WO2012155352A1

WO2012155352A1 - Dihydroisoxazole compounds, parasiticidal uses and formulations thereof

Info

Publication number: WO2012155352A1
Application number: PCT/CN2011/074294
Authority: WO
Inventors: Zengyun AN; Liang Chen; Shuhui Chen; Jean Marie Defauw; Scott Dale HOLMSTROM; Ping Hu; Chongzhi TANG; William Hunter White; Wentao Wu; Yang Zhang
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 2011-05-19
Filing date: 2011-05-19
Publication date: 2012-11-22
Anticipated expiration: 2013-11-19
Also published as: CA2835436C; DK2710000T3; CY1116450T1; JP5989099B2; HK1191337A1; SI2710000T1; IL229007A0; CN103547576B; WO2012158396A1; JP2014515347A; ME02113B; PT2710000E; US8889710B2; EP2918583A1; CR20130486A; TW201307337A; MX2013013446A; KR101586553B1; UA110519C2; PH12013502374A1

Abstract

Provided are dihydroisoxazole compounds useful for controlling parasites both in animals and agriculture. Further provided are methods for controlling parasite infestations of an animal by administering an effective amount of a compound as described above, or a pharmaceutically acceptable salt thereof, to an animal, as well as formulations for controlling parasite infestations using the compounds described above or an acceptable salt thereof, and an acceptable carrier.

Description

DIHYDROISOXAZOLE COMPOUNDS, PARASITICIDAL USES

AND FORMULATIONS THEREOF

Ectoparasites such as fleas, lice, flies, mosquitoes, ticks and mites, as well as endoparasites such as gastrointestinal tract nematodes, flukes, and filarids, are problematic for man and animal alike. Such parasites seriously impact productivity in the domesticated animal industry by reducing weight gain, causing poor quality hide, wool, and meat, and in some cases resulting in death. Ecto- and endoparasites are also responsible, in part, for the spread of disease and discomfort in food and companion animals. Ectoparasites in particular are known to harbor and transmit a variety of microbial pathogens, including bacteria, viruses and protozoan parasites, many of which are pathogenic to humans, other warm-blooded mammals and birds. Diseases in which ectoparasites have been implicated include, but are not limited to, malaria, lymphatic- and blood-born filariasis, trachoma, trypanosomiasis, Leishmaniasis, Rocky Mountain Spotted Fever, Lyme Disease, babesiosis, and food-borne illnesses due to Salmonella, E. coli and Campylobacter, for example.

The medical importance of parasiticide infestations has prompted the development of reagents capable of controlling such. Commonly encountered methods to control parasiticide infestation, for example, have generally focused on use of insecticides, which are often unsuccessful or unsatisfactory for one or more of the following reasons: (1) failure of owner or applicator compliance (frequent administration is required); (2) behavioral or physiological intolerance of the animal to the pesticide product or means of administration; (3) the emergence of ectoparasites resistant to the reagent; and (4) negative impact on the environment and/or toxicity.

Specifically, ticks parasitize wild as well as domesticated animals and humans, and are known or suspected to be responsible for the transmission of pathogens including bacteria, viruses and protozoan parasites. Currently, ticks are considered to be second in the world to mosquitoes as vectors of human diseases, but they are considered to be the most important vector of pathogens in North America. Effective elimination of tick infestations is difficult and often impractical, due to the need for concomitant treatment of the immediate host as well as the environmental reservoir. Presently, tick control is effected by integrated pest management in which different control methods are adapted to one area or against one tick species with due consideration to their environmental effects. While the use of insecticides and pesticides have been beneficial, alternative or improved compounds, formulations, and methods are needed. Desirable compounds, formulations, and methods would not only provide alternative therapies, but would also overcome at least some limitations of current approaches. Such limitations include toxicity and safety of both the animal and the user/owner, limited efficacy (potency and duration), and resistance issues. Also impacting the beneficial use of insecticides and pesticides are administration obstacles, which include mode and recurrence of administration. For example, reducing the frequency of administration while maintaining efficacy is desirable, as excessive and repeated treatment of animals is often inconvenient and/or difficult.

The present invention encompasses parasiticidal compounds, methods, and formulations for use in and on animals and plants, and which provide alternative options for combating parasiticidal infestations, particularly ectoparasiticidal infestations. Further, certain aspects of the invention overcome at least some limitations in the use of current insecticides and pesticides, particularly in providing effective long term, safe control of parasites.

Provided are compounds, and salts thereof, of formula I:

I wherein A is

n is 0 or 1 ; R¹ is thienyl or phenyl, said thienyl or phenyl substituted with 2 or 3 of the same or different halo atoms;

R² is at each occurrence independently hydrogen, C₁-C5 alkyl, C3-C6 cycloalkyl, or C₁-C5 haloalkyl;

R³ is -½-(^CH2)P-^R4 _; p is at each occurrence independently 0 or 1 ;

R⁴ is Ci-C₅ alkyl, Ci-C₅ haloalkyl, Ci-C₅ cyanoalkyl, Ci-C₅ alkylthio, C₃-C₆ cycloalkyl optionally substituted with hydroxy, halo, or C₁-C5 alkyl: C3-C5 cyclohetero alkyl optionally substituted with C₁-C5 alkyl, C₃-C₆ cycloalkyl, or C₁-C5 haloalkyl: phenyl, thienyl,

_¾(CH_2)p^ ^R5

pyridinyl, or O , wherein one of the carbons in said cycloalkyls, independently, or cycloheteroalkyl may form a carbonyl group, and wherein said phenyl, thienyl, or pyridinyl is optionally substituted with halo or a carbamoyl group;

R⁵ is hydroxy, -0-(Ci-C₅ alkyl), or

R⁶ is hydrogen, C₁-C5 alkyl, C₁-C5 haloalkyl, C₁-C5 cyanoalkyl, C₁-C5 alkylthio, or C₂-C5 alkynyl; or R² and R³ combine to form, with the nitrogen to which they are attached,

Yi, Y₂, and Y₃ are carbon or nitrogen with at most only one of Yi, Y₂, and Y₃ being nitrogen, and when Yi, Y₂, or Y₃ is a carbon, each may be substituted by C₁-C5 alkyl; R⁷ is hydrogen, halo, C₁-C5 alkyl, or

R is hydroxy, -0-(Ci-C₅ alkyl), or

(CH₂) -R⁹

R²

R⁹ is C1-C5 alkyl,

R¹⁰ is hydrogen, C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 cyanoalkyl, C1-C5 alkylthio, or C2-C5 alkynyl.

The invention provides a formulation, including a pharmaceutical formulation, comprising a compound or salt of formula I and one or more acceptable carriers. The formulation may further comprise at least one additional active ingredient. A pharmaceutical formulation of the invention may be a human pharmaceutical formulation or a veterinary pharmaceutical formulation.

The invention provides a method of controlling ecto- and endoparasite infestations of an animal in need thereof comprising administering an effective amount of a compound or salt of formula I to said animal. The method may further provide administering at least one other active ingredient to said animal. The animal may be a mammal, and may be a human or a companion animal, for example, a dog or cat.

The present invention provides a method for preventing and treating diseases transmitted through parasites comprising administering at least one compound of the invention to an animal in need thereof.

The invention provides a method for controlling parasites, characterized in that a compound of formula I is allowed to act on the pests and/or their habitat. The invention provides the use of compounds or salts thereof of formula I for controlling pests. The invention provides a compound or salt of formula I for use in therapy. The invention further provides a compound or salt of formula I for use in controlling ecto- and endoparasite infestations. The invention also provides use of a compound or salt of formula I for the manufacture of a formulation or medicament for controlling ecto- and endoparasite infestations.

The host animal may be a mammal or non-mammal, such as a bird (turkeys, chickens) or fish. Where the host animal is a mammal, it may be a human or non-human mammal. Non-human mammals include domestic animals, such as livestock animals and companion animals. Livestock animals include cattle, camellids, pigs, sheep, goats, and horses. Companion animals include dogs, rabbits, cats, and other pets owned and maintained in close association with humans as part of the human-animal bond.

Parasites, sometimes also referred to as pests, include both ectoparasites and endoparasites. Ectoparasites include insect and acarine pests which commonly infest or infect animals, and include the egg, larval, pupal, nymphal, and adult stages thereof. Such pests include fleas, lice, mosquitoes, mites, ticks, beetles, and blood-sucking, biting, or nuisance fly species. Endoparasites include nematode pests which commonly infect animals, and include the egg, larval, and adult stages thereof. Such pests include helminths (hookworms, tapeworms, heartworms), and are commercially important because they cause serious diseases in animals, e.g. in sheep, pigs, goats, cattle, horses, donkeys, camels, dogs, cats, rabbits, guinea-pigs, hamsters, chicken, turkeys, guinea fowls and other farmed birds, as well as exotic birds. Typical nematodes are Haemonchus, Trichostrcngyius, Qstertagia, Nematotiirus, Cooperia, Ascaris, Bunostonum, Gesophagostonum, Charbertia, Trichuris, Strongyius, Trichonema, Dictyocaulus, Capsliarsa, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancyiostoma, Uncinaria, Toxascaris and Par 'ascaris. The trematodes include, in particular, the family of Fasciolideae, especially Fasciola hepatica.

Controlling refers to either ameliorating or eliminating a current infestation, or preventing an infestation, in or on an animal host or a plant.

Effective amount refers to the amount of a compound of formula I, or a salt thereof, sufficient to control an ecto- or endoparasite infestation, and includes causing a measurable reduction in the ecto- or endoparasite infestation population, and as such will depend upon several factors. For use on or in animals, ranges for a compound of formula I, or a salt thereof, in the methods include from 0.01 to 1000 mg/kg and more desirably, 0.1 to 100 mg/kg of the animal's body weight. The frequency of the administration will also be dependent upon several factors, and can be a single dose administered once a day, once a week, or once a month, for a duration determined by the attending doctor or veterinarian. Additional active ingredients may be administered with a compound of formula I.

Pharmaceutically acceptable as used in this application, for example with reference to salts and formulation components such as carriers, includes "veterinarily acceptable", and thus includes both human and animal applications independently.

Salts of the compounds of the invention, including pharmaceutically acceptable salts, and common methodology for preparing them, are known in the art. See, e.g., P. Stahl, et ah, HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA Wiley-VCH, 2002); S.M. Berge, et ah, "Pharmaceutical Salts," Journal of Pharmaceutical Sciences, Vol. 66, No. 1 , January 1977.

The compounds of the invention and their salts may be formulated as pharmaceutical compositions for administration. Such pharmaceutical compositions and processes for making the same are known in the art for both humans and non-human mammals. See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, (A. Gennaro, et al, eds., 19^th ed., Mack Publishing Co., 1995). Formulations can be administered through various means, including oral administration, parenteral administration such as injection (intramuscular, subcutaneous, intravenous, intraperitoneal) or the like; topical application with or without transdermal penetration such as dipping, spray, bathing, washing, pouring-on and spotting-on, and dusting, or the like. Additional active ingredients may be included in the formulation containing a compound of the invention or a salt thereof.

