NZ616409B2 - Parasiticidal dihydroisoxazole compounds - Google Patents

Abstract

Disclosed are dihydroisoxazole compounds of formula I where the substituents are as defined herein for example 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-1-carboxamide. The compounds are intended for use 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. Also provided are compounds and processes useful for making the dihydroisoxazole compounds. 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. Also provided are compounds and processes useful for making the dihydroisoxazole compounds.

Description

PARASITICIDAL DIHYDROISOXAZOLE COMPOUNDS 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 one or more of the limitations of current approaches. Such limitations include toxicity and safety of both the animal and the user/owner, limited efficacy (e.g., 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.

It is an object of the present invention to go some way towards satisfying one or more of these desiderata, and/or to at least provide the public with a useful choice.

In this specification where reference has been made to patent specifications, other external documents, or other sources of information, this is generally for the purpose of providing a context for discussing the features of the invention. Unless specifically stated otherwise, reference to such external documents is not to be construed as an admission that such documents, or such sources of information, in any jurisdiction, are prior art, or form part of the common general knowledge in the art.

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: 3 wherein A is or 1 ; n is 0 or 1; R is thienyl or phenyl, said thienyl or phenyl substituted with 2 or 3 of the same or different halo atoms; R is at each occurrence independently hydrogen, C –C alkyl, C –C 1 5 3 6 cycloalkyl, or C –C haloalkyl; (CH ) R 3 2 p R is ; p is at each occurrence independently 0 or 1; R is C –C alkyl, C –C haloalkyl, C –C cyanoalkyl, C –C alkylthio, 1 5 1 5 1 5 1 5 C –C cycloalkyl optionally substituted with hydroxy, halo, or C –C alkyl; C –C 3 6 1 5 3 5 cycloheteroalkyl optionally substituted with C –C alkyl, C –C cycloalkyl, or C –C 1 5 3 6 1 5 (CH ) haloalkyl; phenyl, thienyl, 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; R is hydroxy, -O-(C –C alkyl), or ; R is hydrogen, C –C alkyl, C –C haloalkyl, C –C cyanoalkyl, C –C 1 5 1 5 1 5 1 5 alkylthio, or C –C alkynyl; or R and R combine to form, with the nitrogen to which they are attached, Y , Y , and Y are carbon or nitrogen with at most only one of Y , Y , and 1 2 3 1 2 Y being nitrogen, and when Y , Y , or Y is a carbon, each may be substituted by C –C 3 1 2 3 1 5 alkyl; R is hydrogen, halo, C –C alkyl, or (CH ) R is hydroxy, -O-(C –C alkyl), or (CH ) R is C –C alkyl, or O ; and R is hydrogen, C –C alkyl, C –C haloalkyl, C –C cyanoalkyl, C –C 1 5 1 5 1 5 1 5 alkylthio, or C –C 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 use of a compound or salt of formula I in the manufacture of a medicament.

Described herein is 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.

More specifically, the invention provides a method of controlling a parasite infestation in or on a non-human mammal in need thereof comprising administering an effective amount of a compound or salt of formula I to said mammal.

The present invention provides a method for preventing and treating diseases transmitted through parasites comprising administering at least one compound of the invention to a non-human 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 a compound or salt of formula I for controlling a parasite infestation in or on an animal. 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 invention also provides use of a compound or salt of formula I in the manufacture of a medicament for controlling a parasite infestation in or on an animal in need thereof.

The invention provides compounds of Formula II, or a salt thereof, of the formula 1 11 wherein n is 0 or 1; R is thienyl or phenyl, said thienyl or phenyl substituted with 2 or 3 of the same or different halo atoms; and R is hydroxy, -O-(C -C alkyl), or a halo atom.

These compounds have utility as intermediates in the processes for preparing certain compounds of Formula I. These Formula II compounds may be chemically modified to result in certain Formula I compounds.

More particularly, the invention provides a process for preparing a compound of formula I, comprising reacting a compound of formula II with a compound of the formula . The invention also provides a compound of formula I prepared by this process.

In the description in this specification reference may be made to subject matter which is not within the scope of the appended claims. That subject matter should be readily identifiable by a person skilled in the art and may assist in putting into practice the invention as defined in the appended claims.

The term “comprising” as used in this specification and claims means “consisting at least in part of”. When interpreting statements in this specification and claims which include the term “comprising”, other features besides the features prefaced by this term in each statement can also be present. Related terms such as “comprise”, “comprises”, and “comprised” are to be interpreted in similar manner.

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, Trϊchonema, Dictyocaulus, Capsliarsa, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancyiostoma, Uncinaria, Toxascaris and Parascaris. 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 al., HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA/Wiley-VCH, 2002); S.M. Berge, et al., “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 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.

C –C 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.

C –C alkynyl refers to straight chain and branched alkynyls having two to five carbon atoms, and includes ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 3-methylbutynyl, 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, difluoromethyl, fluoromethyl, 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.

C –C cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

C –C 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- J and examples for preparing the compounds of the invention. The Schemes, examples, and information contained therein are illustrative, and can be modified in ways known in the art to obtain the desired results.

Scheme A n-BuLi, CF CO Et Ar-X or Mg, CF CO Et F C Ar 3 2 3 O O OH F C Ar F C Na, MeOH LDA, THF, -78 C O or K CO , DMF O CF O NH OH-HCl, LiOH LiOH SOCl , Pyridine 2 Ar THF:MeOH:H O S THF:H O = 3:1 2 pyr O S = 3:2:1 HATU, NEt , NHR R 2 N N R CH Cl OH N Ar S S Ar R F C F C Preparation 1 Methyl 2,2,2-trifluoro(3,4,5-trichlorothiophenyl)ethanone Cl 3 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 NH Cl solution (100 mL). Extract the aqueous mixture with EtOAc (100 mL X 3). The combined organic layers are washed with brine, dried over anhydrous Na SO , 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(3,4,5-trichloro- thiophenyl)-ethanone as a brown oil (10.4 g, 81.9%). F NMR (400 MHz, CDCl ) δ -73.38 (s, 3F).

Preparation 2 Methyl 3-acetyl-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxylate 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-1,2-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 Na SO , 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]thiophenecarboxylate as a white solid (10 g, 27.6%). MS (m/z): 239 (M+1).

Preparation 3 Methyl 3-acetyl-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxylate Stir a mixture of Cyclopentane-1,2-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 carboxylic acid methyl ester as a pale yellow solid (206mg, 4.5 %). MS (m/z): 225 (M+1).

Preparation 4 Methyl 3-(3-(3,5-dichlorophenyl)-4,4,4-trifluorohydroxybutanoyl)-4,5,6,7-tetrahydrobenzo[c]t hiophenecarboxylate 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]thiophenecarboxylate (7.4 g, 3.11 mmol) in dry THF (80 mL) at -78 C under N . After stirring for 1.5 h, add 1-(3,5-Dichloro-phenyl)- 2,2,2-trifluoro-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 NH Cl aqueous solution. Extract the aqueous mixture with EtOAc (100 mL ×3).

The combined organic layers are washed with brine, dried over anhydrous Na SO 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-trifluorohydroxybutanoyl) -4,5,6,7-tetrahydrobenzo[c]thiophenecarboxylate as an orange solid (9.1 g, 60.4 %).

MS (m/z): 481 (M+1).

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

Prep.

Chemical name Structure Physical data 3-[3-(3,5-Dichloro- phenyl)-4,4,4-triflu orohydroxy-buty ryl]-5,6-dihydro-4H MS (m/z): 465 (M-1). -cyclopenta[c]thiop henecarboxylic acid methyl ester 3-[4,4,4-Trifluoro-3 -hydroxy(3,4,5-tr ichloro-thiophen F C O yl)-butyryl]-4,5,6,7- 6 MS (m/z): 519 (M-1). tetrahydro-benzo[c] thiophenecarbox ylic acid methyl ester 3-[4,4,4-Trifluoro-3 -hydroxy(3,4,5-tr ichloro-phenyl)-but 7 yryl]-4,5,6,7-tetrahy MS (m/z): 515 (M+1) dro-benzo[c]thioph enecarboxylic acid methyl ester Prep.

Chemical name Structure Physical data 3-[3-(3,5-Dichloro- 4-fluoro-phenyl)-4, 4,4-trifluorohydr oxy-butyryl]-4,5,6, 8 MS (m/z): 499 (M+1) 7-tetrahydro-benzo[ c]thiophenecarbo xylic acid methyl ester 3-[4,4,4-Trifluoro-3 -hydroxy(3,4,5-tr ichloro-phenyl)-but 9 yryl]-5,6-dihydro-4 MS (m/z): 501 (M+1) H-cyclopenta[c]thio phenecarboxylic acid methyl ester 3-[3-(3,5-Dichloro- 4-fluoro-phenyl)-4, 4,4-trifluorohydr oxy-butyryl]-5,6-di MS (m/z): 485 (M+1) hydro-4H-cyclopent a[c]thiophenecar boxylic acid methyl ester Preparation 11 3-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-butenoyl]-4,5,6,7-tetrahydro-benzo[c]thioph enecarboxylic acid methyl ester Stir a mixture of methyl 3-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro hydroxyl butanoyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxylate (9.1 g, 18.9 mmol), SOCl (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 NH Cl aqueous solution. Extract the aqueous mixture with DCM (100 mL ×3). The combined organic layers are washed with brine, dried over anhydrous Na SO 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-butenoyl]-4,5,6,7- tetrahydro-benzo[c]thiophenecarboxylic acid methyl ester as an orange solid (8.75 g, 100 %). (m/z): 463 (M+1).

The following compounds are prepared essentially by the method of Preparation 11.

Prep.

Chemical name Structure Physical data 3-[3-(3,5-Dichloro- phenyl)-4,4,4-triflu oro-butenoyl]-5, 6-dihydro-4H-cyclo 12 MS (m/z): 447 (M-1). penta[c]thiophene-1 O -carboxylic acid methyl ester 3-[4,4,4-Trifluoro-3 -(3,4,5-trichloro-thi ophenyl)-bute noyl]-4,5,6,7-tetrah ydro-benzo[c]thiop 13 MS (m/z): 501 (M-1). henecarboxylic acid methyl ester]thiophenec arboxylic acid methyl ester 3-[4,4,4-Trifluoro-3 -(3,4,5-trichloro-ph enyl)-butenoyl]- O 14 4,5,6,7-tetrahydro-b MS (m/z): 497 (M+1). enzo[c]thiophene Cl carboxylic acid methyl ester Prep.

Chemical name Structure Physical data 3-[3-(3,5-Dichloro- 4-fluoro-phenyl)-4, 4,4-trifluoro-bute noyl]-4,5,6,7-tetrah MS (m/z): 481 (M+1). ydro-benzo[c]thiop henecarboxylic acid methyl ester 3-[4,4,4-Trifluoro-3 -(3,4,5-trichloro-ph enyl)-butenoyl]- 16 5,6-dihydro-4H-cyc MS (m/z): 483 (M+1). lopenta[c]thiophene Cl carboxylic acid methyl ester 3-[3-(3,5-Dichloro- 4-fluoro-phenyl)-4, 4,4-trifluoro-bute 17 noyl]-5,6-dihydro-4 MS (m/z): 467 (M+1).

H-cyclopenta[c]thio Cl phenecarboxylic acid methyl ester Preparation 18 3-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl] -4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid methyl ester Stir a mixture of 3-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-butenoyl]- 4,5,6,7- tetrahydro-benzo[c]thiophenecarboxylic acid methyl ester (8.75 g, 18.9 mmol), NaOH (2.65 g, 66.1 mmol) and NH OH-HCl(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 conc. HCl to pH = 1 and extract the resultant mixture with EtOAc (50 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na SO and concentrated under vacuum.

Purify the residue by silica gel chromatograph (PE:EtOAc 50:1) to afford 3-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-4,5,6,7-tetrahyd ro-benzo[c]thiophenecarboxylic acid methyl ester as an orange solid (8.1 g, 93.1%).

MS (m/z): 478 (M+1).

The following compounds are prepared essentially by the method of Preparation 18.

Prep.

