediate compound in the form of solids. The yield 485 mg1H NMR (CDCl3) δ 8.17 (s, 1H), 7.65 (d, 2H), 7.50 (d, 2H), 5.32 (s, 1H), 4.37-4.50 (m, 2H), 4.28 (m, 2H), 1.45-1.55 (m, 9H). LC/MS: retention time is 2,926 minutes; MS: calculated for (C15H19FN2O3) 294,13 found 195,0 N-BOC.

Preparatory example 8: tert-Butyl-3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-carboxylate

To a solution of tert-butyl-3-fluoro-3-(4-((hydroxyimino)methyl)-phenyl)azetidin-1-carboxylate (Preparation example 7, 486 mg, of 1.65 mmol) in DMF (8 ml) in two portions over 10 minutes was added NCS (232 mg, of 1.65 mmol). The reaction mixture was stirred at room temperature over night. The reaction mixture was diluted with EtOAc (8 ml) was added 1,2,3-trichloro-5-(1,1,1-Cryptocom-2-EN-2-yl)benzene (546 mg, of 1.98 mmol) and then potassium bicarbonate (248 mg, 2.48 mmol). The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under vacuum. The residue was partitioned between EtOAc (50 ml) and water (50 ml). The aqueous layer was extracted with EtOAc (3×50 ml). The combined organic layers were dried and condensible. Untreated layer was absorbed on silica and subjected XP�matography on a column of silica 40D, elwira gradient: 0% -40% EtOAc/hexane for 20 minutes. The fractions containing the target substance were combined and concentrated to give 526 mg of a white solid.1H NMR (CDCl3) δ 7.74 (d, 2H), 7.67 (s, 2H), 7.56 (d, 2H), 4.39-4.51 (m, 2H), 4.24 (m, 2H), 4.12 (d, 1H), 3.72 (d, 1H), 1.5 (s, 9H).

Preparatory example 9: 3-(4-(3-Torasemide-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

To a solution of 250 mg of tert-butyl-3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-carboxylate (Preparation example 8) in 2 ml of CH2Cl2was added 1 ml of trifluoroacetic acid. The reaction mixture was stirred overnight under a positive pressure of nitrogen. The reaction mixture was concentrated. The residue was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with 2x EtOAc (20 ml). The combined organic phases were dried over Na2SO4and condensible to obtain 188 mg of the compound in the form of a film. Analysis by TLC showed a much more polar spot. The crude product was used in subsequent reactions. MS: calculated for (C19H13Cl3F4N2O) 466,00 found 467,9 M+N.

Example 1: 1-(3-Fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)alanon

To Rast�oru 3-(4-(3-torasemide-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (Preparatory example 9, 94 mg) in 2 ml of CH2Cl2was added pyridine (0.05 ml), and then acetyl chloride (31 mg). The reaction mixture was allowed to stir at room temperature for 1 hour. Was added water (3 ml). The reaction mixture was diluted with 3 ml of CH2Cl2was stirred for 30 minutes and poured through the device for the extraction phases. CH2Cl2layer collected and concentrated. The crude reaction product was absorbed on silica and subjected to column chromatography on silica 12g, elwira gradient from 50% EtOAc/hexane to 100% EtOAc/hexane with obtaining 90 mg of the target compound as a white foam.1H NMR (CDCl3) δ 7.76 (d, 2H)7.67 m (s, 2H), 7.56 (d, 2H), 4.71-4.31 (m, 4H), 4.12 (d, 1H), 3.72 (d, 1H), 2.01 (s, 3H). LC/MS: retention time is 3,591 minutes; MS: calculated for (C21H15Cl3F4N2O2) 509,714 found 511 M+N.

Example 2: Cyclopropyl(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)methanon

To a solution of 3-(4-(3-torasemide-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (Preparatory example 9, 94 mg) in 2 ml of CH2Cl2was added pyridine (0.05 ml), and then cyclopropanecarbonitrile (31 mg). The reaction mixture was allowed to stir at room temperature for 1 hour. Was added water (10 ml). �actionnow the mixture was diluted with an additional 10 ml of CH 2Cl2was stirred for 30 minutes at room temperature, then passed through the tube to separate the phases. CH2Cl2layer collected and condensible. Untreated layer was absorbed on silica and subjected to column chromatography on silica 12g, elwira gradient: 20% EtOAc/hexane to 80% EtOAc/hexane. The fraction containing the target substance were combined and concentrated. To the obtained film was added Et2O (about ½ ml). Putting the flask in the conditions of high vacuum overnight led to the formation of the product as a white foam (87 mg).1H NMR (CDCl3) δ M. D. 7.76 (d, 2H), 7.67 (s, 2H), 7.58 (d, 2H), 4.8-4.7 (m, 1H), 4.6-4.2 (m, 3H), 4.12 (d, 1H), 3.72 (d, 1H), 1.5-1.4 (m, 1H), 1.08 (m, 2H), 0.86 (m, 2H). LC/MS: retention time is 3,710 minutes, MS: calculated for (C23H17Cl3F4N2O2) 534,03 found 535,0 M+N.

Example 3: 3-Fluoro-N-methyl-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-carboxamide

The compound was obtained using methods analogous to the method described in Example 2 using methylisocyanate instead of cyclopropanecarbonitrile. The yield 124 mg (94%).1H NMR (CDCl3) δ 7.73 (d, 2H), 7.66 (s, 2H), 7.56 (d, 2H), 4.49-4.40 (m, 2H), 4.28-4.17 (m, 3H), 4.10 (d, 1H), 3.70 (d, 1H), 2.86 (d, 3H). LC/MS: retention time is 3,559 minutes, MS: calculated for (C21H16 Cl3F4N3O2) 523,02 found 524,0 M+N.

Example 4: N-Ethyl-3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-carboxamide

The compound was obtained using methods analogous to the method described in Example 2, using utilitzant instead of cyclopropanecarbonitrile. Yield 130 mg (96%).1H NMR (CDCl3) δ 7.73 (d, 2H), 7.66 (s, 2H), 7.56 (d, 2H), 4.49-4.38 (m, 2H), 4.27-4.15 (m, 3H), 4.10 (d, 1H), 3.70 (d, 1H), 3.31 (m, 2H), 1.18 (t, 3H). LC/MS: retention time is 3,638 minutes, MS: calculated for (C22H18Cl3F4N3O2) 537,04 found 538,0 M+N.

Example 5: N-Cyclopropyl-3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-carboxamide

The compound was obtained using methods analogous to the method described in Example 2, using cyclopropylethanol instead of cyclopropanecarbonitrile. Yield 130 mg (94%).1H NMR (CDCl3) δ 7.73 (d, 2H), 7.66 (s, 2H), 7.56 (d, 2H), 4.55-4.40 (m, 3H), 4.28-4.19 (m, 2H), 4.10 (d, 1H), 3.70 (d, 1H), 2.65 (m, 1H), 0.78 (m, 2H), 0.55 (m, 2H). LC/MS: retention time is 3,647 minutes, MS: calculated for (C23H18Cl3F4N3O2) 549,04 found 550,0 M+N.

Preparatory example 10: tert-Butyl-3-(4-(diethoxylate)phenyl)-3-hydroxyazetidine-1-carboxylate

The cerium chloride (71,4 g, 290 mmol) was suspended in tetrahydrofuran (600 ml) and heated to 65°C for 2.5 hours, then cooled to room temperature. In a separate flask 4-bromobenzaldehyde-diethylacetal (100 g, 386 mmol) was dissolved in tetrahydrofuran (750 ml). Added magnesium shavings (5.9 g, 241 mmol) and dibromoethane (0.5 ml) and the mixture was heated up to the formation of phlegm for 2.5 hours until, until the magnesium has reacted completely. The heat was removed, and the Grignard solution was cooled in an ice bath. A suspension of cerium chloride/tetrahydrofuran was cooled in an ice bath to 0°C. in Portions was added the Grignard solution, and the mixture was stirred at 0°C for 45 minutes. Portions was added N-(tert-butoxycarbonyl)azetidine (41,3 g, 241 mmol) dissolved in tetrahydrofuran (200 ml) and the reaction mixture was allowed to stir at 0°C for 30 minutes. The reaction mixture was quenched with a saturated solution of sodium carbonate (500 ml) and then was diluted with ethyl acetate (2000 ml). The organic phase was washed with water (3×500 ml), separated, dried over anhydrous magnesium sulfate, was filtered and was evaporated to dryness to obtain a yellow oil having a mass of 120 g, which was purified by normal-phase chromatography column (SiO2600g, loaded as a solution in 25 ml of dichloromethane, linear gradient from 10% tert-butyl methyl ether in n-heptane to 100% tert-BU�Eletropaulo air for 60 minutes 150 ml/min, fraction volume of 55 ml method is used, the Threshold OR Slope"), to obtain a light yellow oil having a weight of 65 g, which after analysis by NMR was considered representing a target acutally product.1H NMR (CDCl3) δ M. D.: 7.50 (4H), 5.50 (1H), 4.15 (2H), 4.30 (2H), 3.55 (4H), 1.50 (9H), 1.25 (6H); m/z (electrospray ionization (EMI)) 252 [M+H-Boc]+.

Preparatory example 11: (E)-tert-Butyl-3-hydroxy-3-(4-((hydroxyimino)methyl)phenyl)-azetidin-1-carboxylate

The product of Preparatory example 10 (54 g, 195 mmol) was dissolved in methanol (800 ml) and water (400 ml). Portions was added hydroxylamine hydrochloride (14 g, 200 mmol) and the mixture stirred at room temperature for 60 minutes. To remove excess methanol, the reaction mixture was evaporated. The aqueous residue was extracted with ethyl acetate (3000 ml), separated, dried over anhydrous magnesium sulfate, was filtered and was evaporated to dryness with getting thick yellow syrup that has a mass of 49 g1H NMR (CDCl3) δ M. D.: 8.15 (1H), 7.60 (2H), 7.50 (2H), 4.20 (4H), 1.52 (9H); m/z (EMI) 193 [M+H-BOC]+.

Preparatory example 12: tert-Butyl-3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-hydroxyazetidine-1-carboxylate

The product of Preparatory example 11 (56 g, 192 mmol) was dissolved in ethyl acetate (1000 ml) and n�remedial at room temperature. Portions was added T-chlorosuccinimide (29,9 g, 224 mmol). After 60 minutes the reaction mixture was added potassium bicarbonate (57,5 g, 575 mmol), water (5 ml) and 1,3-dichloro-2-fluoro-5-(3,3,3-Cryptocom-1-EN-2-yl)benzene (49,7 g, 192 mmol). The mixture was stirred over night at room temperature. The reaction mixture was quenched with water (750 ml), diluted with ethyl acetate (1500 ml); the layers were shaken to dissolve all the solid phases were separated; the organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to suspension (approximately 1 liter). Added hexane (1 liter) and the mixture was shaken and filtered to give a white precipitate on the filter was washed with an additional 300 ml of hexanol and dried using a pump, getting a white solid having a weight of 52 g1P NMR (DMSO-d6) δ M. D.: 7.80 (2H), 7.75 (2H), 7.62 (2H), 4.32 (2H), 4.05 (4H), 1.40 (9H); m/z (EMI) 449 [M+H-Boc]+, 547 [M-H]+.

Preparatory example 13: 3-(4-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-3-ol

To a suspension of the product of Preparatory example 12 (52 g, 95 mmol) in methanol (650 ml) was added concentrated aqueous hydrochloric acid (38 ml). Under stirring the mixture was heated. At about 50°C, the suspension began to fade - the formation of a solution by boiling to reflux. After boiling with britishtelecom for 2 hours, the reaction mixture was cooled to room temperature and was evaporated under reduced pressure, carrying out the distillation with toluene to give a white solid which was suspended in toluene (1000 ml) and was filtered under reduced pressure. The filter cake was washed with hexane (500 ml) and then dried in a vacuum oven at 50°C to give a white solid substance with a mass of 42 g1H NMR (DMSO-d6) δ M. D.: 7.80 (6H), 4.30 (4H), 4.12 (2H); m/z (EMI) 449 [M+H]+, 447 [M-H]+.

Preparatory example 14: tert-Butyl-3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-carboxylate

Reference to the literature: J. Org. Chem. 2010, 75, 3401-3411. Trihydrochloride triethylamine (5.3 g, is 32.8 mmol) was dissolved in dichloromethane (97 ml). Was added triethylamine (2.3 ml, 16.4 mmol) and the solution was cooled to -78°C. To the cooled mixture was added XtalFluor-E (5.6 g, at 24.6 mmol), and then the product of Preparatory example 12 (9 g, 16.4 mmol). This led to the formation of a thick suspension. The cooling was removed and the mixture with stirring was allowed to warm to room temperature. The suspension was dissolved with getting a light brown solution. After stirring at room temperature over night the reaction mixture was quenched by addition of saturated aqueous sodium carbonate solution (100 ml) and dichloromethane (100 ml). Then the layers were separated. The organic phase was dried over anhydrous magnesium sulfate, Fi�trevali and evaporated to dryness to obtain a brown oil, having a mass of 9 g1H NMR (CDCl3) δ M. D.: 7.75 (2H), 7.60 (2H), 7.55 (2H), 4.45 (2H), 4.25 (2H), 4.15 (1H), 3.70 (1H), 1.50 (9H); m/z (EMI) 451 [M+H-Boc]+, 549 [M-H]+.

Preparatory example 15: 5-(3,5-Dichlorophenyl)-3-(4-(3-torasemide-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

To a solution of tert-butyl-3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-carboxylate (Preparation example 14) in methanol (10 ml) was added a methanolic solution of HCl (10 ml of a 1.25 M solution). The reaction mixture was heated to 65°C for 1.5 hours. The reaction mixture was concentrated on a rotary vacuum evaporator to obtain viscous oil. After addition of CH2Cl2a precipitate formed. Volatiles were removed under reduced pressure obtaining 573 mg specified in the title compound as a white solid.1H NMR (DMSO-d6) δ 9.8-9.6 (br s, 2H), 7.9-7.8 (m, 3H), 7.75 (d, 2H), 7.63 (d, 2H), 4.64-4.29 (m, 6H). LC/MS: retention time is 3,039 minutes, MS: calculated for (C19H14Cl2F4N2O) 432,04 found 433,0 M+N.

Example 6: Cyclopropyl(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)methanon

To a solution of 5-(3,5-dichlorophenyl)-3-(4-(3-torasemide-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (Prepare�iny example 15, 65 mg) in 2 ml of CH2Cl2was added triethylamine (50 µl), and then cyclopropanecarbonitrile (19 mg). The reaction mixture was allowed to stir at room temperature for 30 minutes. Was added water (5 ml). The reaction mixture was diluted with additional 5 ml of CH2Cl2was stirred for 5 minutes at room temperature, then passed through the tube to separate the phases. CH2Cl2layer collected and condensible. Untreated layer was absorbed on silica and subjected to column chromatography on silica 12g, elwira gradient: 0% to 100% ethyl acetate in heptane. The fraction containing the target substance were combined and concentrated. To the obtained film was added Et2O (about ½ ml). Putting the flask in the conditions of high vacuum overnight led to the formation of white foam. The target product yield 67 mg (98%).1H NMR (CDCl3) δ M. D. 7.76 (d, 2H), 7.63-7.51 (s, 4H), 7.45 (s, 1H), 4.8-4.7 (m, 1H), 4.6-4.3 (m, 3H), 4.12 (d, 1H), 3.74 (d, 1H), 1.6-1.4 (m, 1H), 1.07 (m, 2H), 0.86 (m, 2H). LC/MS: retention time is 3,654 minutes, MS: calculated for (C23H18Cl2F4N2O2) 500,07 found 501,0 M+N.

Example 7 1-(3-(4-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpropan-1-he

The compound was obtained using methods analogous to� method described in Example 6, using isobutyrophenone instead of cyclopropanecarbonitrile. The yield 146 mg (95%).1H NMR (CDCl3) δ 7.76 (d, 2H), 7.58-7.51 (m, 4H), 7.45 (m, 1H), 4.71-4.58 (m, 1H), 4.56-4.32 (m, 3H), 4.12 (d, 1H), 3.73 (d, 1H), 2.53 (m, 1H), 1.22-1.14 (m, 6H). LC/MS: retention time is 3,660 minutes, MS: calculated for (C23H20Cl2F4N2O2) 502,08 found 503,0 M+N.

Example 8: 3-(4-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-fluoro-N-methylaziridine-1-carboxamide

The compound was obtained using methods analogous to the method described in Example 6, using methylisocyanate instead of cyclopropanecarbonitrile. The yield 118 mg (96%).1H NMR (CDCl3) δ 7.73 (d, 2H), 7.61-7.51 (m, 4H), 7.44 (m, 1H), 4.50-4.39 (m, 2H), 4.28-4.16 (m, 3H), 4.10 (d, 1H), 3.71 (d, 1H), 2.87 (d, 3H). LC/MS: retention time is 2,965 minutes, MS: calculated for (C21H17Cl2F4N3O2) 489,06 found 490,0 M+N.

Example 9: 3-(4-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-ethyl-3-torasemide-1-carboxamide

The compound was obtained using methods analogous to the method described in Example 6, using utilitzant instead of cyclopropanecarbonitrile. The yield 123 mg (97%).1H NMR (CDCl3) δ 7.73 (d, 2H), 7.59-7.50 (m, 4H), 7.44 (m, 1H), 4.50-4.38 (m, 2H), 4.27-4.14 (m, 3H), 4.10 (d, 1H), 3.71 (d, 1H), 3.3 (m, 2H), 1.18 (t, 3H). LC/MS: retention time is 3,018 minutes, MS: calculated for (C22H19Cl2F4N3O2) 503,08 found 504,0 M+N.

Example 10: N-Cyclopropyl-3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-carboxamide

The compound was obtained using methods analogous to the method described in Example 6, using cyclopropylethanol instead of cyclopropanecarbonitrile. The yield 124 mg (96%).1H NMR (CDCl3) δ 7.73 (d, 2H), 7.58-7.51 (m, 4H), 7.44 (m, 1H), 4.55-4.39 (m, 3H), 4.29-4.19 (m, 2H), 4.10 (d, 1H), 3.71 (d, 1H), 2.65 (m, 1H), 0.77 (m, 2H), 0.55 (m, 2H). LC/MS: retention time is 3,026 minutes, MS: calculated for (C23H196Cl2F4N3O2) 515,08 found 516,0 M+N.

Preparatory example 16: 5-(3,5-Dichloro-4-fluorophenyl)-3-(4-(3-torasemide-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

The product was obtained according to the methods described in preparation examples 12, 14, and 15, using 1,3-dichloro-2-fluoro-5-(3,3,3-Cryptocom-1-EN-2-yl)benzene.1H NMR (DMSO-d6) δ 10.0-9.6 (br s, 2H), 7.9-7.7 (m, 6H), 4.68-4.24 (m, 6H). LC/MS: retention time is 3,020 minutes, MS: calculated for (C19H13Cl2F5N2O) 450,03 found 450,9 M+N.

Example 11: 1-(3-(4-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-ftores�tidin-1-yl)propane-1-he

The compound was obtained from compound of Preparatory example 16 according to the method described in Example 6, using propionitrile instead of cyclopropanecarbonitrile.1H NMR (CDCl3) δ 7.74 (d, 2H), 7.60 (d, 2H), 7.54 (d, 2H), 4.66-4.30 (m, 4H), 2.22 (m, 1H), 1.19 (m, 3H). LC/MS: retention time is 3,611 minutes, MS: calculated for (C22H17Cl2F5N2O2) 506,6 found 507,0 M+N.

Example 12: 1-(3-(4-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)butane-1-he

To a solution of butyric acid (50 mg) in DMF (5 ml) was added HATU (200 mg) and then triethylamine (150 μl). The resulting solution was stirred at ambient temperature for 15 minutes, then one portion was added the hydrochloride of 5-(3,5-dichloro-4-fluorophenyl)-3-(4-(3-torasemide-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (Preparatory example 16, 100 mg). The reaction mixture was stirred at ambient temperature for 16 hours. The solvent was removed in vacuo, and the residue was distributed between water (10 ml) and CH2Cl2(10 ml). The organic phase was collected and condensible. Untreated phase was absorbed on silica and subjected to column chromatography on silica 12g, elwira gradient: 0% to 100% ethyl acetate in heptane. Fractions with�holding the target substance, were pooled and concentrated. To the obtained film was added Et2O (about ½ ml). Putting the flask in the conditions of high vacuum overnight led to the formation of white foam. Yield 86 mg (80%).1H NMR (CDCl3) δ 7.75 (d, 2H), 7.61 (d, 2H), 7.55 (d, 2H), 4.68-4.33 (m, 4H), 4.12 (d, 1H), 3.72 (d, 1H), 2.19 (m, 2H), 1.73 (m, 2H), 1.01 (m, 3H). LC/MS: retention time is 3,688 minutes, MS: calculated for (C23H19Cl2F5N2O2) 520,07 found 521,0 M+N.

Example 13: 2-Cyclopropyl-1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)alanon

The compound was obtained from compound of Preparatory example 16 according to the method described in Example 12, using cyclopropylamine acid instead of butyric acid. The yield 73 mg (67%).1H NMR (CDCl3) δ 7.74 (d, 2H), 7.60 (d, 2H), 7.54 (d, 2H), 4.67-4.33 (m, 4H), 4.10 (d, 1H), 3.70 (d, 1H), 2.03 (m, 2H), 1.09 (m, 1H), 0.61 (m, 2H), 0.20 (m, 2H). LC/MS: retention time is 3,694 minutes, MS: calculated for (C24H19Cl2F5N2O2) 532,07 found 533,0 M+N.

Example 14: 3-(3-(4-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3-oxopropanenitrile

The compound was obtained from compound of Preparatory example 16 according to the method described in Example 12, using zanoxolo acids� instead of butyric acid. Yield 88 mg (55%).1H NMR (CDCl3) δ 7.77 (d, 2H), 7.60 (d, 2H), 7.55 (d, 2H), 4.79 (m, 1H), 4.71-4.40 (m, 3H), 4.11 (d, 1H), 3.71 (d, 1H), 3.40 (s, 2H). LC/MS: retention time is 3,533 minutes, MS: calculated for (C22H14Cl2F5N3O2) 517,04 found 539,9 M+H+Na+.

Example 15: 1-(3-(4-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylthio)alanon

The compound was obtained from compound of Preparatory example 16 according to the method described in Example 12, using 2-(methylthio)acetic acid instead of butyric acid. The yield 208 mg (94%).1H NMR (CDCl3) δ 7.75 (d, 2H), 7.60 (d, 2H), 7.55 (d, 2H), 4.72 (m, 1H), 4.61-4.34 (m, 3H), 4.11 (d, 1H), 3.71 (d, 1H), 3.15 (s, 2H), 2.26 (s, 3H). LC/MS: retention time is 3,637 minutes, MS: calculated for (C22H17Cl2F5N2O2S) 538,03 found 538,9 M+H+).

Example 16: 1-(3-(4-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methoxyethanol

The compound was obtained from compound of Preparatory example 16 according to the method described in Example 6, using methoxyacetophenone instead of cyclopropanecarbonitrile. Yield 114 mg (88%).1H NMR (CDCl3) δ 7.74 (d, 2H), 7.60 (d, 2H), 7.54 (d, 2H), 4.82-4.68 (m, 1H), 4.66-4.34 (m, 3H), 4.15-4.04 (m, 3H), 3.71 (d, 1H), 3.42 (s, 3H). LC/MS: retention time is 3,43 minutes MS: calculated for (C22H17Cl2F5N2O3) 522,05 found 523,0 M+N.

Example 17: Cyclobutyl(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)methanon

The compound was obtained from compound of Preparatory example 16 according to the method described in Example 6, using cyclobutanecarbonitrile instead of cyclopropanecarbonitrile. The yield 115 mg (88%).1H NMR (CDCl3) δ 7.73 (d, 2H), 7.59 (d, 2H), 7.51 (d, 2H), 4.59-4.26 (m, 4H), 4.10 (d, 1H), 3.71 (d, 1H), 3.12 (m, 1H), 2.38 (m, 2H), 2.16 (m, 2H), 2.07-1.87 (m, 2H). LC/MS: retention time is 3,743 minutes, MS: calculated for (C24H19Cl2F5N2O2) 532,07 found 533,0 M+N.

Example 18: 1-(3-(4-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpropan-1-he

The compound was obtained from compound of Preparatory example 16 according to the method described in Example 6, using isobutyrophenone instead of cyclopropanecarbonitrile. The yield 166 mg (90%).1H NMR (CDCl3) δ 7.74 (d, 2H), 7.60 (d, 2H), 7.53 (d, 2H), 4.70-4,29 (m, 4H), 4.10 (d, 1H), 3.71 (d, 1H), 2.51 (m, 1H), 1.17 (m, 6H). LC/MS: retention time is 3,685 minutes, MS: calculated for (C23H19Cl2F5N2O2) 520,07 found 521,0 M+N.