Carrier is used herein to describe any ingredient other than the active component(s) in a formulation. The choice of carrier will to a large extent depend on factors such as the particular mode of administration or application, the effect of the carrier on solubility and stability, and the nature of the dosage form.

C₁-C5 alkyl refers to straight chain and branched alkyls having one to five carbon atoms, and includes methyl, ethyl, propyl, n-butyl, iso-butyl, pentyl, isopentyl, and neopentyl. C2-C5 alkynyl refers to straight chain and branched alkynyls having two to five carbon atoms, and includes ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 3-methyl-l-butynyl, pentynyl, isopentynyl, and neopentynyl.

Halogen or halo refers to fluorine, bromine, chlorine, and iodine.

Haloalkyl as used herein refers to an alkyl (as noted above) substituted with one or more halo atoms. Such groups include trifluoromethyl, methylchloride, dichloromethyl, pentylchloride, butyl chloride, and isopropyl chloride.

Cyanoalkyl as used herein refers to an alkyl (as noted above) substituted with a cyano group.

Alkylthio as used herein refers to an alkyl (as noted above) having a sulfur in the group.

C3-C6 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. C3-C5 cycloheteroalkyl refers to a saturated ring which has 3 to 5 carbons and a hetero atom. The hetero atom may be sulfur, oxygen, nitrogen, or a sulfonyl group.

Diseases transmitted through parasites, particularly ectoparasites, are, for example bacterial, viral, rickettsial and protozoal vector-borne diseases. Examples of viral diseases transmitted through arboviruses, i.e. arthropod borne viruses, are Crimean-Congo Hemorhagic Fever (CCHF), Febrile illness, Papataci fever, Encephalitis, Meningitis, which are caused by Bunyaviridae such as Bunyavirus, Nairovirus or Phlebovirus; Bluetongue, meningoencephalits, Febrile illness, hemorhagic fever, which are caused by Reoviridae, such as Orbivirus, Colitivirus; Febrile illness, rash, encephalitis, polyarthritis, lymphadenitis, which are caused by Togaviridae, such as Sindbisvirus, Chikungunya Virus; tick-borne meningoencephalitis, Dengue hemorhagic fever, encephalitis, Febrile illness, Yellow fever, which are caused by Flaviviridae, such as Flavivirus (including diverse sub-groups). Examples of bacterial diseases transmitted through parasites are Rickettsiosis, such as Rocky Mountain spotted fever, tick typhus caused by infection through Rickettsia ssp; Tularemia caused by infection through Francisella tularensis; Borreliosis or Spirochaetosis, such as Lyme disease, or relapsing fever, caused, by infection through Borrelia ssp.; Ehrllichiosis caused by infection through Ehrlichia ssp.; Plague, caused by infection through Yersinia ssp. Examples of protozoal or rickettsial borne diseases are Babesiosis, such as Texas fever, red water disease, Q-fever caused by infection through Babesia ssp.; Theileriosis, such as east coast fever, Mediterranean coast fever, caused by infection through Theileria ssp.; Nagana disease, Sleeping sickness caused by infection through Trypanosoma ssp., Anaplasmosis caused by infection through Anaplasma ssp.; Malaria caused by infection through Plasmodium ssp.; Leishmaniasis caused by infection through Leishmania ssp.

Given their activity, certain of the compounds of the invention are suitable as soil insecticides against pests in the soil, as well as insecticides for plants, such as cereals, cotton, rice, maize, soya, potatoes, vegetables, fruit, tobacco, hops, citrus, and avocados. Certain

compounds according to the invention are suitable for protecting plants and plant organs, for increasing the harvest yields, and for improving the quality of the harvested material which are encountered in agriculture, in horticulture, in forests, in gardens, and leisure facilities, and in the protection of stored products and of materials. They may be employed as plant protection agents.

All plants and plant parts can be treated in accordance with the invention. Plants are to be understood as meaning in the present context all plants and plant populations such as desired and undesired wild plants or crop plants (including naturally occurring crop plants). Crop plants can be plants which can be obtained by conventional plant breeding and optimization methods or by biotechnological and genetic engineering methods or by combinations of these methods, including the transgenic plants and including the plant cultivars protectable or not protectable by plant breeders' rights. Plant parts are to be understood as meaning all parts and organs of plants above and below the ground, such as shoot, leaf, flower and root, examples which may be mentioned being leaves, needles, stalks, stems, flowers, fruit bodies, fruits, seeds, roots, tubers and rhizomes. The plant parts also include harvested material, and vegetative and generative propagation material, for example cuttings, tubers, rhizomes, offshoots and seeds.

Treatment according to the invention of the plants and plant parts with the active compounds is carried out by conventional and known means, including directly acting on, or by allowing the compounds to act on, the surroundings, habitat or storage space by the customary treatment methods, for example by immersion, spraying, evaporation, fogging, scattering, painting on, injection and, in the case of propagation material, in particular in the case of seeds, also by applying one or more coats.

The compounds can be converted to the customary formulations, such as solutions, emulsions, wettable powders, water- and oil-based suspensions, powders, dusts, pastes, soluble powders, soluble granules, granules for broadcasting, suspension-emulsion concentrates, natural materials impregnated with active compound, synthetic materials impregnated with active compound, fertilizers and microencapsulations in polymeric substances.

These formulations are produced in a known manner, for example by mixing the active compounds with extenders, that is liquid solvents and/or solid carriers, optionally with the use of surfactants, that is emulsifiers and/or dispersants and/or foam-formers. The formulations are prepared either in suitable plants or else before or during the application.

Suitable for use as auxiliaries are substances which are suitable for imparting to the composition itself and/or to preparations derived therefrom (for example spray liquors, seed dressings) particular properties such as certain technical properties and/or also particular biological properties. Typical suitable auxiliaries are extenders, solvents, and carriers.

Following are Schemes A-E and examples for preparing the compounds of the invention.

Scheme A

X = CI, Br, or I Preparation 1

Methyl 2,2,2-trifluoro-l-(3,4,5-trichlorothiophen-2-yl)ethanone

Add a solution of n-BuLi (21.6 mL, 2.5 M in hexane, 54.0 mmol) to a solution of

2,3,4,5-tetrachloro-thiophene (10 g, 45.0 mmol) in dry THF (160 mL) at -78 °C and stir the mixture for 2 hours. Add a solution of trifluoro-acetic acid ethyl ester (9.59 g, 67.6 mmol) in THF (15 mL) and stir at -78 °C for additional 2.5 hours. Quench the reaction with saturated NH₄CI solution (100 mL). Extract the aqueous mixture with EtOAc (100 mL X 3). The combined organic layers are washed with brine, dried over anhydrous Na₂SC>4, and evaporate under vacuum. Purify the residue by a flash column on silica gel eluting with PE:EtOAc (10: 1 to 5: 1) to afford 2,2,2-trifluoro-l-(3,4,5-trichloro- thiophen-2-yl)-ethanone as a brown oil (10.4 g, 81.9%). ¹³F NMR (400 MHz, CDC1₃) δ -73.38 (s, 3F).

Preparation 2

Methyl 3-acetyl-4,5,6,7-tetrah drobenzo[c]thiophene- 1 -carboxylate

Add methyl 2-(2-oxopropylthio)acetate (35.4 g, 183.2 mmol) to a freshly prepared solution of solid sodium (8.78 g, 381.5 mmol) in dry MeOH (300 mL) at 0 °C, followed by addition of a solution of cyclohexane-l,2-dione (20 g, 152.6 mmol) in MeOH (30 mL). Stir the mixture at 0° C for 30 min and then at 50-60 °C for additional 1.5 hour. Remove the solvent under vacuum and dilute the residue with water (100 mL). Extract the aqueous mixture with ethyl acetate (100 mL X 3). The combined organic layers are washed with brine, dried over anhydrous Na₂SC>4, and evaporated under vacuum. Purify the residue by a flash column on silica gel eluting with PE:EtOAc (50: 1 to 30: 1) to afford methyl

3-acetyl-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxylate as a white solid (10 g, 27.6%). MS (m z): 239 (M+l).

Preparation 3

Methyl 3-acetyl-4,5,6,7-tetrah drobenzo[c]thiophene- 1 -carboxylate

Stir a mixture of Cyclopentane-l,2-dione (2.00 g, 20.4 mmol), methyl

2- (2-oxopropylthio)acetate ( 3.31 g, 20.4 mmol) and potassium carbonate (5.63 g, 40.8 mmol) in DMF (40 mL) at 80 °C for 4 hours. Filter off the mixture and remove the solvent under vacuum. Purify the residue by a flash column on silica gel eluting with PE:EtOAc (8: 1 to 6: 1) to afford

3- Acetyl-5,6-dihydro-4H-cyclopenta[c]thiophene-l- carboxylic acid methyl ester as a pale yellow solid (206mg, 4.5 %). MS (m/z): 225 (M+l).

Preparation 4

Methyl

3-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-4,5,6,7-tetrahydrobenzo[c]thiophe ne- 1 -carboxylate

Add a solution of LDA (2M in THF, 19.5 mL, 3.89 mmol) to a suspension of

3-acetyl-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxylate (7.4 g, 3.11 mmol) in dry THF (80 mL) at -78°C under N₂. After stirring for 1.5 h, add l-(3,5-Dichloro-phenyl)- 2,2,2-trifiuoro-ethanone (9.9 g, 3.73 mmol) to the reaction mixture and stir the resultant mixture at the same temperature for additional 2 hours. Quench the reaction with saturated NH4CI aqueous solution. Extract the aqueous mixture with EtOAc (100 mL X 3). The combined organic layers are washed with brine, dried over anhydrous Na₂S04 and concentrated under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc 50: 1) to afford methyl

3-(3-(3,5-dichlorophenyl)- 4,4,4-trifluoro-3-hydroxybutanoyl)

-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxylate as an orange solid (9.1 g, 60.4 %). MS (m/z) 481 (M+l).

The following compounds are prepared essentially by the method of Preparation 4.

Prep.

Chemical name Structure Physical data No.

3-[3-(3,5-Dichloro-ph

enyl)-4,4,4-trifluoro-

3 -hy droxy-butyry 1] -5 ,

6-dihydro-4H-cyclop

5 enta[c]thiophene- 1 -ca MS (m/z): 465 (M-1). rboxylic acid methyl

ester

3-[4,4,4-Trifiuoro-3-h

ydroxy-3-(3,4,5-trichl

oro-thiophen-2-yl)-bu

6 tyryl]-4,5,6,7-tetrahy MS (m/z): 519 (M-1). dro-benzo [c]thiophen

e- 1 -carboxylic acid

methyl ester

Prep.