Chemical name Structure Physical data 3-[5-(3,5-Dichloro-phe nyl)trifluoromethyl- 4,5-dihydro-isoxazol-3 19 -yl]-5,6-dihydro-4H-cy MS (m/z): 464 (M+1). clopenta[c]thiophene-1 -carboxylic acid methyl ester 3-[5-(3,4,5-Trichloro-t hiophenyl)trifluo romethyl-4,5-dihydro-i soxazolyl]-4,5,6,7-t MS (m/z): 516 (M-1). etrahydro-benzo[c]thio Cl phenecarboxylic acid methyl ester 3-[5-(3,4,5-Trichloro-t hiophenyl)trifluo romethyl-4,5-dihydro-i 21 soxazolyl]-4,5,6,7-t MS (m/z): 512 (M+1). etrahydro-benzo[c]thio phenecarboxylic acid methyl ester Prep.

Chemical name Structure Physical data 3-[5-(3,5-Dichlorofl uoro-phenyl)trifluor omethyl-4,5-dihydro-is 22 oxazolyl]-4,5,6,7-te MS (m/z): 496 (M+1). trahydro-benzo[c]thiop Cl henecarboxylic acid methyl ester 3-[5-(3,4,5-Trichloro-p henyl)trifluorometh yl-4,5-dihydro-isoxazo 23 lyl]-5,6-dihydro-4H MS (m/z): 498 (M+1). -cyclopenta[c]thiophen Cl ecarboxylic acid methyl ester 3-[5-(3,5-Dichlorofl uoro-phenyl)trifluor omethyl-4,5-dihydro-is 24 oxazolyl]-5,6-dihyd MS (m/z): 482 (M+1). ro-4H-cyclopenta[c]thi ophenecarboxylic acid methyl ester Preparation 25 3-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl] -4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid Stir a mixture of 3-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro- isoxazolyl]-4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid methyl ester (8.1 g, 17.0 mmol) and LiOH-H O (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 conc. HCl to pH = 1, and extract the resultant mixture with EtOAc (100 mL×3).The combined organic layers are washed brine, dried over anhydrous Na SO and concentrated under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc 1:1) to afford 3-[5-(3,5-Dichloro- phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-4,5,6,7-tetrahydro-benzo[c]thiophe necarboxylic acid as pale yellow solid (6.8 g, 86.4 %). MS (m/z): 464 (M+1).

The following compounds may be prepared essentially by the method of Preparation 25.

Prep.

Chemical name Structure Physical data 3-[5-(3,5-Dichloro-phe nyl)trifluoromethyl- 4,5-dihydro-isoxazol-3 OH 26 MS (m/z): 448 (M-1). -yl]-5,6-dihydro-4H-cy clopenta[c]thiophene-1 -carboxylic acid Prep.

Chemical name Structure Physical data 3-[5-(3,4,5-Trichloro-t hiophenyl)trifluo romethyl-4,5-dihydro-i 27 soxazolyl]-4,5,6,7-t MS (m/z): 502 (M-1). etrahydro-benzo[c]thio phenecarboxylic acid 3-[5-(3,4,5-Trichloro-p henyl)trifluorometh yl-4,5-dihydro-isoxazo 3 28 MS (m/z): 496 (M-1). lyl]-4,5,6,7-tetrahyd N ro-benzo[c]thiophene- 1-carboxylic acid 3-[5-(3,5-Dichlorofl uoro-phenyl)trifluor F C OH omethyl-4,5-dihydro-is 29 MS (m/z): 480 (M-1). oxazolyl]-4,5,6,7-te N trahydro-benzo[c]thiop henecarboxylic acid 3-[5-(3,5-Dichlorofl uoro-phenyl)trifluor omethyl-4,5-dihydro-is oxazolyl]-5,6-dihyd F MS (m/z): 466 (M-1). ro-4H-cyclopenta[c]thi ophenecarboxylic acid Prep.

Chemical name Structure Physical data 3-[5-(3,4,5-Trichloro-p henyl)trifluorometh yl-4,5-dihydro-isoxazo 31 MS (m/z): 482 (M-1). lyl]-5,6-dihydro-4H -cyclopenta[c]thiophen ecarboxylic acid Example 32 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N-((R)oxopyr rolidinyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide Stir a mixture of 3-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl] -4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic 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)aminopyrrolidinone 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 ×3). The combined organic layers are washed brine, dried over anhydrous Na SO and concentrated under vacuum. Purify the residue by preparative HPLC to afford 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5- dihydroisoxazolyl)-N-((R)oxopyrrolidinyl)-4,5,6,7-tetrahydrobenzo[c]thiophene- 1-carboxamide as a white solid (730 mg, 73.0 %). MS (m/z): 546 (M+1); H NMR (400 MHz, CDCl ) 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 32.

Chemical name Structure Physical data N,N-Dimethyl(4-{3 MS (m/z): 659 (M+1); H -[5-(3,4,5-trichloro-thi NMR (400 MHz, CDCl ) δ ophenyl)trifluoro 4.07-4.02 (m, 2H), 3.68-3.80 methyl-4,5-dihydro-is (m, 4H), 3.49-3.41 (m, 2H), oxazolyl]-4,5,6,7-te 3.09-3.01 (s, 3H), 3.01-2.95 Cl F C trahydro-benzo[c]thio (s, 3H), 2.91-2.85 (m, 2H), phenecarbonyl}-pip 2.84-2.78 (m, 4H), 2.69-2.63 erazinyl)-acetamide (m, 2H), 1.87-1.72 (m, 4H). ({3-[5-(3,5-Dichloro-p henyl)trifluorometh Prep yl-4,5-dihydro-isoxazo Cl O No. lyl]-4,5,6,7-tetrahyd MS (m/z): 535 (M+1). 34 ro-benzo[c]thiophene- 1-carbonyl}-amino)-ac etic acid methyl ester Chemical name Structure Physical data ({3-[5-(3,4,5-Trichloro -thiophenyl)trifl uoromethyl-4,5-dihydr Prep O o-isoxazolyl]-4,5,6, Cl S N No. MS (m/z): 575 (M+1). 7-tetrahydro-benzo[c]t Cl hiophenecarbonyl}- amino)-acetic acid methyl ester MS (m/z): 588 (M+1); H 3-(5-(3,5-dichlorophen NMR (400 MHz, CDCl ) yl)(trifluoromethyl) δ7.52-7.48 (m, 2H), -4,5-dihydroisoxazol-3 7.48-7.44 (m, 1H), 7.01-6.95 -yl)-N-(2-oxo(2,2,2 36 (s, 1H), 6.79-6.71 (s, 1H), 3 CF -trifluoroethylamino)et 3 4.21-4.18 (m, 2H), 4.06-3.91 hyl)-5,6-dihydro-4H-c (m, 3H), 3.65-3.59 (d, yclopenta[c]thiophene J=17.2, 1H), 2.98-2.87 (m, carboxamide 4H), 2.59-2.49 (m, 2H). 3-[5-(3,5-Dichloro-phe MS (m/z): 567 (M+1); H nyl)trifluoromethyl- NMR (400 MHz, CDCl ) δ 4,5-dihydro-isoxazol-3 7.48 (s, 2H), 7.44 (s, 1H), -yl]-4,5,6,7-tetrahydro 6.59-6.58 (s, 1H), 4.91-4.89 O N HN O -benzo[c]thiophene (m, 1H), 4.64-4.59 (m, 2H), carboxylic acid 4.07-4.03 (m, 3H), 3.70-3.65 (1,1-dioxo-thietanyl (m, 1H), 2.97-2.91 (m, 4H), )-amide 1.80-1.86 (m, 4H).

Chemical name Structure Physical data MS (m/z): 559 (M+1); H NMR (400 MHz, CDCl ) 3-(5-(3,5-dichlorophen δ7.48 (s, 2H), 7.43 (s, 1H), yl)(trifluoromethyl) 5.73 (d, J=7.6 Hz, 1H), -4,5-dihydroisoxazol-3 4.46-4.42 (m, 1H), 4.06-4.02 38 -yl)-N-(3-oxocyclohex (d, J=16 Hz, 1H), 3.68-3.64 yl)-4,5,6,7-tetrahydrob (d, J=16 Hz, 1H), 2.93-2.89 enzo[c]thiopheneca (m, 4H), 2.82-2.77 (m, 1H), rboxamide 2.47-2.30 (m, 3H), 2.17-2.15 (m, 1H), 2.02-1.95 (m, 1H), 1.88-1.78 (m, 6H).

MS (m/z): 559 (M+1); H 3-[5-(3,5-Dichloro-phe NMR (400 MHz, CDCl ) δ nyl)trifluoromethyl- 7.49-7.44 (m, 3H), 5.77 (d, J 4,5-dihydro-isoxazol-3 = 7.6 Hz, 1H), 4.27-4.10 (m, -yl]-4,5,6,7-tetrahydro 1H), 4.04 (d, J = 17.2 Hz, 39 -benzo[c]thiophene N 1H), 3.66 (d, J = 17.2 Hz, carboxylic acid O 1H), 3.20 -3.05 (m, 4H), (1,1-dioxo-hexahydro- 2.94-2.86 (m, 4H), 2.42-2.40 1l6-thiopyranyl)-a (m, 2H), 2.26-2.16 (m, 2H), mide 1.79-1.74 (m, 4H).

Chemical name Structure Physical data 3-[5-(3,5-Dichloro-phe MS (m/z): 628 (M+1); H nyl)trifluoromethyl- NMR (400 MHz, CDCl ) δ 4,5-dihydro-isoxazol-3 7.52-7.43 (m, 3H), 6.65-6.56 -yl]-4,5,6,7-tetrahydro (m, 1H), 4.61-4.51 (m, 1H), 40 -benzo[c]thiophene 4.18-4.01 (m, 2H), 3.99-3.51 carboxylic acid (m, 4H), 3.09-2.81 (m, 5H), [2-oxo(2,2,2-trifluo 2.11-1.99 (m, 1H), 1.81-1.72 ro-ethyl)-pyrrolidin (m, 4H). yl]-amide MS (m/z): 532 (M+1); H NMR (400 MHz, CDCl ) δ 3-(5-(3,5-dichlorophen 7.52-7.48 (m, 2H), 7.48-7.44 yl)(trifluoromethyl) (m, 1H), 6.59-6.50 (s, 1H), -4,5-dihydroisoxazol-3 6.14-6.08 (s, 1H), 4.48-4.41 41 -yl)-N-((R)oxopyrr N (m, 1H), 4.06-3.94 (d, olidinyl)-5,6-dihydr J=17.2, 1H), 3.65-3.59 (d, o-4H-cyclopenta[c]thi J=17.2, 1H), 3.51-3.42 (m, ophenecarboxamide 2H), 3.07-2.84 (m, 5H), 2.58-2.48 (m, 2H), 2.11-2.01 (m, 1H).

N-(2-(cyanomethylami MS (m/z): 545 (M+1); H no)oxoethyl)(5-( NMR (400 MHz, CDCl ) δ 3,5-dichlorophenyl) 7.58-7.52 (s, 1H),7.52-7.48 (trifluoromethyl)-4,5-d (m, 2H), 7.48-7.44 (m, 1H), CF N ihydroisoxazolyl)-5 6.86-6.78 (s, 1H), 4.26-4.19 ,6-dihydro-4H-cyclope (m, 4H), 4.04-3.97 (d, nta[c]thiophenecarb J=17.2, 1H), 3.65-3.59 (d, Chemical name Structure Physical data oxamide J=17.2, 1H), 3.09-2.84 (m, 4H), 2.58-2.48 (m, 2H).

MS (m/z): 544 (M+1); H 3-(5-(3,5-dichlorophen NMR (400 MHz, CDCl ) δ yl)(trifluoromethyl) 7.52-7.48 (m, 2H), 7.48-7.44 -4,5-dihydroisoxazol-3 (m, 1H), 6.86-6.68 (m, 2H), -yl)-N-(2-oxo(prop- 43 4.19-4.05 (m, 4H), 4.04-3.97 CF N 2-ynylamino)ethyl)-5, (d, J=17.2, 1H), 3.65-3.59 (d, 6-dihydro-4H-cyclope J=17.2, 1H), 3.03-2.87 (m, nta[c]thiophenecarb 4H), 2.58-2.48 (m, 2H), oxamide 2.29-2.26 (s, 1H).