Example 19: 1-(3-(4-(5-(3,5-Dichloro-4-fluorophenyl)-5-(tripto�methyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he

The compound was obtained from compound of Preparatory example 16 according to the method described in Example 6, using 3,3,3-triphosphorylated instead of cyclopropanecarbonitrile. Yield 96 mg (70%).1H NMR (CDCl3) δ 7.76 (d, 2H), 7.60 (d, 2H), 7.53 (d, 2H), 4.76-4.65 (m, 1H), 4.61-4.38 (m, 3H), 4.10 (d, 1H), 3.71 (d, 1H), 3.09 (m, 2H). LC/MS: retention time is 3,712 minutes, MS: calculated for (C22H14Cl2F8N2O2) 560,03 found 561,0 M+N.

Example 20: N-Cyclopropyl-3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-carboxamide

The compound was obtained from compound of Preparatory example 16 according to the method described in Example 6, using cyclopropylethanol instead of cyclopropanecarbonitrile. The yield 126 mg (94%).1H NMR (CDCl3) δ 7.73 (d, 2H), 7.60 (d, 2H), 7.56 (d, 2H), 4.56-4.39 (m, 3H), 4.29-4.18 (m, 2H), 4.10 (d, 1H), 3.70 (d, 1H), 2.65 (m, 1H), 0.78 (m, 2H), 0.55 (m, 2H). LC/MS: retention time is 3,233 minutes, MS: calculated for (C23H18Cl2F5N3O2) 533,07 found 534,0 M+N.

Example 21: 3-(4-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-fluoro-N-methylaziridine-1-carboxamide

The compound was obtained from compound of Preparatory example 16 according to the method described in P�the emer 6, using methylisocyanate instead of cyclopropanecarbonitrile. Yield 44 mg (94%).1H NMR (CDCl3) δ 7.71 (d, 2H), 7.59-7.53 (m, 4H), 4.45 (d, 1H), 4.39 (d, 1H), 4.23 (d, 1H), 4.21 (d, 1H), 4.24-4.17 (m, 3H), 4.08 (d, 1H), 3.68 (d, 1H), 2.83 (d, 3H). LC/MS: retention time is 3,001 minutes, MS: calculated for (C21H16Cl2F5N3O2) 507, found 508 M+N.

Example 22: 3-(4-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-ethyl-3-torasemide-1-carboxamide

The compound was obtained from compound of Preparatory example 16 according to the method described in Example 6, using utilitzant instead of cyclopropanecarbonitrile. Yield 44 mg (91%).1H NMR (CDCl3) δ 7.71 (d, 2H), 7.59-7.53 (m, 4H), 4.44 (d, 1H), 4.39 (d, 1H), 4.24-4.17 (m, 3H), 4.08 (d, 1H), 3.68 (d, 1H), 3.33-3.26 (m, 2H), 1.16 (t, 3H). LC/MS: retention time is 3,531 minutes, MS: calculated for (C22H18Cl2F5N3O2) 521, found 522 M+N.

Example 23: 3-(4-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-carboxamide

To a suspension hydrochloride salt azetidine (Preparatory example 16, 0,200 g, 0,410 mmol) in CH2Cl2(5 ml) was added triethylamine (0,070 ml, 0,492 mmol). Was then added trimethylsilyltriflate (0,308 ml of 2.05 mmol) and the reaction mixture stirred at room temperature�re during the night. Was added a saturated aqueous solution of Na2CO3(5 ml) and the reaction mixture was stirred for 5 minutes. The organic phase was separated, washed with brine and dried (anhydrous Na2SO4). The solvent was evaporated under reduced pressure to obtain an off-white solid. The residue was purified by chromatography [system Teledyne Isco CombiFlash Rf, RediSep cartridge Rf 24g silica gel, gradient elution from CH2Cl2to CH2Cl2-MeOH (95:5) for 10 CV (10 column volumes)] to obtain purified target compound as white solids (0,089 g, 44%). LC/MS: Rtis 378 minutes, m/z 494 [M+H]+.

Preparatory example 17: 3-(4-(5-(3,4-Dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-3-ol

Obtained according to the methods described in Preparatory example 12 preparation example 13, using 1,2-dichloro-3-(trifluoromethyl)-5-(3,3,3-Cryptocom-1-EN-2-yl)benzene. Preparatory example 18: 5-(3,4-Dichloro-5-(trifluoromethyl)phenyl)-3-(4-(3-torasemide-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

Obtained according to the methods described in preparation examples 12, 14 and 15 using 1,2-dichloro-3-(trifluoromethyl)-5-(3,3,3-Cryptocom-1-EN-2-yl)benzene.1H NMR (DMSO-d6) δ M. D.: 8.20 (1H), 7.93 (1H), 7.86 (2H), 7.75 (2�), 4.62-4.36 (6H); m/z (chemical ionization (HEE)) 501 [M+H]+.

Example 24: Cyclopropyl(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-hydroxyazetidine-1-yl)methanon

The compound was obtained from compound of Preparatory example 17 according to the method described in Example 6, using cyclopropanecarboxylic instead of cyclopropanecarbonitrile. The yield 112 mg (88%).1H NMR (CDCl3) δ 7.96 (d, 1H), 7.85 (d, 1H), 7.71 (m, 2H), 7.62 (m, 2H), 4.51 (m, 2H), 4.29 (m, 2H), 4.16 (d, 1H), 3.95(s, 1H), 3.73 (d, 1H), 1.47 (m, 1H), 1.01 (m, 2H), 0.82 (m, 2H). LC/MS: retention time is 3,564 minutes, MS: calculated for (C24H18Cl2F6N2O3) 566,06 found 567,0 M+N.

Example 25: Cyclobutyl(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-hydroxyazetidine-1-yl)methanon

The compound was obtained from compound of Preparatory example 17 according to the method described in Example 6, using cyclobutanecarbonitrile instead of temporomandibularjoint. The yield 111 mg (85%).1H NMR (CDCl3) δ 7.96 (d, 1H), 7.85 (d, 1H), 7.70 (m, 2H), 7.58 (m, 2H), 4.37-4.21 (m, 4H), 4.15 (m, 1H), 4.04 (d, 1H), 3.72 (m, 1H), 3.10 (m, 1H), 2.33 (m, 2H), 2.12 (m, 2H), 2.06-1.83 (m, 2H). LC/MS: retention time is 3,650 minutes, MS: calculated for (C25H20Cl2F6N2O3) 580,08 found 581,0 M+N.

Example 26: 3-(4-(5-(3,4-Dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-fluoro-N-methylaziridine-1-carboxamide

The compound was obtained from compound of Preparatory example 18 according to the method described in Example 6, using methylisocyanate instead of temporomandibularjoint. The yield 132 mg (94%).1H NMR (CDCl3) δ 7.96 (m, 1H), 7.85 (m, 1H), 7.73 (d, 2H), 7.57 (d, 2H), 4.50-4.39 (m, 2H), 4.28-4.11 (m, 4H), 3.72 (d, 1H), 2.86 (d, 3H). LC/MS: retention time is 3,090 minutes, MS: calculated for (C22H16Cl2F7N3O2) 557,05 found 558,0 M+N.

Example 27: 3-(4-(5-(3,4-Dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-ethyl-3-torasemide-1-carboxamide

The compound was obtained from compound of Preparatory example 18 according to the method described in Example 6, using utilitzant instead of cyclopropanecarbonitrile. The yield 141 mg (98%).1H NMR (CDCl3) δ 7.96 (m, 1H), 7.85 (m, 1H), 7.74 (d, 2H), 7.57 (d, 2H), 4.49-4.38 (m, 2H), 4.27-4.11 (m, 4H), 3.72 (d, 1H), 3.31 (m, 2H), 1.18 (t, 3H). LC/MS: retention time is RUB 3,133 minutes, MS: calculated for (C23H18Cl2F7N3O2) 571,01 found 572,0 M+N.

Example 28: N-Cyclopropyl-3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-carboxamide

The compound was obtained from compound of Preparatory example 18 according to the method described in Example 6, using cyclopropylethanol instead of cyclopropanecarbonitrile. The yield 142 mg (97%).1H NMR (CDCl3) δ 7.96 (m, 1H), 7.85 (m, 1H), 7.74 (d, 2H), 7.56 (d, 2H), 4.55-4.38 (m, ZN), 4.29-4.19 (m, 2H), 4.16 (d, 1H), 3.72 (d, 1H), 2.64 (m, 1H), 0.78 (m, 2H), 0.55 (m, 2H). LC/MS: retention time is 3,152 minutes, MS: calculated for (C24H18Cl2F7N3O2) 583,07 found 584,0 M+N.

Example 29: 3-(4-(5-(3,4-Dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-ethyl-3-hydroxyazetidine-1-carboxamide

The compound was obtained from compound of Preparatory example 17 according to the method described in Example 6, using utilitzant instead of cyclopropanecarbonitrile. Yield 50 mg (94%).1H NMR (CDCl3) δ 7.94 (s, 1H), 7.83 (s, 1H), 7.68 (d, 2H), 7.62 (d, 2H), 4.21-4.11 (m, 6H), 3.90 (s, 1H), 3.70 (d, 1H), 3.26 (q, 2H), 1.13 (t, 3H). LC/MS: retention time is 3,179 minutes, MS: calculated for (C23H19Cl2F6N3O3) 569 found 570 M+N.

Example 30: N-Cyclopropyl-3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-hydroxyazetidine-1-carboxamide

The compound was obtained from compound of Preparatory example 17 according to the method described in Example� 6, using cyclopropanecarboxylate. Yield 51 mg (94%).1H NMR (CDCl3) δ 7.94 (s, 1H), 7.83 (s, 1H), 7.68 (d, 2H), 7.62 (d, 2H), 4.49 (s, 1H), 4.23-4.18 (m, 4H), 4.13 (d, 1H), 3.70 (d, 1H), 3.3.8 (s, 1H), 2.63-2.59 (m, 1H), 0.76-0.72 (m, 2H), 0.53-0.49 (m, 2H). LC/MS: retention time is 3,481 minutes, MS: calculated for (C24H19Cl2F6N3O3) 581, found 582 M+N.

Preparatory example 19: 3-(4-(5-(3,5-Bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-3-ol

Obtained according to the methods described in Preparatory example 12 preparation example 13, using 1,3-bis(trifluoromethyl)-5-(3,3,3-Cryptocom-1-EN-2-yl)benzene.

Preparatory example 20: 5-(3,5-Bis(trifluoromethyl)phenyl)-3-(4-(3-torasemide-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

Obtained according to the methods described in preparation examples 12, 14 and 15, using 1,3-bis(trifluoromethyl)-5-(3,3,3-Cryptocom-1-EN-2-yl)benzene.1H NMR (DMSO-d6) δ M. D.: 8.36 (1H), 8.22 (2H), 7.87 (2H), 7.76 (2H), 4.62-4.42 (6H); m/z (HEE) 501 [M+H]+.

Example 31: 3-(4-(5-(3,5-Bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-fluoro-N-methylaziridine-1-carboxamide

The compound was obtained from compound of Preparatory example 20 according to the method described in Example 6, using metalis�the cyanate instead of cyclopropanecarbonitrile. The yield 131 mg (94%).1H NMR (CDCl3) δ 8.10 (s, 2H), 7.98 (s, 1H), 7.75 (d, 2H), 7.57 (d, 2H), 4.50-4.39 (m, 2H), 4.28-4.17 (m, 4H), 3.76 (d, 1H), 2.86 (d, 3H). LC/MS: retention time is 3,015 minutes, MS: calculated for (C23H17F10N3O2) 557,12 found 558,0 M+N.

Example 32: 3-(4-(5-(3,5-Bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-ethyl-3-torasemide-1-carboxamide

The compound was obtained from compound of Preparatory example 20 according to the method described in Example 6, using utilitzant instead of cyclopropanecarbonitrile. The yield 131 mg (92%).1H NMR (CDCl3) δ 8.10 (s, 2H), 7.98 (s, 1H), 7.75 (d, 2H), 7.57 (d, 2H), 4.50-4.39 (m, 2H), 4.27-4.16 (m, 4H), 3.76 (d, 1H), 3.31 (m, 2H), 1.18 (t, 3H). LC/MS: retention time is 3,089 minutes, MS: calculated for (C24H19F10N3O2) 571,13 found 572,0 M+N.

Example 33: 3-(4-(5-(3,5-Bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-cyclopropyl-3-torasemide-1-carboxamide

The compound was obtained from compound of Preparatory example 20 according to the method described in Example 6, using cyclopropylethanol instead of cyclopropanecarbonitrile. The yield 141 mg (96%).1H NMR (CDCl3) δ 8.10 (s, 2H), 7.98 (s, 1H), 7.75 (d, 2H), 7.57 (d, 2H), 4.55-4.39 (m, 3H), 4.28-4.18 (m, 3H), 3.77 (d, 1H), 2.65 (m, 1H), 0.78 (m, 2H), 0.55 (m, 2H). LC/MS: retention time of the components�t 3,086 minutes MS: calculated for (C25H19F10N3O2) 583,13 found 584,0 M+N.

Example 34: 3-(4-(5-(3,5-Bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-cyclopropyl-3-hydroxyazetidine-1-carboxamide

The compound was obtained from compound of Preparatory example 19 according to the method described in Example 6, using cyclopropylethanol instead of cyclopropanecarbonitrile. The yield 119 mg (89%).1H NMR (CDCl3) δ 8.10 (s, 2H), 7.97 (s, 1H), 7.71 (m, 2H), 7.64 (m, 2H), 4.57 (d, 1H), 4.28-4.16 (m, 6H), 3.77 (d, 1H), 2.61 (m, 1H), 0.74 (m, 2H), 0.52 (m, 2H). LC/MS: retention time is 2,989 minutes, MS: calculated for (C25H20F9N3O3) 581,14 found 582,0 M+N.

Preparatory example 21: 3-(4-(5-(3-Chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-3-ol

Obtained according to the methods described in Preparatory example 12 preparation example 13, using 1-chloro-3-(trifluoromethyl)-5-(3,3,3-Cryptocom-1-EN-2-yl)benzene.

Preparatory example 22: 5-(3-Chloro-5-(trifluoromethyl)phenyl)-3-(4-(3-torasemide-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

Obtained according to the methods described in preparation examples 12, 14 and 15 using 1-chloro-3-(trifluoromethyl)-5-(3,3,3-Cryptocom-1-EN-2-yl)benzene.1H �Mr (DMSO-d 6) δ M. D.: 8.10 (1H), 7.99 (1H), 7.87-7.85 (3H), 7.75 (2H), 4.62-4.37 (6H); m/z (HEE) 467 [M+H]+.

Example 35: 3-(4-(5-(3-Chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-ethyl-3-hydroxyazetidine-1-carboxamide

The compound was obtained from compound of Preparatory example 21 according to the method described in Example 6, using utilitzant instead of cyclopropanecarbonitrile. The yield 121 mg (90%).1H NMR (CDCl3) δ 7.84 (s, 1H), 7.77 (m, 1H), 7.74-7.68 (m, 3H), 7.66-7.62 (m, 2H), 4.22-4.13 (m, 6H), 3.74 (d, 1H), 3.30 (m, 2H), 1.16 (t, 3H). LC/MS: retention time is 3,312 minutes, MS: calculated for (C23H20ClF6N3O3) 535,11 found 536,0 M+N.

Example 36: 3-(4-(5-(3-Chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-ethyl-3-torasemide-1-carboxamide

The compound was obtained from compound of Preparatory example 22 according to the method described in Example 6, using utilitzant instead of cyclopropanecarbonitrile. The yield 133 mg (99%).1H NMR (CDCl3) δ 7.84 (s, 1H), 7.79-7.68 (m, 4H), 7.57 (d, 2H), 4.49-4.38 (m, 2H), 4.27-4.12 (m, 4H), 3.74 (d, 1H), 3.32 (m, 2H), 1.18 (t, 3H). LC/MS: retention time is 3,571 minutes, MS: calculated for (C23H19ClF7N3O2) 537,11 found 538,0 M+N.

Example 37: 3-(4-(5-(3-Chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-�ecoprofile-3-torasemide-1-carboxamide

The compound was obtained from compound of Preparatory example 22 according to the method described in Example 6, using cyclopropylethanol instead of cyclopropanecarbonitrile. The yield 131 mg (95%).1H NMR (CDCl3) δ 7.83 (s, 1H), 7.79-7.68 (m, 4H), 7.56 (d, 2H), 4.55-4.39 (m, 3H), 4.29-4.20 (m, 2H), 4.16 (d, 1H), 3.74 (d, 1H), 2.65 (m, 1H), 0.78 (m, 2H), 0.55 (m, 2H). LC/MS: retention time is 3,574 minutes, MS: calculated for (C22H17ClF7N3O2) 549,11 found 550,0 M+N.

Example 38: 3-(4-(5-(3-Chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-fluoro-N-methylaziridine-1-carboxamide

The compound was obtained from compound of Preparatory example 22 according to the method described in Example 6, using methylisocyanate instead of cyclopropanecarbonitrile. The yield 126 mg (96%).1H NMR (CDCl3) δ 7.83 (s, 1H), 7.79-7.68 (m, 4H), 7.57 (d, 2H), 4.50-4.39 (m, 2H), 4.28-4.12 (m, 4H), 3.74 (d, 1H), 2.86 (d, 3H). LC/MS: retention time is 3,487 minutes, MS: calculated for (C22H17ClF7N3O2) 523,09 found 524,0 M+N.

Example 39: 1-(3-(4-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)alanon

To a solution of 5-(3,5-dichlorophenyl)-3-(4-(3-torasemide-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (Preparatory example 15, 200 mg, 0,462 mmol) in �chlormethine (3 ml) was added triethylamine (0,192 ml), and then acetic anhydride (50,2 µl). The reaction mixture was allowed to stir at room temperature over night. The solution was diluted with water and allowed to stir for 10 minutes. The mixture was passed through a phase separating agent ISCO Phase Separator. The organic phase blows from the North by a stream of nitrogen, then placed in a deep vacuum with the formation of 200 mg of a white foam (91% yield).1H NMR (400 MHz, CDCl3-d) δ M. D. 2.01 (s, 3H), 3.73 (d, 1H), 3.92 (qd, 1H), 4.12 (d, 1H), 4.32-4.56 (m, 3H), 4.59-4.70 (m, 1H), 7.46 (t, 1H), 7.52-7.59 (m, 4H), 7.76 (d, 2H), LC/MS: retention time is 3,510 min; MS: calculated for (C21H16Cl2F4N2O2) 474,052 found 475,0 M+N.

Example 40: Cyclopropyl(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)methanon

The compound was obtained from compound of Preparatory example 16 according to the method described in Example 6, using cyclopropylethanol instead of cyclopropanecarbonitrile. Yield: 87% glassy solids.1H NMR (400 MHz, CDCl3-d) δ M. D. 0.85 (t, Hz, 2H), 1.06 (dd, 2H), 1.42-1.51 (m, 1H), 3.71 (d, 1H), 4.11 (d, 1H), 4.28-4.82 (m, 4H), 7.53-7.64 (m, 4H), 7.75 (d, 2H), LC/MS: retention time is 3,675 minutes; MS; calculated for (C23H17Cl2F5N2O2) 518,059 found 519 M+N.

Example 41: 2-Cyclopropyl-1-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-DIH�dreisessel-3-yl)phenyl)-3-torasemide-1-yl)alanon

The compound was obtained from compound of Preparatory example 15 according to the method described in Example 12, using 2-cyclopropylethanol acid instead of butyric acid.1H NMR (400 MHz, CDCl3-d) δ M. D.-0.04-0.04 (m, 2H), 0.41 (d, 2H), 0.86-0.92 (m, 1H), 1.95 (d, 2H), 3.51 (d, 1H), 3.90 (d, 1H), 4.12-4.46 (m, 4H), 7.24 (t, 1H), 7.30-7.37 (m, 4H), 7.54 (d, 2H), LC/MS: retention time is 3,682 minutes; MS: calculated for (C24H20Cl2F4N2O2) 514,084 found 515,0 [M+H]+.

Example 42: 3-(3-(4-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3-oxopropanenitrile

The compound was prepared from the compound of Preparatory example 15 according to the method described in Example 12, using 2-zanoxolo acid instead of butyric acid to obtain a glassy solid.1H NMR (400 MHz, CDCl3-d) δ M. D. 3.41 (s, 1H), 3.73 (d, 1H), 4.12 (d, 1H), 4.41-4.72 (m, 4H), 4.76-4.86 (m, 1H), 7.46 (t, 1H), 7.54-7.58 (m, 4H), 7.78 (d, 2H); MS: calculated for (C22H15Cl2F4N3O2) 499,048 found 500,0 [M+H]+.

Example 43: 1 -(3-(4-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he

The compound was obtained from compound of Preparatory example 15 according to the method described in PR�least 6, using 3,3,3-triphosphorylated instead of cyclopropanecarbonitrile.1H NMR (400 MHz, CDCl3-d) δ M. D. 3.09 (q, 2H), 3.64 (d, 1H), 4.10 (d, 1H), 4.39-4.63 (m, 4H), 7.37 (t, 1H), 7.44-7.46 (m, 4H), 7.76 (d, 2H); MS: calculated for (C22H15Cl2F7N2O2) 543,266 found 544,0 [M+H]+.

Example 44: 1-(3-(4-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methoxyethanol

The compound was prepared from the compound of Preparatory example 15 according to the method described in Example 6, using 2-methoxyacetanilide instead of cyclopropanecarbonitrile to give a white solid.1H NMR (400 MHz, CDCl3-d) δ M. D. 3.44 (s, 3H), 3.73 (d, 1H), 4.09-4.14 (m, 3H), 4.37-4.63 (m, 3H), 4.65-4.85 (m, 1H), 7.43-7.49 (m, 1H), 7.51-7.60 (m, 4H), 7.76 (d, 2H); MS: calculated for (C22H18Cl2F4N3O3) 505,295, found m/z (EMI) 506,0 [M+H]+.

Example 45: 1-(3-(4-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)propane-1-he

The compound was prepared from the compound of Preparatory example 15 according to the method described in Example 6, using propionitrile instead of cyclopropanecarbonitrile to give a white solid.1H NMR (400 MHz, CDCl3-d) δ M. D. 1.14-1.25 (m, 3H), 2.24 (m, 2H), 3.73 (d, 1H), 4.11 (d, 1H), 4.32-4.67 (m, 4H), 7.46 (t, 1H), 7.52-7.60(m, 4H), 7.76 (d, 2H); MS: calculated for (C22H18Cl2F4N2O2) 489,296, found m/z (EMI) 490,0 [M+H]+.

Example 46: 1-(3-(4-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)butane-1-he

The compound was prepared from the compound of Preparatory example 15 according to the method described in Example 6, using butyryl chloride instead of cyclopropanecarbonitrile to give a white solid.1H NMR (400 MHz, CDCl3-d) δ M. D. 1.01 (t, 3H), 1.73 (m, 2H), 2.19 (m, 2H), 3.73 (d, 1H), 4.11 (d, 1H), 4.33-4.66 (m, 4H), 7.46 (t, 1H), 7.53-7.58 (m, 4H), 7.76 (d, 2H); MS: calculated for (C23H20Cl2F4N2O2) 503,323, found m/z (EMI) 503,0 [M+H]+.

Examples 47-82

The examples given in Table 1 below, was obtained in the following conditions:

.

Isoxazolidinone (0,05 mmol) was dissolved in dimethylformamide (0.5 ml). The mixture was added to the respective acid (0.2 mmol) followed by the addition of a solution of hexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea (0.10 mmol) in dimethylformamide (0.5 ml) and Et3N (0.5 mmol). The resulting mixture was shaken at ambient temperature for 16 hours. The solvent was removed by distillation under vacuum, and the crude product was purified preparative jhud (Waters,Gemini NX C18 21×100 mm, 5 μm, Mobil�th phase a: 0.1% of TFA in H 2O mobile phase b: acetonitrile, linear gradient from 30% to 100% over 8 min, hold for 1 min, 20 ml/min, peaks were collected by mass). The following values of retention time (RT) was obtained using the following method of analysis: Agilent 1200 column: Gemini NX C18 of 4.6×50 mm, 3 µm mobile phase A: 0.1% of TFA in H2O mobile phase b: acetonitrile, linear gradient from 30% to 100% over 5 minutes, hold for 1 minute, 1.5 ml/min.