Chemical name Structure Physical data No. hene- 1 -carboxylic

acid methyl ester

Preparation 11

3-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l- carboxylic acid methyl ester

Stir a mixture of methyl 3-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro -3- hydroxyl

butanoyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxylate (9.1 g, 18.9 mmol), SOCl₂ (9.0 g, 5.5 mL, 75.6 mmol) and pyridine (2.99 g, 3.1 mL, 37.8 mmol) in anhydrous DCM (100 mL) at ambient temperature overnight. Dilute the resultant mixture with saturated NH₄CI aqueous solution. Extract the aqueous mixture with DCM (100 mLX 3). The combined organic layers are washed with brine, dried over anhydrous a₂S04 and concentrated under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc 50: 1) to afford

3-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-4,5,6,7- tetrahydro-benzo[c]thiophene-l -carboxylic acid methyl ester as an orange solid (8.75 g, 100 %). (m/z): 463 (M+l). The following compounds are prepared essentially by the method of Preparation

11.

Prep.

Chemical name Structure Physical data No.

3-[3-(3,5-Dichloro-ph

enyl)-4,4,4-trifluoro- but-2-enoyl]-5,6-dihy

12 dro-4H-cyclopenta[c] MS (m/z): 447 (M-1). thiophene- 1 -carboxyl

ic acid methyl ester

3-[4,4,4-Trifiuoro-3-(

3 ,4,5 -trichloro-thioph

en-2-yl)-but-2-enoyl]

-4,5,6,7-tetrahydro-be F₃C 0

13 nzo [c]thiophene- 1 -ca MS (m/z): 501 (M-1). rboxylic acid methyl

ester]thiophene- 1 -car

boxylic acid methyl

ester

3-[4,4,4-Trifiuoro-3-(

3,4,5-trichloro-phenyl

)-but-2-enoyl]-4,5,6,7

14 MS (m/z): 497 (M+1).

-tetrahydro-benzo[c]t

hiophene- 1 -carboxyli

c acid methyl ester Prep.

Chemical name Structure Physical data No.

3-[3-(3,5-Dichloro-4- fluoro-phenyl)-4,4,4-t

r ifluoro -but-2 -enoy 1] -

15 4,5,6,7-tetrahydro-be MS (m/z): 481 (M+l). nzo [c]thiophene- 1 -ca

rboxylic acid methyl

ester

3-[4,4,4-Trifluoro-3-(

3,4,5-trichloro-phenyl

)-but-2-enoyl]-5,6-di

16 hydro-4H-cyclopenta MS (m z): 483 (M+l).

[c]thiophene- 1 -carbo

xylic acid methyl

ester

3-[3-(3,5-Dichloro-4- fluoro-phenyl)-4,4,4-t

r ifluoro -but-2 -enoy 1] -

17 5,6-dihydro-4H-cyclo 0 yJi MS (m/z): 467 (M+l). penta[c]thiophene- 1 -c

arboxylic acid methyl

ester Preparation 18

3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl] -4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid methyl ester

Stir a mixture of 3-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]- 4,5,6,7- tetrahydro-benzo[c]thiophene-l-carboxylic acid methyl ester (8.75 g, 18.9 mmol), NaOH (2.65 g, 66.1 mmol) and NH₂0H-HC1 (2.6 g, 37.8 mmol) in MeOH (60 mL) and water (15 mL) at room temperature for 2.5 hour. After removal of solvent under vacuum, dilute the residue with ice water (50 mL). Acidify the aqueous mixture with cone. HC1 to pH = 1 and extract the resultant mixture with EtOAc (50 mL X 3). The combined organic layers are washed with brine, dried over anhydrous Na₂SC>4 and concentrated under vacuum. Purify the residue by silica gel

chromatograph (PE:EtOAc 50: 1) to afford

3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benz o[c]thiophene-l-carboxylic acid methyl ester as an orange solid (8.1 g, 93.1%). MS (m/z): 478 (M+l).

The following compounds are prepared essentially by the method of Preparation

18.

Prep.

Chemical name Structure Physical data No.

3-[5-(3,5-Dichloro-phen

yl)-5-trifiuoromethyl-4,5

-dihydro-isoxazol-3-yi]-

19 MS (m/z): 464 (M+1).

5 ,6-dihydro-4H-cyclope

CI

nta[c]thiophene- 1 -carbo

xylic acid methyl ester

3-[5-(3,4,5-Trichloro-thi

ophen-2-yl)-5-trifiuorom

ethyl-4,5-dihydro-isoxaz

20 ol-3-yl]-4,5,6,7-tetrahydr MS (m/z): 516 (M-l). o-benzo [c]thiophene- 1 -c

arboxylic acid methyl

ester

3-[5-(3,4,5-Trichloro-thi

ophen-2-yl)-5-trifiuorom

ethyl-4,5-dihydro-isoxaz 0

21 ol-3-yl]-4,5,6,7-tetrahydr MS (m/z): 512 (M+1). o-benzo [c]thiophene- 1 -c

arboxylic acid methyl

ester

3-[5-(3,5-Dichloro-4-fiu

22 MS (m/z): 496 (M+1). oro-phenyl)-5-trifluorom

ethyl-4,5-dihydro-isoxaz Prep.

Chemical name Structure Physical data No. ol-3-yl]-4,5,6,7-tetrahydr

o-benzo [c]thiophene- 1 -c

arboxylic acid methyl

ester

3-[5-(3,4,5-Trichloro-ph

enyl)-5-trifluoromethyl- 4,5-dihydro-isoxazol-3-y

23 MS (m/z): 498 (M+1).

1] -5 ,6-dihydro-4H-cyclo

penta[c]thiophene- 1 -carb

oxylic acid methyl ester

3-[5-(3,5-Dichloro-4-flu

oro-phenyl)-5-trifluorom

ethyl-4,5-dihydro-isoxaz

24 ol-3-yl]-5,6-dihydro-4H- MS (m/z): 482 (M+1). cyclopenta[c]thiophene- 1 -carboxylic acid methyl

ester

Preparation 25

3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol- -4,5, 6,7-tetrahydro-benzo[c]thiophene-l -carboxylic acid

Stir a mixture of 3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro- isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid methyl ester (8.1 g, 17.0 mmol) and LiOH-H₂0 (3.57 g, 84.9 mmol) in MeOH (64 mL) and water (16 mL) at room temperature overnight. After removal of organic solvent under vacuum, dilute the residue with ice water (80 mL). Acidify the aqueous mixture with cone. HC1 to pH = 1, and extract the resultant mixture with EtOAc (100 mL X 3). The combined organic layers are washed brine, dried over anhydrous Na₂SC>4 and concentrated under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc 1 : 1) to afford 3-[5-(3,5-Dichloro- phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-car boxylic acid as pale yellow solid (6.8 g, 86.4 %). MS (m/z): 464 (M+l).

The following compounds may be prepared essentially by the method of

Preparation 25.

Prep.

Chemical name Structure Physical data No.

3-[5-(3,4,5-Trichloro-ph

enyl)-5-trifluoromethyl- 0

4,5-dihydro-isoxazol-3-y

28 MS (m/z): 496 (M-1). l]-4,5,6,7-tetrahydro-ben

zo [c]thiophene- 1 -carbox

ylic acid

3-[5-(3,5-Dichloro-4-flu

oro-phenyl)-5-trifluorom 0

ethyl-4,5-dihydro-isoxaz

29 MS (m/z): 480 (M-1). ol-3-yl]-4,5,6,7-tetrahydr

o-benzo [c]thiophene- 1 -c

arboxylic acid

3-[5-(3,5-Dichloro-4-flu

oro-phenyl)-5-trifluorom

ethyl-4,5-dihydro-isoxaz

30 MS (m/z): 466 (M-1). ol-3-yl]-5,6-dihydro-4H- cyclopenta[c]thiophene- 1 -carboxylic acid

3-[5-(3,4,5-Trichloro-ph

enyl)-5-trifluoromethyl- 4,5-dihydro-isoxazol-3-y

31 MS (m/z): 482 (M-1).

1] -5 ,6-dihydro-4H-cyclo

penta[c]thiophene- 1 -carb

oxylic acid Example 32

3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((R)-2-oxopyrrolidm

3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide

Stir a mixture of 3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]

-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid (850 mg, 1.84 mmol), HATU (837 mg, 2.20 mmol) and DIEA (539 mg, 0.8 mL, 4.6 mmol) in DCM (8 mL) at room temperature for 15 min, followed by addition of (R)-3-aminopyrrolidin-2-one hydrochloride (315 mg, 2.76 mmol). Stir the reaction mixture at room temperature for additional 1.5 hour. Dilute the reaction mixture with water (20 mL) and extract with DCM (20 mL X 3). The combined organic layers are washed brine, dried over anhydrous Na₂SC>4 and concentrated under vacuum. Purify the residue by preparative HPLC to afford 3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-N-((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carb oxamide as a white solid (730 mg, 73.0 %). MS (m/z): 546 (M+l); 1H NMR (400 MHz, CDC1₃) δ 7.52-7.46 (m, 3H), 6.49 (s, 1H), 5.83 (s, 1H), 4.51-4.48 (m, 1H), 4.22 (d, J=17.2, 1H), 3.85 (d, J=17.2, 1H), 3.52-3.47 (m, 2H), 3.09-2.87 (m, 5H), 2.12-2.03 (m, 1H), 1.89-1.73 (m, 4H).

The following compounds may be prepared essentially by the method of Example

Ex.

Chemical name Structure Physical data o.

N,N-Dimethyl-2-(4-{3-[ MS (m/z): 659 (M+l); 1H 5 - (3 ,4 ,5 -trichloro -thioph NMR (400 MHz, CDC1₃) δ en-2-yl)-5-trifluorometh 4.07-4.02 (m, 2H), 3.68-3.80 yl-4,5-dihydro-isoxazol- (m, 4H), 3.49-3.41 (m, 2H),

33

3 -yl] -4,5 ,6 ,7-tetrahydro- 3.09-3.01 (s, 3H), 3.01-2.95 (s, benzo[c]thiophene- 1 -car 3H), 2.91-2.85 (m, 2H), bonyl}-piperazin-l-yl)-a 2.84-2.78 (m, 4H), 2.69-2.63 cetamide (m, 2H), 1.87-1.72 (m, 4H).

({3-[5-(3,5-Dichloro-phe

nyl)-5-trifluoromethyl-4,

5-dihydro-isoxazol-3-yl]

34 -4,5,6,7-tetrahydro-benz MS (m/z): 535 (M+l). o [c]thiophene- 1 -carbony

l}-amino)-acetic acid

methyl ester

({3-[5-(3,4,5-Trichloro-t

hiophen-2-yl)-5-trifluoro

methyl-4,5-dihydro-isox

35 azol-3-yl]-4,5,6,7-tetrah MS (m/z): 575 (M+l). ydro-benzo[c]thiophene- 1 -carbonyl} -amino)-acet

ic acid methyl ester

Ex.

Chemical name Stracture Physical data o.

2.58-2.48 (m, 2H), 2.29-2.26 (s,

1H).