N-(2-oxo(2,2,2-trifl MS (m/z): 636(M+1); H uoroethylamino)ethyl) NMR (400 MHz, CDCl ) δ (5-(3,4,5-trichlorop 7.62 (s, 2H), 7.32 (br, 1H), henyl)(trifluoromet 6.95 (br, 1H), 4.26-4.25 (m, 44 H hyl)-4,5-dihydroisoxaz F C CF 2H), 4.06-3.83 (m, 3H), 3.66 Cl H olyl)-4,5,6,7-tetrahy (d, J = 16.8 Hz, 1H), drobenzo[c]thiophene- 2.98-2.89 (m, 4H), 1.79 (br, 1-carboxamide 4H).

Chemical name Structure Physical data MS (m/z): 580(M+1); H N-((R)oxopyrrolidi NMR (400 MHz, CDCl ) δ nyl)(5-(3,4,5-tric 7.62 (s, 2H), 6.62 (br, 1H), hlorophenyl)(trifluo 6.17 (br, 1H), 4.47-4.46 (m, 45 romethyl)-4,5-dihydroi 1H), 4.07-4.02 (m, 1H), soxazolyl)-4,5,6,7-t 3.75-3.64 (m, 1H), 3.49-3.43 etrahydrobenzo[c]thio (m, 2H), 3.02-2.88 (m, 2H), phenecarboxamide 2.09-2.01 (m, 1H), 1.77 (br, 4H).

N-(2-(cyanomethylami MS (m/z): 593(M+1); H no)oxoethyl)(5-( NMR (CDCl , 400 MHz) δ 3,4,5-trichlorophenyl)- 7.63 (s, 2 H), 7.47 (m, 1 H), -(trifluoromethyl)-4,5 46 H 6.81 (m, 1 H), 4.22 (m, 4 H), -dihydroisoxazolyl) F C 3 CN Cl H 4.06 (d, J=17.2, 1 H), 3.70 -4,5,6,7-tetrahydroben (d, J=17.2, 1 H), 2.90 (m, 4 zo[c]thiophenecarb H), 1.79 (m, 4 H). oxamide MS (m/z): 592(M+1). H N-(2-oxo(propyn NMR (CDCl3, 400 MHz) δ ylamino)ethyl)(5-(3 7. 63 (s, 2 H), 6.78 (m, 1 H), ,4,5-trichlorophenyl)-5 6.50 (m, 1 H), 4.15 (m, 2 H), -(trifluoromethyl)-4,5- 47 Cl H 4.10 (m, 2 H), 4.05 (d, F C N dihydroisoxazolyl)- 3 J=16.8, 1 H), 3.67 (d, 4,5,6,7-tetrahydrobenz J=16.8, 1 H), 2.95 (m, 2 H), o[c]thiophenecarbo 2.90 (m, 2 H), 2.26 (m, 1 H), xamide 1.79 (m, 4H).

Chemical name Structure Physical data 3-(5-(3,5-dichlorofl MS (m/z): 620(M+1); H uorophenyl)(trifluor NMR (CDOD , 400 MHz) δ omethyl)-4,5-dihydroi 7.76 (d, J=6.4, 2H), 4.25 (d, soxazolyl)-N-(2-ox 48 F J=17.6, 1H), 4.07 (s, 2H), o(2,2,2-trifluoroeth F C N 3 CF Cl H 4.04-3.92 (m, 3H), 3.01-2.98 ylamino)ethyl)-4,5,6,7 (m, 2H), 2.90-2.89 (m, 2H), -tetrahydrobenzo[c]thi 1.79 (m, 4H). ophenecarboxamide MS (m/z): 564(M+1); H 3-(5-(3,5-dichlorofl NMR (CDOD , 400 MHz) δ uorophenyl)(trifluor 7.76 (d, J=6.4, 2H), 4.63 (t, omethyl)-4,5-dihydroi J=9.6, 1H), 4.24 (d, J=17.6, soxazolyl)-N-((R)-2 Cl 49 1H), 4.02 (d, J=17.6, 1H), -oxopyrrolidinyl)-4, NH 3.44-3.40 (m, 2H), 2.99-2.98 ,6,7-tetrahydrobenzo[ (m, 2H), 2.89 (m, 2H), c]thiophenecarboxa 2.59-2.52 (m, 1H), 2.23-2.18 mide (m, 1H), 1.79-1.77 (m, 4H).

N-(2-(cyanomethylami MS (m/z): 577(M+1); H no)oxoethyl)(5-( NMR (CDOD , 400 MHz) δ 3,5-dichlorofluorop 7.77 (d, J=6.4, 2H), henyl)(trifluoromet 50 F 4.28-4.21 (m, 3H), 4.05-4.00 hyl)-4,5-dihydroisoxaz F C N (m, 3H), 3.00(t, J=6.0, 2H), olyl)-4,5,6,7-tetrahy 2.93-2.90 (m, 2H), 1.81-1.80 drobenzo[c]thiophene- (m, 4H). 1-carboxamide Chemical name Structure Physical data 3-(5-(3,5-dichlorofl MS (m/z): 576(M+1); H uorophenyl)(trifluor NMR (CDOD , 400 MHz) δ omethyl)-4,5-dihydroi 7.76 (d, J=6.4, 2H), 4.24 (d, soxazolyl)-N-(2-ox Cl J=17.6, 1H), 4.03-3.99 (m, o(propynylamin H 5H), 2.98 (t, J=6.0, 2H), o)ethyl)-4,5,6,7-tetrah 2.88-2.86 (m, 2H), 2.62 (t, ydrobenzo[c]thiophen J=2.4, 1H), 1.79-1.77 (m, ecarboxamide 4H).

N-(2-oxo(2,2,2-trifl MS (m/z): 622 (M+1); H uoroethylamino)ethyl) NMR (CDCl3, 400 MHz) δ (5-(3,4,5-trichlorop 7.64 (s, 2 H), 6.81 (brs, 1 H), henyl)(trifluoromet 6.73 (brs, 1 H), 4.22 (d, 52 H F C N hyl)-4,5-dihydroisoxaz 3 CF J=4.8, 2 H), 3.99 (m, 3 H), olyl)-5,6-dihydro-4 3.64 (d, J=17.2, 1 H), 2.99 (t, H-cyclopenta[c]thioph J=7.6, 2 H), 2.91 (t, J=7.6, 2 enecarboxamide H), 2.55 (m, 2 H).

N-((R)oxopyrrolidi MS (m/z): 566 (M+1); H nyl)(5-(3,4,5-tric NMR (CDCl3, 400 MHz) δ hlorophenyl)(trifluo 7. 62 (s, 2 H), 6.46 (brs, 1 romethyl)-4,5-dihydroi H), 6.16 (brs, 1 H), 4.47 (m, soxazolyl)-5,6-dihy 1 H), 3.99 (d, J=17.2, 1 H), dro-4H-cyclopenta[c]t 3.61 (d, J=17.2, 1 H), 3.47 hiophenecarboxami (m, 2 H), 2. 93 (m, 5 H), 2.53 de (m, 2 H), 2.09 (m, 1 H).

Chemical name Structure Physical data MS (m/z): 579 (M+1); H N-(2-(cyanomethylami NMR (CDCl3, 400 MHz) δ no)oxoethyl)(5-( 7.62 (s, 2 H), 7.21 (brs, 1 H), 3,4,5-trichlorophenyl)- 6.71 (brs, 1 H), 4.22 (d, -(trifluoromethyl)-4,5 54 H J=6.0, 2 H), 4.18 (d, J=5.2, 2 F3C N -dihydroisoxazolyl) Cl H H), 4.02 (d, J=17.2, 1 H), -5,6-dihydro-4H-cyclo 3.63 (d, J=17.2, 1 H), 2.96 (t, penta[c]thiophenec J=7.2, 2 H), 2. 89 (t, J=7.2, 2 arboxamide H), 2.56 (m, 2 H).

MS (m/z): 578 (M+1); H N-(2-oxo(propyn NMR (CDCl3, 400 MHz) δ ylamino)ethyl)(5-(3 7.62 (s, 2 H), 6.82 (brs, 1 H), ,4,5-trichlorophenyl)-5 6.65 (brs, 1 H), 4.15 (d, -(trifluoromethyl)-4,5- J=4.8, 2 H), 4.10 (d, J =2.4, 55 H F C N dihydroisoxazolyl)- J =4.2, 2 H), 4.02 (d, J=16.8, Cl H 2 ,6-dihydro-4H-cyclop 1 H), 3.62 (d, J=16.8, 1 H), enta[c]thiophenecar 2.98 (t, J=7.2, 2 H), 2. 88 (t, boxamide J=7.2, 2 H), 2.55 (m, 2 H), 2. 27 (t, J=2.4, 2 H).

Chemical name Structure Physical data N-(2-oxo(2,2,2-trifl MS (m/z): 648 (M+1); H uoroethyl)pyrrolidin-3 NMR (CDCl3, 400 MHz) δ -yl)(5-(3,4,5-trichlo 7. 62 (s, 2 H), 6.5 (brs, 1 H), rophenyl)(trifluoro 4.50 (m, 1 H), 4.09 (m, 1 H), 56 N methyl)-4,5-dihydrois F C 4.00 (d, J=17.2, 1 H), 3.84 Cl 3 oxazolyl)-5,6-dihyd (m, 1 H), 3.58 (m, 3 H), 2. 93 ro-4H-cyclopenta[c]thi (m, 5 H), 2.52 (m, 2 H), 2.04 ophenecarboxamide (m, 1 H). 3-(5-(3,5-dichlorofl MS (m/z): 606 (M+1); H uorophenyl)(trifluor NMR (CDCl3, 400 MHz) δ omethyl)-4,5-dihydroi 7.56 (d, J=6.0, 2 H), 6.92 (t, soxazolyl)-N-(2-ox J=6.4, 1 H), 6.76 (t, J=4.8, 1 57 o(2,2,2-trifluoroeth H F3C CF 3 H), 4.21 (d, J=4.8, 1 H), 3.98 Cl H ylamino)ethyl)-5,6-dih (m, 3 H), 3.61 (d, J=16.8, 1 ydro-4H-cyclopenta[c] H), 2.97 (t, J=7.6, 2 H), 2.89 thiophenecarboxam (t, J=7.6, 2 H), 2.55 (m, 2H) MS (m/z): 550 (M+1); H 3-(5-(3,5-dichlorofl NMR (CDCl3, 400 MHz) δ uorophenyl)(trifluor 7.56 (d, J=6.4, 2 H), 6.46 omethyl)-4,5-dihydroi (brs, 1 H), 6.32 (brs, 1 H), soxazolyl)-N-((R)-2 58 4.47 (m, 1 H), 3.99 (d, -oxopyrrolidinyl)-5, J=17.2, 1 H), 3.61 (d, 6-dihydro-4H-cyclope J=17.2, 1 H), 3.48 (m, 2 H), nta[c]thiophenecarb 2. 93 (m, 5 H), 2.53 (m, 2 H), oxamide 2.06 (m, 1 H).

Chemical name Structure Physical data MS (m/z): 563 (M+1); H N-(2-(cyanomethylami NMR (CDCl3, 400 MHz) δ no)oxoethyl)(5-( 7.56 (d, J=6.0, 2 H), 7.41 3,5-dichlorofluorop (brs, 1 H), 6.84 (brs, 1 H), henyl)(trifluoromet 59 4.20 (m, 4 H), 3.99 (d, hyl)-4,5-dihydroisoxaz H J=16.8, 1 H), 3.63 (d, olyl)-5,6-dihydro-4 J=16.8, 1 H), 2.95 (t, J=7.2, H-cyclopenta[c]thioph 2 H), 2. 88 (t, J=7.2, 2 H), enecarboxamide 2.53 (m, 2 H).