Table 1
Example No.R1aR1bR1cR3R5m/z (EMI) [M+H]+RT (min)
47CF3HCF3Fcyclobutyl583Of 4.66
48CF3nCF3F the cyclopropyl5694,45
49CF3HCF3Fisopropyl5714,55
50CF3nClFpropyl5384,55
51CF3HClFethyl5244,34
52CF3nClFmethyl5104,07
53CF3nClF-CH2CN535 4,21

54ClHClF517Of 3.98
55ClFClF535Of 4.04
56ClClClF-CH2OCH35394,43
57ClClCF3OHisopropyl569The 8.75
58ClClCF3OHpropyl569 8,77
59CF3HCF3F5834,55
60CF3HCF3F-CH2OH5593,83
61CF3HClF-CH2SCH35564,44
62CF3HClFcyclobutyl550Of 4.66
63CF3ClClF-CH2C(O)NH25865,15
64ClFClF5623,71
65ClClClF5514,29
66ClHClFisobutyl5179,61
67ClClClF-CH2SCH35559,59
68ClFClOHethyl5057,76
69CF HClFthe cyclopropyl5364,44
70ClFClF5454,03
71CF3HCF3F6202,75
72CF3HClF550A 4.53
73CF3ClClFethyl5577,31
74CF3 ClClFthe cyclopropyl569A 7.58
75CF3ClClFmethyl5436,67
76CF3ClClFisopropyl5717,84
77CF3ClClF-CH2CN5686,72
78ClClClF5727,40

79CF3 NCF3Fethyl5574,36
80CF3ClClFcyclopentyl5978.66 roubles
81CF3ClClF-CH2SCH35897,56
82ClFClHEthe cyclopropyl5178
indicates the point of attachment, RT - retention time

The following names according to the IUPAC nomenclature for sample (47-82) from Table 1 include: 5-[3,5-bis(trifluoromethyl)phenyl]-3-{4-[1-(cyclobutanecarbonyl)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole (47); 5-[3,5-bis(trifluoromethyl)phenyl]-3-{4-[1-(cyclopropanecarbonyl)-3-ft�azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole (48); 5-[3,5-bis(trifluoromethyl)phenyl]-3-[4-(3-fluoro-1-isobutyrylacetate-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole(49); 3-[4-(1-butyryl-3-torasemide-3-yl)phenyl]-5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole (50); 5-[3-chloro-5-(trifluoromethyl)phenyl]-3-[4-(3-fluoro-1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole(51); 3-[4-(1-acetyl-3-torasemide-3-yl)phenyl]-5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole(52); 3-[3-(4-{5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-torasemide-1-yl]-3-oxopropanenitrile(53); 1-[(3-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)carbonyl]cyclopropanol(54); 1-[(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)carbonyl]cyclopropanol(55); 3-{4-[3-fluoro-1-(methoxyacetyl)azetidin-3-yl]phenyl}-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(56); 3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-1-isobutyrylacetate-3-ol (57); 1 butyryl-3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)azetidin-3-ol (58); 5-[3,5-bis(trifluoromethyl)phenyl]-3-{4-[1-(cyclopropylethyl)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole(59); 2-[3-(4-{5-[3,5-bis(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-fluoro�slidin-1-yl]-2-oxoethyl (60); 5-[3-chloro-5-(trifluoromethyl)phenyl]-3-(4-{3-fluoro-1-[(methylthio)acetyl]azetidin-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (61); 5-[3-chloro-5-(trifluoromethyl)phenyl]-3-{4-[1-(cyclobutanecarbonyl)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole(62); 3-[3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-torasemide-1-yl]-3-oxopropanoic (63); N-(1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-torasemide-1-carbonyl)cyclopropyl)formamide(64); 1-[(3-fluorine-3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-yl)carbonyl]tikarapara (65); 5-(3,5-dichlorophenyl)-3-{4-[3-fluoro-1-(3-methylbutanoyl)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole(66); 3-(4-{3-fluoro-1-[(methylthio)acetyl]azetidin-3-yl}phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(67); 3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-1-Propionaldehyde-3-ol (68); 5-[3-chloro-5-(trifluoromethyl)phenyl]-3-{4-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole (69); 5-(3,5-dichloro-4-fluorophenyl)-3-{4-[3-fluoro-1-(1H-pyrazol-3-ylcarbonyl)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole(70); 4-{2-[3-(4-{5-[3,5-bis(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-torasemide-1-yl]-2-oxoethyl}pyridine (71); 5-[3-chloro-5-(trifluoromethyl)phenyl]-3-{4-[1-(Cyclops�obyazatel)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole (72); 5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-3-[4-(3-fluoro-1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole(73); 3-{4-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]phenyl}-5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole(74); 3-[4-(1-acetyl-3-torasemide-3-yl)phenyl]-5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole (75); 5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-3-[4-(3-fluoro-1-isobutyrylacetate-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole(76); 3-[3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-torasemide-1-yl]-3-oxopropanenitrile(77); 4-[(3-fluorine-3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-yl)carbonyl]pyridine (78); 5-[3,5-bis(trifluoromethyl)phenyl]-3-[4-(3-fluoro-1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole(79); 3-{4-[1-(cyclopentanecarbonyl)-3-torasemide-3-yl]phenyl}-5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole (80); 5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-3-(4-{3-fluoro-1-[(methylthio)acetyl]azetidin-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (81) and 1-(cyclopropanecarbonyl)-3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-3-ol (82).

Preparatory example 23: Methyl 3-bromo-4-identit

A solution of methyl ester 4-amino-3-bromo-benzoic acid (5,0 �, 22,0 mmol, Aldrich) in acetone (35 ml) was treated with 6M HCl (35 ml). The solution was cooled to 0°C and treated with NaNO2dropwise (1.84 g, 26,1 mmol) dissolved in 10 ml of water. After stirring at 0°C for 2 hours the reaction mixture was slowly treated with potassium iodide (5,47 g, a 32.6 mmol) dissolved in 20 ml of water. The reaction mixture was allowed to warm to room temperature and to stir for 1 hour. The reaction mixture was diluted with water and was extracted with EtOAc (2×150 ml). The combined organic phase was dried (Na2SO4) and concentrated under vacuum. The residue was subjected to chromatography (column Redi-Sep 80g) with elution from 100% heptane to EtOAc:heptane (20:80) and receiving the intermediate compound (4.1 g, 55%) as a solid.1H NMR (CDCl3): 8.27 (1H), 7.98 (1H), 7.64 (1H), 3.94 (3H).

Preparatory example 24: (3-Bromo-4-itfinal)methanol

A solution of methyl 3-bromo-4-identita (Preparative example 23, 4.3 g, 12.6 mmol) in Chisel was cooled under N2to -78°C. DIBAL-H was slowly added to the solution, which was stirred at -78°C for 45 minutes and then left to reach room temperature. Then the reaction mixture was diluted with 1M HCl (40 ml) and stirred for 30 minutes. Next, the reaction mixture was diluted with water and was extracted with CH2Cl2. The organic phase was dried (Na2SO4 ) and concentrated under vacuum to give the intermediate (3.2 g, 82%) as a solid.1H NMR (CDCl3): 7.85 (1H), 7.67 (1H), 7.02 (1H), 4.65 (2H), 1.76 (1H, HE).

Preparatory example 25: 3-Bromo-4-identilied

A solution of (3-bromo-4-itfinal)methanol (Preparation example 24, 3.1 g, 9.9 mmol) in a mixture of CH2Cl2/water (2:1, 225 ml) was treated with NaHCO3(915 mg, 10.9 mmol), NaBr (1060 mg, 10.2 mmol) and a free radical TEMPO (40 mg, 0.2 mmol). The resulting mixture was cooled to 0°C and dropwise added a solution of NaOCl (0.8 ml, 10% aqueous). The reaction mixture under stirring was allowed to reach room temperature. After 30 minutes analysis by TLC indicated approximately 50% conversion to a less polar spot. Repeating the sequence of operations using the same equivalents of reagents. Analysis by TLC (25:75 EtOAc:heptane) showed that there was still unreacted starting material. The reaction mixture was separated and the organic phase with stirring was treated with 1.0 x periodinane dess-Martin (2.1 g, 4.9 mmol). After 10 minutes analysis by TLC indicated complete conversion to a less polar spot. The organic phase was washed with saturation. NaHCO3, dried over Na2SO4, was filtered and was evaporated to obtain an orange solid. Untreated substance m�RGALI chromatography (column Redi-Sep 80g) with elution from 100% heptane to EtOAc/heptane (50:50) and receiving the intermediate compound (2.7 g, 87%) as a white solid.1H NMR (CDCl3): 9.94 (1H), 8.10 (2H), 7.50 (1H).

Preparatory example 26: (E/Z)-3-Bromo-4-identilied-oxime

To a solution of 3-bromo-4-identilied (Preparative example 25, 1000 mg, 3.2 mmol) in EtOH (50 ml) was added NH2OH.HCl (345 mg, 4.8 mmol) and water (10 ml). The reaction mixture was heated to 50°C for 1 hour and then was allowed to stir for 18 hours at room temperature. To remove EUN the reaction mixture was concentrated under vacuum. To the residue was added water and was extracted with EtOAc (2×75 ml). The combined organic phase was dried (Na2SO4) and concentrated under vacuum to give the intermediate (1035 mg, 98%) as a glassy substance. M/z (HI)=326 [M+H]+.

Preparatory example 27: 3-(3-Bromo-4-itfinal)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

To a solution of (E/Z)-3-bromo-4-identilied-oxime (1000 mg, 3.1 mmol) in DMF (25 ml) portions was added NCS (Preparation example 26, 500 mg, 3.7 mmol). The reaction mixture was stirred at room temperature for 18 hours. Analysis by TLC (50:50 EtOAc:heptane) shows a slightly less polar spot without the original substance. The reaction mixture was diluted with EtOAc (100 ml) and washed with water (2×50 ml). The organic phase was dried over su�hatom sodium and concentrated to give chloroxylenol intermediate connection (1056 mg, 96%) as a solid. Then to ethylacetate (70 ml) solution chloroquine (1000 mg, 2.8 mmol) and 1,2,3-trichloro-5-(1,1,1-Cryptocom-2-EN-2-yl)benzene (765 mg, 2.8 mmol) was added potassium bicarbonate (310 mg, 3.1 mmol). The mixture was allowed to stir at room temperature for at least 48 hours. The reaction mixture was filtered and concentrated under vacuum. The residue was subjected to chromatography (column Redi-Sep 80g) with elution from 100% heptane to EtOAc:heptane (20:80) and receiving the intermediate compound (1.53 g, 92%) as a solid.1H NMR (CDCl3): 7.95 (1H), 7.88 (1H), 7.65 (2H), 7.33 (1H),4.07(1H), 3.67 (1H).

Preparatory example 28: 1-Benzhydryl-3-(2-bromo-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-3-ol

In kiln dried flask containing 3-(3-bromo-4-itfinal)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

(Preparation example 27, 1000 mg, 1,67 mmol) in THF (25 ml) at -40°C was slowly added isopropylaniline (1,7 ml 2,OM solution). The reaction mixture was stirred at -40°C for 1.5 under nitrogen. Was slowly added 1-benzhydrylamine-3-one (520 mg) in 4 ml THF). The reaction mixture was stirred at -40°C for another 30 minutes and was allowed to come to room temperature. The stirring was continued for 2 hours at room temperature. �actionnow the mixture was quenched with saturated NH 4Cl and was extracted with EtOAc (2×75 ml). The combined organic phase was dried (Na2SO4) and concentrated under vacuum. Untreated phase was subjected to chromatography (column Redi-Sep 40g) with elution from 100% heptane to EtOAc:heptane (60:40), collecting the intermediate compound (615 mg, 52%) as a glassy substance.1H NMR (CDCl3): 7.87 (1H), 7.66-7.63 (3H), 7.45 (4H), 7.36-7.21 (7H), 4.39 (1H), 4.07 (1 H), 3.73-3.58 (5H), 3.06 (1 H); m/z (HEE) 711 [M+H]+.

Preparatory example 29: 3-(4-(1-Benzhydryl-3-torasemide-3-yl)-3-bromophenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

Trihydrochloride triethylamine (0.3 ml, 1.7 mmol) and triethylamine (of 0.11 ml, 0.8 ml) was dissolved in dichloromethane (30 ml) and cooled to -78°C. To the cooled mixture was added XtalFluor-E (310 mg, 1.4 mmol) and then 1-benzhydryl-3-(2-bromo-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-3-ol (Preparation example 28, 600 mg, 0.8 mmol). The cooling was removed and the mixture with stirring was allowed to warm to room temperature for 2 hours. The reaction mixture was poured into a saturated aqueous solution of sodium carbonate (100 ml) and the organic phase was separated, dried over anhydrous sodium sulfate, was filtered and was evaporated to dryness. Untreated phase was subjected to chromatography (column Redi-Sep 40g) with elution from 100% heptane to EtOAc:heptane (20:80) and �rucenim intermediate compound (523 mg, 87%) as a glassy substance.1H NMR (CDCl3) δ M. D.: 7.90 (1H), 7.69-7.66 (3H), 7.47-7.21 (11H), 4.46 (1H), 4.08 (1H), 3.90-3.66 (5H); m/z (HEE) 713 [M+H]+.

Preparatory example 30: 3-(3-Bromo-4-(3-torasemide-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

To a solution of 3-(4-(1-benzhydryl-3-torasemide-3-yl)-3-bromophenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

(Preparation example 29, 515 mg, 0,76 mmol) in MeCN/DCM (5:1, 60 ml) at 0°C was added 1-chloroethyl-chloroformate (275 μl, 2.5 mmol). The reaction mixture was heated up to the formation of phlegm for 3 hours, then under stirring was allowed to cool to room temperature for 18 hours. Then the reaction mixture was concentrated under vacuum, pererestorani in anhydrous MeOH (50 ml) and heated to reflux for 1 hour. The reaction mixture was cooled, concentrated under reduced pressure and to the residue was added diethyl ether. The resulting precipitate was filtered, rinsed with diethyl ether and air dried to obtain the intermediate compound (365 mg, 87%) as a solid. M/z (HEE) 713 [M+H]+.

Example 83: (3-(2-Bromo-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(cyclopropyl)methanon

Received from the connection �podgotovitelnoe of example 30 according to the method described in Example 6.1H NMR (CDCl3) δ M. D.: 7.98 (1H), 7.71 (1H), 7.66 (2H), 7.53 (1H), 4.96-4.46 (4H), 4.09 (1H), 3.70 (1H), 1.49 (1H), 1.11-0.77 (4H); m/z (HEE) 615 [M+H]+.

Example 84: 2-(1-(Cyclopropanecarbonyl)-3-torasemide-3-yl)-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)benzonitrile

To a solution of (3-(2-bromo-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(cyclopropyl)methanone (Example 83, 35 mg, 0,06 mmol) in DMF was added zncn extension (15 mg, 0.12 mmol) and the reaction mixture degassed by purging with N2. Was added Pd(PPh3)4(4 mg, of 0.003 mmol) and the reaction mixture was heated under conditions of microwave radiation at 150°C for 15 minutes. Then the reaction mixture was diluted with water and was extracted with EtOAc (75 ml). The organic phase was dried (Na2SO4) and concentrated under vacuum. The crude product was subjected to chromatography (column Redi-Sep 12g) with elution from 100% heptane to EtOAc:heptane (60:40) and receiving the final product (18 mg, 56%) as a solid.1H NMR (CDCl3) δ M. D.: 8.08 (1H), 8.00 (1H), 7.70 (1H), 7.66 (2H), 4.98-4.52 (4H), 4.12 (1H), 3.73 (1H), 1.49 (1H), 1.10-0.81 (4H); m/z (HEE) 560 [M+H]+.

Example 85: 5-(3-Chloro-5-(trifluoromethyl)phenyl)-3-(4-(3-fluoro-1-(methyl-sulfonyl)azetidin-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

To a solution of 5-(3-chloro-5-(three�tormentil)phenyl)-3-(4-(3-torasemide-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (Preparatory example 22, 95 mg, 0,2 mmol) in CH2Cl2(5 ml) was added triethylamine (0.15 ml, 1.1 mmol) and DMAP (5 mg, 0.04 mmol). The contents were stirred for 30 minutes, then added methanesulfonamide (25 mg, 0.2 mmol) and the reaction mixture was stirred for 18 hours at room temperature. Then the reaction mixture was concentrated to about 3 ml by blowing nitrogen and directly injected into the column Redi-Sep 24g. The crude material was subjected to chromatography with elution from 100% heptane to EtOAc:heptane (30:70) and receiving the final product (95 mg, 94%) as a solid.1H NMR (CDCl3) δ M. D.: 7.85 (1H), 7.79-7.77 (3H), 7.72 (1H), 7.64 (2H), 4.50-4.42 (2H), 4.34-4.27 (2H), 4.18 (1H), 3.76 (1H), 3.03 (3H); m/z (HEE) 545 [M+H]+.

Preparatory example 31: 2-Bromo-4-(diethoxylate)-1-torbenson

A 10 ml vial equipped with a stirring element was loaded with 1 g of 3-bromo-4-fluoro-benzaldehyde, 2 ml of triethylorthoformate and 5 ml of anhydrous ethanol. Was then added 50 mg of tribromide of tetrabutylammonium and the reaction mixture was stirred at ambient temperature overnight. Analysis by TLC indicates complete conversion in a slightly less polar product. The crude reaction mixture was poured into NaHCO3and extracted with ethyl acetate (2×25 ml). The combined phases are dried over MgSO4and filtered through a layer of silicon dioxide, the Solvent reduced in volume under vacuum and secrete a colorless oil (1 g). Diethylacetamide intermediate compound used as such in next step. 74% yield.

Preparatory example 32: 1-Benzhydryl-3-(2-bromo-4-(diethoxylate)phenyl)azetidin-3-carbonitril

2-Bromo-4-(diethoxylate)-1-torbenson (Preparation example 31, 1 g) and 1-benzhydrylamine-3-carbonitrile (2.7 g) was dissolved in anhydrous THF (4 ml). Then all at once was added KHMDS (2.2 g). The solution immediately became dark brown. The reaction mixture was stirred at room temperature over night. Analysis by LC-MS confirmed full conversion to the desired product: [433] at approximately 3,31 min and [505] at approximately 3,62 min. Both peaks correspond to the target product: one is an aldehyde and the other is an acetal. The crude reaction mixture was concentrated to oil and loaded into the cartridge SiO280g, then suirable gradient: 0-100% ethyl acetate in heptane. The target fractions were collected and concentrated in vacuo. The resulting oil was suspended in methanol and treated with ultrasound for 30 seconds, and the resulting white powder was filtered and used as such in next step. 55% yield. LC-MS [505].

Preparatory example 33: 3-(2-Bromo-4-(dimethoxymethyl)phenyl)azetidin-3-carbonitril

The product of Prepa�conscious people of example 32 (500 mg) was dissolved in acetonitrile and the reaction mixture was cooled to 0°C, then all at once added chloroethylphosphonic (0.2 ml). The reaction mixture was heated up to the formation of phlegm for 2 hours. Analysis by LC-MS indicates the formation of the target peak at approximately 2,329 min [339], but there remained a certain amount of the original substance. Added another equivalent of chloroethylphosphonic, and the reaction mixture is left to stir for another hour at boiling with reflux. Analysis by TLC indicates the completion of the reaction. The crude reaction mixture was concentrated in vacuo and the resulting yellow oil was dissolved in MeOH, and again heated up to the formation of phlegm within 30 minutes. Analysis by TLC indicates complete conversion to the basic spot. The reaction mixture was concentrated to oil, and added 20 ml of diethyl ether. Then the resin was treated with ultrasound for 15 minutes, and the solid is filtered and analyzed. Analysis by LC-MS ([311] at approximately 2,036 minutes) confirms the target product, although ethylacetate due to heating before the formation of phlegm in methanol is already mutilateral. Was used as such in next step. Assumed quantitative yield.

Preparatory example 34: tert-Butyl-3-(2-bromo-4-(dimethoxymethyl)phenyl)-3-cyanoacetate-1-carboxylate

The product of Preparatory example 33 (300 mg) and boc anhydride (252 mg) were mixed in CH2Cl2(4 ml) and added base Hunya (500 ál). The reaction mixture was allowed to stir at room temperature for 1 hour, and then analysed by TLC (50/50 ethyl acetate/heptane), which indicated completion of reaction. The crude mixture was concentrated to oil and subjected to column chromatography on SiO225g, elwira gradient: 0-100% ethyl acetate in heptane. The target fractions were collected and concentrated in vacuo. Analysis methods LC-MS and NMR confirmed the desired product [m/z 411], used as such in next step. A mixture of aldehyde and dimethoxyacetate.

Preparatory example 35: tert-Butyl-3-(2-bromo-4-((hydroxyimino)methyl)phenyl)-3-cyanoacetate-1-carboxylate

The product of Preparatory example 34 (320 mg) was added to 4 ml of MeOH was added 1 ml of water, and then hydroxylamine hydrochloride (85 mg). The reaction mixture was stirred at room temperature; after 30 minutes, analysis by LC-MS indicates the formation of a new peak at 2,976 min, no ionization. After 60 minutes analysis by LC-MS indicates a slight over reaction, so the mixture was heated to 65°C for 10 minutes. Analysis by LC-MS already indicates complete conversion to the desired product with a mass [446]at approximately 3,165 min. The crude reaction mixture was concentrated to a minimal volume (white suspension), then was extracted with ethyl acetate/NaHCO3. Ethylacetate layer is dried over MgSO4, filtered and concentrated in vacuo, and the resulting resin was analyzed by NMR. Shows the target product, 300 mg, used as such in next step.

Preparatory example 36: tert-Butyl-3-(2-bromo-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-cyanoacetate-1-carboxylate

The oxime from Preparatory example 35 (130 mg) was mixed with N-chlorosuccinimide (50 mg) in ethyl acetate, and the reaction mixture was stirred at 55°C for 15 minutes. Analysis by LC-MS confirms the formation of the target product (the starting material has completely disappeared). To the reaction mixture were added triliteral (95 mg), and then the JISC3(63 mg). The reaction mixture was allowed to stir at room temperature over night. Analysis by LC-MS indicates the completion of the reaction. The mixture was filtered through a layer of MgSO4and the yellow solution was concentrated to give a solid substance. Analysis by LC-MS confirmed the desired product with a mass [553] at approximately 4,059 minutes the Solid was charged to a column of silica 25d and suirable gradient: 0-100% ethyl acetate/heptane. Target fracc�and concentrated and collected white powder. 95 mg, 46% yield.

Preparatory example 37: 3-(2-Bromo-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-3-carbonitril

The product of Preparatory example 36 (90 mg) was dissolved in anhydrous methanol. Added a methanolic HCl solution (300 μl) and heated to 65°C. After 3 hours, analysis by LC-MS shows desired product [m/z 553] at approximately 3,195 min. Then the mixture was concentrated to dryness and the solid was added diethyl ether (6 ml). The resulting suspension was treated with ultrasound for 10 minutes and then filtered fine white powder. It was used as such in next step. Analysis by LC-MS confirmed the desired product [553]. 75 mg (98%) yield.

Example 86: 3-(2-Bromo-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-1-(cyclopropanecarbonyl)azetidin-3-carbonitril

The product of Preparatory example 37 (75 mg) was dissolved in CH2Cl2(5 ml) and added base Hunya (74 mg, 97 μl). The reaction mixture was stirred at room temperature for 1 minute, then add cyclopropanecarbonitrile (18,4 mg, 16 μl) and the mixture was stirred for 15 minutes. Analysis by LC-MS indicates the formation of the desired product [m/z 621] at approximately 3,73 min. the Mixture was concentrated�, charged into a column (SiO225g and suirable gradient of ethyl acetate in heptane (0-50% over 8 CV). The target fraction was isolated and concentrated under vacuum. 60 mg, 62% yield. NMR (400 MHz) δ M. D.: 7.99 (s, 1H), 7.74 (d, 1H), 7.64 (s, 2H), 7.49 (d, 1H), 5.05 (m, 1H), 4.73 (m, 2H), 4.65 (m, 1H), 4.08 (d, 1H), 3.68 (d, 1H), 1.41 (m, 1H), 1.10-1.06 (m, 2H), 0.91-0.86 (m, 2H); LC-MS: [m/z 621] @ 3,73 minutes.

Example 87: 1-(Cyclopropanecarbonyl)-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-3-carbonitril

The compound of Example 86 (60 mg) was dissolved in THF (2 ml) and then dropwise added Rieke Zn (zinc Rica) in THF (2 ml of a 0.7 n solution). Then the mixture was treated with ultrasound for 5 minutes. Analysis by LC-MS (THF with a few drops of acetic acid) indicates about 50% conversion. Was added 4 equivalent Zn and again treated with ultrasound for 15 minutes. Analysis by LC-MS shows that the reaction proceeds to about 90% conversion. Was then added approximately 200 µl of acetic acid; the reaction mixture was stirred for 2 minutes, then filtered through celite. The solution was concentrated under vacuum and the remaining oil was dissolved in ethyl acetate and washed with NaHCO3, then dried over MgSC > 4, filtered and concentrated in vacuo. The remaining oil is purified by reversed-phase chromatography. Yield 55 mg. Analysis by LC-MS confirms �spruce product [m/z 542]. NMR (400 MHz) δ M. D.: 7.78 (d, 2H), 7.67 (d, 2H), 7.66 (s, 2H), 4.99 (m, 1H), 4.71 (m, 1H), 4.53 (m, 1H), 4.39 (m, 1H), 4.10 (d, 1H), 3.71 (d, 1H), 1.45-1.39 (m, 1H), 1.10-1.06 (m, 2H), 0.91-0.86 (m, 2H).