N-(2-oxo-2-(2,2,2-trifluo MS (m/z): 636(M+1); 'H NMR roethylamino)ethyl)-3-(5 (400 MHz, CDC1₃) δ 7.62 (s, -(3,4,5-trichlorophenyl)- 2H), 7.32 (br, 1H), 6.95 (br,

44 5-(trifluoromethyl)-4,5-d 1H), 4.26-4.25 (m, 2H), ihydroisoxazol-3-yl)-4,5, 4.06-3.83 (m, 3H), 3.66 (d, J = 6,7-tetrahydrobenzo[c]th 16.8 Hz, 1H), 2.98-2.89 (m, iophene- 1 -carboxamide 4H), 1.79 (br, 4H).

MS (m/z): 580(M+1); 'H NMR

N-((R)-2-oxopyrrolidin- (400 MHz, CDCI₃) δ 7.62 (s, 3-yl)-3-(5-(3,4,5-trichlor

2H), 6.62 (br, lH), 6.17 (br, ophenyl)-5-(trifluoromet

1H), 4.47-4.46 (m, 1H),

45 hyl)-4,5-dihydroisoxazol

4.07-4.02 (m, 1H), 3.75-3.64 -3-yl)-4,5,6,7-tetrahydro

(m, 1H), 3.49-3.43 (m, 2H), benzo[c]thiophene- 1 -car

3.02-2.88 (m, 2H), 2.09-2.01 boxamide

(m, 1H), 1.77 (br, 4H). Ex.

Chemical name Structure Physical data o.

N-(2-(cyanomethylamin MS (m/z): 593(M+1); 'H NMR o)-2-oxoethyl)-3-(5-(3,4, (CDC1₃, 400 MHz) δ 7.63 (s, 2 5-trichlorophenyl)-5-(trif H), 7.47 (m, 1 H), 6.81 (m, 1

46 luoromethyl)-4,5-dihydr H), 4.22 (m, 4 H), 4.06 (d,

oisoxazol-3-yl)-4,5,6,7-t J=17.2, 1 H), 3.70 (d, J=17.2, 1 etrahydrobenzo[c]thioph H), 2.90 (m, 4 H), 1.79 (m, 4 ene- 1 -carboxamide H).

MS (m/z): 592(M+1). 'H NMR

N-(2-oxo-2-(prop-2-ynyl

(CDC13, 400 MHz) δ 7. 63 (s, 2 amino)ethyl)-3-(5-(3,4,5

H), 6.78 (m, 1 H), 6.50 (m, 1 -trichlorophenyl)-5-(trifl

H), 4.15 (m, 2 H), 4.10 (m, 2

47 uoromethyl)-4,5-dihydro

H), 4.05 (d, J=16.8, 1 H), 3.67 isoxazol-3-yl)-4,5,6,7-tet

(d, J=16.8, 1 H), 2.95 (m, 2 H), rahydrobenzo [c]thiophen

2.90 (m, 2 H), 2.26 (m, 1 H), e-1 -carboxamide

1.79 (m, 4H).

3-(5-(3,5-dichloro-4-fluo

MS (m/z): 620(M+1); 'H NMR rophenyl)-5-(trifluorome

(CDOD₃, 400 MHz) δ 7.76 (d, thyl)-4,5-dihydroisoxazo

J=6.4, 2H), 4.25 (d, J=17.6, l-3-yl)-N-(2-oxo-2-(2,2,2

48 1H), 4.07 (s, 2H), 4.04-3.92 (m, -trifluoroethylamino)eth

3H), 3.01-2.98 (m, 2H), yl)-4,5,6,7-tetrahydroben

2.90-2.89 (m, 2H), 1.79 (m, zo [c]thiophene- 1 -carbox

4H).

amide Ex.

Chemical name Structure Physical data o.

MS (m/z): 564(M+1); 'H NMR

3-(5-(3,5-dichloro-4-fluo (CDOD₃, 400 MHz) δ 7.76 (d, rophenyl)-5-(trifluorome J=6.4, 2H), 4.63 (t, J=9.6, 1H), thyl)-4,5-dihydroisoxazo 4.24 (d, J=17.6, 1H), 4.02 (d,

49 l-3-yl)-N-((R)-2-oxopyrr J=17.6, 1H), 3.44-3.40 (m, 2H), olidin-3-yl)-4,5,6,7-tetra 2.99-2.98 (m, 2H), 2.89 (m, hydrobenzo [c]thiophene- 2H), 2.59-2.52 (m, 1H), 1 -carboxamide 2.23-2.18 (m, 1H), 1.79-1.77

(m, 4H).

N-(2-(cyanomethylamin

o)-2-oxoethyl)-3-(5-(3,5- MS (m/z): 577(M+1); 'H NMR dichloro-4-fluorophenyl) (CDOD₃, 400 MHz) δ 7.77 (d, -5-(trifluoromethyl)-4,5- J=6.4, 2H), 4.28-4.21 (m, 3H),

50

dihydroisoxazol-3-yl)-4, 4.05-4.00 (m, 3H), 3.00(t, 5,6,7-tetrahydrobenzo[c] J=6.0, 2H), 2.93-2.90 (m, 2H), thiophene- 1 -carboxamid 1.81-1.80 (m, 4H).

e

3-(5-(3,5-dichloro-4-fluo MS (m/z): 576(M+1); 'H NMR rophenyl)-5-(trifluorome (CDOD₃, 400 MHz) δ 7.76 (d, thyl)-4,5-dihydroisoxazo J=6.4, 2H), 4.24 (d, J=17.6,

51 l-3-yl)-N-(2-oxo-2-(prop 1H), 4.03-3.99 (m, 5H), 2.98 (t, -2-ynylamino)ethyl)-4,5 , J=6.0, 2H), 2.88-2.86 (m, 2H), 6,7-tetrahydrobenzo[c]th 2.62 (t, J=2.4, 1H), 1.79-1.77 iophene- 1 -carboxamide (m, 4H).

Ex.

Chemical name Structure Physical data o.

MS (m/z): 547 (M+l); IH NMR (CDC13, 400 MHz) 57.48

3-(5-(3,5-dichlorophenyl (s, 2H), 7.42 (s, IH), 6.23 (s, )-5-(trifluoromethyl)-4,5 IH), 4.08-4.02 (m, 2H), -dihydroisoxazol-3-yl)-N 3.91-3.86 (m, IH), 3.81-3.76

64 -((tetrahydrofuran-2-yl) (m, 2H), 3.69-3.65 (m, J=16 methyl)-4,5,6,7-tetrahyd

Hz, IH), 3.34-3.28 (m, IH), robenzo [c]thiophene- 1 -c 3.00-2.85 (m, 4H), 2.06-1.98 arboxamide (m, IH), 1.96-1.89 (m, 2H),

1.79-1.77 (m, 4H), 1.64-1.59

(m, IH).

MS (m/z): 537 (M+l); IH

3-(5-(3,5-dichlorophenyl

NMR (CDC13, 400 MHz) 5 )-5-(trifluoromethyl)-4,5

7.49 (s, 2H), 7.43 (s, IH), 6.33 -dihydroisoxazol-3-yl)-N

(s, IH), 4.07-4.03 (d, J=16 Hz,

65 -(2-(methylthio)ethyl)-4,

Y IH), 3.69-3.62 (m, 3H), 2.98 (s, 5,6,7-tetrahydrobenzo[c] o

2H), 2.92-2.90 (m, 2H), thiophene- 1 -carboxamid

2.76-2.74 (m, 2H), 2.14 (s, 3H), e

1.80-1.79 (m, 4H).

3-(5-(3,5-dichlorophenyl

MS (m/z): 559 (M+l); IH )-5-(trifluoromethyl)-4,5

NMR (CDC13, 400 MHz) 5 -dihydroisoxazol-3-yl)-N

7.49 (s, 2H), 7.43 (s, IH),

66 -(3 ,3 ,3 -trifluoropropyl)-4

6.08-6.05 (m, IH), 4.06-4.02 ,5,6,7-tetrahydrobenzo[c o

(d, J=16 Hz, IH), 3.72-3.64 (m, ]thiophene- 1 -carboxami 3H), 2.94-2.85 (m, 4H), de

2.51-2.40 (m, 2H), 1.80-1.78 Ex.

Chemical name Structure Physical data o.

(m, 4H).

MS (m/z): 561 (M+l); 1H

3-(5-(3,5-dichlorophenyl

NMR (CDC13, 400 MHz) δ )-5-(trifluoromethyl)-4,5

7.49 (s, 2H), 7.43 (s, 1H), 6.85 -dihydroisoxazol-3-yl)-N

(s, 1H), 4.21 (s, 1H), 4.09-4.02

67 -(3-hydroxycyclohexyl)- (m, 2H), 3.69-3.64 (d, J=20 Hz, 4,5,6,7-tetrahydrobenzo[

1H), 2.96-2.89 (m, 5H), c]thiophene- 1 -carboxami

2.05-1.78 (m, 9H), 1.49-1.38 de

(m, 2H).

MS (m/z): 558 (M+l); 1H

3-(5-(3,5-dichlorophenyl NMR (CDC13, 400 MHz) δ )-5-(trifluoromethyl)-4,5 8.36 (s, 1H), 8.32-8.29 (m, 1H), -dihydroisoxazol-3-yl)-N 8.16 (d, J=2.4 Hz, 1H),

68 -(5-fluoropyridin-2-yl)-4 7.51-7.44 (m, 3H), 7.43 (s, 1H), ,5,6,7-tetrahydrobenzo[c 4.09-4.05 (d, J=16 Hz, 1H), ]thiophene- 1 -carboxami 3.71-3.67 (d, J=16 Hz, 1H), de 3.09 (s, 2H), 2.94-2.93 (m, 2H),

1.83 (s, 4H) Ex.

Chemical name Structure Physical data o.

MS (m/z): 547 (M+l); IH

3-(5-(3,5-dichlorophenyl

NMR (CDC13, 400 MHz) δ )-5-(trifluoromethyl)-4,5

7.49 (s, 2H), 7.40 (s, IH), 6.23 -dihydroisoxazol-3-yl)-N

(d, .7=9.6 Hz, IH), 4.18-4.16 (s,

69 -(tetrahydro-2H-pyran-3-

CF₃ o IH), 4.07-4.03 (d, J=16 Hz, yl)-4,5,6,7-tetrahydroben CI

IH), 3.83-3.77 (m, 2H), zo [c]thiophene- 1 -carbox

3.69-3.57 (m, 3H), 2.98-2.90 amide

(m, 4H), 1.90-1.75 (m, 8H).

MS (m/z): 535 (M+l); IH

3-(5-(3,5-dichlorophenyl NMR (CDC13, 400 MHz) δ )-5-(trifluoromethyl)-4,5 7.49 (s, 2H), 7.44 (s, 1H), 6.18 -dihydroisoxazol-3-yl)-N (d, J= 7.6 Hz, IH), 5.40-5.34

70

-(thietan-3-yl)-4,5,6,7-tet ) F₃C 0 ^S (m, 1H), 4.06 (d, J = 17.2 Hz,

CI

rahydrobenzo [c]thiophen IH), 3.66 (d, J= 17.2 Hz, IH), e-l-carboxamide 3.46-3.36 (m, 4H), 2.97-2.90

(m, 4H), 1.81-1.78 (m, 4H).