MS (m/z): 632 (M+1); H 3-(5-(3,5-dichlorofl NMR (CDCl3, 400 MHz) δ uorophenyl)(trifluor 7.58 (d, J=6.0, 2H), omethyl)-4,5-dihydroi 6.60-6.57 (m, 1H), 4.56-4.50 soxazolyl)-N-(2-ox (m, 1H), 4.14-4.00 (m, 2H), 60 o(2,2,2-trifluoroeth 3.87-3.83 (m, 1H), 3.67-3.55 Cl 3 yl)pyrrolidinyl)-5,6 (m, 3H), 3.01-2.86 (m, 5H), -dihydro-4H-cyclopent 2.57-2.50 (m, 2H), 2.10-2.05 a[c]thiophenecarbo (m, 1H). xamide Chemical name Structure Physical data MS (m/z): 562 (M+1); H 3-(5-(3,5-dichlorofl NMR (CDCl3, 400 MHz) δ uorophenyl)(trifluor 7.58 (d, J=6.0, 2H), 6.85 omethyl)-4,5-dihydroi (brs, 1H), 6.70 (brs, 1H), soxazolyl)-N-(2-ox 4.18 (d, J=4.8, 2H), 61 F o(propynylamin 3 H 4.14-4.12 (m, 2H), 4.04 (d, Cl O o)ethyl)-5,6-dihydro-4 J=17.2, 1H), 3.65 (d, J=17.2, H-cyclopenta[c]thioph 1H), 3.00(t, J=7.2, 2H), 2.90 enecarboxamide (t, J=7.2, 2H), 2.60-2.55 (m, 2H), 2.29 (s, 1H). 3-(5-(3,5-dichlorophen MS (m/z): 602 (M+1); 1H yl)(trifluoromethyl) NMR (CDCl3, 400 MHz) δ -4,5-dihydroisoxazol-3 7.52-7.46 (m, 3H), 7.12-7.01 -yl)-N-(2-oxo(2,2,2 Cl (m, 1H), 6.85-6.78 (m, 1H), 62 H -trifluoroethylamino)et CF N 4.28-4.20 (m, 2H), 4.08-3.91 3 CF hyl)-4,5,6,7-tetrahydro (m, 3H), 3.68 (d, J=17.2, benzo[c]thiophenec 1H), 3.07-2.87 (m, 4H), arboxamide 1.89-1.73 (m, 4H).

Chemical name Structure Physical data MS (m/z): 548 (M+1); 1H NMR (CDCl3, 400 MHz) 3-(5-(3,5-dichlorophen δ H NMR (CDCl , 400 yl)(trifluoromethyl) MHz)  7.49 (s, 2H), 7.42 -4,5-dihydroisoxazol-3 (m, 1H), 6.80 (s, 1H), 5.96 63 -yl)-N-(2-(ethylamino) (s, 1H), 4.09-4.02 (m, 3H), CF N oxoethyl)-4,5,6,7-te 3.69-3.65 (d, J=16 Hz, 1H), trahydrobenzo[c]thiop 3.40-3.33 (m, 2H), 3.00 (s, henecarboxamide 2H), 2.92-2.90(m, 2H), 1.79 (s, 4H), 1.26-1.17 (m, 3H).

MS (m/z): 547 (M+1); 1H NMR (CDCl3, 400 MHz) 3-(5-(3,5-dichlorophen δ7.48 (s, 2H), 7.42 (s, 1H), yl)(trifluoromethyl) 6.23 (s, 1H), 4.08-4.02 (m, -4,5-dihydroisoxazol-3 2H), 3.91-3.86 (m, 1H), 64 -yl)-N-((tetrahydrofura 3.81-3.76 (m, 2H), 3.69-3.65 nyl)methyl)-4,5,6,7 (m, J=16 Hz, 1H), 3.34-3.28 -tetrahydrobenzo[c]thi (m, 1H), 3.00-2.85 (m, 4H), ophenecarboxamide 2.06-1.98 (m, 1H), 1.96-1.89 (m, 2H), 1.79-1.77 (m, 4H), 1.64-1.59 (m, 1H).

Chemical name Structure Physical data MS (m/z): 537 (M+1); 1H 3-(5-(3,5-dichlorophen NMR (CDCl3, 400 MHz) δ yl)(trifluoromethyl) 7.49 (s, 2H), 7.43 (s, 1H), -4,5-dihydroisoxazol-3 6.33 (s, 1H), 4.07-4.03 (d, 65 -yl)-N-(2-(methylthio) J=16 Hz, 1H), 3.69-3.62 (m, ethyl)-4,5,6,7-tetrahyd 3H), 2.98 (s, 2H), 2.92-2.90 robenzo[c]thiophene-1 (m, 2H), 2.76-2.74 (m, 2H), -carboxamide 2.14 (s, 3H), 1.80-1.79 (m, 4H).

MS (m/z): 559 (M+1); 1H 3-(5-(3,5-dichlorophen NMR (CDCl3, 400 MHz) δ yl)(trifluoromethyl) 7.49 (s, 2H), 7.43 (s, 1H), -4,5-dihydroisoxazol-3 6.08-6.05 (m, 1H), 4.06-4.02 66 -yl)-N-(3,3,3-trifluoro H (d, J=16 Hz, 1H), 3.72-3.64 CF 3 propyl)-4,5,6,7-tetrahy (m, 3H), 2.94-2.85 (m, 4H), drobenzo[c]thiophene- 2.51-2.40 (m, 2H), 1.80-1.78 1-carboxamide (m, 4H).

MS (m/z): 561 (M+1); 1H 3-(5-(3,5-dichlorophen NMR (CDCl3, 400 MHz) δ yl)(trifluoromethyl) 7.49 (s, 2H), 7.43 (s, 1H), -4,5-dihydroisoxazol-3 6.85 (s, 1H), 4.21 (s, 1H), 67 -yl)-N-(3-hydroxycycl CF 4.09-4.02 (m, 2H), 3.69-3.64 ohexyl)-4,5,6,7-tetrahy (d, J=20 Hz, 1H), 2.96-2.89 drobenzo[c]thiophene- (m, 5H), 2.05-1.78 (m, 9H), 1-carboxamide 1.49-1.38 (m, 2H).

Chemical name Structure Physical data MS (m/z): 558 (M+1); 1H 3-(5-(3,5-dichlorophen NMR (CDCl3, 400 MHz) δ yl)(trifluoromethyl) 8.36 (s, 1H), 8.32-8.29 (m, -4,5-dihydroisoxazol-3 1H), 8.16 (d, J=2.4 Hz, 1H), 68 -yl)-N-(5-fluoropyridi 7.51-7.44 (m, 3H), 7.43 (s, CF O nyl)-4,5,6,7-tetrahy 1H), 4.09-4.05 (d, J=16 Hz, drobenzo[c]thiophene- 1H), 3.71-3.67 (d, J=16 Hz, 1-carboxamide 1H), 3.09 (s, 2H), 2.94-2.93 (m, 2H), 1.83 (s, 4H) MS (m/z): 547 (M+1); 1H 3-(5-(3,5-dichlorophen NMR (CDCl3, 400 MHz) δ yl)(trifluoromethyl) 7.49 (s, 2H), 7.40 (s, 1H), -4,5-dihydroisoxazol-3 6.23 (d, J=9.6 Hz, 1H), 69 -yl)-N-(tetrahydro-2H- 4.18-4.16 (s, 1H), 4.07-4.03 pyranyl)-4,5,6,7-tet (d, J=16 Hz, 1H), 3.83-3.77 rahydrobenzo[c]thioph (m, 2H), 3.69-3.57 (m, 3H), enecarboxamide 2.98-2.90 (m, 4H), 1.90-1.75 (m, 8H).

Chemical name Structure Physical data MS (m/z): 535 (M+1); 1H 3-(5-(3,5-dichlorophen NMR (CDCl3, 400 MHz) δ yl)(trifluoromethyl) 7.49 (s, 2H), 7.44 (s, 1H), -4,5-dihydroisoxazol-3 6.18 (d, J = 7.6 Hz, 1H), 70 -yl)-N-(thietanyl)-4, 5.40-5.34 (m, 1H), 4.06 (d, J ,6,7-tetrahydrobenzo[ = 17.2 Hz, 1H), 3.66 (d, J = c]thiophenecarboxa 17.2 Hz, 1H), 3.46-3.36 (m, mide 4H), 2.97-2.90 (m, 4H), 1.81-1.78 (m, 4H).

MS (m/z): 547 (M+1); 1H NMR (CDCl3, 400 MHz) δ 3-(5-(3,5-dichlorophen 7.47 (s, 2H), 7.41 (s, 1H), yl)(trifluoromethyl) 5.74-5.72 (d, J=7.6 Hz, 1H), -4,5-dihydroisoxazol-3 4.19-4.11 (m, 1H), 4.10-4.06 71 -yl)-N-(tetrahydro-2H- (d, J=16 Hz, 1H), 4.04-3.96 pyranyl)-4,5,6,7-tet (m, 2H), 3.69-3.65 (d, J=16 rahydrobenzo[c]thioph Hz, 1H), 3.53-3.43 (m, 2H), enecarboxamide 2.94-2.88 (m, 4H), 2.00-1.97 (m, 2H), 1.77 (s, 4H), 1.60-1.50 (m, 2H).

N-(1-cyclopropylox MS (m/z): 586 (M+1); 1H opyrrolidinyl)(5- NMR (CDCl3, 400 MHz) δ (3,5-dichlorophenyl)-5 7.49 (s, 2 H), 7.43 (s, 1H), 72 N -(trifluoromethyl)-4,5- 6.50 (brs, 1 H), 4.43-4.40 (m, dihydroisoxazolyl)- 1 H), 4.04 (d, J =16.8, 1 H), 4,5,6,7-tetrahydrobenz 3.65 (d, J =16.8, 1 H), o[c]thiophenecarbo 3.42-3.30 (m, 2 H), 2.99-2.82 Chemical name Structure Physical data xamide (m, 5 H), 1.91-1.80 (m, 5 H), 0.83-0.763 (m, 4 H) N-(2-oxo(propyn ylamino)ethyl)(5-(3 MS (m/z): 600 (M+1); 1H ,4,5-trichlorothiophen- NMR (CDCl3, 400 MHz) δ 2-yl)(trifluorometh 6.92-6.77 (m, 2H), 4.21-4.09 Cl O yl)-4,5-dihydroisoxazo H (m, 4H), 4.08-4.04 (m, 2H), Cl 3 O lyl)-4,5,6,7-tetrahyd 3.09-2.88 (m, 4H), 1.87-1.71 robenzo[c]thiophene-1 (m, 4H). -carboxamide Chemical name Structure Physical data MS (m/z): 631 (M+1); 1H 3-[5-(3,4,5-Trichloro- NMR (CDCl3, 400 MHz) δ phenyl)trifluoromet 7.62 (s, 2H), 5.89-5.87 (m, hyl-4,5-dihydro-isoxaz 1H), 4.28-4.20 (m, 1H), olyl]-4,5,6,7-tetrahy 4.07-4.03 (d, J=16 Hz, 1H), Cl S dro-benzo[c]thiophene F C 3.70-3.66 (d, J=16 Hz, 1H), carboxylic acid 3.20-3.12 (m, 4H), 2.94-2.89 (1,1-dioxo-hexahydro- (m, 4H), 2.42-2.39 (m, 2H), thiopyranyl)-amide 2.27-2.17 (m, 2H), 1.79 (s, 4H).

N-(2-oxo(2,2,2-trifl MS (m/z): 664 (M+1); 1H uoroethyl)pyrrolidin-3 NMR (CDCl3, 400 MHz) δ -yl)(5-(3,4,5-trichlo 7.63 (s, 2 H), 6.45 (brs, 1 H), rophenyl)(trifluoro Cl 76 4.53 (brs, 1 H), 4.09 (m, 2 methyl)-4,5-dihydrois F C Cl 3 H), 3.85 (m, 1 H), 3.58 (m, 3 oxazolyl)-4,5,6,7-te H), 2.95 (m, 4 H), 2.02 (m, 1 trahydrobenzo[c]thiop H), 1.79 (m, 4 H). henecarboxamide Chemical name Structure Physical data MS (m/z): 583 (M+1); 1H NMR (CDCl3, 400 MHz) δ N-(tetrahydro-2H-pyra 7.61 (s, 2H), 5.70-5.68 (d, nyl)(5-(3,4,5-tric J=8.0 Hz, 1H), 4.19-4.11 (m, hlorophenyl)(trifluo 1H), 3.70-3.66 (d, J=16 Hz, 77 romethyl)-4,5-dihydroi 1H), 4.00-3.97 (m, 2H), soxazolyl)-4,5,6,7-t 3.68-3.64 (d, J=16 Hz, 1H), etrahydrobenzo[c]thio 3.54-3.48 (m, 2H), 2.94-2.88 phenecarboxamide (m, 4H), 2.00-1.98 (m, 2H), 1.79 (s, 4H), 1.64-1.50 (m, 2H).