Preparatory example 38: tert-Butyl ether 3-(4-formyl-phenyl)-azetidin-1-carboxylic acid

To a stirred suspension of activated zinc (5,636 t g, 86,19 mmol, 2 equivalent) in dry DMF (20 ml) was added dibromoethane (1.89 g, of 10.77 mmol, 0.25 equivalent), pre-dissolved in dry DMF (5 ml) and the reaction mixture was heated at 70°C for 30 minutes in a nitrogen atmosphere. After 30 minutes the reaction mixture was cooled to room temperature. To the resulting reaction mixture was added chlorotrimethylsilane (1.12 g, of 10.77 mmol, 0.25 equivalent), pre-dissolved in dry DMF (5 ml), and stirred for 15 minutes followed by the addition of 3-iodo-N-BOC-azetidine with 15.24 g, 53,86 mmol, 1.25 EQ.), pre-dissolved in dry DMF (30 ml) and the reaction mixture was heated at 40°C for 30 minutes in a nitrogen atmosphere. The reaction mixture was treated with ultrasound for 30 minutes; during ultrasonic zinc powder evenly suspendirovanie with the provision of the turbid reaction mixture. To ultrasonically treated reaction mixture (zincate) was added 4-identilied (10 g, 43,099 mmol, 1 EQ.), pre-dissolved in dry DMF (42 ml), and then three 2-furyl�ospin (1.1 g, 4,73 mmol, 0.1 EQ.) and Tris(dibenzylidene-acetone)-dipalladium(0) (1.18 g, 1,292 mmol, 0.03 equivalent). The obtained reaction mixture was heated at 70°C for 18 hours in a nitrogen atmosphere. Reaction progression was monitored by TLC using 10% ethyl acetate in hexane, and visualization was performed under UV light (254 nm). Of 0.3 and 0.7 was a checkpoint for a new spot and source of the substance, respectively. After consuming the maximum of the initial substance (18 hours) the reaction mixture was quenched with saturated ammonium chloride (100 ml) and was extracted with ethyl acetate (3×100 ml). The combined organic layer was dried over sodium sulfate and concentrated in vacuum to give a brown liquid (15 g, crude). The crude compound was purified by column chromatography using silica 100-200 mesh. The target compound was suirable 10% ethyl acetate in hexano with obtaining 6.5 g (57,79%) liquid brown.1H NMR and LC-MS did not contradict each other.1H NMR (400 MHz, DMSO-d6) δ: 1.40 (s, 9H), 3.86-3.89 (m, 3H), 4.26-4.29 (m, 2H), 7.57 (d, J=8,04 Hz, 2H), 7.90 (d, J=8,16 Hz, 2H), 9.99 (s, 1H). LC-MS (m/z):=262,30 (M+H).

*** Activation of zinc: zinc powder (5 g) was stirred with 10% HCl solution (20 ml) for 5 minutes at room temperature and decanted. This procedure was repeated twice and was filtered through a Buchner funnel, washed with in�Oh (3×25 ml), acetone (2×20 ml), well dried in vacuum to yield the activated zinc (2 g).

Preparatory example 39: tert-Butyl ether 3-[4-(hydroxyimino-methyl)-phenyl]-azetidin-1-carboxylic acid

To a stirred suspension mpem-butyl ether 3-(4-formyl-phenyl)-azetidin-1-carboxylic acid (Preparation example 38, 6.5 g, 24,904 mmol, 1 equivalent) in a mixture of ethanol:water (1:1, 120 ml) was added hydroxylamine hydrochloride (2.5 g, 37,356 mmol, 1.5 equivalent), and then sodium acetate (3,67 g, 44,82 mol, 1.8 EQ.). The obtained reaction mixture was stirred at room temperature for 0.5 hours. Reaction progression was monitored by TLC using 20% ethyl acetate in hexane, and visualization was performed under UV light (254 nm). Of 0.32 and 0.67 was a checkpoint for a new spot and source of the substance, respectively. After consuming the original substance, the solvent was evaporated under reduced pressure and was extracted with DCM (3×25 ml). After evaporation of volatiles was obtained a light yellow solid (6.5 g, 94,51%). LC-MS and1H NMR did not contradict each other.1H NMR (400 MHz, DMSO-d6) δ 1.39 (s, 9H), 3.81 (broadened s, 3H), 4.42 (broadened s, 2H), 7.36 (d, J=8 Hz, 2H), 7.57 (d, J=8 Hz, 2H), 8.12 (s, 1H), 11.19 (s, 1H). LC-MS (m/z):=277,30 (M+H).

Preparatory example 40: tert-Butyl ether 3-{4-[5-(3,5-dichloro-phenyl)-5-triform�Teal-4,5-dihydro-izocsazol-3-yl]-phenyl}-azetidin-1-carboxylic acid

To a stirred solution of mpem-butyl ether 3-[4-(hydroxyimino-methyl)-phenyl]-azetidin-1-carboxylic acid (Preparation example 39, 1 g 3,62 mmol, 1.0 equivalent) in DMF (6.0 ml) was added NCS (725,26 mg, 5.43 mmol, 1.5 equivalent) and heated to 50°C for 1 hour. Reaction progression was monitored by TLC using 5% methanol in dichloromethane. After complete consumption of the original substance, the reaction mixture was cooled to 0°C followed by addition of potassium bicarbonate (543,18 mg, 5.43 mmol, 1.5 equivalent) and pre-dissolved 1,3-dichloro-5-(1-trifluoromethyl-vinyl)-benzene (1.04 g, 4,345 mmol, 1.2 equivalent) in solution in DMF (4.0 ml). The obtained reaction mixture was stirred at room temperature for 16 hours in a nitrogen atmosphere. Reaction progression was monitored by TLC using 20% ethyl acetate in hexane, and visualization was performed under UV light (254 nm). 0.6 and 0.5 represented a reference point for the desired product and starting material. After consuming the original substance, the reaction mixture was quenched with water (40 ml) and was extracted with diethyl ether (3×50 ml). The combined organic layer was washed with brine (20 ml), dried over anhydrous sodium sulfate and concentrated in vacuum to yield of 1.50 g (uncleaned) substances. After further purification of colonic�Oh chromatography (neutral alumina) using 10% ethyl acetate in hexane as eluent received not quite white solid (1.3 g, 69,84%).1H NMR and LC-MS did not contradict each other.1H NMR (400 MHz, DMSO-d6) δ 1.39 (s, 9H), 3.84 (m, 3H), 4.25-4.38 (m, 4H), 7.47 (d, J=8 Hz, 2H), 7.62 (d, J=1 Hz, 2H), 7.71 (d, J=8 Hz, 2H), 7.81 (t, J=2 Hz, 1H). LC-MS (m/z):=513 (M-H).

Preparatory example 41: Hydrochloride salt of 3-(4-azetidin-3-yl-phenyl)-5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol

A stirred solution of tert-butyl methyl ether 3-{4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-azetidin-1-carboxylic acid (Preparation example 40, 1 g, 1,94 mmol, 1 EQ.) in MeOH (10 ml) was purged with HCl (g) at 0°C for 0.5 hours and then the reaction mixture was boiled to reflux at 70°C for 0.5 hours. Reaction progression was monitored by TLC; after complete consumption of the original substance, the reaction mixture was evaporated under reduced pressure to dryness to obtain 1.15 g (crude) of the substance, which was washed with methyl tert-butyl ether (10 ml × 2) to give 1.1 g (95,21%).1H-NMR and LC-MS did not contradict each other.1H NMR (400 MHz, DMSO-d6) δ 4.05 (t, J=8 Hz, 2H), 4.15-4.21 (m, 1H), 4.24-4.39 (m, 4H), 7.55 (d, J=8 Hz, 2H), 7.62 (d, J=1 Hz, 2H), 7.74 (d, J=8 Hz, 2H), 7.81 (t, J=2 Hz, 1 H), 8.99 (bs, 2H). LC-MS (m/z):=415 (M+H).

Preparatory example 42: Hydrochloride salt of 3-(4-(azetidin-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole

1H NMR (400 MHz, DMSO-d6) δ 4.06 (t, J=17 Hz, 2H), 4.15-4.19 (m, 1H), 4.24-4.29 (m, 2H), 4.35 (t, J=18 Hz, 2H), 7.55 (d, J=8 Hz, 2H), 7.74 (d, J=8 Hz, 2H), 7.84 (s, 2H), 9.004 (bs, 2H). LC-MS (m/z):=488,90 (M+H).

Example 88: 1-(3-(4-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-methylpropan-1-he

The compound was obtained from compound of Preparatory example 41 using a technique similar to the method described in Example 6, using isobutyramide instead of cyclopropanecarbonitrile.1H NMR (DMSO-d6) δ M. D.: 7.81 (1H), 7.72 (2H), 7.63 (2H), 7.49 (2H), 4.59-3.81 (8H), 1.0 (6H); m/z (elektrorazpredelenie+ (ER+), chemical ionization at atmospheric pressure (head), I guess.) 485 [M+H]+.

Example 89: 2-Methyl-1-(3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)propane-1-he

The specified connection was obtained from the compound of Preparatory example 42 using a technique similar to the method described in Example 6, using isobutyramide instead of cyclopropanecarbonitrile.1NAMR (DMSO-d6) δ M. D.: 7.84 (2H), 7.72 (2H), 7.50 (2H), 4.59-3.84 (8H), 1.0 (6H); m/z (EI+head, I guess.) 519 [M+H]+.

Example 90: Cycloprop�l-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)methanon

The specified connection was obtained from the compound of Preparatory example 41 using a technique similar to the method described in Example 6, using isobutyramide instead of cyclopropanecarbonitrile.1NAMR (DMSO-d6) δ M. D.: 7.81 (1H), 7.72 (2H), 7.63 (2H), 7.51 (2H), 4.66-3.16 (8H), 0.72 (4H); m/z (EI+head, I guess.) 483 [M+H]+.

Example 91: Cyclopropyl-(3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)methanon

The specified connection was obtained from the compound of Preparatory example 42 using a technique similar to the method described in Example 6, using isobutyramide instead of cyclopropanecarbonitrile.1NAMR (CDCl3) δ M. D.: 7.84 (2H), 7.71 (2H), 7.51 (2H), 4.69-3.18 (8H), 0.72 (4H); m/z (EI+head, I guess.) 517 [M+H]+.

Example 92: 1-(3-(4-(5-(3,5-Dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)alanon

The specified connection was obtained from the compound of Preparatory example 41 using a technique similar to the method described in Example 1.1NAMR (CDCl3) δ M. D. 7.81 (1H), 7.72 (2H), 7.63 (2H), 7.51 (2H), 4.53-3.80 (7H), 1.80 (OA); m/z (EI+head, I guess.) 457 [M+H]+.

Example 93: 1-(3-(4-(5-(3,4,5-Trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)alanon

The specified connection was obtained from the compound of Preparatory example 42 using a technique similar to the method described in Example 1.1NAMR (CDCl3) δ M. D.: 7.84 (2H), 7.71 (2H), 7.50 (2H), 4.53-3.83 (7H), 1.80 (3H); m/z (EI+head, I guess.) 491 [M+H]+.

Preparatory example 43 - oxidation of sulfide to sulfoxide:

1-(3-(4-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylsulfinyl)-Etalon (Example 162)

A solution of (meta)periodate sodium (49 mg, 0,23 mmol) in a mixture of 1:1 methanol/water (6 ml) was cooled with an ice bath and added dropwise via pipette solution 1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylthio)ethanone (102 mg, 0,19 mmol) in methanol (about 2 ml). A precipitate formed and the reaction mixture was allowed to stir in an ice bath in place, slowly warming to ambient temperature over night. Upon completion the reaction mixture was distributed between water (5 ml) and CH2Cl2(5 ml). The aqueous phase was extracted with additional CH2Cl2(2×5 ml). The organic phase was collected and condensible. Untreated phase was absorbed on silica and subjected to column chromatography on silica 12g, elwira gradient from 100% ethyl acetate in heptane. The fraction containing the target substance were combined and concentrated. To the obtained film was added CH2Cl2(approximately 100 µl). Putting the flask in the conditions of high vacuum overnight led to the formation of white foam. Yield 90 mg (86%). LC/MS: retention time is 3,317 minutes; MS: calculated for (C22H17Cl2F5N2O3S) 554,03 found 555,0 M+H+).

Preparatory example 44: amide combination of parallel chemical synthesis

Isoxazolidinone (0,05 mmol) was dissolved in dimethylformamide (0.5 ml); this solution was added to the respective acid (0.1 mmol) followed by the addition of a solution of hexaflurophosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea in dimethylformamide (0.5 ml) and triethylamine (0.5 mmol). The resulting mixture was shaken at ambient temperature for 16 hours. The solvent was removed by distillation under vacuum and the crude product was purified preparative jhud. An example of this preparative method is shown below:

3-(4-(3-Torasemide-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (0,05 mmol) was dissolved in dimethylformamide (0.5 ml); this solution was added to butyric acid (0.1 mmol) followed by the addition of a solution of hexaflurophosphate O-(7-azabenzo�resol-1-yl)-N,N,N',N'-tetramethylurea in dimethylformamide (0.5 ml) and triethylamine (0.5 mmol). The resulting mixture was shaken at ambient temperature for 16 hours. The solvent was removed by distillation under vacuum and the crude product was purified preparative jhud to obtain 3.2 mg of 1-(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)butane-1-one. MH+ 537; the retention time of the case 9.83 minutes.

Preparatory example 45: urea formation parallel chemical synthesis

A solution of isoxazolidine (0,05 mmol) in DMF (1 ml) was treated with triethylamine (0.20 mmol). Added a solution of the appropriate isocyanate (0,055 mmol) in DMF (0.5 ml) and the reaction mixture was stirred at ambient temperature for 16 hours. The solvent was removed under reduced pressure and the crude product was purified preparative jhud. An example of this preparative method is shown below:

3-(4-(Azetidin-3-yl)phenyl)-5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (0,05 mmol) was dissolved in DMF (1 ml) was added triethylamine (0.20 mmol), and then the solution isocyanatomethyl. The resulting solution was stirred at ambient temperature for 16 hours. The solvent was removed under reduced pressure and the crude product was purified preparative jhud with obtaining 3-(4-(5-(3,4-dichloro-5-(cryptomate�)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-M-methylaziridine-1-carboxamide (11.2 mg), MN+ 540,1; retention time 6.14 minutes.

Preparatory example 46: asadoorian

Asignee intermediate compounds can be obtained according to the following procedure for 3-(4-(3-azido-1-benzhydrylamine-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (intermediate compound of Example 163).

To a solution of 1.19 g (of 1.88 mmol, 1.0 EQ.) 1-benzhydryl-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-3-ol in 17 ml of CH2Cl2was added via syringe 500 μl (2.8 mmol, 1.5 EQ.) pure diisopropylethylamine followed by the addition of 438 mg (2.5 mmol, 1.3 EQ.) solid metilsulfonovy anhydride. After stirring for 3.5 hours at room temperature, an aliquot of the reaction mixture was placed in 1.0 ml of methanol and analyzed by LC/MS. Chromatography showed that the starting material consumed. The reaction mixture was diluted with 20 ml of CH2Cl2and 20 ml of a saturated solution of NaHCO3. After stirring for 2 hours, the layers were separated using a cartridge of a phase separating agent biotage AB Phase Separator. The organic layer was concentrated under reduced pressure to obtain 1.29 g (96% yield) of the intermediate 1-benzhydryl-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-3-yl-methane�sulfonate in the form of light yellow solids. A sample of 227 mg of 1-benzhydryl-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-3-yl-methanesulfonate (0.35 mmol, 1.0 EQ.) and for 72.1 mg of sodium azide (1.1 mmol, 3.1 EQ.) were weighed into a flask of 100 ml, to which was added 3 ml of anhydrous DMSO. After stirring for 1.5 hours at room temperature the reaction mixture was diluted with 30 ml of CH2Cl2and 15 ml of a saturated solution of NaHCO3. After stirring this mixture for 1 hour the layers were separated using a cartridge of a phase separating agent biotage AB Phase Separator. The aqueous layer washed with additional amount of CH2Cl2and the combined organic layers were concentrated by evaporation in a stream of gaseous N2. The crude oil was purified by column chromatography on silica gel, elwira 100% CH2Cl2. By evaporation of the appropriate fractions received 144,5 mg of product, representing 3-(4-(3-azido-1-benzhydrylamine-3-yl)phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole, (63% yield) as vitreous yellow solids: MS 656 [M+H]; jhud: the retention time of 3,600 minutes.

Preparatory example 47: chiral separation of enantiomers of example, separation of an individual enantiomer from the racemic mixture, the racemic mixture of Example 18 was separated on a chiral column with get�of the compound of Example 177 according to the following jhud-method of chiral separation: analytical supercritical fluid chromatography (SFC systems) Berger, chiral IC column of 4.6×250 mm, 5 μm, mobile phase (A) consisted of CO2and mobile phase (B) consisted of 0.1% TEA in methanol. Linear gradient from 5% to 65% In 12 minutes, 3 ml/min at 100 bar (10 MPa). Preparative SFC systems was performed on a column (Berger Multigram with IC 30×250 mm, 5 μm, mobile phase (A) WITH2and mobile phase (B) methanol, isocratic elution of 25% at 100 ml/min and 120 bar (12 MPa). The compound of Example 172 is an individual enantiomer from the racemate of Example 19. The compound of Example 176 represents an individual enantiomer from the racemate of Example 24.

Conditions jhud used to obtain values for retention time and mass of the compounds of the Examples in Tables 2, 3 and 4 was based on the following methods. Each retention time in the relevant tables are listed with the notation "a", "b", "C", "d", "e" or "f". Each character relates to the conditions and methods of separation jhud. For the method "and" data on mass spectra (MS) were obtained using a mass spectrometer with Agilent chemical ionization at atmospheric pressure. Method: Acquity jhud with chromatography performed on a column (Waters VEINS C18 (2.1 x 50 mm, 1.7 μm) at 50°C. the Mobile phase was a binary gradient of water (containing 0.1% trifluoroacetic acid) and acetonitrile (5-100% acetonitrile for

time app�and 5 minutes) at 254 nm. For method "b" jhud with the chromatography was performed on a column Gemini NX-50×4,60 mm, 5 μm. The mobile phase was a binary gradient of buffer a (10 mm ammonium acetate (pH 4.6) and acetonitrile (gradient: 10-100% acetonitrile during run 12 minutes at a flow rate of 1 ml/min) at 254 nm. For method "C" jhud with the chromatography was performed on a column Gemini NX-50×4,60 mm, 5 μm. The mobile phase was a binary gradient of buffer a (10 mm ammonium acetate (pH 4.6) and acetonitrile (gradient: 50-100% acetonitrile at run time 4.5 minutes at a flow rate of 1 ml/min) at 254 nm. For method "d" jhud with the chromatography was performed on a column (Waters Alliance 2795 with ZQ MS-ESI+ with column Gemini NX C18 4,6 x 100, 5 µm. The mobile phase was a binary gradient of water (containing 0.05% trifluoroacetic acid) and acetonitrile (gradient: 50-95% acetonitrile during run 12 min, flow rate 1 ml/min) at 254 nm. For method "e" jhud with the chromatography was performed on a column (Waters Alliance 2795 with ZQ MS-ESI+ with column Gemini NX C18 4,6×150, 5 μm. The mobile phase was a binary gradient of water (containing 0.1% trifluoroacetic acid) and acetonitrile (gradient: 50-95% acetonitrile during run 12 min, flow rate 1 ml/min) at 254 nm. For fashion T SFC systems-chromatography was performed on a column Berger 2-EP 5 µm, a 4.6×250 mm Mobile phase was a binary gradient of CO2/sub> and 0.1% triethylamine in MeOH (gradient: 5-65% 0.1% tea in MeOH at run time 9 minutes, flow rate 3 ml/min).

Using a technique similar to that described herein, compounds were obtained (Examples 94-185) of the formula (2C), which are presented in Table 2.

td align="center"> H
Table 2
Example No.R1aR1bR1cR3R5m/z (EMI) [M+H]+RT (min)
94ClClClOHisopropyl535Of 10.05 e
95ClClClFCH2CF357711,19 e
96ClClCl FCH2-cyclopropyl549To 11.35 e
97ClClClFpropyl537Case 9.83 d
98ClClClFisopropyl5379,8 d
99ClClClFethyl5239,44 d
100CF3HClFisopropyl537,1A 4.53 d
101CF3HClFCH2OHRUB 525.1 3,76 d
102CF3HClFcyclopentyl563,14,85 d
103CF3ClClFpropyl571,17,86 d
104ClHClHethylOf 471.16,2 d
105ClHClH499,15,27 d
106ClHClHCH2Och3487,1To 5.62 d
107ClClHCH2-cyclopropyl565,17,69 d
108CF3ClClHCH35257,11 d
109CF3ClClHethyl539,17,2 d
110CF3HClHpropyl519,16,96 d
111CF3ClClHpropyl553.1Of 7.82 d
112CF3Cl ClHCH2OH5415,53 d
113CF3ClClH567,1For 6.24 d
114CF3ClClHCH2SCH3571Of 7.42 d
115CF3HClHCH2-cyclopropyl531,16,97 d
116CF3HClHCH2OCH3521,15,72 d
117CF3ClClCH2CN5506,72 d

118CF3NClN533,15,39 d
119CF3ClClNCH2Och3555,16,58 d
120CF3NClNethyl505,1System 6.34 d
121ClClClNpropyl519,1Of 7.82 d
122CF3NCl Nisopropyl519,16,94 d
123ClClClN5336,14 d
124ClClClNethyl5057,17 d
125ClClClNCH2SCH35377,41 d
126ClClClNCH2Och3521Is 6.42 d
127ClClClNCH2-cyclopropyl 531,1Of 7.82 d
128ClFClNCH2SCH35216,55 d
129ClFClNCH2Och3505,15,74 d
130ClFClN517,15,41 d
131ClFClNethyl489,16,4 d
132ClFClNisopropyl503,17,03 d
133ClFClF5703,674 a
134ClFClOHCH2CF35593,483 a
135CF3ClClFCH2CF36113.2 a
136ClFClF560Of 7.42 d
137ClFClF5365,28 d
138 ClFClF5576,13 d
139ClFClF560,15.7 d
140ClFClFCH2S(O)2CH3571Is 6.51 d
141ClFClF559,16,7 d

Cl
142ClFClF5466,71 d
143ClFClFCF2CH35438,54 d
144CF3ClClF6003,295 a
145ClFClFC(OH)(CH3)2537,16,74 d
146ClFClFCH2CH=CH2519,17.23 percent (d
147ClFClFCH2S(O)2N(CH3)26006,99 d
148FClFCH2SCF3592,93,54 a
149ClFClFCH(och3)CH3537,16,93 d
150ClFClF5557,32 d
151ClFClFCH(CH3)CH2OH537,16,39 d
152ClFClF537,16,43 d
153Cl FClF537,16,44 d
154ClFClClthe cyclopropylndnd-a
155CF3ClClClthe cyclopropylndnd-a
156ClNNFthe cyclopropyl466,905,88 b
157ClFFHEthe cyclopropyl498,80 [M-H]Is 5.58 b
158CF3FF Fthe cyclopropyl534,60 [M-H]6,16 b
159ClFClF5233,419 a
160ClFClF5233,406 a
161ClFClF5373,414 a
162ClFClFCH2S(O)CH35553,317 a
163ClClClN3 the cyclopropyl5583,176 a
164ClClClN3ethyl5463,271 a
165ClFClFCH2SC(O)CH35673,604 a
166FNNFethyl436,902,38 c

2,60
[M-N]
167ClHHFethyl455,20
168ClClHFethyl486,70 [M-N]6,11 b
169CF3HHFthe cyclopropyl498,90 [M-N]5,90 b
170ClHFFthe cyclopropyl482,90 [M-N]5,45 b
171FFHFthe cyclopropyl467,00 [M-N]2,55
172ClFClFCH2CF3ndnd-a
173 ClHClF5163,562 a
174ClClClF5523,667 a
175ClFClF534,03,58 a
176CF3ClClHEthe cyclopropylndnd-a
177ClFClFisopropylndnd-a
178ClF ClFCH2S(O)2CH2CN5963,55 d
179ClFClFCH2CH2S(O)2CH35853,43 d
180ClFClFCH2S(O)2CH2CF36393,66 d
181ClFClFCH2S(O)2N(CH3)26003,55 d
182ClFClFCH2S(O)2phenyl6333,65 d
183Cl FClFCHCH3S(O)2CH35853,51 d
184CF3ClClNHC(O)-cyclopropylthe cyclopropyl6346,315 f
185CF3ClClNH2the cyclopropyl5676,23 f
means a point of connection;
^ is an individual enantiomer, isolated on a chiral column;
nd means "not determined";

Jhud-methods a, b, C, d and e are as defined elsewhere herein.