MS (m/z): 547 (M+l); IH

3-(5-(3,5-dichlorophenyl NMR (CDC13, 400 MHz) δ )-5-(trifluoromethyl)-4,5 7.47 (s, 2H), 7.41 (s, IH), -dihydroisoxazol-3-yl)-N 5.74-5.72 (d, J=7.6 Hz, IH),

71 -(tetrahydro-2H-pyran-4- 4.19-4.1 1 (m, IH), 4.10-4.06 yl)-4,5,6,7-tetrahydroben

(d, J=16 Hz, IH), 4.04-3.96 (m, zo [c]thiophene- 1 -carbox 2H), 3.69-3.65 (d, J=16 Hz, amide IH), 3.53-3.43 (m, 2H),

2.94-2.88 (m, 4H), 2.00-1.97 (m, 2H), 1.77 (s, 4H), 1.60-1.50 Ex.

Chemical name Stracture Physical data o.

(m, 2H).

MS (m/z): 586 (M+l); 1H

N-( 1 -cyclopropyl-2-oxo NMR (CDC13, 400 MHz) δ pyrrolidin-3-yl)-3-(5-(3, 7.49 (s, 2 H), 7.43 (s, 1H), 6.50 5-dichlorophenyl)-5-(trif (brs, 1 H), 4.43-4.40 (m, 1 H),

72 luoromethyl)-4,5-dihydr 4.04 (d, J=16.8, 1 H), 3.65 (d, oisoxazol-3-yl)-4,5,6,7-t

J = 16.8, 1 H), 3.42-3.30 (m, 2 etrahydrobenzo[c]thioph H), 2.99-2.82 (m, 5 H), ene- 1 -carboxamide 1.91-1.80 (m, 5 H), 0.83-0.763

(m, 4 H)

N-(2-oxo-2-(prop-2-ynyl

MS (m/z): 600 (M+l); 1H amino)ethyl)-3-(5-(3,4,5

NMR (CDC13, 400 MHz) δ -trichlorothiophen-2-yl)- 6.92-6.77 (m, 2H), 4.21-4.09

74 5-(trifluoromethyl)-4,5-d

cr 0 (m, 4H), 4.08-4.04 (m, 2H), ihydroisoxazol-3-yl)-4,5,

3.09-2.88 (m, 4H), 1.87-1.71 6,7-tetrahydrobenzo[c]th

(m, 4H).

iophene- 1 -carboxamide

Ex.

Chemical name Stracture Physical data o.

1.79 (s, 4H), 1.64-1.50 (m, 2H).

MS (m/z): 622 (M+l); 1H

N-( 1 -cyclopropyl-2-oxo

NMR (CDC13, 400 MHz) δ pyrrolidin-3-yl)-3-(5-(3,

8.00 (s, 2 H), 6.53 (brs, 1 H), 4,5-trichlorophenyl)-5-(t

4.43 (m, 1 H), 4.04 (d, J=17.2,

78 rifluoromethyl)-4,5-dihy

1 H), 3.65 (d, J=17.2, 1 H), droisoxazol-3-yl)-4,5,6,7

3.36 (m, 2 H), 2.83 (m, 5 H), -tetrahydrobenzo[c]thiop

2.73 (m, 1 H), 1.84 (m, 5 H), hene- 1 -carboxamide

0.79 (m, 4 H).

3-[5-(3,5-Dichloro-4-flu MS (m/z): 585 (M+l); 1H oro-phenyl)-5-trifluorom NMR (CDC13, 400 MHz) δ ethyl-4,5-dihydro-isoxaz 7.76 (d, J=6.0, 2H), 4.65-4.56 ol-3-yl]-4,5,6,7-tetrahydr (m, 1H), 4.53 (t, J=4.8, 2H),

79

o-benzo [c]thiophene- 1 -c 4.28-4.23 (m, 3H), 4.02 (d, arboxylic acid J=17.6, lH), 2.97 (t, J=6.0, (1,1 -dioxo-thietan-3-yl)- 2H), 2.90 (t, J=6.0, 2H), amide 1.80-1.76 (m, 4H). Ex.

Chemical name Structure Physical data o.

3-[5-(3,5-Dichloro-4-flu MS (m/z): 613 (M+l); 1H oro-phenyl)-5-trifluorom NMR (CDC13, 400 MHz) δ ethyl-4,5-dihydro-isoxaz 7.56(d,J=6.0,2H), 5.75 (d, ol-3-yl]-4,5,6,7-tetrahydr J=7.2, 1 H),4.06 (d,J=16.8, 1

80

o-benzo [c]thiophene- 1 -c H),3.65 (d,J=16.8, 1 H),3.13 arboxylic acid (m,4H),2.91 (m,4H),2.41 (1,1 -dioxo-hexahydro-th (m,2H),2.23 (m, 2 H), 1.84 iopyran-4-yl)-amide (m, 4 H).

3-(5-(3,5-dichloro-4-fluo MS (m/z): 577 (M+l); 1H rophenyl)-5-(trifluorome NMR (CDC13, 400 MHz) δ thyl)-4,5-dihydroisoxazo 7.48(d, J=6.0,2H), 5.67 (d,

81 1-3 -yl)-N-(4-oxocyclohe J=6.8, 1H),4.33 (m, 1H), xyl)-4,5,6,7-tetrahydrobe

3.98(d,J=16.8, lH),3.58(d, nzo[c]thiophene- 1 -carbo J=16.8, 1H), 2.82 (m, 4H), 2.40 xamide (m, 6H), 1.65 (m, 6H)

3-(5-(3,5-dichloro-4-fluo MS (m/z): 646 (M+l); 1H rophenyl)-5-(trifluorome NMR (CDC13 , 400 MHz) δ 7. thyl)-4,5-dihydroisoxazo 50

l-3-yl)-N-(2-oxo-l -(2,2,2 6.44 (dd, J,=4.8, J₂=12.0, 1 H),

82

-trifluoroethyl)pyrrolidin 4.46 (m, 1 H),3.98 (m, 2 H), -3-yl)-4,5,6,7-tetrahydro 3.78 (m, 1 H), 3.55 (m, 3 H), benzo[c]thiophene- 1 -car 2.83 (m, 5H), 1.963 (m, 1 H), boxamide 1.71 (m,4H). Ex.

Chemical name Structure Physical data o.

MS (m/z): 565 (M+l); 1H

3-(5-(3,5-dichloro-4-fluo NMR (CDC13, 400 MHz) δ rophenyl)-5-(trifluorome 7.49 (d, J=5.6, 2 H), 5.59 (d, thyl)-4,5-dihydroisoxazo J=7.6, 1 H), 4.10 (m, 1 H), 3.98

83 l-3-yl)-N-(tetrahydro-2H (d, J=16.8, 1 H), 3.91 (m, 2 H), -pyran-4-yl)-4,5,6,7-tetra 3.58 (d, J=16.8, 1 H), 3.45 (m, hydrobenzo [c]thiophene- 2 H), 2.84 (m, 4 H), 1.95 (m, 2 1 -carboxamide H), 1.72 (m, 4 H), 1.49 (m, 3

H).

MS (m/z): 604 (M+l); 1H NMR (CDC13, 400 MHz) δ

N-( 1 -cyclopropyl-2-oxo

7.77 (d, J=6.0, 2H), 4.62 (t, pyrrolidin-3-yl)-3-(5-(3,

J=9.6, 1H), 4.24 (d, J=17.6, 5-dichloro-4-fluorophen

1H), 4.02 (d, J=17.6, 1H), yl)-5-(trifluoromethyl)-4

84 3.43-3.39 (m, 2H), 2.99-2.96 ,5-dihydroisoxazol-3-yl)

(m, 2H), 2.90-2.88 (m, 2H), -4,5,6,7-tetrahydrobenzo

2.75-2.69 (m, 1H), 2.50-2.42 [c]thiophene- 1 -carboxa

(m, 1H), 2.10-1.99 (m, 1H), mide

1.81-1.78 (m, 4H), 0.85-0.82

(m, 4H).

3-(5-(3,5-dichlorophenyl MS (m/z): 545 (M+l); 1H )-5-(trifluoromethyl)-4,5 NMR (CDC13, 400 MHz) δ

85 -dihydroisoxazol-3-yl)-N 7.52-7.44 (m, 3H), 5.72-5.68 -(4-oxocyclohexyl)-5,6- o (m, 1H), 4.48-4.37 (m, 1H), dihydro-4H-cyclopenta[c 4.04-3.97 (d, J=17.2, 1H), ]thiophene- 1 -carboxami 3.65-3.59 (d, J=17.2, 1H), Ex.

Chemical name Structure Physical data o. de 2.92-2.84 (m, 4H), 2.58-2.48

(m, 6H), 2.47-2.31 (m, 2H), 1.84-1.71 (m, 2H).

MS (m/z): 614 (M+l); 1H

3-(5-(3,5-dichlorophenyl

NMR (CDC13, 400 MHz) )-5-(trifluoromethyl)-4,5

57.52-7.44 (m, 3H), 6.43-6.38 -dihydroisoxazol-3-yl)-N

(s, 1H), 4.52-4.48 (m, 1H), -(2-oxo- 1 -(2,2,2-trifluor

86 _N 4.17-4.05 (m, 2H), 4.04-3.97 oethyl)pyrrolidin-3-yl)-5 Q Y^NY

(d, .7=17.2, 1H), 3.89-3.77 (m, ,6 -dihydro -4H- cy clopent

1H), 3.68-3.51 (m, 3H), a[c]thiophene- 1 -carboxa

2.93-2.82 (m, 5H), 2.58-2.46 mide

(m, 2H), 2.08-1.97 (m, 1H).

Example 87

(A) 3-((R)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((R)-2- oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide and

(B) 3-((S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((R)-2- oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide

Separate 3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)

-N-((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide (6.2 g 11.29 mmol) by SFC (Column: Chiralcel OD 250 X 30mm I.D., 5um. Mobile phase: Supercritical C0₂/ MeOH=60/40, Flow rate:200 ml/min) to afford two diastereoisomers

3-((R)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((R)-2-oxo pyrrolidin-3-yl)- 4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide (2.7 g, 4.92 mmol) and 3-((S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((R)-2-oxopyrroli din-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide (2.6 g, 4.74 mmol) as a white solid.

(A) MS (m/z): 619.1 (M+73). ^!H NMR (CDC1₃, 400 MHz) δ 7.49 (s, 2H), 7.42 (s, 1H ), 6.56 (d, J=4.4 Hz 1H), 6.03 (s, 1H), 4.50-4.44 (m, 1H), 4.06-4.02 (d, J=16 Hz, 1H), 3.69-3.65 (d, J=16 Hz, 1H), 3.48-3.43 (m, 2H), 3.03-2.98 (m, 5H), 2.11-2.00 (m, 1H), 1.78 (s, 4H).