N-(1-cyclopropylox MS (m/z): 622 (M+1); 1H opyrrolidinyl)(5- NMR (CDCl3, 400 MHz) δ (3,4,5-trichlorophenyl) 8.00 (s, 2 H), 6.53 (brs, 1 H), (trifluoromethyl)-4, Cl 4.43 (m, 1 H), 4.04 (d, -dihydroisoxazolyl J=17.2, 1 H), 3.65 (d, )-4,5,6,7-tetrahydrobe J=17.2, 1 H), 3.36 (m, 2 H), nzo[c]thiophenecar 2.83 (m, 5 H), 2.73 (m, 1 H), boxamide 1.84 (m, 5 H), 0.79 (m, 4 H).

Chemical name Structure Physical data 3-[5-(3,5-Dichlorofl MS (m/z): 585 (M+1); 1H uoro-phenyl)trifluor NMR (CDCl3, 400 MHz) δ omethyl-4,5-dihydro-i 7.76 (d, J=6.0, 2H), soxazolyl]-4,5,6,7-t 4.65-4.56 (m, 1H), 4.53 (t, 79 etrahydro-benzo[c]thio J=4.8, 2H), 4.28-4.23 (m, F C S phenecarboxylic 3H), 4.02 (d, J=17.6, 1H), acid 2.97 (t, J=6.0, 2H), 2.90 (t, (1,1-dioxo-thietanyl J=6.0, 2H), 1.80-1.76 (m, )-amide 4H). 3-[5-(3,5-Dichlorofl MS (m/z): 613 (M+1); 1H uoro-phenyl)trifluor NMR (CDCl3, 400 MHz) δ omethyl-4,5-dihydro-i 7.56 (d, J=6.0, 2 H), 5.75 (d, soxazolyl]-4,5,6,7-t J=7.2, 1 H), 4.06 (d, J=16.8, 80 etrahydro-benzo[c]thio N O 1 H), 3.65 (d, J=16.8, 1 H), phenecarboxylic 3.13 (m, 4 H), 2.91 (m, 4 H), acid 2.41 (m, 2 H), 2.23 (m, 2 H), (1,1-dioxo-hexahydro- 1.84 (m, 4 H). thiopyranyl)-amide MS (m/z): 577 (M+1); 1H 3-(5-(3,5-dichlorofl NMR (CDCl3, 400 MHz) δ uorophenyl)(trifluor omethyl)-4,5-dihydroi 7.48(d ，J=6.0, 2H), 5.67 (d, 81 soxazolyl)-N-(4-ox N J=6.8, 1H), 4.33 (m, 1H), Cl O ocyclohexyl)-4,5,6,7-t 3.98(d, J=16.8, 1H), 3.58 (d, etrahydrobenzo[c]thio J=16.8, 1H), 2.82 (m, 4H), phenecarboxamide 2.40 (m, 6H), 1.65 (m, 6H) Chemical name Structure Physical data 3-(5-(3,5-dichlorofl MS (m/z): 646 (M+1); 1H uorophenyl)(trifluor NMR (CDCl3, 400 MHz) δ omethyl)-4,5-dihydroi 7. 50 (dd, J =2.4, J =6.0, 2 soxazolyl)-N-(2-ox Cl H), 6.44 (dd, J =4.8, J =12.0, 82 o(2,2,2-trifluoroeth 1 H), 4.46 (m, 1 H), 3.98 (m, yl)pyrrolidinyl)-4,5, 2 H), 3.78 (m, 1 H), 3.55 (m, 6,7-tetrahydrobenzo[c] 3 H), 2.83 (m, 5 H), 1.963 thiophenecarboxam (m, 1 H), 1.71 (m, 4 H).

MS (m/z): 565 (M+1); 1H 3-(5-(3,5-dichlorofl NMR (CDCl3, 400 MHz) δ uorophenyl)(trifluor 7.49 (d, J=5.6, 2 H), 5.59 (d, omethyl)-4,5-dihydroi J=7.6, 1 H), 4.10 (m, 1 H), soxazolyl)-N-(tetra 83 3.98 (d, J=16.8, 1 H), 3.91 hydro-2H-pyranyl)- (m, 2 H), 3.58 (d, J=16.8, 1 4,5,6,7-tetrahydrobenz H), 3.45 (m, 2 H), 2.84 (m, 4 o[c]thiophenecarbo H), 1.95 (m, 2 H), 1.72 (m, 4 xamide H), 1.49 (m, 3 H).

Chemical name Structure Physical data MS (m/z): 604 (M+1); 1H NMR (CDCl3, 400 MHz) δ N-(1-cyclopropylox 7.77 (d, J=6.0, 2H), 4.62 (t, opyrrolidinyl)(5- J=9.6, 1H), 4.24 (d, J=17.6, (3,5-dichlorofluoro 1H), 4.02 (d, J=17.6, 1H), phenyl)(trifluorome Cl 84 3.43-3.39 (m, 2H), 2.99-2.96 thyl)-4,5-dihydroisoxa (m, 2H), 2.90-2.88 (m, 2H), zolyl)-4,5,6,7-tetrah 2.75-2.69 (m, 1H), 2.50-2.42 ydrobenzo[c]thiophen (m, 1H), 2.10-1.99 (m, 1H), ecarboxamide 1.81-1.78 (m, 4H), 0.85-0.82 (m, 4H).

MS (m/z): 545 (M+1); 1H 3-(5-(3,5-dichlorophen NMR (CDCl3, 400 MHz) δ yl)(trifluoromethyl) 7.52-7.44 (m, 3H), 5.72-5.68 -4,5-dihydroisoxazol-3 (m, 1H), 4.48-4.37 (m, 1H), 85 -yl)-N-(4-oxocyclohex N 4.04-3.97 (d, J=17.2, 1H), yl)-5,6-dihydro-4H-cy 3.65-3.59 (d, J=17.2, 1H), clopenta[c]thiophene- 2.92-2.84 (m, 4H), 2.58-2.48 1-carboxamide (m, 6H), 2.47-2.31 (m, 2H), 1.84-1.71 (m, 2H).

Chemical name Structure Physical data MS (m/z): 614 (M+1); 1H 3-(5-(3,5-dichlorophen NMR (CDCl3, 400 MHz) yl)(trifluoromethyl) δ7.52-7.44 (m, 3H), -4,5-dihydroisoxazol-3 6.43-6.38 (s, 1H), 4.52-4.48 -yl)-N-(2-oxo(2,2,2 (m, 1H), 4.17-4.05 (m, 2H), 86 N -trifluoroethyl)pyrrolid F C 4.04-3.97 (d, J=17.2, 1H), inyl)-5,6-dihydro-4 3.89-3.77 (m, 1H), 3.68-3.51 H-cyclopenta[c]thioph (m, 3H), 2.93-2.82 (m, 5H), enecarboxamide 2.58-2.46 (m, 2H), 2.08-1.97 (m, 1H).

Example 87 3-((R)(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N-((R) oxopyrrolidinyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide and 3-((S)(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N-((R) oxopyrrolidinyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide Cl Cl NH NH F C F C Cl Cl Separate 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl) -N-((R)oxopyrrolidinyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide (6.2 g 11.29 mmol) by SFC (Column: Chiralcel OD 250 ×30mm I.D., 5um. Mobile phase: Supercritical CO / MeOH=60/40, Flow rate:200 ml/min) to afford two diastereoisomers 3-((R)(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N-((R)ox o pyrrolidinyl)- 4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide (2.7 g, 4.92 mmol) 3-((S)(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N-((R)ox opyrrolidinyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide (2.6 g, 4.74 mmol) as a white solid.

(A) MS (m/z): 619.1 (M+73). H NMR (CDCl , 400 MHz)  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). H NMR (CDCl , 400 MHz)  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 (COCl) , trace DMF NHR R , Pyridine N N R O O O CH Cl Cl N Ar Ar S Ar S F C F C F C O 3 O 3 O Preparation 88 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)- 4,5,6,7-tetrahydrobenzo[c]thiophenecarbonyl chloride Stir a mixture of 3-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-4,5,6,7-tetrahyd ro-benzo[c]thiophenecarboxylic 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)(trifluoromethyl)-4,5-dihydroisoxazolyl)- 4,5,6,7-tetrahydrobenzo[c]thiophenecarbonyl chloride as a yellow solid (615 mg, 98%).

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

Prep.

Chemical name Structure Physical data 3-[5-(3,4,5-Trichloro-t hiophenyl)trifluo romethyl-4,5-dihydro- isoxazolyl]-4,5,6,7-t etrahydro-benzo[c]thio phenecarbonyl chloride Example 90 N-(4-carbamoylphenyl)(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5- dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide Stir a mixture of 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydr obenzo[c]thiophenecarbonyl 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)(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxaz olyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide as a white solid (36 mg, 62.0%). MS (m/z): 582.1 (M+1). H NMR (CDCl , 400 MHz)  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.

Chemical name Structure Physical data MS (m/z): 628 (M+1); 3-[5-(3,4,5-Trichloro-thio H NMR (400 MHz, phenyl)trifluoromet DMSO-d ,) δ 8.08-8.02 hyl-4,5-dihydro-isoxazol- (m, 1H), 7.81-7.78 (m, 3-yl]-4,5,6,7-tetrahydro-b 91 S N 1H), 4.58-4.43 (t, 2H), enzo[c]thiophenecarbo 3.13-2.84 (m, 4H), xylic acid 1.79-1.64 (m, 4H). (3-carbamoyl-thiophen yl)-amide Scheme C LiOH N O HATU, NEt , NHR R O H H MeOH:H O = 4:1 CH Cl Ar Ar S S 2 2 O OH O F C Preparation 92 2-(3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)- 4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamido)acetic acid Cl N Stir a mixture of methyl 2-(3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5- dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamido)acetate (534 mg, 1.0 mmol) and LiOH-H O (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 conc. HCl to pH = 1, and extract the resultant mixture with EtOAc (15 mL×3).The combined organic layers are washed brine, dried over anhydrous Na SO and concentrated under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc 1:1) to afford 2-(3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrah ydrobenzo[c]thiophenecarboxamido)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 Preparation 92.

Prep.

Chemical name Structure Physical data ({3-[5-(3,4,5-Trichloro -thiophenyl)triflu oromethyl-4,5-dihydro O Cl S 93 -isoxazolyl]-4,5,6,7 MS (m/z): 561 (M+1). -tetrahydro-benzo[c]thi ophenecarbonyl}-a mino)-acetic acid Example 94 N-(2-(cyanomethylamino)oxoethyl)(5-(3,5-dichlorophenyl) (trifluoromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophene carboxamide Cl N Stir a mixture of 2-(3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5- dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamido)acetic acid (230 mg, 0.44 mmol), HATU (251 mg, 0.66 mmol) and NEt (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 mL ×3). The combined organic layers are washed with brine, dried over anhydrous Na SO and concentrated under vacuum. Purify the residue by preparative HPLC to afford N-(2-(cyanomethylamino)oxoethyl)(5-(3,5- dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c] thiophenecarboxamide as a white solid (110 mg, 44.7 %). MS (m/z): 559.1 (M+1). H NMR (DMSO-d , 400 MHz)  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.

Chemical name Structure Physical data 3-(5-(3,5-dichlorophen MS (m/z): 558 (M+1); H yl)(trifluoromethyl) NMR (CDCl , 400 MHz)  -4,5-dihydroisoxazol-3 7.49-7.42 (m, 3H), 6.85 (br, -yl)-N-(2-oxo(prop- 95 H 1H), 6.72 (br, 1H), 4.17-4.03 2-ynylamino)ethyl)-4, CF N (m, 5H), 3.68 (d, J = 17.2 ,6,7-tetrahydrobenzo[ Hz, 1H), 3.00-2.90 (m, 4H), c]thiophenecarboxa 2.25 (s, 1H), 1.79 (br, 4H). mide N-(2-(cyanomethylami no)oxoethyl)(5-( MS (m/z): 599 (M+1); H 3,4,5-trichlorothiophen NMR (CDCl , 400 MHz)  yl)(trifluorometh 96 H 4.28-4.18 (m, 4H), 4.10-4.07 yl)-4,5-dihydroisoxazo CF Cl 3 (m, 2H), 3.04-2.87 (m, 4H), lyl)-4,5,6,7-tetrahyd 1.88-1.73 (m, 4H). robenzo[c]thiophene-1 -carboxamide Scheme D S LiOH-H O O NH(OMe)Me-HCl S S O MeOH, H O OH HATU, NEt Z O OH MeMgBr CF Y Cl SOCl , Pyridine LiHMDS, THF, -78 C CH Cl , rt THF, -78 C Z CF O LiOH-H O THF:H O = 3:1 CF Preparation 201 4-chlorobenzo[b]thiophenecarboxylic acid Stir a mixture of methyl 4-chlorobenzo[b]thiophenecarboxylate (1.0 g, 4.44 mmol) and LiOH-H O (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 conc. HCl solution to pH = 1. Extract the resultant mixture with EtOAc (15 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na SO and evaporate under vacuum to afford 4-chlorobenzo[b]thiophenecarboxylic acid as a white solid (0.94 g, 100 %).