The following title compounds of Examples 94-185 from Table 2 include:

1-isobutyryl-3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-3-ol(94); 3-{4-[3-fluoro-1-(3,3,3-triptocaine)azetidin-3-yl]phenyl}-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(95); 3-{4-[1-(cycloprop�acetil)-3-torasemide-3-yl]phenyl}-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (96); 3-[4-(1-butyryl-3-torasemide-3-yl)phenyl]-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(97); 3-[4-(3-fluoro-1-isobutyrylacetate-3-yl)phenyl]-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(98); 3-[4-(3-fluoro-1-Propionaldehyde-3-yl)phenyl]-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (99); 5-[3-chloro-5-(trifluoromethyl)phenyl]-3-[4-(3-fluoro-1-isobutyrylacetate-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole(100); 2-[3-(4-{5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-torasemide-1-yl]-2-oxoethyl (101); 5-[3-chloro-5-(trifluoromethyl)phenyl]-3-{4-[1-(cyclopentanecarbonyl)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole(102); 3-[4-(1-butyryl-3-torasemide-3-yl)phenyl]-5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole (103); 5-(3,5-dichlorophenyl)-3-[4-(1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole(104); 1-[(3-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-yl)carbonyl]cyclopropanol (105); 5-(3,5-dichlorophenyl)-3-{4-[1-(methoxyacetyl)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole(106); 3-{4-[1-(cyclopropylethyl)azetidin-3-yl]phenyl}-5-[3,4-dichloro-5-(trifluoromethyl)-phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole(107); 3-[4-(1-acetylisatin-3-yl)phenyl]-5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole (108); 5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-3-[4-(1-prop�nilutamide-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole (109); 3-[4-(1-butyrylacetate-3-yl)phenyl]-5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole(110); 3-[4-(1-butyrylacetate-3-yl)phenyl]-5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole(111); 2-[3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)azetidin-1-yl]-2-oxoethyl(112); 1-{[3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)azetidin-1-yl]carbonyl}cyclopropanol (113); 5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-3-(4-{1-[(methylthio)acetyl]azetidin-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (114); 5-[3-chloro-5-(trifluoromethyl)phenyl]-3-{4-[1-(cyclopropylethyl)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole (115); 5-[3-chloro-5-(trifluoromethyl)phenyl]-3-{4-[1-(methoxyacetyl)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole(116); 3-[3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)azetidin-1-yl]-3-oxopropanenitrile(117); 1-{[3-(4-{5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)azetidin-1-yl]carbonyl}-cyclopropanol (118); 5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-3-{4-[1-(methoxyacetyl)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole (119); 5-[3-chloro-5-(trifluoromethyl)phenyl]-3-[4-(1-Propionaldehyde-3-yl)-phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole(120); 3-[4-(1-butyrylacetate-3-yl)phenyl]-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-DIH�dreisessel (121); 5-[3-chloro-5-(trifluoromethyl)phenyl]-3-[4-(1-isobutyrylacetate-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole(122); 1-[(3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-yl)carbonyl]cyclopropanol(123); 3-[4-(1-propionylacetate-3-yl)phenyl]-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(124); 3-(4-{1-[(methylthio)acetyl]azetidin-3-yl}phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(125); 3-{4-[1-(methoxyacetyl)azetidin-3-yl]phenyl}-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(126); 3-{4-[1-(cyclopropylethyl)azetidin-3-yl]phenyl}-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (127); 5-(3,5-dichloro-4-fluorophenyl)-3-(4-{1-[(methylthio)acetyl]azetidin-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (128); 5-(3,5-dichloro-4-fluorophenyl)-3-{4-[1-(methoxyacetyl)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole(129); 1-[(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-yl)carbonyl]-cyclopropanol (130); 5-(3,5-dichloro-4-fluorophenyl)-3-[4-(1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole (131); 5-(3,5-dichloro-4-fluorophenyl)-3-[4-(1-isobutyrylacetate-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole (132); 5-(3,5-dichloro-4-fluorophenyl)-3-(4-{1-[(3,3-diversecity-1-yl)carbonyl]-3-torasemide-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(133); 3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroiso�ol-3-yl]phenyl}-1-(3,3,3-triptocaine)azetidin-3-ol (134); 5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-3-{4-[3-fluoro-1-(3,3,3-triptocaine)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole (135); 5-(3,5-dichloro-4-fluorophenyl)-3-(4-{3-fluoro-1-[(4-methyl-1,3-oxazol-5-yl)carbonyl]azetidin-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (136); N-[2-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-2-oxoethyl]formamide(137); 4-[(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)carbonyl]pyridazin(138); 1-[2-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-2-oxoethyl]-1H-1,2,4-triazole (139); 5-(3,5-dichloro-4-fluorophenyl)-3-(4-{3-fluoro-1-[(methyl-sulfonyl)acetyl]azetidin-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (140); 5-(3,5-dichloro-4-fluorophenyl)-3-{4-[3-fluoro-1-(1H-pyrazol-1-ylacetic)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole (141); 5-(3,5-dichloro-4-fluorophenyl)-3-{4-[3-fluoro-1-(1,3-oxazol-5-ylcarbonyl)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole (142); 5-(3,5-dichloro-4-fluorophenyl)-3-{4-[1-(2,2-diperbadankan)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole(143); 1-{[3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-torasemide-1-yl]carbonyl}azetidin-3-ol(144); 1-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-2-methyl-1-oxopropyl--ol (145); 3-[4-(1-but-3-enoyl-3-torasemide-3-yl)-phenyl]-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(146); 2-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-N,N-dimethyl-2-oxetanemethanol (147); 5-(3,5-dichloro-4-fluorophenyl)-3-[4-(3-fluoro-1-{[(trifluoromethyl)thio]acetyl}azetidin-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole (148); 5-(3,5-dichloro-4-fluorophenyl)-3-{4-[3-fluoro-1-(2-methoxypropanol)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole (149); 5-(3,5-dichloro-4-fluorophenyl)-3-(4-{1-[(2,2-diversicolor)carbonyl]-3-torasemide-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(150); 3-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-2-methyl-3-oxoprop-1-ol (151); (2S)-4-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-4-oxobutyl-2-ol(152); 4-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-4-oxobutyl-2-ol(153); 3-{4-[3-chloro-1-(cyclopropanecarbonyl)azetidin-3-yl]phenyl}-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(154); 3-{4-[3-chloro-1-(cyclopropanecarbonyl)azetidin-3-yl]phenyl}-5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole (155); 5-(3-chlorophenyl)-3-{4-[1-(temporarycareer)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole(156); 3-{4-[5-(3-chloro-4,5-differenl)-5-trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-1-(cyclopropanecarbonyl)-azetidin-3-ol (157); 3-{4-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]phenyl}-5-[3,4-debtor-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole(158); (23)-1-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-1-oxoprop-2-ol (159); (2R)-1-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-1-oxoprop-2-ol (160); (2S)-4-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-4-oxobutyl-2-ol (161); 5-(3,5-dichloro-4-fluorophenyl)-3-(4-{3-fluoro-1-[(methylsulfinyl)acetyl]azetidin-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(162); 3-{4-[3-azido-1-(cyclopropanecarbonyl)azetidin-3-yl]phenyl}-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(163); 3-[4-(3-azido-1-Propionaldehyde-3-yl)phenyl]-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(164); 8-[2-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-2-oxoethyl]attentioin (165); 5-(3-fluorophenyl)-3-[4-(3-fluoro-1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole (166); 5-(3-chlorophenyl)-3-[4-(3-fluoro-1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole (167); 5-(3,4-dichlorophenyl)-3-[4-(3-fluoro-1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole(168); 3-{4-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-5-[3-(trifluoromethyl)phenyl]-4,5-dihydroiso�ATOL (169); 5-(3-chloro-5-fluorophenyl)-3-{4-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole(170); 3-{4-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]phenyl}-5-(3,4-differenl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(171); 1 -(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he(172); 3-{4-[1-(azetidin-1-ylcarbonyl)-3-torasemide-3-yl]phenyl}-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(173); 3-{4-[1-(azetidin-1-ylcarbonyl)-3-torasemide-3-yl]phenyl}-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole(174); 3-{4-[1-(azetidin-1-ylcarbonyl)-3-torasemide-3-yl]phenyl}-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (175); 1-(cyclopropanecarbonyl)-3-{4-[(5K)-5-[3,4-dichloro-5-(trifluoromethyl)-phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-3-ol (176); 5-(3,5-dichloro-4-fluorophenyl)-3-[4-(3-fluoro-1-isobutyrylacetate-3-yl)-phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole(177), {[2-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-2-oxoethyl]sulfonyl}acetonitrile(178), 1-(3-{4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-3-methanesulfonyl-propane-1-he(179), 1-(3-{4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-2-(2,2,2-Cryptor-econsultancy)-Etalon (180), dimethenamid-(3-{4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-2-oxo-econsultancy acid (181), 2-benzolsulfonat-1-(3-{4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-Etalon(182), 1-(3-{4-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-2-methanesulfonyl-propane-1-he (183), (1-cyclopropanecarbonyl-3-{4-[5-(3,4-dichloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-azetidin-3-yl)-amide cyclopropanecarbonyl acid (184) and (3-amino-3-{4-[5-(3,4-dichloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-azetidin-1-yl)-cyclopropyl-methanon (185).

Using techniques similar to those expressed herein, have been obtained compounds (Examples 186-205) of the formula (2d), which are presented in Table 3.

Table 3
Example No.R1aR1bR1cRaR3R6m/z (EMI) [M+H]+RT (min)
186ClClClH FHndnd a
187ClClClHHthe cyclopropyl5326,68 d
188ClHClHHthe cyclopropyl498,15,8 d
189CF3ClClHOHpropylndnd a
190CF3ClClmethylOHmethyl5703.0 a
191ClClCl/td> HHethyl5206,69 d
192ClFClHHmethyl490,1Of 5.32 d
193CF3ClClHHmethyl540,16,14 d
194ClHClHHethyl486,15,8 d
195ClFClHHethyl504,15,94 d
196CF3 HClHHmethyl506,1Of 5.32 d
197CF3HClHHthe cyclopropyl532,15,91 d
198ClFClHHthe cyclopropylOf 516.15,94 d
199CF3ClClHHthe cyclopropyl566,16,74 d
200CF3ClClHFCH2CF36263,461 a
201ClClClmethylFmethyl5383,278 units a
202CF3ClClmethylFmethyl5723,422 a
203CF3ClClHFCH2CH2CF36403,238 a
204CF3ClClHF6003,305 a
205ClClClmethylmethyl5613,724 a
means a point of connection;
nd means "not determined";

Jhud-methods a, b, c, d and e are as defined elsewhere herein.

The following names according to the IUPAC nomenclature of the compounds of Examples 186-205 from Table 3 include:

3-fluoro-3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-carboxamide (186); N-cyclopropyl-3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-carboxamide (187); N-cyclopropyl-3-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-carboxamide(188); 3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-hydroxy-N-propylamide-1-carboxamide(189); 3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-hydroxy-N,N-dimethylamide-1-carboxamide (190); N-ethyl-3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-carboxamide(191); 3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-N-methylaziridine-1-carboxamide(192); 3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-N-methylaziridine-carboxamide (193); 3-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-N-utilisation-1-carboxamide(194); 3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-N-utilisation-1-carboxamide(195); 3-(4-{5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-N-methylaziridine-1-carboxamide(196); 3-(4-{5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-N-cyclopropylamines-1-carboxamide (197); N-cyclopropyl-3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-carboxamide (198); N-cyclopropyl-3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)azetidin-1-carboxamide(199); 3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-fluoro-N-(2,2,2-trifluoroethyl)azetidin-1-carboxamide (200); 3-fluoro-N,N-dimethyl-3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-carboxamide(201); 3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-fluoro-N,N-dimethylamide-1-carboxamide(202); 3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-fluoro-N-(3,3,3-cryptochromes)azetidin-1-carboxamide(203); 3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-fluoro-N-oxetan-3-ilization-1-carboxamide (204) and 3-N,N-dimethyl-3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-carboxamide (205).

Using techniques similar to those expressed herein, have been obtained compounds (Examples 206-218) of the formula (2E), which are presented in Table 4.

Ftd align="center"> CN
Table 4
Example No.R1aR1bR1cR2R3R5m/z (EMI) [M+H]+RT (min)
206ClFClCNFthe cyclopropyl5443,573 and
207ClFClCNFmethyl5183,046 and
208ClFClCNCH2CF35863,206 and
209ClFClCNFethyl5323,534 and
210ClFClCNFisopropyl5463,657 and
211ClFClCNFCH2OH5346,19 d
212ClFClCNFpropyl546,17,17 d
213ClFClFcyclobutyl558,17,3 d
214ClFClCNFcyclopentyl572,17,54 d
215ClFClCNFCH2Och35486,74 d
216ClFClCNFCH2-cyclopropyl558,17,15 d
217ClFClCNFn-butyl560,17,44 d
218Cl FClCNFCH2SCH35647,02 d

Jhud-methods a, b, C, d and e are as defined elsewhere herein.

The following names according to the IUPAC nomenclature of the compounds of Examples 206-218 from Table 4 include:

2-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]-5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]benzonitrile (206); 2-(1-acetyl-3-torasemide-3-yl)-5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]benzonitrile(207); 5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]-2-[3-fluoro-1-(3,3,3-triptocaine)azetidin-3-yl]benzonitrile(208); 5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]-2-(3-fluoro-1-Propionaldehyde-3-yl)benzonitrile(209); 5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]-2-(3-fluoro-1-isobutyrylacetate-3-yl)benzonitrile(210); 5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]-2-(3-fluoro-1-glycolylated-3-yl)benzonitrile (211); 2-(1-butyryl-3-torasemide-3-yl)-5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]benzonitrile(212); 2-[1-(cyclobutanecarbonyl)-3-torasemide-3-yl]-5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]Ben�onitrile (213); 2-[1-(cyclopentanecarbonyl)-3-torasemide-3-yl]-5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]benzonitrile(214); 5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]-2-[3-fluoro-1-(methoxyacetyl)azetidin-3-yl]the benzonitrile(215); 2-[1-(cyclopropylethyl)-3-torasemide-3-yl]-5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]benzonitrile(216); 5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]-2-(3-fluoro-1-pentanolide-3-yl)benzonitrile (217) and 5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]-2-{3-fluoro-1-[(methylthio)acetyl]-azetidin-3-yl}-benzonitrile (218).

Example 219: 2-[1-(Cyclopropanecarbonyl)-3-torasemide-3-yl]-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]pyridine;

Using the above methods of 2-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]pyridine were obtained from 6-bromonicotinate and tert-butyl-3-oxoazetidin-1-carboxylate. MS 533,80 [M-N], jhud: retention time 6,41 minutes. Jhud-method "b".1H NMR (400 MHz, CDCl3) d 0.79-0.86 (m, 2H), 1.03-1.05 (m, 2H), 1.44-1.47 (m, 1H), 3.70 (d, J=16,88 Hz, 1H), 4.10 (d, J=17,28 Hz, 1H), 4.34-4.52 (m, 2H), 4.61 (dd, J=9,48, 22,36 Hz, 1H), 4.84 (dd, J=of 9.56, 20,32 Hz, 1H), 7.63 (s, 2H), 7.65 (s, 1H), 8.07-8.11 (m, 1H), 8.85 (s, 1H).

Example 220: (3-(4-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-yl)phenyl)-3-torasemide-1-yl)(1-oxidation-3-yl)-methanon

The specified connection was obtained from the compound of Preparatory example 16 according to the method of Example 12, using 1-oxide tietan-3-carboxylic acid instead of butyric acid. The yield 133 mg (70%).1H NMR (CDCl3) δ 7.69 (d, 2H), 7.58 (d, 2H), 7.47 (m, 2H), 4.67-4.32 (m, 4H), 4.09 (d, 1H), 3.91-3.64 (m, 4H), 3.60-3.33 (m, 2H). LC/MS: retention time is 3,355 minutes, MS: calculated for (C23H17Cl2F5N2O3S) 566,03 found 567,0 M+H+).

Example 221: (3-(4-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(1,1-deoxidation-3-yl)-methanon

The solution(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(1-oxidation-3-yl)-methanone (30 mg) in methanol (2 ml) was added to a solution of oxone (160 mg) in water (1 ml), cooled in an ice bath. The reaction mixture was allowed to slowly warm to ambient temperature, then stirred at ambient temperature for 16 hours. The bulk of the methanol was removed under reduced pressure, then the remaining aqueous phase was extracted with DCM (2×5 ml). The organic phase was collected and condensible. Untreated phase was absorbed on silica and subjected to column chromatography on silica 4g, elwira gradient from 0% to 100% of etelaat�and in heptane. The fraction containing the target substance were combined and concentrated. Putting the flask in the conditions of high vacuum overnight led to the formation of white foam. The output of 15.7 mg (51%).1H NMR (DMSO-D6) δ 7.82 (m, 4H), 7.69 (m, 2H), 4.67 (d, 2H), 4.46-4.29 (m, 8H), 3.56-3.43 (m, 1H). LC/MS: retention time is 3,455 minutes, MS; calculated for (C23H17Cl2F5N2O4S) 582,02, nd M+H+).

Example 222: 1-(3-(4-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpropan-1-thione

1-(3-(4-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpropan-1-he (500 mg, 1.9 mmol) was dissolved in toluene (35 ml). Added reagent Lawesson (790 mg, 1.9 mmol) and the reaction mixture was boiled with reflux for 2 hours, then cooled to room temperature and was allowed to stir over night. The reaction mixture was filtered and the filtrate concentrated under vacuum. The crude residue from the filtrate was subjected to chromatography (column Redi-Sep 40g), elwira from 100% heptane to a mixture of 25:75 EtOA:heptane to give product (415 mg, 80%) as a solid.1NAMR (CDCl3): 7.77 (2H), 7.61 (2H), 7.54 (2H), 4.68 (4H), 4.12 (1H), 3.72 (1H), 2.88 (1H), 1.28 (6H); m/z (HEE) 537 ([M+H]+.

Example 223: (1-(3-(4-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)FeNi�)-3-torasemide-1-yl)-2-methylpiperidin)-cyanamide

1-(3-(4-(5-(3,5-Dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpropan-1-thione (325 mg, 0.6 mmol) was dissolved in CH2Cl2(15 ml) at 0°C and added metalcraft (130 µl, 1.2 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. Then the solution was cooled to 0°C and added dropwise a solution of cyanamide (54 mg, 1,2 mmol) and base Hunya (220 μl, 1.2 mmol) in THF. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. To this solution was added water and the reaction mixture was extracted with CH2Cl2. The organic phase was dried (Na2SO4) and concentrated under vacuum. Untreated phase was subjected to chromatography (column Redi-Sep 24g), elwira from 100% heptane to a mixture of 50:50 EtOAc:heptane to give product (104 mg, 31%) as a solid.1NAMR (CDCl3): 7.79 (2H), 7.61 (2H), 7.54 (2H), 4.68 (4H), 4.12 (1H), 3.72 (1H), 3.44 (1H), 1.38 (6H); m/z (HEE) 545 [M+H]+.

The compounds of Examples 224 and 225 were obtained according to the methods and circuits disclosed in this specification.

Example 224: (1-(3-Fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-azetidin-1-yl)-2-methanesulfonyl-atanan

Example 225: 1-(3-{4-[5-(3,4-Dichloro-5-trifluoromethyl-phenyl)-5-trift�rmutil-4,5-dihydro-izocsazol-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-2-methanesulfonyl-atanan

NMR data for selected compounds, as disclosed herein, are presented in Table 5.

Table 5.
NMR data for selected compounds
Compound No.Solvent1H NMR (δ M. D.)
54CDCl37.76 (d, 2H), 7.61-7.52 (d, 4H), 7.46 (t, 1H),5.17-4.18 (m, 4H), 4.12 (d, 1H), 3.73 (d, 1H),2.46 (s, 1H), 1.43 (q, 2H), 1.08 (q, 2H)
55CDCl37.75 (d, 2H), 7.61 (d, 2H), 7.57 (m, 2H), 5.15-4.20 (m, 4H), 4.12 (d, 1H), 3.72 (d, 1H), 2.95 (s, 1H), 1.41 (q, 2H), 1.07(q, 2H)
57CDCl37.97 (d, 1H), 7.87 (d, 1H), 7.72 (m, 2H), 7.61(m, 2H), 4.49-4.12 (m, 5H), 3.84-3.69 (m, 2H), 2.52 (m, 1H), 1.15 (d, 6H)
58CDCl37.97 (d, 1H), 7.86 (d, 1H), 7.72 (m, 2H), 7.61 (m, 2H), 4.46-4.12 (m, 5H), 4.01 (d, 1H), 3.74 (m, 1H), 2.16 (t, 2H), 1.68 (m, 2H) 0.98 (t, 3H)
68DMSO-d67.82 (d, 2H), 7.74 (d, 2H), 7.64 (d, 2H), 6.53 (s,

1H), 4.40-4.22 (m, 4H), 4.03 (m, 2H), 2.15 (q, 2H), 1.00 (t, 2H)
133CDCl37.75 (d, 2H), 7.61 (d, 2H), 7.55 (d, 2H), 4.48 (m, 2H), 4.38-4.24 (m, 6H), 4.11 (d, 1H), 3.72 (d, 1H)
134CDCl37.72 (d, 2H), 7.66-7.53 (m, 4H), 4.56-4.28 (m, 4H), 4.12 (d, 1H), 3.90 (s, 1H), 3.72 (d, 1H), 3.07 (m, 2H)
135CDCl37.97 (m, 1H), 7.86 (m, 1H), 7.78 (d, 2H), 7.55 (d, 2H), 4.78-4.66 (m, 1H), 4.63-4.39 (m, 3H), 4.17 (d, 1H), 3.74 (d, 1H), 3.11 (m, 2H)
137CDCl38.29 (d, 1H), 7.77 (d, 2H), 7.61 (d, 2H), 7.55 (d, 2H), 6.58 (br s, 1H), 4.73-4.39 (m, 4H), 4.18-3.93 (m, 3H), 3.72 (d, 1H)
140CDCl37.77 (d, 2H), 7.60 (m, 4H), 4.81 (d, 2H), 4.57 (m, 1H), 4.44 (m, 1H), 4.11 (d, 1H), 3.90 (s, 2H), 3.72 (d, 1H), 3.20 (s, 3H)
141CDCl37.73 (d, 2H), 7.64-7.57 (m, 4H), 7.50 (d, 2H), 6.39 (m, 1H), 4.96 (m, 2H), 4.59-4.48 (m, 1H), 4.46-4.33 (m, 2H), 4.28-4.17 (m, 1H), 4.14-4.07 (m, 1H), 3.71 (d, 1H)
144CDCl37.96 (m, 1H), 7.85 (m, 1H), 7.75 (d, 2H), 7.58 (d, 2H), 4.72-7.61 (m, 1H), 4.49-4.38 (m, 2H), 4.29-4.19 (m, 4H), 4.15 (d, 1H), 3.92-3.87 (m, 2H), 3.72 (d, 1H), 2.57 (m, 1H)
145CDCl37.76 (d, 2H), 7.61 (d, 2H), 7.55 (d, 2H), 4.95-4.33 (m, 4H), 4.12 (d, 1H), 3.72 (d, 1H), 2.99 (s, 1H), 1.50 (s, 6H)
153CDCl37.76 (d, 2H), 7.61 (d, 2H), 7.55 (d, 2H), 4.71-4.35 (m, 4H), 4.34-4.23 (m, 1H), 4.12 (d, 1H),3.72 (d, 2H), 2.41-2.21 (m, 2H), 1.28 (d, 3H)
165DMSO-d67.85-7.79 (m, 4H), 7.69 (d, 2H), 4.82-4.69 (m, 2H), 4.44-4.30 (m, 4H), 3.70 (d, 2H), 2.38 (s,

3H)
178CDCl37.8 (2H), 7.5-7.7 (4H), 4.2-4.9 (6H), 4.0-4.2 (3H), 3.7 (1H)
179CDCl37.8 (2H), 7.6-7.7 (4H), 4.3-4.8 (4H), 4.0-4.2(1H), 3.7-3.8 (1H), 3.3-3.6 (2H), 3.05 (3H), 2.7-2.9 (2H)
1807.8 (2H), 7.5-7.7 (4H), 4.65-4.9 (2H), 4.3-4.65 (2H), 3.9-4.3 (5H), 3.6-3.8 (1H)
181DMSO-d67.8-7.9 (4H), 7.7 (2H), 4.7-4.9 (2H), 4.3-4.5 (4H), 4.15 (2H), 2.85 (6H)
182CDCl38.0 (2H), 7.7-7.8 (3H), 7.5-7.7 (6H), 4.7-4.9 (2H), 4.3-4.6 (2H), 3.9-4.2 (3H), 3.7-3.8(1H)
183CDCl37.8 (2H), 7.5-7.7 (4H), 4.9-5.2 (1H), 4.3-4.8(3H), 4.0-4.2 (1H), 3.6-3.9 (2H), 3.0 (3H), 1.7 (3H).
187CDCl37.69-7.64 (m, 4H), 7.41 (d, 2H), 4.43-4.34 (m, 3H), 4.11 (d, 1H), 3.98 (m, 2H), 3.86-3.77 (m, 1H), 3.70 (d, 1H), 2.68-2.61 (m, 1H), 0.76 (m, 2H) 0.54 (m, 2H)
188CDCl37.67 (m, 2H), 7.54 (d, 2H), 7.45 (t, 1H), 7.41 (d, 2H), 4.44-4.35 (m, 3H), 4.10 (d, 1H), 3.97 (m, 2H), 3.85-3.76 (m, 1H), 3.71 (d, 1H), 2.68-2.60 (m, 1H), 0.76 (m, 2H) 0.54 (m, 2H).
190CDCl37.98 (d, 1H), 7.87 (d, 1H), 7.70 (m, 4H), 4.27(m, 4H), 4.17 (d, 1H), 3.73 (d, 1H), 3.62 (s, 1H), 2.92 (s, 6H)
200CDCl37.97 (s, 1H), 7.86 (s, 1H), 7.76 (d, 2H), 7.56 (d, 2H), 4.85 (m, 1H), 4.60-4.43 (m, 2H), 4.40-4.25(m, 2H), 4.18 (d, 1H), 3.92 (m, 2H), 3.75 (d, 1H)
201CDCl37.72 (d, 2H), 7.66 (s, 2H), 7.57 (d, 2H), 4.51-4.41 (m, 2H), 4.31-4.21 (m, 2H), 4.10 (d, 1H),3.70 (d, 1H),2.92(s,6H)
202CDCl37.96 (m, 1H), 7.85 (m, 1H), 7.73 (d, 2H), 7.58