(B) MS (m/z): 619.1 (M+73). 1H MR (CDC1₃, 400 MHz) δ 7.49 (m, 2H), 7.41 (m, 1H ), 6.77-6.73 (m, 1H), 6.38-6.31 (m, 1H), 4.51-4.45 (m, 1H), 4.05-4.01 (d, J=16 Hz, 1H), 3.71-3.67 (d, J=16 Hz, 1H), 3.49-3.39 (m, 2H), 3.00-2.85 (m, 5H), 2.04-2.03 (m, 1H), 1.74 (s, 4H).

Scheme B

NH R¹R², Pyridine

Ar

Preparation 88

3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- 4,5,6,7-tetrahydrobenzo[c]thiophene-l-carbonyl chloride

Stir a mixture of

3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benz o[c]thiophene-l-carboxylic acid (600 mg, 1.2 mmol), 2 drops DMF in oxalyl dichloride (5 mL) at ambient temperature for 3 hours. Remove the solvent under vacuum to afford

3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- 4,5,6,7-tetrahydrobenzo[c]thiophene-l-carbonyl chloride as a yellow solid (615 mg, 98 %).

The following compound is prepared essentially by the method of Preparation 88.

Example 90

N-(4-carbamoylphenyl)-3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide

Stir a mixture of

3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo [c]thiophene- 1 -carbonyl chloride (48 mg, 0.1 mmol) and 4-aminobenzamide (27 mg, 0.2 mmo) in pyridine (3 mL) at ambient temperature overnight. After removal solvent under vacuum, purify the residue by preparative HPLC to afford

N-(4-carbamoylphenyl)-3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl) -4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide as a white solid (36 mg, 62.0%). MS (m/z): 582.1 (M+l). 1H NMR (CDC1₃, 400 MHz) δ 7.84 (d, J=8.4 Hz, 2H), 7.65-7.63 (m, 3H), 7.49 (s, 2H), 7.44 (s, 1H), 6.03 (s, 1H), 5.61 (s, 1H), 4.09-4.05 (d, J=16 Hz, 1H), 3.72-3.68 (d, J=16 Hz, 1H), 3.07 (s, 2H), 2.94 (s, 2H), 1.76 (s, 4H).

The following compound is prepared essentially by the method of Example 90.

Ex.

Chemical name Structure Physical data No.

-2-yl)-amide

Scheme C

Example 92

2-(3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- 4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamido)acetic acid

Stir a mixture of methyl 2-(3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamido)acetate (534 mg, 1.0 mmol) and LiOH-H₂0 (168 mg, 4.0 mmol) in MeOH (20 mL) and water (5 mL) at room temperature for overnight. After removal of organic solvent under vacuum, dilute the residue with ice water (10 mL). Acidify the aqueous mixture with cone. HC1 to pH = 1 , and extract the resultant mixture with EtOAc (15 mL X 3). The combined organic layers are washed brine, dried over anhydrous Na₂SC>4 and concentrated under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc 1 : 1) to afford

2-(3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobe nzo[c]thiophene-l-carboxamido)acetic acid as a pale yellow solid (427 mg, 82.0 %). MS (m/z): 521(M+1).

The following compound is prepared essentially by the method of Example 92.

Example 94

N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichlorophenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l- carboxamide

Stir a mixture of 2-(3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamido)acetic acid (230 mg, 0.44 mmol), HATU (251 mg, 0.66 mmol) and Et₃ (133 mg, 1.32 mmol) in DCM (5 mL) at room temperature for 15 min, followed by addition of 2-aminoacetonitrile hydrochloride (61 mg, 0.65 mmol). Stir the reaction mixture at room temperature for additional 1.5 hour. Dilute the reaction mixture with water (20 mL) and extract with DCM (20 mLX 3). The combined organic layers are washed with brine, dried over anhydrous Na₂SC>4 and concentrated under vacuum. Purify the residue by preparative HPLC to afford

N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5- dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophe ne-l-carboxamide as a white solid (110 mg, 44.7 %). MS (m/z): 559.1 (M+l). 1H NMR

(DMSC /e, 400 MHz) δ 8.64 (t, J=5.6 Hz, 1H), 8.22 (t, J=5.6 Hz, 1H ), 7.81-7.80 (m 1H), 7.68 (s, 2H), 4.35-4.22 (m, 2H), 4.16-4.15 (m, 2H), 3.88-3.86 (m, 2H), 2.94-2.86 (m, 4H), 1.70-1.69 (m, 4H).

The following compounds are prepared essentially by the method of Example 94.

Ex.

Chemical name Structure Physical data o.

3-(5-(3,5-dichlorophenyl MS (m/z): 558 (M+l); ^JH )-5-(trifluoromethyl)-4,5 NMR (CDCI₃, 400 MHz) δ -dihydroisoxazol-3-yl)-N 7.49-7.42 (m, 3H), 6.85 (br,

95 -(2-oxo-2-(prop-2-ynyla lH), 6.72 (br, 1H), 4.17-4.03 mino)ethyl)-4,5,6,7-tetra (m, 5H), 3.68 (d, J = 17.2 Hz, hydrobenzo [c]thiophene- 1H), 3.00-2.90 (m, 4H), 2.25 (s, 1 -carboxamide 1H), 1.79 (br, 4H).

N-(2-(cyanomethylamin

o)-2-oxoethyl)-3-(5-(3,4,

MS (m/z): 599 (M+l); ^!H 5 -trichlorothiophen-2 -yl)

NMR (CDCI₃, 400 MHz) δ -5-(trifluoromethyl)-4,5-

96 4.28-4.18 (m, 4H), 4.10-4.07 dihydroisoxazol-3-yl)-4, cr ^s

(m, 2H), 3.04-2.87 (m, 4H), 5,6,7-tetrahydrobenzo[c]

1.88-1.73 (m, 4H).

thiophene- 1 -carboxamid

e

Scheme D

Preparation 201 4-chlorobenzo[b]thiophene-2-carboxylic

Stir a mixture of methyl 4-chlorobenzo[b]thiophene-2-carboxylate (1.0 g, 4.44 mmol) and LiOH-H₂0 (0.56 g, 13.3 mmol) in MeOH (30 mL) and water (10 mL) at room temperature overnight. Concentrate the reaction mixture under vacuum and then dilute the residue with ice water (20 mL). Acidify the aqueous mixture with cone. HC1 solution to pH = 1. Extract the resultant mixture with EtOAc (15 mLx3). The combined organic layers are washed with brine, dried over anhydrous Na₂SC>4 and evaporate under vacuum to afford

4-chlorobenzo[b]thiophene-2-carboxylic acid as a white solid (0.94 g, 100 %). ^!H NMR (400 MHz, CDC1₃) δ 8.10-8.02 (m, 2H), 7.61-7.51 (m, 2H) The following compounds are prepared essentially by the method of Preparation

201.

Preparation 204

4-chloro-N-methoxy-N-meth lbenzo[b]thiophene-2-carboxamide

Stir a mixture of 4-chlorobenzo[b]thiophene-2-carboxylic acid (0.94 g, 4.44 mmol),

Ν,Ο-dimethylhydroxylamine hydrochloride (0.86 g, 8.87 mmol), DCC (1.1 g, 5.32 mmol) and DIEA (1.43 g, 1.9 mL, 11.08 mmol) in DCM (8 mL) at ambient temperature for 2 hours. Filter the reaction mixture and the filtrate was washed with brine, dried over anhydrous Na₂SC>4 and concentrated under vacuum. Purify the residue by column chromatography on silica gel eluting with PE: EtOAc (5: 1 to 3: 1) to afford

4-chloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide as white solid (0.85 g, 75.2 %). 'H NMR (400 MHz, CDC1₃) δ 8.10-8.02 (m, 2H), 7.61-7.51 (m, 2H), 3.84-3.79 (s, 3H), 3.37-3.35 (s, 3H).

The following compound is prepared essentially by the method of Preparation 204.

boxamide / \

Preparation 207 l-(4-chlorobenzo b]thiophen-2-yl)ethanone

Add a solution of C¾MgBr (3 M in THF, 1.7 ml, 4.99 mmol) to a suspension of

4-chloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide (0.85 g, 3.33 mmol) in dry THF (10 mL) at 0 °C. Then stir the mixture for overnight at ambient temperature. Quench the reaction with saturated NH₄CI aqueous solution (15 mL) and extract the aqueous mixture with EtOAc (10 mLx3). The combined organic layers are washed with brine, dried over anhydrous Na₂S0₄ and concentrated under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc = 6: 1) to afford l-(4-chlorobenzo[b]thiophen-2-yl)ethanone as white solid (0.6 g, 86.9 %). ^!H NMR (400 MHz, CDCI₃) δ 8.10-8.07 (s, 1H), 7.75 (d, J=5.2, 1H), 7.47-7.36 (m, 2H), 2.72-2.68 (s, 3H).

The following compounds are prepared essentially by the method of Preparation

207.

Prep Physical

Chemical name Structure

No. data

1 -(5-Bromo-thieno [2 ,3 -b]p MS (m/z):

209

yridin-2-yl)-ethanone 258 (M+l).

l-Thieno[2,3-b]pyridin-2- MS (m/z):

210

yl-ethanone OH 178 (M+l)

Preparation 211 l-(4-chlorobenzo[b]thiophen-2- -3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-l-one

Add a solution of LiHMDS (1 M in THF, 4.3 ml, 4.31 mmol) to a mixture of

l-(4-chlorobenzo[b]thiophen-2-yl)ethanone (0.6 g, 2.87 mmol) in dry THF (10 mL) at -78 °C under N₂. After stirring 1.5 hour at -78 °C, add l-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (836 mg, 3.44 mmol) to the reaction mixture and stir the resultant mixture for additional 2 hours. Quench the reaction with saturated NH₄CI solution and extract the aqueous mixture with EtOAc (10 mLx3). The combined organic layers are washed with brine, dried over anhydrous Na₂S04 and concentrated under vacuum afford crude

l-(4-chlorobenzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-l-one as brown solid (1.1 g, 84.6%). 'H NMR (400 MHz, CDCI₃) δ 8.10-8.07 (s, 1H), 7.75 (d, J=5.2, 1H), 7.47-7.36 (m, 2H), 2.72-2.68 (s, 3H).

The following compounds are prepared essentially by the method of Preparation

21 1.

Preparation 220 l-(4-chlorobenzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-en-l-one

Stir a mixture of

l-(4-chlorobenzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-l-one (1.1 g, crude, 2.43 mmol), SOCl₂ (1.16 g, 0.7 mL, 9.43 mmol) and pyridine (384 mg, 0.4 mL, 4.86 mmol) in anhydrous DCM (10 mL) at ambient temperature for overnight. Dilute the mixture with saturated NH₄CI solution and extract the aqueous mixture with DCM (10 mLx3). The combined organic layers are washed with brine, dried over anhydrous a₂S04 and concentrated under vacuum to afford crude

l-(4-chlorobenzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-en-l-one as brown solid (1.05 g, 100%). 1H NMR (400 MHz, CDC1₃) 58.12-8.10 (s, 1H), 7.69-7.64 (m, 1H), 7.47-7.44 (m, 2H), 7.38-7.35 (m, 2H), 7.27-7.24 (m, 1H), 6.96 -6.92 (s, 1H).