H NMR (400 MHz, CDCl ) 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.

Prep Physical Chemical name Structure No. data Thieno[2,3-c]pyridinecarb MS (m/z): oxylic acid 180(M+1) -Bromo-thieno[2,3-b]pyridi MS (m/z): necarboxylic acid 260 (M+1).

Preparation 204 4-chloro-N-methoxy-N-methylbenzo[b]thiophenecarboxamide Stir a mixture of 4-chlorobenzo[b]thiophenecarboxylic acid (0.94 g, 4.44 mmol), N,O-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 is washed with brine, dried over anhydrous Na SO 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]thiophenecarboxamide as white solid (0.85 g, 75.2 %). H NMR (400 MHz, CDCl ) 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.

Prep. Physical Chemical name Structure No. data N-methoxy-N-methylthien MS (m/z): 205 o[2,3-c]pyridinecarboxa 223 (M+1). mide -bromo-N-methoxy-N-me MS (m/z): 206 thylthieno[2,3-b]pyridine-2 S N O 301 (M+1). -carboxamide Preparation 207 1-(4-chlorobenzo[b]thiophenyl)ethanone Add a solution of CH MgBr (3 M in THF, 1.7 ml, 4.99 mmol) to a suspension of 4-chloro-N-methoxy-N-methylbenzo[b]thiophenecarboxamide (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 NH Cl aqueous solution (15 mL) and extract the aqueous mixture with EtOAc (10 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na SO and concentrated under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc = 6:1) to afford 1-(4-chlorobenzo[b]thiophenyl)ethanone as white solid (0.6 g, 86.9 %). H NMR (400 MHz, CDCl ) 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-Thieno[2,3-c]pyridin- MS (m/z): 2-yl-ethanone 178 (M+1). 1-(5-Bromo-thieno[2,3- MS (m/z): 209 b]pyridinyl)-ethanon 258 (M+1). 1-Thieno[2,3-b]pyridin- S MS (m/z): 2-yl-ethanone 178 (M+1) Preparation 211 1-(4-chlorobenzo[b]thiophenyl)(3,5-dichlorophenyl)-4,4,4-trifluorohydroxybutan one Add a solution of LiHMDS (1 M in THF, 4.3 ml, 4.31 mmol) to a mixture of 1-(4-chlorobenzo[b]thiophenyl)ethanone (0.6 g, 2.87 mmol) in dry THF (10 mL) at -78 C under N . After stirring 1.5 hour at -78 C, add 1-(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 NH Cl solution and extract the aqueous mixture with EtOAc (10 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na SO and concentrated under vacuum afford crude 1-(4-chlorobenzo[b]thiophenyl)(3,5-dichlorophenyl)-4,4,4-trifluorohydroxybutan one as brown solid (1.1 g, 84.6%). H NMR (400 MHz, CDCl ) 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 211.

Prep.

Chemical name Structure Physical data 3-(3,5-Dichloro-phenyl)-4,4, OH O 4-trifluorohydroxythien MS (m/z): 418 212 CF o[2,3-c]pyridinyl-butan (M-1) 3-(3,5-Dichloro-phenyl)-4,4, OH O 4-trifluorohydroxy(5-br MS (m/z): 498 omo-thieno[2,3-b]pyridin (M-1). yl)-butanone 3-(3,5-Dichloro-phenyl)-4,4, OH O 4-trifluorohydroxythien MS (m/z): 418 214 CF o[2,3-b]pyridinyl-butan (M-1).

OH O 1-(benzo[d]thiazolyl)(3 Cl N MS (m/z): 418 215 ,5-dichlorophenyl)-4,4,4-trifl CF (M-1). uorohydroxybutanone 3-(3,5-dichlorophenyl)-4,4,4- OH O trifluorohydroxy(3-met MS (m/z): 431 216 CF hylbenzo[b]thiophenyl)but (M-1). anone 3-(3,5-dichlorophenyl)-4,4,4- OH O trifluorohydroxy(5-met MS (m/z): 431 217 CF hylbenzo[b]thiophenyl)but (M-1). anone Prep.

Chemical name Structure Physical data 1-(5-chlorobenzo[b]thiophen OH O yl)(3,5-dichlorophenyl) MS (m/z): 451 218 CF -4,4,4-trifluorohydroxybut (M-1). anone OH O 1-(benzo[b]thiophenyl) MS (m/z): 417 219 (3,5-dichlorophenyl)-4,4,4-tri CF (M-1). fluorohydroxybutanone Preparation 220 1-(4-chlorobenzo[b]thiophenyl)(3,5-dichlorophenyl)-4,4,4-trifluorobutenone Stir a mixture of 1-(4-chlorobenzo[b]thiophenyl)(3,5-dichlorophenyl)-4,4,4-trifluorohydroxybutan one (1.1 g, crude, 2.43 mmol), SOCl (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 NH Cl solution and extract the aqueous mixture with DCM (10 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na SO and concentrated under vacuum to afford crude 1-(4-chlorobenzo[b]thiophenyl)(3,5-dichlorophenyl)-4,4,4-trifluorobutenone as brown solid (1.05 g, 100%). H NMR (400 MHz, CDCl ) δ8.12-8.10 (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 3-(3,5-Dichloro-pheny CF O l)-4,4,4-trifluorothi MS (m/z): 400 (M-1). eno[2,3-c]pyridinyl -butenone 3-(3,5-Dichloro-pheny CF O l)-4,4,4-trifluoro(5- MS (m/z): 480 (M-1). 222 bromo-thieno[2,3-b]py ridinyl)-buten 3-(3,5-Dichloro-pheny CF O l)-4,4,4-trifluorothi MS (m/z): 400 (M-1). eno[2,3-b]pyridinyl -butenone 1-(benzo[b]thiophen-2 CF O -yl)(3,5-dichloroph MS (m/z): 399 enyl)-4,4,4-trifluorobu tenone 1-(benzo[d]thiazoly CF O l)(3,5-dichlorophen MS (m/z): 400 yl)-4,4,4-trifluorobut-2 -enone 3-(3,5-dichlorophenyl) CF O -4,4,4-trifluoro(3-m MS (m/z): 413 ethylbenzo[b]thiophen yl)butenone Prep.

Chemical name Structure Physical data 3-(3,5-dichlorophenyl) CF O -4,4,4-trifluoro(5-m MS (m/z): 413 ethylbenzo[b]thiophen yl)butenone 1-(5-chlorobenzo[b]thi CF O ophenyl)(3,5-dic MS (m/z): 433 hlorophenyl)-4,4,4-trif luorobutenone Example 229 3-(4-chlorobenzo[b]thiophenyl)(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydr oisoxazole Stir a mixture of 1-(4-chlorobenzo[b]thiophenyl)(3,5-dichlorophenyl)-4,4,4-trifluorobutenone (1.05 g, crude, 2.43 mmol), NaOH (389 mg, 9.72 mmol) and NH OH-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 mL×3). The combined organic layers are washed with brine, dried over anhydrous Na SO and concentrated under vacuum. Purify the residue by preparative HPLC to afford 3-(4-chlorobenzo[b]thiophenyl)(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydr oisoxazole as white solid (305 mg, 28.1 %). MS (m/z): 450 (M+1). H NMR (400 MHz, CDCl ) δ  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.

Chemical name Structure Physical data MS (m/z): 417 (M+1). H NMR (400 MHz, CDCl ) δ 2-[5-(3,5-Dichlor 9.17 (s, 1H), 8.55-8.57 (d, J = o-phenyl)triflu .6, 1H), 7.68-7.69 (d, J = 5.6, oromethyl-4,5-di 230 J = 1.2, 1H), 7.51-7.52 (d, J = hydro-isoxazol CF 1.2, 2H), 7.49 (S, 1H), yl]-thieno[2,3-c]p 7.45-7.46 (t, J = 3.6, 1H), yridine 4.17-4.21 (d, J = 16.8, 1H), 3.79-3.83 (d, J = 16.8, 1H).

MS (m/z): 497 (M+1). 1H -Bromo[5-(3, NMR (400 MHz, CDCl ) δ -dichloro-phenyl 8.65-8.66 (d, J = 1.6, 1H ), )trifluorometh 8.18-8.19 (d, J = 2.0, 1H), 7.51 yl-4,5-dihydro-is (S, 2H), 7.45-7.46 (d, J = 1.6, oxazolyl]-thie 1H), 7.32 (S, 1H), 4.13-4.17 (d, no[2,3-b]pyridine J = 16.8, 1H), 3.75-3.79 (d, J = 16.8, 1H).

MS (m/z): 417 (M+1). H NMR (400 MHz, CDCl ) δ 8.62-8.64 2-[5-(3,5-Dichlor (d, J = 4.4, J = 1.6, 1H), o-phenyl)triflu 8.05-8.07 (d, J = 8.0, J = 1.6, oromethyl-4,5-di 232 1H), 7.51-7.52 (d, J = 1.2, 2H), hydro-isoxazol CF 7.44-7.45 (t, J = 3.6, 1H), 7.41 yl]-thieno[2,3-b]p (s, 1H), 7.33-7.36 (m, 1H), yridine 4.15-4.19 (d, J = 16.8, 1H), 3.77-3.81 (d, J = 16.8, 1H). 3-(benzo[b]thiop MS (m/z): 416 (M+1). 1H henyl)(3,5- NMR (400 MHz, CDCl ) δ dichlorophenyl)-5 7.84 (d, J=8.0, 1H), 7.82 (d, -(trifluoromethyl) J=8.0, 1H), 7.55-7.50 (m, 2H), Chemical name Structure Physical data -4,5-dihydroisoxa 7.48-7.34 (m, 4H), 4.20 (d, zole J=16.8, 1H), 3.80 (d, J=17.6, 1H). 3-(benzo[d]thiazo MS (m/z): 417 (M+1). 1H lyl)(3,5-dic NMR (400 MHz, CDCl ) δ hlorophenyl)(t 8.07 (d, J = 7.2, 1H), 7.93 (d, rifluoromethyl)-4 S J=7.2, 1H), 7.58-7.47 (m, 5H), ,5-dihydroisoxaz 4.37 (d, J=18.0, 1H), 4.00 (d, ole J=18.0, 1H) -(3,5-dichloroph MS (m/z): 430 (M+1). 1H enyl)(3-methyl NMR (400 MHz, CDCl ) δ benzo[b]thiophen 7.83-7.78 (m, 2H), 7.53 (s, 2H), yl)(trifluoro 7.53-7.43 (m, 3H), 4.17 (d, J methyl)-4,5-dihy = 16.8, 1H), 3.79 (d, J = 16.8, droisoxazole 1H), 2.67 (s, 3H).

MS (m/z): 430 (M+1). 1H -(3,5-dichloroph NMR (400 MHz, CDCl ) δ enyl)(5-methyl 7.71 (d, J = 8.0, 1H), 7.57 (s, benzo[b]thiophen 1H), 7.53 (s, 2H), 7.43 (t, J = yl)(trifluoro 3.2, 1H), 7.36 (d, J = 7.0, 1H), methyl)-4,5-dihy 7.24 (d, J = 7.0, 1H), 4.17 (d, J droisoxazole = 16.8, 1H), 3.78 (d, J = 16.8, 1H), 2.47 (s, 3H). 3-(5-chlorobenzo MS (m/z): 450 (M+1). 1H [b]thiophenyl) NMR (400 MHz, CDCl ) δ (3,5-dichlorop O 7.76-7.75 (m, 2H), 7.51 (s, 2H), henyl)(trifluor 7.45-7.44 (m, 1H), 7.40-7.38 omethyl)-4,5-dih (m, 2H), 4.18 (d, J = 16.8, 1H), ydroisoxazole 3.78 (d, J = 17.6, 1H).