(d, 2H), 4.51-.41 (m, 2H), 4.31-4.21 (m, 2H), 4.15 (d, 1H), 3.72 (d, 1H), 2.92 (s, 6H)
203CDCl37.96 (m, 1H), 7.85 (m, 1H), 7.74 (d, 2H), 7.56 (d, 2H), 4.52-4.40 (m, 3H), 4.29-4.20 (m, 2H), 4.16 (d, 1H), 3.72 (d, 1H), 3.54 (m, 2H), 2.46-2.33 (m, 2H)
204CDCl37.96 (m, 1H), 7.85 (m, 1H), 7.75 (d, 2H), 7.56 (d, 2H), 5.05-4.92 (m, 3H), 4.85 (d, 1H), 4.54-4.47 (m, 3H), 4.44 (d, 1H), 4.32-4.22 (m, 2H), 4.16 (d, 1H), 3.73 (d, 1H)
213CDCl38.07 (s, 1H), 7.99 (m, 1H), 7.68 (m, 1H), 7.60 (d, 2H), 4.74-4.47 (m, 4H), 4.11 (d, 1H),), 3.73 (d,1H). 3.14 (m, 1H), 2.45-2.29 (m, 2H), 2.27-1.86 (m, 4H)
216CDCl38.06 (s, 1H), 7.98 (m, 1H), 7.68 (m, 1H), 7.58 (d, 2H), 4.80-4.48 (m, 4H), 4.10 (d, 1H), 3.72 (d, 1H), 2.15 (d, 2H), 1.12-1.02 (m, 1H), 0.59 (m, 2H), 0.18 (m, 2H)
224CDCl37.77 (d, 2H), 7,67 (s, 2H), 7.59 (d, 2H), 4.81 (d, 2H), 4.63-4.38 (m, 2H), 4.11 (d, 1H), 3.90 (s, 2H), 3.72 (d, 1H), 3.20 (s, 3H)
225CDCl3.97 (m, 1H), 7.86 (m, 1H), 7.77 (d, 2H), 7.59 (d, 2H), 4.81 (d, 2H), 4.64-4.39 (m, 2H), 4.17 (d, 1H), 3.90 (s, 2H), 3.73 (d, 1H), 3.20 (s, 3H)

In addition to the previous Example 225, the following compounds can be obtained according to the above-mentioned Schemes and Preparatory examples, and they are covered by the present�important feature of the invention in this description. Such compounds of formula (1) include:

2,2-dichloro-1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)Etalon; 1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-fluoro-2-methylpropan-1-he; 1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3-(methylthio)propane-1-he; 1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3-(methyl-sulfonyl)propane-1-he; (3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(tietan-3-yl)methanon; 1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3,3,3-Cryptor-2-methylpropan-1-he; 1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methyl-2-(methyl-sulfonyl)propane-1-he; 1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)propane-1-he; (3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(1-(methyl-sulfonyl)cyclopropyl)methanon; 5-(3,5-dichloro-4-fluorophenyl)-3-(4-(3-fluoro-1-(1,1,1,3,3,3-hexaferrite-2-yl)azetidin-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole; 1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)�enyl)-3-torasemide-1-yl)-3,3-ditropan-1-it; 2-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-M-methyl-2-oxetanemethanol; 2-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-M-isopropyl-2-oxetanemethanol; 1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(3-hydroxyazetidine-1-yl)Etalon; 1-(3-(4-(5-(3,5-dichloro-4-hydroxyphenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpropan-1-he; (3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(Titan-2-yl)methanon; N-(1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methyl-1-oxoprop-2-yl)acetamide; 1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-merkapto-2-methylpropan-1-he; 1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3,3,3-Cryptor-2-hydroxy-2-methylpropan-1-he; 1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3-hydroxy-2,2-DIMETHYLPROPANE-1-he; 3-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2,2-dimethyl-3-oxopropanenitrile; 1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)FeNi�)-3-torasemide-1-yl)-3,3-ditropan-1-it; S-(1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methyl-1-oxoprop-2-yl)attentioin; 1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methyl-2-(methylthio)-propane-1-he; 1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methyl-2-(methyl-sulfonyl)propane-1-he; 1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methyl-1-oxoprop-2-sulfonamide; 1-(1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methyl-1-oxoprop-2-yl)urea; 1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylsulfinyl)Etalon; 1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)Etalon; 1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(1H-pyrazol-1-yl)-Etalon; 1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-hydroxy-2-methylpropan-1-he; (3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-tietan-3-yl-methanon; (E)-N-(1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-PIF�azetidin-1-yl)-2-methylpiperidin)cyanamide; 1-(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-methylpropan-1-he; 3,3,3-Cryptor-1-(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)propane-1-he; 1-(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-(methylthio)Etalon; 1-(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-(methylsulfinyl)Etalon; 1-(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-(methyl-sulfonyl)Etalon; 1-(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-(1H-pyrazol-1-yl)Etalon; 1-(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-hydroxy-2-methylpropan-1-it; (3-fluoro-3-{4-[5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-azetidin-1-yl)-tietan-3-yl-methanon; (3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)(1-oxidation-3-yl)methanon; (1,1-deoxidation-3-yl)(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)methanon; (E)-N-(1-(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-methylpiperidin)cyanamide; 1-(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-d�hydrosocial-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpropan-1-it; the cyclopropyl-(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)methanon; 1-(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he; 1-(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylthio)Etalon; 1-(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylsulfinyl)-Etalon; 1-(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)-Etalon; 1-(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(1H-pyrazol-1-yl)-Etalon; 1-(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-hydroxy-2-methylpropan-1-he; (3-{4-[5-(3,4-dichloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-3-torasemide-1-yl)-tietan-3-yl-methanon; (3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(1-oxidation-3-yl)-methanon; (3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(1,1-deoxidation-3-yl)methanon; (E)-N-(1-(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)Hairdryer�l)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpiperidin)-cyanamide; 1-(3-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpropan-1-he; (3-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(cyclopropyl)methanon; 1-(3-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he; 1-(3-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylthio)Etalon; 1-(3-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylsulfinyl)Etalon; 1-(3-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)Etalon; 1-(3-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(1H-pyrazol-1-yl)Etalon; 1-(3-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-hydroxy-2-methylpropan-1-he; (3-{4-[5-(3-chloro-4-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-tietan-3-yl-methanon; (3-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(1-oxidation-3-yl)-methanon; (3-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-ft�azetidin-1-yl)(1,1-deoxidation-3-yl)-methanon; (E)-N-(1-(3-(4-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpiperidin)cyanamide; 1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-methylpropan-1-he; cyclopropyl-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)methanon; 3,3,3-Cryptor-1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)-phenyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)propane-1-he; 1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-(methylthio)Etalon; 1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-(methylsulfinyl)Etalon; 1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-(methyl-sulfonyl)Etalon; 1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-(1H-pyrazol-1-yl)Etalon; 1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-hydroxy-2-methylpropan-1-it; (3-fluoro-3-{4-[5-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-4,5-dihydro-izocsazol-3-yl]-phenyl}-azetidin-1-yl)-tietan-3-yl-methanon; (3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)(1-oxidation-3-yl)methanon; (1,1-dioxido�ethane-3-yl)(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-methanon; (E)-N-(1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-methylpiperidin)cyanamide; 1-(3-(4-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpropan-1-he; cyclopropyl-(3-(4-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-methanon; 1-(3-(4-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he; 1-(3-(4-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylthio)Etalon; 1-(3-(4-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylsulfinyl)-Etalon; 1-(3-(4-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)-Etalon; 1-(3-(4-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(1H-pyrazol-1-yl)-Etalon; 1-(3-(4-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-hydroxy-2-methylpropan-1-he; (3-{4-[5-(3,4-debtor-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-tietan-3-yl-methanon; (3-(4-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(1-oxidation-3-yl)-methanon; (3-(4-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(1,1-deoxidation-3-yl)-methanon; (E)-N-(1-(3-(4-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpiperidin)-cyanamide; 1-(3-(4-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpropan-1-he; (3-(4-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(cyclopropyl)methanon; 1-(3-(4-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he; 1-(3-(4-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylthio)Etalon; 1-(3-(4-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylsulfinyl)Etalon; 1 -(3-(4-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)Etalon; 1-(3-(4-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(1H-pyrazol-1-yl)Etalon; 1-(3-(4-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-hydroxy-2-methylpropan-1-he; (3-{4-[5-(3-chloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-tietan-3-yl-methanon; (3-(4-(5-(3-chloro-4-fluorophenyl)-5-(Tr�permitil)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(1-oxidation-3-yl)methanon; (3-(4-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(1,1-deoxidation-3-yl)methanon; (E)-N-(1-(3-(4-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpiperidin)-cyanamide; 1-(3-(4-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpropan-1-he; (3-(4-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(cyclopropyl)methanon; 1-(3-(4-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he; 1-(3-(4-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylthio)Etalon; 1-(3-(4-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylsulfinyl)-Etalon; 1-(3-(4-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)-Etalon; 1-(3-(4-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(1H-pyrazol-1-yl)Etalon; 1-(3-(4-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-hydroxy-2-methylpropan-1-he; (3-{4-[5-(3-chloro-5-fluorophenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-tietan-3-yl-methanon; (3-(4-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroiso�Zol-3-yl)phenyl)-3-torasemide-1-yl)(1-oxidation-3-yl)methanon; (3-(4-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(1,1-deoxidation-3-yl)methanon; (E)-N-(1-(3-(4-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpiperidin)cyanamide; 1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-methylpropan-1-he; cyclopropyl(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)methanon; 3,3,3-Cryptor-1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)propane-1-he; 1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-(methylthio)Etalon; 1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-(methylsulfinyl)Etalon; 1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-(methyl-sulfonyl)Etalon; 1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-(1H-pyrazol-1-yl)Etalon; 1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-hydroxy-2-methylpropan-1-it; (3-fluoro-3-{4-[5-trifluoromethyl-5-(3,4,5-tryptophanyl)-4,5-dihydro-izocsazol-3-yl]-phenyl}-azetidin-1-yl)-tietan-3-yl-methanon; (3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole�l-3-yl)phenyl)azetidin-1-yl)(1-oxidation-3-yl)methanon; (1,1-deoxidation-3-yl)(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)methanon; (E)-N-(1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-methylpiperidin)cyanamide; 2-(1-(cyclopropanecarbonyl)-3-torasemide-3-yl)-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)benzonitrile; cyclopropyl-(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-hydroxyazetidine-1-yl)-methanon; 1-(3-(5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-methylpropan-1-he; cyclopropyl-(3-(5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)methanon; 1-(3-(5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he; 1-(3-(5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methylthio)Etalon; 1-(3-(5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methylsulfinyl)Etalon; 1-(3-(5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)Etalon; 1-(3-(5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)2-(1H-pyrazol-1-yl)Etalon; 1-(3-(5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-hydroxy-2-methylpropan-1-he; (3-{5-[5-(3,5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-pyridin-2-yl}-3-fluoro-azetidin-1-yl)-tietan-3-yl-methanon; (3-(5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(1-oxidation-3-yl)methanon; (3-(5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(1,1-deoxidation-3-yl)methanon; (E)-N-(1-(3-(5-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-methylpiperidin)cyanamide; 1-(3-fluoro-3-(5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-methylpropan-1-he; cyclopropyl-(3-fluoro-3-(5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)methanon; 3,3,3-Cryptor-1-(3-fluoro-3-(5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)propane-1-he; 1-(3-fluoro-3-(5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(methylthio)Etalon; 1-(3-fluoro-3-(5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(methylsulfinyl)-Etalon; 1-(3-fluoro-3-(5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2(methyl-sulfonyl)-Etalon; 1-(3-fluoro-3-(5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(1H-pyrazol-1-yl)-Etalon; 1-(3-fluoro-3-(5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-hydroxy-2-methylpropan-1-it; (3-fluoro-3-{5-[5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-pyridin-2-yl}-azetidin-1-yl)-tietan-3-yl-methanon; (3-fluoro-3-(5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)(1-oxidation-3-yl)methanon; (1,1-deoxidation-3-yl)(3-fluoro-3-(5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-methanon; (E)-N-(1-(3-fluoro-3-(5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-methylpiperidin)cyanamide; 1-(3-(5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-methylpropan-1-he; cyclopropyl-(3-(5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)methanon; 1-(3-(5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he; 1-(3-(5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methylthio)-Etalon; 1-(3-(5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihyd�isoxazol-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methylsulfinyl)Etalon; 1-(3-(5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)Etalon; 1-(3-(5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(1H-pyrazol-1-yl)Etalon; 1-(3-(5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-hydroxy-2-methylpropan-1-he; (3-{5-[5-(3,4-dichloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-pyridin-2-yl}-3-torasemide-1-yl)-tietan-3-yl-methanon; (3-(5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(1-oxidation-3-yl)methanon; (3-(5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(1,1-deoxidation-3-yl)methanon; (E)-N-(1-(3-(5-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-methylpiperidin)cyanamide; 1-(3-(5-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-methylpropan-1-he; (3-(5-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(cyclopropyl)methanon; 1-(3-(5-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-3,3,3-three�tourproben-1-it; 1-(3-(5-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methylthio)Etalon; 1-(3-(5-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methylsulfinyl)Etalon; 1-(3-(5-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)Etalon; 1-(3-(5-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(1H-pyrazol-1-yl)Etalon; 1-(3-(5-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-hydroxy-2-methylpropan-1-he; (3-{5-[5-(4-chloro-3-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-pyridin-2-yl}-3-fluoro-azetidin-1-yl)-tietan-3-yl-methanon; (3-(5-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(1-oxidation-3-yl)methanon; (3-(5-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(1,1-deoxidation-3-yl)methanon; (E)-N-(1-(3-(5-(5-(4-chloro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-methylpiperidin)cyanamide; 1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-methylpropan-1-he; cyclopropyl(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)methanon; 3,3,3-Cryptor-1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)-phenyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)propane-1-he; 1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(methylthio)Etalon; 1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(methylsulfinyl)Etalon; 1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(methyl-sulfonyl)Etalon; 1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(1H-pyrazol-1-yl)Etalon; 1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-hydroxy-2-methylpropan-1-it; (3-fluoro-3-{5-[5-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-4,5-dihydro-izocsazol-3-yl]-pyridin-2-yl}-azetidin-1-yl)-tietan-3-yl-methanon; (3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)(1-oxidation-3-yl)-methanon; (1,1-deoxidation-3-yl)(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)methanon; (E)-N-(1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3-(trifluoromethyl)phenyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-methylpiperidin)cyanamide; 1-(3-(5-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-Digi�Rotisol-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-methylpropan-1-it; the cyclopropyl-(3-(5-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)methanon; 1-(3-(5-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he; 1-(3-(5-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methylthio)Etalon; 1-(3-(5-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methylsulfinyl)Etalon; 1-(3-(5-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)Etalon; 1-(3-(5-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(1H-pyrazol-1-yl)Etalon; 1-(3-(5-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-hydroxy-2-methylpropan-1-he; (3-{5-[5-(3,4-debtor-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-pyridin-2-yl}-3-torasemide-1-yl)-tietan-3-yl-methanon; (3-(5-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(1-oxidation-3-yl)methanon; (3-(5-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(1,1-dioxido�ethane-3-yl)methanon; (E)-N-(1-(3-(5-(5-(3,4-debtor-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-methylpiperidin)cyanamide; 1-(3-(5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-methylpropan-1-he; (3-(5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(cyclopropyl)-methane; 1-(3-(5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he; 1-(3-(5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methylthio)-Etalon; 1-(3-(5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methylsulfinyl)Etalon; 1-(3-(5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)Etalon; 1-(3-(5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(1H-pyrazol-1-yl)Etalon; 1-(3-(5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-hydroxy-2-methylpropan-1-he; (3-{5-[5-(3-chloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-pyridin-2-yl}-3-torasemide-1-yl)-tietan-3-yl-methanon; (3-(5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(1-oxide�tietan-3-yl)methanon; (3-(5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(1,1-deoxidation-3-yl)methanon; (E)-N-(1-(3-(5-(5-(3-chloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-methylpiperidin)cyanamide; 1-(3-(5-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-methylpropan-1-he; (3-(5-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(cyclopropyl)methanon; 1-(3-(5-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he; 1-(3-(5-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methylthio)Etalon; 1-(3-(5-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methylsulfinyl)Etalon; 1-(3-(5-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(methyl-sulfonyl)Etalon; 1-(3-(5-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-(1H-pyrazol-1-yl)Etalon; 1-(3-(5-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-hydroxy-2-methylpropan-1-he; (3-{5-[5-(3-chloro-5-fluorophenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-pyridin-2-yl}-3-torasemide-1-yl)-tietan-3-yl-�Manon; (3-(5-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(1-oxidation-3-yl)methanon; (3-(5-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)(1,1-deoxidation-3-yl)methanon; (E)-N-(1-(3-(5-(5-(3-chloro-5-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)-3-torasemide-1-yl)-2-methylpiperidin)cyanamide; 1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-methylpropan-1-he; cyclopropyl-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)methanon; 3,3,3-Cryptor-1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)propane-1-he; 1-(3-fluoro-3-(4-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)phenyl)-1,2-diazetidine-1-yl)-2-(methylthio)Etalon; 1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(methylsulfinyl)-Etalon; 1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(methyl-sulfonyl)-Etalon; 1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-(1H-pyrazol-1-yl)-Etalon; 1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-hydroxy-2-methyl�ropan-1-it; (3-fluoro-3-{5-[5-trifluoromethyl-5-(3,4,5-tryptophanyl)-4,5-dihydro-izocsazol-3-yl]-pyridin-2-yl}-azetidin-1-yl)-tietan-3-yl-methanon; (3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)(1-oxidation-3-yl)-methanon; (1,1-deoxidation-3-yl)(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-methanon and (E)-N-(1-(3-fluoro-3-(5-(5-(trifluoromethyl)-5-(3,4,5-tryptophanyl)-4,5-dihydroisoxazole-3-yl)pyridin-2-yl)azetidin-1-yl)-2-methylpiperidin)cyanamide, their stereoisomers, their pharmaceutically or veterinary acceptable salts.

BIOLOGICAL TESTS

Tested the biological activity of the compounds of the present invention against fleas, ticks, flies and/or lice using the testing methods described below.

Analysis of recharge of jagalchi small cow (Haematobia irritans)

Compounds of formula (1) was dissolved in DMSO and an aliquot was added to citrated bovine blood in a membrane-covered Petri dish. Each Petri dish was placed approximately ten gigalos and covered. These insects were allowed to feed on treated blood cell. Insects were kept at approximately 80°F (26,67°C) at a minimum of approximately 50% relative humidity. Insects were checked for paralyzing effect and mortality at times about 2 and 24 hours. Ultimate Dan�s were recorded in the form of a 90% lethal dose (LD 90) in µg/ml In this assay the compounds of Examples 8-10, 28, 32-34, 36, 38, 54, 160, 168-69, 171, 209 and 221 showed LD90less than or equal to 0.3 micrograms/ml. in addition, in this assay the compounds of Examples 3-5, 11, 13-16, 20-22, 26-27, 31, 37, 40, 42, 45, 56, 59, 84-85, 87, 95, 99, 117, 137, 141, 145, 148, 152-53, 158, 162, 200, 206-07, 220 and 224 showed LD90less than or equal to 1 μg/ml. moreover, in this assay the compounds of Examples 1, 2, 6, 12, 46, 60, 65,69, 77, 98, 108, 112, 133, 135, 138, 140, 142-44, 147, 154, 163, 170, 179, 187, 193, 197, 199, 201-02, 204, 216, 219, 222 and 225 showed LD90less than or equal to 3 μg/ml.

Analysis of local impacts on gigaku autumn (Stomoxys calcitrans} of a compound of formula (1) was dissolved in acetone and 1 µl was placed on the thorax of jagalchi under anesthesia (n=10). Insects were allowed to recover and were incubated for 24 hours at room temperature. Insects were checked for paralyzing effect and mortality at times about 2 and 24 hours. The resulting data is recorded in the form of a 90% lethal dose (LD90) in µg/insect. In this assay the compounds of Examples 1 and 11 showed LD90less than or equal to 0.01 µg/insect. Furthermore, in this assay the compounds of Examples 2, 9, 12 and 99 showed LD90less than or equal to 0.03 µg/insect. Furthermore, in this assay the compounds of Examples 6, 16, 26, 28, 33, 36, 37 and 98 showed LD90less than or equal to 0.1 MK�/insect. Furthermore, in this assay the compounds of Examples 3, 14, 19, 27, 46, 84, 91 and 188 showed LD90less than or equal to 1 µg/insect.

Analysis of feeding Mature individuals fleas (Ctenocephalidei felis) under the membrane

Compounds of formula (1) was dissolved in DMSO and aliquots added to citrated bovine blood in a membrane-covered Petri dish pre-warmed to 37°C. the Tubes to feed containing approximately 30-35 Mature species of fleas were placed on Petri dishes. Fleas left to eat for about 2 hours. Fleas were observed in relation to the paralyzing action and/or death at times about 2 and 24 hours. The resulting data is recorded in the form of a 90% lethal dose (LD90) in µg/ml In this assay the compound of Example 10 showed LD90less than or equal to 0.03 μg/ml. moreover, in this assay the compounds of Examples 27 and 36 showed LD90less than or equal to 0.1 μg/ml. moreover, in this assay the compounds of Examples 4-5, 11, 19, 23, 28, 32-33, 38, 84, 104, 117, 131, 137, 141, 160-161, 167-169, 175, 215-216 and 221 showed LD90less than or equal to 0.3 micrograms/ml. in addition, in this assay the compounds of Examples 1-3, 6-8, 12-16, 20-22, 26, 31, 37, 40-41, 43, 45-56, 59-60, 68, 72-77, 82, 91, 95-101, 103, 106-107, 109-110, 113, 116, 119-121, 123-126, 128-130, 132-133, 135, 138, 140, 145-146, 148, 152-153, 158, 162-164, 170, 173-174, 176, 197-199, 201-202, 205-210, 212-213, 218-220 and 222-223 showed LD90less than or equal to 1 μg/ml. Besides�, in this assay the compounds of Examples 17, 24-25, 29-30, 34-35, 39, 42, 44, 57-58, 61-65, 67, 69-70, 79-81, 87, 89, 94, 102, 105, 108, 111-112, 114-115, 118, 122, 127, 134, 136, 139, 142-144, 147, 154-157, 165-166, 171, 179, 186-196, 200, 203-204, 211, 214-215, 217 and 224-225 showed LD90less than or equal to 3 μg/ml.

Analysis of blood feeding these ticks (Ornithidorus turicata)

Compounds of formula (1) was dissolved in dimethylsulfoxide (DMSO) and aliquots added to citrated bovine blood in a membrane-covered Petri dish. This Petri dish was then placed on a heating tray. Approximately 5 ticks stage nymphs were placed on the membrane, covered and left to eat. Engorged ticks were removed and placed on a Petri dish with sand. Engorged ticks were observed at time points approximately 24, 48 and 72 hours in respect of paralyzing actions and/or death. The resulting data is recorded in the form of ED100(100% effective dose) and/or LD100(absolute lethal dose) in µg/ml Positive control consisted of fipronil, a DMSO was used as negative control. In this assay the compounds of Examples 11, 19, 40, 169 and 175 showed ED100less than or equal to 0.003 mg/cm2. Furthermore, in this assay the compounds of Examples 2-8, 10-17, 20-21, 26-28, 32-34, 36-38, 41-48, 50-54, 56, 59-60, 65-66, 68, 70, 72-74, 76, 84, 95-99, 103, 131, 133, 135, 141-143, 145-146, 155, 158, 165, 168, 171, 173-174, 202, 206, 209-210, 212-213, 215-216, 218-219 and 221 showed ED100less or R�VNOM 0,03 µg/cm 2. In this assay the compounds of Examples 1, 9, 22-25, 29-31, 35, 39, 49, 55, 57-58, 67, 69, 71, 75, 77, 82, 87, 104, 117, 136-140, 144, 148, 152-154, 160, 170, 187-188, 203-204, 207, 211, 214, 217, 220 and 223 showed ED100less than or equal to 0.3 mg/cm2. Furthermore, in this assay the compounds of Examples 18, 89 and 91 demonstrated ED100less than or equal to 1 mg/cm2. Furthermore, in this assay the compound of Example 86 showed ED100less than or equal to 3 mg/cm2.