The following compounds are prepared essentially by the method of Preparation

220.

Prep.

Chemical name Structure Physical data No.

1 -(5 -chlorobenzo [b]thio CF₃ O

phen-2-yl)-3-(3,5-dichlo MS (m/z): 433

228

rophenyl)-4,4,4-trifluoro

CI

but-2-en-l-one

Example 229

3-(4-chlorobenzo[b]thiophen-2-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxaz ole

Stir a mixture of

l-(4-chlorobenzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-en-l-one (1.05 g, crude, 2.43 mmol), NaOH (389 mg, 9.72 mmol) andNH₂OH-HCl(335 mg, 4.8 mmol) in MeOH (8 mL) and water (8 mL) at ambient temperature for 4 hours. After removal of solvent under vacuum, dilute the residue with ice water (20 mL). Extract the aqueous mixture with EtOAc (15 mLx3). The combined organic layers are washed with brine, dried over anhydrous a₂S04 and concentrated under vacuum. Purify the residue by preparative HPLC to afford

3-(4-chlorobenzo[b]thiophen-2-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxaz ole as white solid (305 mg, 28.1 %). MS (m z): 450 (M+l). 'HNMR (400 MHz, CDC1₃) δδ 7.74 (d, J=8.0, 1H), 7.64-7.60 (s, 1H), 7.57-7.53 (m, 2H), 7.47-7.43 (m, 1H), 7.40-7.32.

The following compounds are prepared essentially by the method of Example 229.

Ex.

Chemical name Structure Physical data

No.

3-(benzo[d]thiazol- MS (m/z): 417 (M+1). IH NMR 2-yl)-5-(3,5-dichlor (400 MHz, CDC1₃) δ 8.07 (d,

234 ophenyl)-5 -(trifluo 7.2, IH), 7.93 (d, J=7.2, IH), romethyl)-4,5-dihy CF₃ 7.58-7.47 (m, 5H), 4.37 (d,

CI ^ά

droisoxazole J=18.0, IH), 4.00 (d, J=18.0, IH)

5 -(3 , 5 -dichlorophe MS (m/z): 430 (M+1). IH NMR nyl)-3-(3-methylbe (400 MHz, CDCI₃) δ 7.83-7.78 nzo [b] thiophen-2 -y (m, 2H), 7.53 (s, 2H), 7.53-7.43

235

1) - 5 - (tri fluor ometh (m, 3H), 4.17 (d, 16.8, IH),

CF₃

yl)-4,5-dihydroisox CI ³ 3.79 (d, 16.8, IH), 2.67 (s, azole 3H).

MS (m/z): 430 (M+1). IH NMR

5 -(3 , 5 -dichlorophe

(400 MHz, CDCI₃) δ 7.71 (d, nyl)-3-(5-methylbe

8.0, IH), 7.57 (s, IH), 7.53 (s, nzo [b] thiophen-2 -y

236 2H), 7.43 (t, 3.2, IH), 7.36 (d, 1) - 5 - (tri fluor ometh

7.0, IH), 7.24 (d, 7.0, IH), yl)-4,5-dihydroisox

4.17 (d, 16.8, IH), 3.78 (d, azole

16.8, IH), 2.47 (s, 3H).

3-(5-chlorobenzo[b MS (m/z): 450 (M+1). IH NMR ]thiophen-2-yl)-5-( (400 MHz, CDCI₃) δ 7.76-7.75 3 ,5-dichlorophenyl (m, 2H), 7.51 (s, 2H), 7.45-7.44

237

) - 5 - (tri fluor omethy (m, IH), 7.40-7.38 (m, 2H), 4.18

CF₃

CI ⁶

l)-4,5-dihydroisoxa (d, J= 16.8, lH), 3.78 (d, J= 17.6, zole IH).

Scheme E

Example 238 methyl

2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thieno[2,3-b]pyridine-5- carboxylate

Stir a mixture of

5-bromo-2-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3- '/]-thieno[2,3-b]p yridine (494 mg, 1 mmol), Pd(dppf)Ci2 (100 mg) and triethyl amine (1 mL) in anhydrous THF (10 mL) and methanol (5 mL) under carbon monoxide (50 psi) at 70 °C for lOh. After removal of solvent under vacuum, purify the residue with silica gel chromatography (eluting with 10% ethyl acetate in petroleum ether) to afford methyl

2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thieno[2,3-b]pyridine-5- carboxylate as a white solid (210 mg, 44.18%). MS (m/z): 475 (M+l). Example 239

2-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-j/]-thieno[2,3-b]pyri

-carboxylic acid

Add a solution of LiOH-H₂0 (76 mg, 2 mmol) in water (0.5 mL) to a solution of methyl 2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thieno[2,3-b]pyridine-5- carboxylate (237 mg, 0.5 mmol) in THF(3 mL). Stir the mixture at temperature for 12 hours. After addition of 10 mL of water, acidify the mixture with concentrated HC1 to PH = 6~7. Extract the resultant mixture with ethyl acetate (3 X 10 mL). The combined organic layers are washed brine, dried over anhydrous Na₂SC>4 and concentrated under vacuum to afford

2-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3- '/]-thieno[2,3-b]pyridine-5 -carboxylic acid as pale yellow solid (170 mg, 73.9%), which is used in next step without further purification. MS (m/z): 461 (M+l).

Example 240

2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(2,2,2-triflu oroethylamino)ethyl)thieno[2,3-b]pyridine-5-carboxamide

Stir a mixture of 2-Amino-N-(2,2,2-trifluoro-ethyl)-acetamide (156 mg, 1 mmol),

2-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-thieno[2,3-b]pyridine-5- carboxylic acid (160 mg, 0.24 mmol), HATU (150 mg, 0.39 mmol) and DIPEA (0.2 mL) at room temperature for for 10 hours. After removal of solvent, purify the mixture by preparetive-HPLC to afford

2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5^

oroethylamino)ethyl)thieno[2,3-b]pyridine-5-carboxamide as a white solid (50 mg, 34.78%). MS (m/z): 599 (M+l). 1H NMR (400 MHz, CDC1₃) δ 9.02 (s, 1H), 8.51 (s, 1H), 7.52 (s, 2H), 7.44-7.41 (m, 2H), 7.22 (s, 1H), 6.64 (s, 1H), 4.27 (d, J= 5.2, 2H), 4.17 (d, J = 16.8, 1H), 4.04-3.95 (m, 2H), 3.80 (d, J = 16.08, 1H).

The following compound is prepared essentially by the method of Example 240.

Ex.

Chemical name Structure Physical data

No.

MS (m/z): 543 (M+l). ^LH NMR

2-(5-(3,5-dichlorophe

(400 MHz, CDCI₃) δ 9.01 (s, 1H), nyl)-5 -(trifluorometh

8.49 (s, 1H), 7.54 (s, 2H), yl)-4,5 -dihydroisoxaz V^NH

7.44-7.40 (m, 2H), 7.15 (S, 1H),

241 ol_3_yl)_N-((R)-2-ox

5.89 (s, 1H), 4.60 (s, lH), 4.18 (d, opyrrolidin-3 -yl)thie

J = 16.8, 1H), 3.80 (d, J = 16.8, no[2,3-b]pyridine-5-c

1H), 3.51-3.48 (m, 2H), 3.00-2.93 arboxamide

(m, 1H), 2.14-2.08 (m, 1H)

In Vitro Helminth Assay

Compounds may be evaluated against one or more life stages of helminth to measure anthelmintic activity. Compounds may be evaluated at a single concentration followed by serial dilution in order to determine minimal effective concentration. Typically, worms are exposed to compounds in a liquid solution for a predetermined period of time. Activity is measured through one or more variables, which may include an effect on worm motility {e.g., moving versus non-moving) or viability (e.g., live versus dead).

In Vivo Activity Against Nematodes Compounds may be evaluated against one or more life stages of helminth infestation in an animal to measure in vivo anthelmintic activity. Compounds may be evaluated a single dose, administered on a milligram per kilogram body weight basis, followed by dose titration in order to determine minimal effective point dose. In a rodent anthelmintic model, for example, adult Mongolian gerbils (Meriones unguiculates) infected with one or more species of Strongylid nematode (e.g., Haemonchus contortus and/or Trichostrongylus colubriformis) are dosed with compounds, administered via oral gavage. Gerbils are necropsied and gastrointestinal tract worm burden is measured and compared to untreated, infected control gerbils to determine the degree of anthelmintic activity. Similar testing may be conducted in higher species (e.g., dogs, cats, sheep, cattle) whereby nematode burden in treated animals is compared to burden in untreated, infected animals to measure the potency and duration of anthelmintic activity.

In Vitro Larval Immersion Microassay (LIM)

The larval immersion microassay may be conducted as described in White, et ah, J. Med. Entomol. 41 : 1034-1042 (2004). Briefly, experimental test articles are formulated in dimethylsulfoxide (DMSO) to prepare a stock solution at a concentration of lOmM. Using

96-well micro titer plates, an aliquot of the lOmM sample is subsequently diluted in a water-based solution containing 1% ethanol and 0.2% Triton X-100, to obtain the desired concentration (typically 0.3mM or lower) of experimental test article in a volume of 0.1ml (minimum n=3 replicates per compound or concentration). Approximately 30-50 Lone star tick larvae

(Ambfyomma americanum) are submerged into each well containing experimental test articles. After a 30 minute immersion period, larvae are removed with a wide -bore pipette tip in 0.05ml of fluid, dispensed into a commercial paper tissue biopsy bag which is sealed at the top with a plastic dialysis clip, inverted and allowed to air dry for 60 minutes. Bags containing larvae are then incubated at approximately 27 degrees Celsius and >90% relative humidity. After 24 hours, bags are opened, live and dead larvae are counted and percent larval mortality is calculated.

The following Examples exhibited > 80% activity when tested in this assay at 300 micromolar: 32, 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77, 78, 79, 80, 81 , 82, 83, 84, 85, 86, 87b, 94, 95, 96, 230, 231, 232, 233, 236, 237, 240, and 241.