Scheme E Pd(dppf)Cl , Et N F C 2 3 O O LiOH THF/CH OH Cl 50 psi, 70 C 3 F C Cl N HATU, DIPEA Preparation 238 methyl 2-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)thieno[2,3-b]pyri dinecarboxylate Stir a mixture of -bromo[5-(3,5-dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-thieno[ 2,3-b]pyridine (494 mg, 1 mmol), Pd(dppf)Cl (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 10h. 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)(trifluoromethyl)-4,5-dihydroisoxazolyl)thieno[2,3-b]pyri dinecarboxylate as a white solid (210 mg, 44.18%). MS (m/z): 475 (M+1).

Preparation 239 2-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-thieno[2,3-b]pyr idinecarboxylic acid Add a solution of LiOH-H O (76 mg, 2 mmol) in water (0.5 mL) to a solution of methyl 2-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)thieno[2,3-b]pyri dinecarboxylate (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 HCl 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 Na SO and concentrated under vacuum to afford 2-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-thieno[2,3-b]pyr idinecarboxylic acid as pale yellow solid (170 mg, 73.9%), which is used in next step without further purification. MS (m/z): 461 (M+1).

Example 240 2-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N-(2-oxo(2,2, 2-trifluoroethylamino)ethyl)thieno[2,3-b]pyridinecarboxamide N CF Stir a mixture of 2-Amino-N-(2,2,2-trifluoro-ethyl)-acetamide (156 mg, 1 mmol), 2-[5-(3,5-dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-thieno[2,3-b]pyri dinecarboxylic 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)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N-(2-oxo(2,2, 2-trifluoroethylamino)ethyl)thieno[2,3-b]pyridinecarboxamide as a white solid (50 mg, 34.78%). MS (m/z): 599 (M+1). H NMR (400 MHz, CDCl ) 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.

Chemical name Structure Physical data MS (m/z): 543 (M+1). H 2-(5-(3,5-dichlorop NMR (400 MHz, CDCl ) δ henyl)(trifluoro 9.01 (s, 1H), 8.49 (s, 1H), 7.54 methyl)-4,5-dihydr (s, 2H), 7.44-7.40 (m, 2H), 7.15 oisoxazolyl)-N-( 3 241 (S, 1H), 5.89 (s, 1H), 4.60 (s, (R)oxopyrrolidin 1H), 4.18 (d, J = 16.8, 1H), yl)thieno[2,3-b]p 3.80 (d, J = 16.8, 1H), yridinecarboxam 3.51-3.48 (m, 2H), 3.00-2.93 (m, 1H), 2.14-2.08 (m, 1H) Scheme F D DIIEA EA,, H HA AT TU U SF SFC C s se ep pa ara rattiio on n Example 242 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N-(2-ox o(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxa mide Stir a mixture of 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5- dihydroisoxazolyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid (1.0 g, 2.14 mmol), N,N-diisopropylethylamine (827 mg, 6.41 mmol), 2-amino-N-(2,2,2-trifluoroethyl) acetamide hydrochloride (658 mg, 2.56 mmol) and HATU (1.2 g, 3.2 mmol) in CH Cl (10 mL) at room temperature for 2 hours. The reaction mixture is diluted with CH Cl (50 mL) and is washed with water (10 mLx 3) and brine.

Then the organic layer is dried over anhydrous Na SO and is concentrated under vacuum.

Purify the residue by preparative HPLC to afford 3-(5-(3,5-dichloro- 4-fluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N-(2-oxo(2,2,2-trifluor oethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxamide as a white solid (1.1 g, 84.6 %). MS (m/z): 606.0 (M+1).

Example 243 (S)(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl) -N-(2-oxo(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene carboxamide 1 g of 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N- (2-oxo(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecar boxamide is separated by SFC to give (S)(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl) -N-(2-oxo(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene carboxamide (400 mg, 80 % yield, 100% ee).

H NMR (400 MHz, CDCl ) δ 7.56 (d, J=6.0, 2 H), 6.92 (t, J=6.4, 1 H), 6.76 (t, J=4.8, 1 H), 4.21 (d, J=4.8, 2 H), 3.98 (m, 3 H), 3.61 (d, J=16.8, 1 H), 2.97 (t, J=7.6, 2 H), 2.89 (t, J=7.6, 2 H), 2.55 (m, 2 H). MS (m/z): 606.0 (M+1).

SFC analysis condition: Column: Chiralcel AD-H 250×4.6mm I.D., 5um.

Mobile phase: ethanol in CO from 5% to 40% over 3 minutes. Flow rate: 2.35 mL/min.

Wavelength: 220 nm. The S-isomer elutes at 1.4 minutes. SFC separation condition: Instrument: Thar SFC 80; Column: AD 250mm*20mm, 20um; Mobile phase: A: Supercritical CO , B: MeOH (0.05% NH H O), A:B =45:55 at 80ml/min; Column Temp: 2 3 2 0 0 0 38 C; Nozzle Pressure: 100Bar; Nozzle Temp: 60 C; Evaporator Temp: 20 C; Trimmer Temp: 25 C; Wavelength: 220nm Scheme G PPh PPh3 3,, C CC Cll4 4 8 82 2..5 5% % 73% 73% 92% 92% 1 1 ffo or r 2 2 s stte ep ps s L LH HD DM MS, S, T TH HF F,, -7 -78 8 C C 94% 94% 3 36 6% % ffo or r 7 7 89% 89% 2 2 s stte ep ps s NH NH O OH H-H -HC Cll,, L LiiO OH H SO SOC Cll ,, p py yri rid diin ne e T TH HF F::H H O O 100% 100% 12 12 11 11 10 14 14 T TH HF F: :Me MeO OH H: :T TH HF F 9 92 2% % ffo or r H HA AT TU U,, D DIIEA EA,, C CH H2 2Cl Cl2 2 2 2 s stte ep ps s 13 13 88% 88% 15 Scheme G(1) Preparation of 1-chlorooxopropanyl acetate (3) A Ac cO OH H,, H H2 2SO SO4 4 ( (C CO OC Cll) )2 2 tto ollu ue en ne e 92% 92% 100% 100% 3a 3a 3b 3b Scheme G(2) Synthesis of 2-amino-N-(2,2-difluoro-ethyl) acetamide hydrochloride H HC Cll//E EA A D DIIE EA A,, H HA AT TU U EA EA 17 17 14 14 16 16 Scheme G(3) Synthesis of 3-[5-(3,5-dichlorofluoro-phenyl) trifluoromethyl-4,5-dihydro-isoxazolyl]-5,6-dihydro-4H-cyclopenta[c] thiophenecarboxylic acid [(2,2-difluoro-ethylcarbamoyl)-methyl]- amide 14 14 D DIIE EA A,, H HA AT TU U,, C CH H3 3CN CN 13 13 15 Example 244 3-[5-(3,5-dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro- isoxazolyl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid [(2,2-difluoro-ethylcarbamoyl)-methyl]-amide F C H A) Synthesis of 2-acetoxy-propionic acid CO H 2 Reflux a mixture of 2-hydroxy-propionic acid (480 ml, 85% in water) and sulfuric acid (2 mL) in acetic acid (2500 mL) and toluene (300 mL) for overnight. After removal of solvent under vacuum, purify the residue by distillation to give 2-acetoxy-propionic acid (550 g, 92%) as colorless oil. H NMR (CDCl , 400 MHz): δ 9.27 (brs, 1H), 5.10 (m, 1H), 2.13 (s, 3H), 1.53 (d, J=7.2, 3H).

B) Synthesis of 1-chlorooxopropanyl acetate COCl Stir a mixture of 2-acetoxy-propionic acid (550 g, 4.16 mol) in oxalyl chloride (500 mL) at room temperature for overnight. After removal of oxalyl chloride under vacuum, ~700g crude product is obtained (quantitative yield crude), which is used directly in the next step. H NMR (CDCl , 400 MHz): δ 5.16 (m, 1H), 2.13 (s, 3H), 1.58 (d, J=7.2, 3H).

C) Synthesis of 1-cyclopentenylpyrrolidine Reflux a mixture of cyclopentanone (600 g, 7.14 mol), pyrrolidine (550 g, 4.68 mol) and toluenesulfonic acid (5.0 g) in toluene (3 L) for 4 hours. After removal of solvent under vacuum, purify the residue by distillation carefully to give 1-cyclopentenyl-pyrrolidineas colorless oil (898g, 6.55 mol, 91.8%). H NMR (CDCl , 400 MHz): δ 4.04 (m, 1H), 3.06 (m, 4H), 2.39 (m, 4H), 1.85 (m, 6H).

D) Synthesis of 1-oxo(2-(pyrrolidinyl)cyclopentenyl)propanyl acetate Add dropwise a solution of 1-chlorooxopropanyl acetate (600 g, 3.98 mol) in toluene (1200 mL) to a solution of 1-cyclopentenyl-pyrrolidine (546.7 g, 3.98 mol) and triethyl amine (483.9 g, 4.78 mol) in toluene (2400 mL). Reflux the mixture for overnight. Filter the mixture and concentrate the filtration to give crude 1-oxo(2-(pyrrolidinyl)cyclopentenyl)propanyl acetate (952 g), which is used in next step without further purification. H NMR (CDCl , 400 MHz): δ 5.27 (m, 1H), 3.56 (m, 2H), 3.16 (m, 2H), 2.83 (m, 1H), 2.58 (m, 3H), 2.10 (s, 3H), 1.93 (m, 2H), 1.82 (m, 4H), 1.36 (d, J=7.2, 3H).

E) Synthesis of 1-oxo(2-oxocyclopentyl)propanyl acetate Stir a mixture of 1-oxo(2-(pyrrolidinyl) cyclopentenyl)propanyl acetate (952.0 g), acetic acid (1500 mL) and water (1500 mL) in tetrahydrofuran (3000 mL) at room temperature for 2 days. Dilute the mixture with water (1200 mL) and dichloromethane (1200 mL). The organic layer is washed with brine, dried over anhydrous Na SO and concentrated under vacuum. Purify the residue by silica gel chromatograph (eluting with 3% to 10% ethyl acetate in petroleum ether) to give 1-oxo(2-oxocyclopentyl)propanyl acetate as oil (573.4g, 2.89 mol, 72.6% for 2 steps).

F) Synthesis of 1-chloro(2-oxocyclopentylidene)propanyl acetate A mixture of 1-oxo(2-oxocyclopentyl)propanyl acetate (8.0 g, 0.04 mol) and tributylphosphane (13.9 g, 0.069 mol) in CCl (100 mL) at 60℃ overnight. After removal of solvent, the residue is purified by silica gel column (eluting with 1% to 2.5% ethyl acetate in petroleum ether) to give a mixture of 1-chloro(2-oxocyclopentylidene)propanyl acetate and 1-(2-chlorocyclopentenyl) oxopropanyl acetate (5.47 g, 6:1 based on HNMR) as yellow oil.

G) Synthesis of methyl 3-(1-hydroxyethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene- 1-carboxylate Add sodium hydride (60% in mineral oil, 2.12 g, 0.053 mol) to a solution of mercapto-acetic acid methyl ester (2.8 g, 0.026 mol) in tetrahydrofuran (100 mL) at -10 ºC~0 ºC and stirred the mixture at -10 ºC~0 ºC for 1 hour. Then add a mixture of 1-chloro(2-oxocyclopentylidene)propanyl acetate and 1-(2-chlorocyclopentenyl) oxopropanyl acetate (5.47 g, 0.025 mol, 6:1) in tetrahydrofuran (15 mL) at 0 ºC. After stiring at 0 ºC for overnight, dilute the reaction mixture with water and extract with ethyl acetate. The combined organic layers are washed with brine, dried over anhydrous Na SO and concentrated. The residue and K CO (6.9 g, 0.05 mol) in MeOH (20 mL) is 2 4 2 3 heated at 50 ºC overnight. The solvent is removed. The residue is purified by silica gel chromatograph (eluting with 2.5% to 10% ethyl acetate in petroleum ether) to give 3-(1-hydroxy-ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid methyl ester (3.2 g, 14.1 mmol, 35.6% for 2 steps) as yellow oil. H NMR (CDCl , 400 MHz): δ .03 (m, 1H), 3.83 (m, 3H), 2.88 (m, 2H), 2.66 (m, 2H), 2.38 (m, 2H), 2.12 (s, 1H), 1.54 (d, J=7.2, 3H).