The bioassays against salmon lice (Lepeophtheirus salmonis}

Two compounds of the formula (1) was dissolved in sea water. Negative controls consisted of sea water, and the positive control was a benzoate emamectin. Ten immature/Mature individuals of salmon lice were exposed for 24 hours. Lice were observed in relation to death, and the resulting data is recorded in the form of a 100% effective concentrations (EC100) based on immobility. In this assay the compounds of Examples 19 and 177 showed the importance of the EU100equal to 50 ppb (parts per billion).

Comparative data: analysis of recharge fleas

Connection to compare T1 and T2 were tested in the analysis of feeding fleas, as described above, and compared with the compounds of Examples 39 and 43, respectively. Connection T1 (WO 2008/122375) and T2 (US 2009/0156643) represent examples of the nearest level of tenkei. Data represent 24-hour PE�IOD of time. The resulting data is recorded in the form of a 90% lethal dose (LD90) in µg/ml In this assay the compounds of Examples 39 and 43 showed LD90less than or equal to 3 mg/cm2and less than or equal to 1 mg/cm2respectively. Compounds for comparison both T1 and T2 showed the values of LD90more than 30 μg/cm2.

1. The compound of formula (1)

where
A represents phenyl, naphthyl or heteroaryl, where the specified heteroaryl is a 5-6-membered monocyclic aromatic ring contains 1 heteroatom N;
each of R1a, R1band R1cindependently represents hydrogen, halogen, cyano, nitro or C1-C6halogenated;
R2represents halogen, cyano or nitro;
R3represents hydrogen, halogen, hydroxyl, cyano, N3or-NHR4;
R4represents hydrogen, -C(O)R5, -C(S)R5, -C(O)NRaR5, -S(O)pRc, -S(O)2NRaR5or-C(NR7)R5;
R5represents hydrogen, C1-C6alkyl, C2-C6of alkenyl, C0-C6alkyls3-C6cycloalkyl, C0-C6alkylphenyl, C0-C6alkyl�heteroaryl, represents a 5-6-membered monocyclic aromatic ring containing 1 to 3 heteroatoms, each independently selected from N, O and S, or C0-C6alkylglycerols where specified heterocycle is a 4-membered monocyclic ring containing 1 heteroatom selected from N, O and S;
R6represents C1-C6halogenated;
R7represents cyano;
Rarepresents hydrogen, C1-C6alkyl or C0-C3alkyls3-C6cycloalkyl;
Rbrepresents hydrogen, C1-C6alkyl or C3-C6cycloalkyl;
Rcrepresents C1-C6alkyl, C1-C6halogenated, C1-C6halogenates3-C6cycloalkyl, C0-C3alkyls3-C6cycloalkyl or C0-C3alkylphenyl, each of which may substituted by at least one substituent selected from cyano or halogen;
each group With1-C6alkyl or C0-C6alkyls3-C6cycloalkyl as R5it may be possible and independently substituted by at least one substituent selected from cyano, halogen, hydroxyl, C1-C6alkoxy, C1-C6halogenoalkane, S1-C6halogenoalkane, -S(O)pRc , -SH, -S(O)pNRaRb, -NRaC(O)Rb, -SC(O)Rcand-C(O)NRaRb; and
where grouping With0-C6alkylglycerol or C1-C6alkylglycerols as R5may be optionally substituted by at least one Deputy, selected from halogen, oxo, hydroxyl, C1-C6alkyl, and-SH;
n represents the integer 0 or 1; and
p is an integer 0, 1 or 2 and its stereoisomers.

2. The compound according to claim 1 having the formula (2A), (2b) or (6A)

where
each of R1a, R1band R1cindependently selected from hydrogen, halogen and C1-C6halogenoalkane;
R2represents halogen or cyano; and
R3represents hydrogen, halogen, hydroxyl, N3or cyano.

3. The compound according to claim 1, where
each of R1a, R1band R1cindependently selected from hydrogen, fluorine, chlorine, bromine and-CF3;
R2represents halogen, or cyano;
R3represents hydrogen, fluorine, chlorine, hydroxyl, N3or cyano; and
R4represents-C(O)R5, -C(O)NRaR5, -S(O)pRc, -C(S)R5, -S(O)2NRaR5or-C(NR7)R5.

4. The compound according to any one of claims. 1-3, where
R2represents cyano;
R3performance�et a hydrogen, fluorine, hydroxyl, N3or cyano;
R4represents-C(O)R5, -C(O)NRaR5or-C(NR7)R5.

5. The compound according to claim 1, selected from the group consisting of the following compounds:
1-(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)Etalon;
the cyclopropyl(3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)methanon;
3-fluoro-N-methyl-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-carboxamide;
N-ethyl-3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-carboxamide;
N-cyclopropyl-3-fluoro-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-carboxamide;
the cyclopropyl(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)methanon;
1-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpropan-1-he;
3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-fluoro-N-methylaziridine-1-carboxamide;
3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-ethyl-3-torasemide-1-carboxamide;
N-cyclopropyl-3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-carboxamide;
1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)propane-1-he;
1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)butane-1-he;
2-cyclopropyl-1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)Etalon;
3-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3-oxopropanenitrile;
1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-(methylthio)Etalon;
1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methoxyethanol;
cyclobutyl(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)methanon;
1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpropan-1-he;
1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he;
N-cyclopropyl-3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-carboxamide;
3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-fluoro-N-methylaziridine-1-carboxamide;
3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-ethyl-3-torasemide-1-carboxamide;
3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydro-from�xazal-3-yl)phenyl)-3-torasemide-1-carboxamide;
the cyclopropyl(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifter-methyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-hydroxyazetidine-1-yl)methanon;
cyclobutyl(3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifter-methyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-hydroxyazetidine-1-yl)methanon;
3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-fluoro-N-methylaziridine-1-carboxamide;
3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-ethyl-3-torasemide-1-carboxamide;
N-cyclopropyl-3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifter-methyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-carboxamide;
3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-ethyl-3-hydroxyazetidine-1-carboxamide;
N-cyclopropyl-3-(4-(5-(3,4-dichloro-5-(trifluoromethyl)phenyl)-5-(trifter-methyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-hydroxyazetidine-1-carboxamide;
3-(4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-fluoro-N-methylaziridine-1-carboxamide;
3-(4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-ethyl-3-torasemide-1-carboxamide;
3-(4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-cyclopropyl-3-torasemide-1-carboxamide;
3-(4-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole--yl)phenyl)-N-cyclopropyl-3-hydroxyazetidine-1-carboxamide;
3-(4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-ethyl-3-hydroxyazetidine-1-carboxamide;
3-(4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-ethyl-3-torasemide-1-carboxamide;
3-(4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-N-cyclopropyl-3-torasemide-1-carboxamide;
3-(4-(5-(3-chloro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-fluoro-N-methylaziridine-1-carboxamide;
1-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)Etalon;
the cyclopropyl(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)methanon;
2-cyclopropyl-1-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)Etalon;
3-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3-oxopropanenitrile;
1-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he;
1-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methoxyethanol;
1-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)propane-1-he;
1-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-fluoro�slidin-1-yl)butane-1-he;
5-[3,5-bis(trifluoromethyl)phenyl]-3-{4-[1-(cyclobutanecarbonyl)-3-fluoro-azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-[3,5-bis(trifluoromethyl)phenyl]-3-{4-[1-(cyclopropanecarbonyl)-3-fluoro-azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-[3,5-bis(trifluoromethyl)phenyl]-3-[4-(3-fluoro-1-isobutyrylacetate-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-[4-(1-butyryl-3-torasemide-3-yl)phenyl]-5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-[3-chloro-5-(trifluoromethyl)phenyl]-3-[4-(3-fluoro-1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-[4-(1-acetyl-3-torasemide-3-yl)phenyl]-5-[3-chloro-5-(trifluoromethyl)-phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-[3-(4-{5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-torasemide-1-yl]-3-oxopropanenitrile;
1-[(3-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)carbonyl]cyclopropanol;
1-[(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)carbonyl]cyclopropanol;
3-{4-[3-fluoro-1-(methoxyacetyl)azetidin-3-yl]phenyl}-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-1-isobutyrylacetate-3-ol;
1 butyryl-3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-Digi�Rotisol-3-yl}phenyl)azetidin-3-ol;
5-[3,5-bis(trifluoromethyl)phenyl]-3-{4-[1-(cyclopropylethyl)-3-fluoro-azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;
2-[3-(4-{5-[3,5-bis(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-torasemide-1-yl]-2-oxoethyl;
5-[3-chloro-5-(trifluoromethyl)phenyl]-3-(4-{3-fluoro-1-[(methylthio)acetyl]-azetidin-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-[3-chloro-5-(trifluoromethyl)phenyl]-3-{4-[1-(cyclobutanecarbonyl)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-[3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-torasemide-1-yl]-3-oxopropanoic;
N-(1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)5-(trifluoromethyl)-4,5-dihydroxysuccinic-3-yl)phenyl)-3-torasemide-1-carbonyl)cyclopropyl)formamide;
1-[(3-fluoro-3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-yl)carbonyl]cyclopropanol;
5-(3,5-dichlorophenyl)-3-{4-[3-fluoro-1-(3-methylbutanoyl)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-(4-{3-fluoro-1-[(methylthio)acetyl]azetidin-3-yl}phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-1-Propionaldehyde-3-ol;
5-[3-chloro-5-(trifluoromethyl)phenyl]-3-{4-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-(3,5-dichloro-4-fluorophenyl)-3-{4-[3-fluoro-1-(1H-Pyra�ol-3-ylcarbonyl)-azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;
4-{2-[3-(4-{5-[3,5-bis(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-torasemide-1-yl]-2-oxoethyl}pyridine;
5-[3-chloro-5-(trifluoromethyl)phenyl]-3-{4-[1-(cyclopropylethyl)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-3-[4-(3-fluoro-1-propionyl-azetidin-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-{4-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]phenyl}-5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-[4-(1-acetyl-3-torasemide-3-yl)phenyl]-5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-3-[4-(3-fluoro-1-isobutyrylacetate-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-[3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-torasemide-1-yl]-3-oxopropanenitrile;
4-[(3-fluoro-3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-yl)carbonyl]methylpyridine;
5-[3,5-bis(trifluoromethyl)phenyl]-3-[4-(3-fluoro-1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-{4-[1-(cyclopentanecarbonyl)-3-torasemide-3-yl]phenyl}-5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-3-(4-{3-fluoro-1-[(methylthio)acetyl]azetidin-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
1-(cyclopropyl�o'neill)-3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-3-ol;
(3-(2-bromo-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(cyclopropyl)methanon;
2-(1-(cyclopropanecarbonyl)-3-torasemide-3-yl)-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)benzonitrile;
5-(3-chloro-5-(trifluoromethyl)phenyl)-3-(4-(3-fluoro-1-(methyl-sulfonyl)-azetidin-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-(2-bromo-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-1-(cyclopropanecarbonyl)azetidin-3-carbonitril;
1-(cyclopropanecarbonyl)-3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-3-carbonitril;
1-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)-2-methylpropan-1-he;
2-methyl-1-(3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)propane-1-he;
the cyclopropyl(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)methanon;
the cyclopropyl(3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)methanon;
1-(3-(4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)Etalon;
1-(3-(4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)azetidin-1-yl)Etalon;
1-isobutyryl-3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-3-ol;
3-{4-[3-fluoro-1-(3,3,3 tryptophanol)azetidin-3-yl]phenyl}-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-{4-[1-(cyclopropylethyl)-3-torasemide-3-yl]phenyl}-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-[4-(1-butyryl-3-torasemide-3-yl)phenyl]-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-[4-(3-fluoro-1-isobutyrylacetate-3-yl)phenyl]-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-[4-(3-fluoro-1-Propionaldehyde-3-yl)phenyl]-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-[3-chloro-5-(trifluoromethyl)phenyl]-3-[4-(3-fluoro-1-isobutyrylacetate-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
2-[3-(4-{5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-torasemide-1-yl]-2-oxoethyl;
5-[3-chloro-5-(trifluoromethyl)phenyl]-3-{4-[1-(cyclopentanecarbonyl)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-[4-(1-butyryl-3-torasemide-3-yl)phenyl]-5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-(3,5-dichlorophenyl)-3-[4-(1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
1-[(3-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-yl)carbonyl]cyclopropanol;
5-(3,5-dichlorophenyl)-3-{4-[1-(methoxyacetyl)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-{4-[1-(cyclopropylethyl)azetidin-3-yl]phenyl}-5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-[4-(1-acetylisatin-3-yl)phenyl]-5-[3,4-dichl�R-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-3-[4-(1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-[4-(1-butyrylacetate-3-yl)phenyl]-5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-[4-(1-butyrylacetate-3-yl)phenyl]-5-[3,4-dichloro-5-(trifluoromethyl)-phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
2-[3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)azetidin-1-yl]-2-oxoethyl;
1-{[3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)azetidin-1-yl]carbonyl}cyclopropanol;
5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-3-(4-{1-[(methylthio)acetyl]-azetidin-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-[3-chloro-5-(trifluoromethyl)phenyl]-3-{4-[1-(cyclopropylethyl)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-[3-chloro-5-(trifluoromethyl)phenyl]-3-{4-[1-(methoxyacetyl)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-[3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)azetidin-1-yl]-3-oxopropanenitrile;
1-{[3-(4-{5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)azetidin-1-yl]carbonyl}cyclopropanol;
5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-3-{4-[1-(methoxyacetyl)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-[3-chloro-5-(trifluoromethyl)phenyl]-3-[4-(1-Propionaldehyde-3-yl)-phenyl]-5-(tripto�methyl)-4,5-dihydroisoxazole;
3-[4-(1-butyrylacetate-3-yl)phenyl]-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-[3-chloro-5-(trifluoromethyl)phenyl]-3-[4-(1-isobutyrylacetate-3-yl)-phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
1-[(3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-yl)carbonyl]cyclopropanol;
3-[4-(1-Propionaldehyde-3-yl)phenyl]-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-(4-{1-[(methylthio)acetyl]azetidin-3-yl}phenyl)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-{4-[1-(methoxyacetyl)azetidin-3-yl]phenyl}-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-{4-[1-(cyclopropylethyl)azetidin-3-yl]phenyl}-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-(3,5-dichloro-4-fluorophenyl)-3-(4-{1-[(methylthio)acetyl]azetidin-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-(3,5-dichloro-4-fluorophenyl)-3-{4-[1-(methoxyacetyl)azetidin-3-yl]-phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;
1-[(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-yl)carbonyl]cyclopropanol;
5-(3,5-dichloro-4-fluorophenyl)-3-[4-(1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-(3,5-dichloro-4-fluorophenyl)-3-[4-(1-isobutyrylacetate-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-(3,5-dichloro-4-fluorophenyl)-3-(4-{1-[(3,3-diversecity-1-yl)carbonyl]-3-torasemide-3-yl}phenyl)-5-(triform�Teal)-4,5-dihydroisoxazole;
3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-1-(3,3,3-triptocaine)azetidin-3-ol;
5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-3-{4-[3-fluoro-1-(3,3,3-triptocaine)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-(3,5-dichloro-4-fluorophenyl)-3-(4-{3-fluoro-1-[(4-methyl-1,3-oxazol-5-yl)carbonyl]azetidin-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
N-[2-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-2-oxoethyl]formamide;
4-[(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)carbonyl]pyridazin;
1-[2-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-2-oxoethyl]-1H-1,2,4-triazole;
5-(3,5-dichloro-4-fluorophenyl)-3-(4-{3-fluoro-1-[(methyl-sulfonyl)acetyl]azetidin-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-(3,5-dichloro-4-fluorophenyl)-3-{4-[3-fluoro-1-(1H-pyrazol-1-ylacetic)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-(3,5-dichloro-4-fluorophenyl)-3-{4-[3-fluoro-1-(1,3-oxazol-5-ylcarbonyl)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-(3,5-dichloro-4-fluorophenyl)-3-{4-[1-(2,2-diperbadankan)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;
1-{[3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-torasemide-1-yl]carbonyl}azetidin-3-ol;
1-(3-{4[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-2-methyl-1-oxoprop-2-ol;
3-[4-(1-but-3-enoyl-3-torasemide-3-yl)phenyl]-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
2-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-N,N-dimethyl-2-oxetanemethanol;
5-(3,5-dichloro-4-fluorophenyl)-3-[4-(3-fluoro-1-{[(trifluoromethyl)thio]acetyl}-azetidin-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-(3,5-dichloro-4-fluorophenyl)-3-{4-[3-fluoro-1-(2-methoxypropanol)azetidin-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-(3,5-dichloro-4-fluorophenyl)-3-(4-{1-[(2,2-diversicolor)carbonyl]-3-torasemide-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-2-methyl-3-oxoprop-1-ol;
(2S)-4-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-4-oxobutyl-2-ol;
4-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-4-oxobutyl-2-ol;
3-{4-[3-chloro-1-(cyclopropanecarbonyl)azetidin-3-yl]phenyl}-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-{4-[3-chloro-1-(cyclopropanecarbonyl)azetidin-3-yl]phenyl}-5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-(3-chlorophenyl)-3-{4-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-{4-[5-(3-chloro-4,5-differenl)-5-(Tr�permitil)-4,5-dihydroisoxazole-3-yl]phenyl}-1-(cyclopropanecarbonyl)-azetidin-3-ol;
3-{4-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]phenyl}-5-[3,4-debtor-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
(2S)-1-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-1-oxoprop-2-ol;
(2R)-1-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-1-oxoprop-2-ol;
(2S)-4-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-4-oxobutyl-2-ol;
5-(3,5-dichloro-4-fluorophenyl)-3-(4-{3-fluoro-1-[(methylsulfinyl)acetyl]-azetidin-3-yl}phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-{4-[3-azido-1-(cyclopropanecarbonyl)azetidin-3-yl]phenyl}-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-[4-(3-azido-1-Propionaldehyde-3-yl)phenyl]-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
S-[2-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-2-oxoethyl]attentioin;
5-(3-fluorophenyl)-3-[4-(3-fluoro-1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-(3-chlorophenyl)-3-[4-(3-fluoro-1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
5-(3,4-dichlorophenyl)-3-[4-(3-fluoro-1-Propionaldehyde-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-{4-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-5-[3-(trifluoromethyl)phenyl]-4,5-dihydroisoxazole�l;
5-(3-chloro-5-fluorophenyl)-3-{4-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]phenyl}-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-{4-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]phenyl}-5-(3,4-differenl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-3,3,3-cryptochrome-1-he;
3-{4-[1-(azetidin-1-ylcarbonyl)-3-torasemide-3-yl]phenyl}-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-{4-[1-(azetidin-1-ylcarbonyl)-3-torasemide-3-yl]phenyl}-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
3-{4-[1-(azetidin-1-ylcarbonyl)-3-torasemide-3-yl]phenyl}-5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole;
1-(cyclopropanecarbonyl)-3-{4-[(5R)-5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-3-ol;
5-(3,5-dichloro-4-fluorophenyl)-3-[4-(3-fluoro-1-isobutyrylacetate-3-yl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole;
{[2-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-2-oxoethyl]sulfonyl}acetonitrile;
1-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-3-methanesulfonate-1-he;
1-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-2-(2,2,2-triftormetilfullerenov)Etalon;
dimethylamide 2-(3-{4-[5-(3,5-di�ENT-4-fluorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]phenyl}-3-torasemide-1-yl)-2-oxo-econsultancy acid;
2-benzolsulfonat-1-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-phenyl}-3-torasemide-1-yl)Etalon;
1-(3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-phenyl}-3-torasemide-1-yl)-2-methanesulfonate-1-he;
(1-cyclopropanecarbonyl-3-{4-[5-(3,4-dichloro-5-triptoreline)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-3-yl)amide cyclopropanecarbonyl acid;
(3-amino-3-{4-[5-(3,4-dichloro-5-triptoreline)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]phenyl}-azetidin-1-yl)cyclopropylmethanol;
3-fluoro-3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-carboxamide;
N-cyclopropyl-3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-carboxamide;
N-cyclopropyl-3-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-carboxamide;
3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-hydroxy-N-propylamide-1-carboxamide;
3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-hydroxy-N,N-dimethylamide-1-carboxamide;
N-ethyl-3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-carboxamide;
3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-N-methylaziridine-1-carboxamide;
3-(4-{5-[3,4 dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-N-methylaziridine-1-carboxamide;
3-{4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-N-utilisation-1-carboxamide;
3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}-N-utilisation-1-carboxamide;
3-(4-{5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-N-methylaziridine-1-carboxamide;
3-(4-{5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-N-cyclopropylamines-1-carboxamide;
N-cyclopropyl-3-{4-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-carboxamide;
N-cyclopropyl-3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)azetidin-1-carboxamide;
3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-fluoro-N-(2,2,2-trifluoroethyl)azetidin-1-carboxamide;
3-fluoro-N,N-dimethyl-3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-carboxamide;
3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-fluoro-N,N-dimethylamide-1-carboxamide;
3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-fluoro-N-(3,3,3-cryptochromes)azetidin-1-carboxamide;
3-(4-{5-[3,4-dichloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl}phenyl)-3-fluoro-N-oxetan-3-ilization-1-carboxamide;
3 azido-N,N-di�ethyl-3-{4-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]phenyl}azetidin-1-carboxamide;
2-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]-5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]benzonitrile;
2-(1-acetyl-3-torasemide-3-yl)-5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]benzonitrile;
5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]-2-[3-fluoro-1-(3,3,3-triptocaine)azetidin-3-yl]benzonitrile;
5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]-2-(3-fluoro-1-Propionaldehyde-3-yl)benzonitrile;
5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]-2-(3-fluoro-1-isobutyrylacetate-3-yl)benzonitrile;
5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]-2-(3-fluoro-1-glycolylated-3-yl)benzonitrile;
2-(1-butyryl-3-torasemide-3-yl)-5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]benzonitrile;
2-[1-(cyclobutanecarbonyl)-3-torasemide-3-yl]-5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]benzonitrile;
2-[1-(cyclopentanecarbonyl)-3-torasemide-3-yl]-5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]benzonitrile;
5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]-2-[3-fluoro-1-(methoxyacetyl)azetidin-3-yl]benzonitrile;
2-[1-(cyclopropylethyl)-3-torasemide-3-yl]-5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]benzonitrile;
5-[5-(3,5-dichlor-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]-2-(3-fluoro-1-pentanolide-3-yl)benzonitrile;
5-[5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]-2-{3-fluoro-1-[(methylthio)acetyl]-azetidin-3-yl}benzonitrile;
2-[1-(cyclopropanecarbonyl)-3-torasemide-3-yl]-5-[5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl]pyridine;
(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(1-oxidation-3-yl)methanon;
(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)(1,1-deoxidation-3-yl)methanon;
1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpropan-1-thione;
(1-(3-(4-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole-3-yl)phenyl)-3-torasemide-1-yl)-2-methylpiperidin)cyanamide;
(1-(3-fluoro-3-{4-[5-(3,4,5-trichlorophenyl)-5-trifluoromethyl-4,5-dihydro-izocsazol-3-yl]-phenyl}-azetidin-1-yl)-2-methysulfonylmethane and
1-(3-{4-[5-(3,4-dichloro-5-trifluoromethyl-phenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-phenyl}-3-fluoro-azetidin-1-yl)-2-methysulfonylmethane,
its stereoisomers.

6. Pharmaceutical or veterinary composition having parasiticidal activity containing a therapeutic amount of a compound of formula (1)

where
A represents phenyl, naphthyl or heteroaryl, where the specified heteroaryl is a 5-6-membered aromatics�e monocyclic ring contains 1 heteroatom N;
each of R1a, R1band R1cindependently represents hydrogen, halogen, cyano, nitro or C1-C6halogenated;
R2represents halogen, cyano or nitro;
R3represents hydrogen, halogen, hydroxyl, cyano, N3or-NHR4;
R4represents hydrogen, -C(O)R5, -C(S)R5, -C(O)NRaR5, -S(O)pRc, -S(O)2NRaR5or-C(NR7)R5;
R5represents hydrogen, C1-C6alkyl, C2-C6of alkenyl, C0-C6alkyls3-C6cycloalkyl, S0-C6alkylphenyl, S0-C6alkylglycerol, which represents a 5-6-membered monocyclic aromatic ring containing 1 to 3 heteroatoms, each independently selected from N, O and S, or C0-C6alkylglycerols where specified heterocycle is a 4-membered monocyclic ring containing 1 heteroatom selected from N, O and S;
R6represents C1-C6halogenated;
R7represents cyano;
Rarepresents hydrogen, C1-C6alkyl or C0-C3alkyls3-C6cycloalkyl;
Rbrepresents hydrogen, C1-C6alkyl or C3-C6cycloalkyl;
Rcis �Wallpaper With 1-C6alkyl, C1-C6halogenated, S1-C6halogenates3-C6cycloalkyl, S0-C3alkyls3-C6cycloalkyl or C0-C3alkylphenyl, each of which may substituted by at least one substituent selected from cyano or halogen;
each group With1-C6alkyl or C0-C6alkyls3-C6cycloalkyl as R5it may be possible and independently substituted by at least one substituent selected from cyano, halogen, hydroxyl, C1-C6alkoxy, C1-C6halogenoalkane, S1-C6halogenoalkane, -S(O)pRc, -SH, -S(O)pNRaRb, -NRaC(O)Rb, -SC(O)Rcand-C(O)NRaRb; and
where grouping With0-C6alkylglycerol or C0-C6alkylglycerols as R5may be optionally substituted by at least one Deputy, selected from halogen, oxo, hydroxyl, C1-C6alkyl, and-SH;
n represents the integer 0 or 1; and
p is an integer 0, 1 or 2;
and pharmaceutically or veterinary acceptable excipient, diluent or carrier.