In Vivo Rodent Acaricide Test (RAT)

Evaluation of experimental test articles may conducted using a modified version of the assay as described in Gutierrez et ah, J. Med. Entomol. 43(3): 526-532(2006). The assay may be modified by using a different tick species (the reference describes Ambfyomma americanum ticks) such as Dermacentor variabilis ticks. Further, the reference describes using topical administration, but oral administration may be used. Briefly, experimental test articles are formulated in a solution of polyethylene glycol-300, propylene glycol and water to the desired concentration, typically 1 - 25 mg/ml, depending on solubility and desired point dose. Tick containment units (comprised of a baby nipple, ventilated screw cap top and reinforcing rubber washer) are attached to the dorsum of adult Sprague-Dawley rats. After attachment of containment units, approximately 10 unfed nymphal stage American dog ticks (Dermacentor variabilis) are placed inside of each containment unit. Approximately 24 hours after infestation, test article formulations are administered to rats via oral gavage. Negative control rats receive polyethylene glycol-300, propylene glycol and water alone. Depending on compound availability, a minimum of three (3) and a maximum of five (5) rats are utilized per treatment group. Forty-eight (48) hours post-treatment, containment units are removed and live and dead ticks were counted. Live tick counts are transformed using the natural logarithm

transformation plus one (Ln count + 1); addition of one to each count serve to adjust for counts that were zero. Geometric mean (GM) group tick counts are obtained via back-transformation of group mean transformed counts and subtracting one. The non-treated control group is used for comparison to the groups receiving experimental test articles for the calculation of percent efficacy (% reduction in live tick counts). The efficacy of treatments is calculated by comparing the geometric mean (GM) number of live ticks observed on treated rats with the GM number of live ticks counted on the negative control rats, using the following formula:

% Efficacy = (GM # live ticks control - GM # live ticks treated) x 100

GM # live ticks control

The following Examples exhibited > 50% efficacy when tested in this assay at a dose of not more than 25 mpk: 32, 36, 38, 39, 41, 42, 43, 45, 46, 47, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 73, 87b, 95, 96, 234, 235, 240, and 241.

Activity in the above assays demonstrates the compounds of the invention are useful for controlling ecto- or endoparasite infestations.

Claims

A compound, or a salt thereof, of formula I

wherein A is

n is 0 or 1 ;

R¹ is thienyl or phenyl, said thienyl or phenyl substituted with 2 or 3 of the same or different halo atoms;

R² is at each occurrence independently hydrogen, C1-C5 alkyl, C3-C6 cycloalkyl, or C1-C5 haloalkyl;

3 · - -(CH₂)_p-R⁴

R^J is p is at each occurrence independently 0 or 1 ;

R⁴ is C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 cyanoalkyl, C1-C5 alkylthio, C₃-C₆ cycloalkyl optionally substituted with hydroxy, halo, or C1-C5 alkyl: C3-C5 cyclohetero alkyl optionally substituted with C1-C5 alkyl, C₃-C₆ cycloalkyl, or C1-C5 haloalkyl: phenyl, thienyl, R⁵

,(CH₂)"

R⁵ is hydroxy, -0-(Ci-C₅ alkyl), or

R⁶ is hydrogen, Ci-C₅ alkyl, Ci-C₅ haloalkyl, Ci-C₅ cyanoalkyl, Ci-C₅ alkylthio, or C₂-C5 alkynyl;

2 3 ·

or R and R combine to form, with the nitrogen to which they are attached,

„ /

o

Yi, Y₂, and Y₃ are carbon or nitrogen with at most only one of Yi, Y₂, and Y₃ being nitrogen, and when Yi, Y₂, or Y₃ is a carbon, each may be substituted by C₁-C5 alkyl;

R⁷ is hydrogen, halo, C₁-C5 alkyl, or

_¾(CH₂)^ ^R8

O ;

R⁸ is hydroxy, -0-(Ci-C₅ alkyl), or

R⁹ is C1-C5 alkyl,

and R is hydrogen, C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 cyanoalkyl, C1-C5 alkylthio, or C2-C5 alkynyl.

2. A compound of claim 1 wherein A is

3. A compound according to any of claims 1-2 wherein 2

R is hydrogen and n is 1.

4. A compound of according to any of claims 1-3 wherein R³ is

5. The compound of claim 1 wherein it is

3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((R)-2-o xopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

N,N-Dimethyl-2-(4-{3-[5-(3,4,5-trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dih ydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carbonyl}-piperazin-l-yl)-acetamide;

({3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7 -tetrahydro-benzo[c]thiophene-l-carbonyl}-amino)-acetic acid methyl ester;

({3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-y l]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carbonyl}-amino)-acetic acid methyl ester;

3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo -2-(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxamide;

3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-t etrahydro-benzo[c]thiophene-l -carboxylic acid (l,l-dioxo-thietan-3-yl)-amide;

3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(3-oxo cyclohexyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-t etrahydro-benzo [c]thiophene- 1 -carboxylic acid (1,1 -dioxo-hexahydro- 116-thiopyran-4-yl)-amide;

3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-t etrahydro-benzo [c]thiophene- 1 -carboxylic acid [2-oxo-l-(2,2,2-trifluoro-ethyl)-pyrrolidin- 3-yl]-amide;

3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((R)-2 -oxopyrrolidin-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxamide;

N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichlorophenyl)-5-(trifluoromet hyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxamide;

3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo -2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxamide;

N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifl uoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

N-((R)-2-oxopyrrolidin-3-yl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5 -dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide; N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluorom ethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

N-(2-oxo-2-(prop-2-ynylamino)ethyl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluoromet hyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamid e;

3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- N-((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifl uoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- N-(2-oxo-2-(prop-2-ynylamino)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifl uoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxamide;

N-((R)-2-oxopyrrolidin-3-yl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5 -dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxamide;

N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluorom ethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxamide;

N-(2-oxo-2-(prop-2-ynylamino)ethyl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluoromet hyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxamide;

N-(2-oxo-l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(5-(3,4,5-trichlorophenyl)-5-(t rifluoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxamid e;

3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxa mide;

3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- N-((R)-2-oxopyrrolidin-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxamide;

N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifl uoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxamide; 3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- N-(2-oxo-l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carb oxamide;

3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- N-(2-oxo-2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxamide;

3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo -2-(2,2,2-trifluoroethylamino)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(eth ylamino)-2-oxoethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((tetra hydrofuran-2-yl)methyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-(me thylthio)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(3,3,3- trifluoropropyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(3-hyd roxycyclohexyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(5-flu oropyridin-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(tetrah ydro-2H-pyran-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(thieta n-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(tetrah ydro-2H-pyran-4-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

N-(l-cyclopropyl-2-oxopyrrolidin-3-yl)-3-(5-(3,5-dichlorophenyl)-5-(trifluoromet hyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

N-(2-oxo-2-(prop-2-ynylamino)ethyl)-3-(5-(3,4,5-trichlorothiophen-2-yl)-5-(triflu oromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

3-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6, 7-tetrahydro-benzo[c]thiophene- 1 -carboxylic acid (1,1 -dioxo-hexahydro-thiopyran-4-yl)-amide; N-(2-oxo-l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(5-(3,4,5-trichlorophenyl)-5-(t rifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

N-(tetrahydro-2H-pyran-4-yl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5 -dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

N-(l-cyclopropyl-2-oxopyrrolidin-3-yl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluoro methyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl] -4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid (l,l-dioxo-thietan-3-yl)-amide;

3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl] -4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid

( 1 , 1 -dioxo-hexahydro-thiopyran-4-yl)-amide;

3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- N-(4-oxocyclohexyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- N-(2-oxo-l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxa mide;

3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- N-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

N-(l-cyclopropyl-2-oxopyrrolidin-3-yl)-3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trif luoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(4-oxo cyclohexyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxamide;

3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo -l-(2,2,2 rifluoroethyl)pyrrolidin-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxamide;

3-((R)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(( R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

3-((S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(( R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

N-(4-carbamoylphenyl)-3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide; 3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl] -4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid (3-carbamoyl-thiophen-2-yl)-amide;

2- (3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- 4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamido)acetic acid;

({3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-y l]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carbonyl}-amino)-acetic acid;

N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichlorophenyl)-5- (trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;

3- (5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo -2-(prop-2-ynylamino)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide; or

N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,4,5-trichlorothiophen-2-yl)-5-(trifl uoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide; or a salt thereof.

6. A compound of claim 1 wherein A is

7. A compound of claim 6 wherein Yi is nitrogen.

8. A compound of claim 6 wherein R⁷ is

9. The compound of claim 1 wherein it is

3-(4-chlorobenzo[b]thiophen-2-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5 -dihydroisoxazole;

2-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-thieno[2

,3-c]pyridine;

5-Bromo-2-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl] -thieno[2,3-b]pyridine;

2- [5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-thieno[2

,3-b]pyridine;

3- (benzo[b]thiophen-2-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydro isoxazole;

3-(benzo[d]thiazol-2-yl)-5-(3,5-dichlorophenyl)-5-(trifiuoromethyl)-4,5-dihydrois oxazole;

5-(3,5-dichlorophenyl)-3-(3-methylbenzo[b]thiophen-2-yl)-5-(trifluoromethyl)-4, 5-dihydroisoxazole;

5-(3,5-dichlorophenyl)-3-(5-methylbenzo[b]thiophen-2-yl)-5-(trifluoromethyl)-4, 5-dihydroisoxazole; 3-(5-chlorobenzo[b]thiophen-2-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5 -dihydroisoxazole;

methyl

2- (5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thieno[2,3-b]pyridine-5- carboxylate;

2-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3- '/]-thieno[2,

3- b]pyridine-5-carboxylic acid;

2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo -2-(2,2,2-trifluoroethylamino)ethyl)thieno[2,3-b]pyridine-5-carboxamide; or

2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((R)-2 -oxopyrrolidin-3-yl)thieno[2,3-b]pyridine-5-carboxamide; or a salt thereof.

10. A formulation comprising a compound or salt of any of claims 1-9 and one or more acceptable carriers.

11. The formulation of claim 10 wherein it further comprises at least one additional active ingredient.

12. The formulation of claim 10 or claim 11 wherein it is a human pharmaceutical formulation.

13. The formulation of claim 10 or claim 1 1 wherein it is a veterinary pharmaceutical formulation.

14. A method of controlling a parasite infestation in or on an animal in need thereof comprising administering an effective amount of a compound or salt of any of claims 1-9 to said animal.

15. The method of claim 14 wherein at least one other active ingredient is administered to said animal.

16. The method of claim 14 or claim 15 wherein said animal is a human.

The method of claim 14 or claim 15 wherein said animal is a companion animal.

18. The method of claim 16 or claim 17 wherein said companion animal is a dog or cat.

19. The method of claim 18 wherein said parasite is a tick.

20. The method of claim 14 wherein said animal is a livestock animal.

21. A method for preventing and treating diseases transmitted through parasites comprising administering an effective amount of a compound of any of claims 1-9 to an animal in need thereof.

22. The method of claim 21 or claim 22 wherein at least one other active ingredient is administered to said animal.

23. The method of claim 21 or claim 22 wherein said animal is a human.

24. The method of claim 21 wherein said animal is a companion animal.

25. The method of claim 24 wherein said companion animal is a dog or cat.

26. The method according to any of claims 21-25 wherein said parasite is a tick.

27. The method of claim 21 or claim 22 wherein said animal is a livestock animal.

28. A method for controlling parasites, characterized in that a compound of any of claims 1 -9 is allowed to act on the pests or their habitat, or both.

29. The method of claim 28 wherein the compound is placed on a plant or an animal.

30. Use of compounds or salts thereof of any of claims 1-9 for controlling parasites.

31. A compound or salt according to any of claims 1 -9 for use in therapy.

32. A compound or salt according to any of claims 1-9 for use in controlling an ectoparasite infestation.