7. Pharmaceutical or veterinary composition according to claim 6, further comprising at least one additional Veta�Inary agent, selected from the group consisting of insecticides, acaricides, de-worming drugs and nematicides.

8. Pharmaceutical or veterinary composition according to claim 7, where the specified additional veterinary agent is selected from the group consisting of abamectin, ivermectin, avermectin, moxidectin, abamectin, eprinomectin, selamectin, doramectin, nemadectin, albendazole, cambendazole, fenbendazole, flubendazole, mebendazole, expensedate, oxibendazole, parbendazole, tetramisole, levamisole, Pyrantel pamoate, oxantel, morantel, indoxacarb, closantel, triclabendazole, clorsulon, niclosamide, praziquantel, epsiprantel, 2-desksaverservice, peripole, perflubron, spiromesifen, tebufenozide, spinosad, spinetoram, Imidacloprid, dinotefuran, metaflumizone, chlorantraniliprole, periglaciation, milbemycin oxime, milbemycin, DEET (N,N'-diethyl-3-methylbenzamide), desiderata, amitraz, fipronil, permethrin and pyrethrin or their mixtures.

9. Pharmaceutical or veterinary composition according to claim 8, where the specified additional veterinary agent is milbemycin oxime.

10. Pharmaceutical or veterinary composition according to claim 8, where the specified additional veterinary agent is a moxidectin.

11. Use of a compound according to any one of claims. 1-5 for �of manufacturing medicines having parasiticidal activity.

12. Use of a compound according to any one of claims. 1-5 in the manufacture of a medicament for the treatment or control of parasitic infection or infestation in an animal, comprising administering to an animal specified medicines.

13. The use according to claim 12, wherein the animal is an animal companion or livestock.

14. The use according to claim 12, wherein the animal is a companion animal is a dog.

15. The use according to claim 12, wherein the livestock is a cattle.

16. The use according to claim 12, wherein the animal is a bird.

17. The use according to claim 12, wherein the animal is a fish.

18. The use according to any one of claims. 12-17, where the compound is administered topically, orally or by injection.

19. The use according to any one of claims. 12-17, where the compound is administered topically.

20. The use according to any one of claims. 12-17, where the compound is administered orally.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining 5-(het)aryl-4-(2-thienyl)-2-(thio)morpholylpyrimidine, represented by the general formula : where X=O or S, Ar=3-nitrophenyl or 2-thienyl. The described method consists in the fact that at the first stage 5-brom-4-(2-thienyl)-2-(thio)morpholylpyrimidine is obtained by interaction with the excess of 2-thienyllithium in the absolute ether at first at a temperature from -20 to -25°C for not less than 1 hour, and then at room temperature for not less than 18 hours, a solution of a mixture of potassium hexacyonoferrate (III) and potassium hydroxide in water are added with further mixing for 4 hours at room temperature, the ether phase is separated and distilled and the obtained remaining part is subjected to chromatographic separation on silica gel with the ratio in the eluent ethylacetate-hexane, 1:3, with (het)arylboric acid and tetrakis(triphenyphosphine)palladium(0) in tetrahydrofurane, a water solution of potassium carbonate is added and the obtained mixture is irradiated by microwave radiation at 155°C for 20 minutes, the solvent is distilled under a reduced pressure, the obtained residual is subjected to chromatographic separation on silica gel with the ratio in the eluent ethylacetate - hexane, 1:2 with obtaining the target product.

EFFECT: claimed is the highly-efficient two-stage method of obtaining 5-(het)aryl-4-(2-thienyl)-2-(thio)morpholylpyrimidines, which can have a wide spectrum of biological activity.

4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to fluorinated aminotriazole derivatives of formula

,

wherein A represents a group specified in furanyl, oxazolyl and thiazolyl, wherein two attachment points of the above group are found in 1,3-position; R1 represents phenyl, which is unsubstituted, mono- or disubstituted, wherein the substitutes are independently specified in a group consisting of halogen, methyl, methoxy group, trifluoromethyl, trifluormethoxy group and dimethylamino group; and R2 represents hydrogen, methyl, ethyl or cyclopropyl. Besides, the invention refers to a pharmaceutical composition containing the compound of formula (I), and to using the compound of formula (I) for preparing a therapeutic agent.

EFFECT: compounds of formula (I) possessing the agonist activity in relation to ALX receptor.

26 cl, 2 tbl, 36 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula (Ip1) or (Ip3) or its pharmaceutically acceptable salt, where G1 represents (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)halogenalkyl, (C1-C4)halogenalkoxy, halogen, cyano or nitro; n equals 0; G2a represents (C3-C4)cycloalkyl or (C3-C4)cycloalkyl(C1-C2)alkyl; G2b represents hydrogen; R1 represents methyl or ethyl; R2 represents phenyl or fluorophenyl; and R3 represents 2-hydroxy-2-methylpropyl or 2-methyl-2-cyanopropyl.

EFFECT: invention relates to application of compound of formula (Ip1 and Ip3) for manufacturing medication or pharmaceutical composition, intended for treating a person with disease or state, selected from type II diabetes mellitus, obesity, glucose intolerance, hyperglycemias, hyperlipidemis, insulin resistance, decrease of cognitive functions and dyslipidemia.

5 cl, 6 tbl, 107 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to isoxazoline FAAH inhibitors of formula (I) or their pharmaceutically acceptable forms, wherein each of G, Ra, Rb, Rc and Rd has a value described in the present application, to pharmaceutical compositions, and methods of treating a FAAH-mediated condition.

EFFECT: developing the method of treating the FAAH-mediated condition.

32 cl, 22 tbl, 351 ex

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compound - 6-methyl-5-morpholynomethyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione of formula 6-methyl-5-morpholynomethyl-1-(thiethan-3-yl)pyrimidine-2,4(1H,3H)-dione of formula: .

EFFECT: novel compound, possessing antioxidant activity, is obtained.

2 cl, 6 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrimidine compounds of general formula (I) or their pharmaceutically acceptable salts, which can be used in treating the diseases related to mTOR kinase or PI3K kinase, such as cancer, immune diseases, viral infections, inflammations, neurological and other disorders. In general formula (I) , R1 means a group (A), wherein P represents C6aryl optionally substituted by a halogen, -OH, -NH2, -OC1-C6alkyl, unsubstituted 6-merous heteroaryl containing 1-2 heteroatoms N, unsubstituted indolyl, unsubstituted indazolyl, Q is specified in -H, -OR, -SR, -halo, -NR3R4, -OS(O)mR, -OC(O)NHR, -S(O)mNR3R4, -NRC(O)R, -NRS(O)mR, -NRC(O)NR3R4 and -NRC(S)NR3R4, wherein each R, R3 and R4 are independently specified in H, C1-C6 alkyl optionally substituted by a halogen, -N(C1-C3alkyl)2, 5-, 6-merous heterocyclic group containing 1-2 heteroatoms specified in N and O, 6-merous heterocyclic group containing 1-2 heteroatoms specified in N and O, optionally substituted by C1-C6alkyl, C6aryl group optionally substituted by one or two substitutes specified in a halogen, -OC1-C3alkyl, -CF3, -NH2, -C(O)NH2, -NHC(O)C1-C3alkyl, -N(C1-C3alkyl)2, -COOH, -SO2NH2, -SO2C1-C3alkyl, -NHSO2C1-C3alkyl, -CO2C1-C6alkyl, dioximethylene group, -NHC(O)CF3, -C(O)NH(CH2)2÷3N(C1-C3alkyl)2, -O(CH2)2N(C1-C3alkyl)2, 6-merous heterocyclyl containing 1-2 heteroatoms specified in N, O and S optionally substituted by oxo, C1-C3alkyl, -SO2C1-C3alkyl, -C(O)-6-merous heterocyclyl optionally substituted by C1-C3alkyl, 6-merous heteroaryl containing 1-2 heteroatoms N optionally substituted by one or two substitutes presenting a 6-merous heterocyclyl or -SC1-C3alkyl, or a 5-, 6-merous heteroaryl group containing 1-2 heteroatoms specified in N, O and S, optionally condensed with a benzene ring and optionally substituted by a halogen, -CO2C1-C3alkyl, oxo, -NHC(O)C1-C3alkyl, C1-C3alkyl, 6-merous heterocyclyl containing 2 heteroatoms specified in N and O optionally substituted by C1-C3alkyl, m means 1 or 2, or R3 and R4 together with a nitrogen atom to which they are attached, form a saturated 5-, 6-merous N-containing heterocyclic group, which is unsubstituted or substituted by C1-C3alkyl, -SO2C1-C3alkyl, oxo, Y is specified in -O-(CH2)n-, -S-(CH2)n- and -S(O)m(CH2)n-, wherein m means 1, n means 0 or an integer from 1 to 2, R2 is specified in H or a group -NR3R4, wherein R3 and R4 are those as specified above, Z is specified in halo, -(CH2)s-COOR, -(CH2)sCONR3R4, -(CH2)sCH2NR3R4, wherein s means 0 or an integer from 1 to 2 and wherein R, R3 and R4 are those as specified above, unsubstituted 6-merous heteroaryl containing one heteroatom N, substituted or unsubstituted heterocyclyl containing two heteroatoms specified in N and O; the substitute is specified in C1-C3alkyl and C1-C3alkylsulphonyl, and W is specified in a morpholine cycle and pyridine cycle. The invention also refers to a method for preparing the compounds of formula (I).

EFFECT: preparing the new pyrimidine compounds.

12 cl, 5 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

,

where R2 is a heteroaryl group and where said monocyclic heteroaryl group is unsubstituted or substituted with one or more groups selected from F, Cl, Br, I, -NR10R11 and C1-C12 alkyl; and groups selected from F, -NH2, -NHCH3, -N(CH3)2, -OH, -OCH3, -C(O)CH3, -NHC(O)CH3, -N(C(O)CH3)2, -NHC(O)NH2, -CO2H, -CHO, -CH2OH, -C(=O)NHCH3, -C(=O)NH2, and -CH3; R3x, R3y, R3z and R3p is hydrogen; R4x, R4y, R4z and R4p are independently selected from a group consisting of: hydrogen, F, Cl, Br, I, and -C(C1-C6 alkyl)2NR10R11; and R10 and R11 are hydrogen, which are phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors.

EFFECT: high effectiveness of compounds.

7 cl, 7 tbl, 50 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

Amide derivative // 2536409

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where R1 is a hydrogen atom or a C1-C6-alkyl group, substituted with one or two substitutes selected from C1-C6-alkoxy group, hydroxyl group, which can be substituted with a C1-C6-alkylcarbonyl group (substituted with one or two substitutes γ), and a 4-6-member saturated monocyclic heterocyclic carbonyl group containing a N atom; γ is a hydroxyl group, amino group, di(C1-C6-alkyl)amino group and carbamoyl group; R2 is a H atom or a C1-C6alkyl group, which can be substituted with a hydroxyl group; or R1 and R2, together with the nitrogen atom with which they are bonded, can be combined to form an azetidine group, a pyrrolidine group or morpholine group, which can be substituted with one hydroxyl group or a hydroxy-C1-C6-alkyl group; R3 and R4 is a C1-C6-alkyl group; R5 is a halogen atom or a C1-C6-alkyl group; R6 is a halogen atom; m and n denote an integer from 0 to 1; V and W are CH; X, Y and Z each independently can be CH or N. The invention also relates to a pharmaceutical composition containing a compound of formula (I), use of the compound of formula (I) and a method of treating sugar diabetes a disease associated with diabetes.

EFFECT: compounds of formula (I), having hypoglycemic activity.

21 cl, 6 tbl, 72 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of general formula [1] or their pharmaceutically acceptable salts, which possess properties of an inhibitor of the JAK2 thyrokinase activity. In general formula radicals are selected from group (I) or (II). In group (I) X represents CH or N; R1 represents a halogen atom and R2 represents H, a halogen atom, CN, or is selected from the groups of formulas

,

or a group -ORP or 5-6-membered heteroaryl, containing 1-4 nitrogen atoms and optionally additionally containing an oxygen or sulphur atom or containing an oxygen atom as a heteroatom, optionally substituted; or (II) X represents -CRA; and RA represents a group of formula , RB represents (a) amino, optionally substituted with one or two groups, selected from the group, consisting of C1-6alkyl, C3-6cycloalkyl, (C3-6cycloalkyl)C1-6alkyl and C1-3alcoxyC1-3alkyl, (b) C1-3alcoxy, (c) hydroxy or (d) a 5-6-membered saturated cyclic amino group, which additionally can contain a heteroatom, selected from an oxygen atom; R1 represents a halogen atom and R2 represents H; R3 -R5 have values given above. Other values of the radicals are given in the invention formula.

EFFECT: compounds can be applied for the prevention or treatment of cancer, for instance hematologic cancer disease or a solid form of cancer, inflammatory disorder, for instance, rheumatoid arthritis, inflammatory intestinal disease, osteoporosis or multiple sclerosis and angiopathy, for instance, pulmonary hypertension, arteriosclerosis, aneurism or varicose veins.

14 cl, 19 tbl, 234 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new aminotetraline derivatives of formula (I) and their physiologically tolerable salts. In formula

,

A means a benzene ring or a ring specified in a group consisting of a 5-merous ring

,

R means the group R1-W-A1-Q-Y-A2-X1-; R1 means hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl-C1-C4-alkyl, halogenated C1-C6-alkyl, tri-(C1-C4-alkyl)-silyl-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkyl, amino-C1-C4-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, an optionally substituted phenyl, C1-C6-alkoxy, di-C1-C6-alkylamino, an optionally substituted 5 or 6-merous heterocyclyl containing 1-3 heteroatoms specified in nitrogen and/or oxygen or sulphur; W means a bond; A1 means a bond; Q means -S(O)2- or -C(O)-; Y means -NR9- or a bond; A2 means C1-C4-alkylene, or a bond; X1 means -O-, C1-C4-alkylene, C2-C4-alkynylene; R2 means hydrogen, halogen, or two radicals R2 together with the ring atom to which they are attached form a benzene ring; R3 means hydrogen. The other radical values are specified in the patent claim. The invention also refers to intermediate products for preparing the compounds of formula (I).

EFFECT: compounds possess the properties of glycine transporter inhibitors, particularly GlyT1 and can find application in treating neurological and psychiatric disorders, such as dementia, bipolar disorder, schizophrenia, etc or for managing pain related to glycerinergic or glutamatergic neurotransmission dysfunction.

20 cl, 2 tbl, 326 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of obtaining (S)-2-methoxy-3-{4[2-(5-methyl-2-phenyloxazol-4-yl)ethoxy]benzo[b]thiophen-7-yl}propionic acid of formula (I) or its salts, in which formula (II) compound or its salt is hydrated in the presence of an iridium-including catalyst, in which the catalyst includes iridium and formula (III) compound, in which R1 stands for hydrogen, isopropyl, phenyl or benzyl and in which R2 stands for phenyl, 3,5-dimethylphenyl or 3,5-di-tert-butylphenyl. The invention also relates to the application of a complex of the catalyst, containing iridium and the formula (III) compound for obtaining the formula (I) compound.

EFFECT: obtaining the formula (I) compound with a high degree of conversion and enantiomeric purity.

6 cl, 4 tbl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula I, or their racemic mixture, or their individual optic isomers, or pharmaceutically acceptable salts possessing the properties of TGR bile acid receptor agonist. The invention also refers to methods for preparing the compounds. In general formula I , X represents amino group R'R"N, wherein the substitutes R' and R" can be optionally identical, or represents hydrogen, C1-C6alkyl, C3-C6cycloalkyl; substituted C1-C6alkyl, wherein the substitute is specified in phenyl or phenoxy, each of which can be substituted by halogen in turn, C1-C3alkyl, C1-C3alkoxy, phenyloxy, C3-C6cycloalkyl, 5-6-merous heteroaryl with 1 nitrogen atom; aryl specified in phenyl optionally substituted by fluorine, C1-C3alkyl, C1-C3 alkoxy; 5-6-merous heteroaryl with nitrogen atom as heteroatom; C2-C4alkenyl, acyl specified in C1-C6alkylcarbonyl or C3-C6cycloalkylcarbonyl; or substituted oxygroup, which represents hydroxy group, wherein hydrogen is substituted by C1-C6alkyl optionally substituted by hydroxy, di(C1-C3alkyl)amino, phenyl, which can be substituted by halogen in turn, C1-C3alkyl, C1-C3alkoxy; C2-C4alkenyl; and 5-6-merous heterocyclyl with nitrogen atom, or sulphur atom, or oxygen atom as heteroatom; R1a and R1b represents hydrogen, C1-C3alkyl, or R1a and R1b together form methylene chain -(CH2)n-, wherein n=2-5; R1c and R1d represents hydrogen, C1-C3alkyl; R2 represents acyl group specified in C1-C6alkylcarbonyl, wherein alkyl can be substituted by phenyl or phenoxy, each of which can be substituted by halogen in turn, C1-C3alkyl, C1-C3alkoxy; C3-C6cycloalkylcarbonyl; phenylcarbonyl, which can be substituted by halogen, C1-C3alkyl, C1-C3alkoxygroup, oxygroup, C1-C3alkylene dioxygroup; 5-6-merous heteroarylcarbonyl with nitrogen atom, or oxygen atom, or sulphur atom as heteroatom, optionally substituted by carboxy, halogen or C1-C3alkoxycarbonyl, substituted aminocarbonyl group, wherein the substitute can be specified in C1-C6alkyl optionally substituted by C1-C3alkoxycarbonyl, halogen, 5-6-merous heteroaryl together with nitrogen atom, or oxygen atom or nitrogen atom as heteroatom; C3-C6cycloalkyl; phenyl optionally substituted by halogen, C1-C3alkyl, C1-C3alkoxy, C1-C3alkoxycarbonyl, C1-C3alkylenedioxygroup; 5-6-merous heteroarym with nitrogen atom, or oxygen atom or nitrogen atom as heteroatom optionally substituted by carboxy, C1-C3alkoxycarbonyl; aminocarbonyl group substituted by C1-C3alkyl; sulphonyl group specified in alkylsuphonyl optionally substituted by hydroxyl group, cyano group, phenyl, which is optionally substituted by C1-C3alkyl, halogen, C1-C3alkoxy group; henylsulphonyl oprtionally substituted by C1-C3alkyl, halogen, C1-C3alkoxy group, cyano group, C1-C3alkylene dioxygroup, or 5-6-merous heteroarylsulphonyl with nitrogen atom, or sulphur atom, or oxygen atom as heteroatom optionally substituted by halogen, C1-C3alkyl, C1-C3alkoxy group; R3 represents hydrogen.

EFFECT: compounds can be used for preparing the pharmaceutical composition applicable in treating or preventing metabolic diseases, such as diabetes, obesity, diabetic obesity, metabolic syndrome, hypercholesterolemia, dislipidemia.

14 cl, 17 dwg, 8 tbl, 16 ex

Antiviral compounds // 2541571

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I, such as below, or its pharmaceutically acceptable salts. What is described is a method for preparing them.

,

wherein: A independently from B means phenyl,

, or ,

and B independently from A means phenyl,

, or ,

and the values Z, Y, D, L1, L2, L3, Z1, Z2 are presented in the patent claim.

EFFECT: compounds are effective for hepatitis C virus (HCV) replication inhibition.

17 cl, 3 tbl, 8 dwg, 177 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining di-{ 4-[(tetrahydro -4H-1,4-oxazin-4-yl)-methylsulphanyl]-phenyl} ether oxalate of formula

as water-soluble substance with fungicidal activity. Essence of method consists in interaction of di-{ 4-[(tetrahydro -4H-1,4-oxazin-4-yl)-methylsulphanyl]-phenyl} ether with equimolar quantity of oxalic acid (COOH)2 at room (~20°C) temperature for 15 min.

EFFECT: output constitutes 99%.

2 cl, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compounds of formula I

and to their pharmaceutically acceptable salts, where A is selected from CH or N; R1 is selected from the group, consisting of C3-6-cycloalkyl, C3-6-cycloalkyl-C1-7-alkyl, C1-7-alkoxy-C1-7-alkyl, halogen-C1-7-alkyl; R2 and R6 independently on each other represent hydrogen of halogen; R3 and R5 independently on each other are selected from the group, consisting of hydrogen, C1-7-alkyl and halogen; R4 is selected from the group, consisting of hydrogen, C1-7-alkyl, halogen and amino; R7 is selected from the group, consisting of C1-7-alkyl, C1-7alkoxy-C1-7-alkyl, C1-7-alkoxyimino-C1-7-alkyl, 4-6-membered heterocyclyl, containing one heteroatom O, phenyl, with said phenyl being non-substituted or substituted with one hydroxy group, and 5-10-membered heteroaryl, containing 1-3 heteroatoms, selected from N, S and O, said heteroaryl is not substituted or is substituted with one or two groups, selected from the group, consisting of C1-7-alkyl, hydroxy, C1-7-alkoxy, cyano, C1-7-alkylaminocarbonyl and halogen. Invention also relates to pharmaceutical composition based on formula I compound and to method of obtaining formula I compound.

EFFECT: obtained are novel heterocyclic compounds, which are agents, increasing level of LDLP.

17 cl, 2 tbl, 89 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to isoxazoline FAAH inhibitors of formula (I) or their pharmaceutically acceptable forms, wherein each of G, Ra, Rb, Rc and Rd has a value described in the present application, to pharmaceutical compositions, and methods of treating a FAAH-mediated condition.

EFFECT: developing the method of treating the FAAH-mediated condition.

32 cl, 22 tbl, 351 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

Amide derivative // 2536409

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where R1 is a hydrogen atom or a C1-C6-alkyl group, substituted with one or two substitutes selected from C1-C6-alkoxy group, hydroxyl group, which can be substituted with a C1-C6-alkylcarbonyl group (substituted with one or two substitutes γ), and a 4-6-member saturated monocyclic heterocyclic carbonyl group containing a N atom; γ is a hydroxyl group, amino group, di(C1-C6-alkyl)amino group and carbamoyl group; R2 is a H atom or a C1-C6alkyl group, which can be substituted with a hydroxyl group; or R1 and R2, together with the nitrogen atom with which they are bonded, can be combined to form an azetidine group, a pyrrolidine group or morpholine group, which can be substituted with one hydroxyl group or a hydroxy-C1-C6-alkyl group; R3 and R4 is a C1-C6-alkyl group; R5 is a halogen atom or a C1-C6-alkyl group; R6 is a halogen atom; m and n denote an integer from 0 to 1; V and W are CH; X, Y and Z each independently can be CH or N. The invention also relates to a pharmaceutical composition containing a compound of formula (I), use of the compound of formula (I) and a method of treating sugar diabetes a disease associated with diabetes.

EFFECT: compounds of formula (I), having hypoglycemic activity.

21 cl, 6 tbl, 72 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and (II), which possess the blocking activity on voltage-sensitive sodium channels, such as TTX-S channels, and their pharmaceutically salts. In general formula (I) and (II), R1 represents -CF3, -CHF2, -OCF3, -OCHF2, -OCH2CHF2/ -OCH2CF3, -OCF2CHF2; -OCF2CF3, -OCH2CH2CF3, -OCH(CH3)CF3, -OCH2C(CH3)F2, -OCH2CF2CHF2, -OCH2CF2CF3, OCH2CH2OCH2CF3, -NHCH2CF3, -SCF3, -SCH2CF3, -CH2CF3 -CH2CH2CF3, -CH2OCH2CF3 and -OCH2CH2OCF3; R2 is specified in (1) hydrogen, (2) halogen (3) -On-C1-6 alkyl, (4) -On-C3-6 cycloalkyl, (5) -On-phenyl, (6) -On-heterocyclic group, (7) -NR7 (C=O)R8; wherein n is equal to 0 or 1, p is equal to 1, 2; R3 and R4 represents hydrogen or C1-6 alkyl, X represents carbon atom; Y represents hydrogen or C1-6 alkyl; Ar represents 4-pyridyl, 4-pyrimidyl or 6-pyrimidyl, which is substituted in the 2nd position by a substitute, which is independently specified in (1) -(C=O)-NR7R8, (2) -NR7(C=O)R8; R9 is specified in: (1) hydrogen, (2) halogen, (3) -On-C1-6 alkyl, wherein alkyl is unsubstituted or substituted by hydroxyl; q is equal to 1, 2 or 3; R10 independently represents hydrogen, C1-6 alkyl, C2-6alkenyl, C3-7 cycloalkyl or phenyl, which is unsubstituted or substituted by one or substitutes independently specified in hydroxyl, -On-C1-6 alkyl and -C3-7 cycloalkyl.

EFFECT: preparing the compounds possessing the blocking activity on voltage-sensitive sodium channels.

7 cl, 2 tbl, 1281 ex

FIELD: chemistry.

SUBSTANCE: herbicide composition contains (a) aminopyralid and (b) 2,4-D.

EFFECT: invention provides synergetic control of selective broadleaf weeds.

5 cl, 1 tbl

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