H) Synthesis of methyl 3-acetyl-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylate Reflux a mixture of 3-(1-Hydroxy-ethyl)-5,6-dihydro-4H-cyclopenta[c] thiophenecarboxylic acid methyl ester (3.2 g, 0.0141 mol) and manganese dioxide (10.8 g, 0.124 mol) in dichloromethane for 2 hours. Filter the hot reaction mixture solution and concentrate the filtration under vacuum. Purify the residue by silica gel chromatograph (eluting with 2% to 10% ethyl acetate in petroleum ether) to give 3-acetyl-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid methyl ester as white solid (3.0 g, 13.39 mmol, 94.5%). H NMR (CDCl , 400 MHz): δ 3.88 (s, 3H), 2.96 (m, 4H), 2.50 (s, 3H), 2.45 (m, 2H).

I) Synthesis of 3-[3-(3,5-Dichlorofluoro-phenyl)-4,4,4-trifluorohydroxy-butyryl]-5,6- dihydro-4H-cyclopenta[c]thiophenecarboxylic acid methyl ester Add a solution of LiHDMS (1M in THF, 75 mL, 75 mmol) to a suspension of 3-acetyl-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid methyl ester (14.0 g, 62.5 mmol) in dry THF (200 mL) at -78 C under N . After stirring at room temperature for 1.5 h, add 1-(3,5-dichlorofluoro-phenyl)-2,2,2-trifluoro-ethanone (17.9 g, 68.7 mmol) in dry THF (100 mL) to the reaction mixture and stir the resultant mixture at the same temperature for additional 2 hours. Quench the reaction with saturated NH Cl aqueous solution. Extract the aqueous mixture with EtOAc (100 mL ×3). The combined organic layers are washed with brine, dried over anhydrous Na SO and concentrated under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc 15:1) to afford 3-[3-(3,5- Dichlorofluoro-phenyl)-4,4,4-trifluorohydroxy-butyryl]-5,6-dihydro-4H-cyclopenta [c]thiophenecarboxylic acid methyl ester as an orange solid (27 g, 89.3%). MS (m/z): 486 (M+1).

J) Synthesis of 3-[3-(3,5-Dichlorofluorophenyl)-4,4,4-trifluorobutenoyl]-5,6- dihydro-4H-cyclopenta[c]thiophenecarboxylic acid methyl ester Stir a mixture of 3-[3-(3,5- Dichlorofluoro-phenyl)-4,4,4-trifluorohydroxyl- butyryl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid methyl ester (26 g, 53.7 mmol), SOCl (12.7 g, 7.8 mL, 0.107 mmol) and pyridine (42.3 g, 0.537 mmol) in anhydrous DCM (300 mL) at room temperature for 3 hours. Concentrate the mixture under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc 12:1) to afford 3-[3-(3,5-Dichlorofluoro-phenyl)-4,4,4-trifluoro-butenoyl]-5,6-dihydro-4H-cyclope nta[c]thiophenecarboxylic acid methyl ester as a pale yellow solid (25 g, 100 %). (m/z): 467 (M+1).

K) Synthesis of 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro- isoxazolyl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid methyl ester Stir a mixture of 3-[3-(3,5-Dichlorofluoro-phenyl)-4,4,4-trifluoro-but enoyl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid methyl ester (25 g, 53.6 mmol), NaOH (8.6 g, 0.214 mol) and NH OH-HCl (7.4 g, 0.107 mmol) in water (100 mL) and THF (200 mL) at room temperature for overnight. After removal of the solvent under vaccum, the solution is diluted with water and extracted with EtOAc (200 mL x 3). The combined organic layer is washed with brine, dried over anhydrous Na2SO4 and concentrated by vacuum to afford 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl -4,5-dihydro-isoxazolyl] -5,6- dihydro-4H-cyclopenta[c]thiophenecarboxylic acid methyl ester as a white solid (26 g), which is used directly in the next step without purification. MS (m/z): 483(M+1).

L) Synthesis of 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro- isoxazolyl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid Stir a mixture of 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5- dihydro-isoxazolyl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid methyl ester (26 g, 54.1 mmol) and LiOH-H O (4.54 g, 0.108 mmol) in water (200 mL) and THF (400 mL) at 50 C for 0.5 hour. After removal of organic solvent under vacuum, dilute the residue with ice water (100 mL). Acidify the aqueous mixture with conc. HCl to pH = 1, and extract the resultant mixture with EtOAc (200 mL×3). Purify the residue by silica gel chromatograph (EtOAc:MeOH 6:1) to afford 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl- 4,5-dihydro-isoxazolyl]-5,6-dihydro-4H- cyclopenta[c]thiophenecarboxylic acid as a white solid (23 g, 91.7 % for 2 steps). MS (m/z): 468 (M+1).

M) Synthesis of [(2,2-difluoro-ethylcarbamoyl)-methyl]-carbamic acid tert-butyl ester N) Boc N To a solution of compound tert-butoxycarbonylamino acetic acid (19.6 g, 0.1 mol) in dichloromethane (200 mL) is added N,N-diisopropylethylamine (13.2 g, 0.1 mol), 2,2-difluoroethylamine (10 g, 0.1 mol) and HATU (23 g, 0.17 mol), after the addition the mixture is stirred at room temperature for 1 hour. After being detected by TLC and LCMS, the reaction mixture is diluted with dichloromethane, then the solution is washed with water and brine, dried over anhydrous Na SO , filtered, concentrated and the residue is dried in vacuum to give 30 g crude product, which is used directly in next step.

O) Synthesis of 2-amino-N-(2,2-difluoro-ethyl) acetamide hydrochloride H N F To a solution of compound [(2,2-difluoro-ethylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (30 g crude product, 0.13 mol) in acetic acid ethyl ester (100 mL) is added 4 M HCl (100 mL, 4 mol/L in acetic acid ethyl ester) dropwise under ice-water bath. After the additon the reaction mixture is warmed to room temperature and stirred for overnight. The precipitate is collected and dried in vacuum to give desired product (20 g, 93 % for two steps) as a white solid. 1H NMR (DMSO-d , 400 MHz): δ 8.91 (t, J=6.0, 1 H), 8.25 (brs, 3 H), 6.21-5.91 (m, 1 H), 3.64-3.53 (m, 4 H).

O) Synthesis of 3-[5-(3,5-dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro- isoxazolyl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid [(2,2-difluoro-ethylcarbamoyl)-methyl]-amide F C H Cl To a solution of compound 3-[5-(3,5-dichlorofluoro-phenyl)trifluoromethyl -4,5-dihydro-isoxazolyl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid (3 g, 6.4 mmol) in acetonitrile (30 mL) is added N,N-diisopropylethylamine (2.5 g, 19 mmol), 2-amino-N-(2,2-difluoro-ethyl)-acetamide hydrochloride (1.34 g, 7.7 mmol) and HATU (3.7 g, 9.6 mmol), after the addition the mixture is stirred at room temperature for 1 hour.

After being detected by TLC and LCMS, the reaction mixture is concentrated and the residue is purified by column chromatography to afford desired product (3 g, 88 %). MS (m/z): 588.1 (M+1).

Scheme H SFC Separation of Example 244 to provide S Form S SF FC C s se ep pa ara rattiio on n 15 SS-1 -15 5 Example 245 (S)[5-(3,5-dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro- isoxazolyl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid [(2,2-difluoro-ethylcarbamoyl)-methyl]-amide F C H 3 g of 3-[5-(3,5-dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro- isoxazolyl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid [(2,2-difluoro-ethylcarbamoyl)-methyl]-amide is separated by SFC separation to give desired product (1.4 g, 93 %). 1H NMR (CDCl , 400 MHz): δ 7.56 (d, J=6.0, 2 H), 6.64 (brs, 1 H), 6.40 (brs, 1 H), 6.03-5.73 (m, 1 H), 4.15 (d, J=5.2, 2 H), 4.01 (d, J=17.2, 1 H), 3.74-3.65 (m, 1 H), 3.62 (d, J=17.2, 1 H), 2.97 (t, J=7.6, 2 H), 2. 89 (t, J=7.6, 2 H), 2.56 (m, 2 H).

SFC conditions are as follows: Instrument: Thar 350 Column: AD 250mm*50mm, 10um Mobile phase: A: Supercritical CO2, B: EtOH, A:B =60:40 at 240ml/min Column Temp: 38 C Nozzle Pressure: 100Bar Nozzle Temp: 60 C Evaporator Temp: 20 C Trimmer Temp: 25 C Wavelength: 220nm Scheme I L LiiO OH H H H2 2O O 18 18 T TH HF/ F/H H O O D DIIEA EA,, H HA AT TU U,, C CH H CN CN 9 91 1% % ffo or r ttw wo o s stte ep ps s 19 19 12 12 21 21 D DIIEA EA,, H HA AT TU U,, C CH H3 3CN CN 92% 92% 22 22 20 SF SFC C 22 22 SS-2 -22 2 Example 246 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro-isoxazol yl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid [(2-fluoro-ethylcarbamoyl)-methyl]-amide A) Synthesis of ({3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro-isoxazol- 3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarbonyl}-amino)-acetic acid methyl ester To a solution of compound 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro -isoxazolyl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid (10.0 g, 21.4 mmol) in dichloromethane (100 mL) is added triethylamine (6.49 g, 64.2 mmol), glycine methyl ester hydrochloride (3.2 g, 25.7 mmol) and HATU (12.2 g, 32.1 mmol), after the addition the mixture is stirred at room temperature for 1 hour. After being detected by TLC and LCMS, the reaction mixture is diluted with dichloromethane, then the solution is washed with water and brine, dried over anhydrous Na SO , filtered, concentrated and the residue is dried in vacuum to give 11 g crude product, which is used directly in next step.

B) Synthesis of ({3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro-isoxazol yl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarbonyl}-amino)-acetic acid Stir a mixture of ({3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro-isoxazol yl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarbonyl}-amino)-acetic acid methyl ester (11 g, 18.6 mmol) and LiOH-H O(1.56 g, 37.2 mmol) in THF (100 mL) and water (50 mL) at room temperature for overnight. After being checked with TLC, the solvent is removed under vacuum, dilute the residue with water (50 mL). Acidify the aqueous mixture with 2M HCl to pH = 3, and extract the resultant mixture with EtOAc (100 mL×3), the combined organic layer is washed with brine, dried over anhydrous Na SO and concentrated under vacuum, the residue is purified by silica gel chromatograph (PE : EtOAc 1:1) to afford ({3-[5-(3,5-Dichlorofluoro-phenyl) trifluoromethyl-4,5-dihydro-isoxazolyl]-5,6-dihydro-4H-cyclopenta[c]thiophene carbonyl}-amino)-acetic acid as a white solid (10.2 g, 90.7 % for two steps). MS (m/z): 525 (M+1).

C) Synthesis of 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro-isoxazol yl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid [(2-fluoro-ethylcarbamoyl)-methyl]-amide To a solution of compound ({3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl -4,5-dihydro-isoxazolyl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarbonyl}-amino)- acetic acid (100 mg, 0.19 mmol) in acetonitrile (5 mL) is added N,N-diisopropylethylamine (49.3 mg, 0.38 mmol), 2-fluoro-ethylamine (14.4 mg, 0.23 mmol) and HATU (108.8 mg, 0.29 mmol), after finished the mixture is stirred at room temperature for 1 hour. After being detected by TLC and LCMS, the reaction mixture is concentrated and the residue is purified by column chromatography to afford desired product (100 mg, 92 %). MS (m/z): 570.1 (M+1).

Example 247 (S)- 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro -isoxazolyl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid [(2-fluoro-ethylcarbamoyl) -methyl]-amide 100 mg of 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-5,6- dihydro-4H-cyclopenta[c]thiophenecarboxylic acid [(2-fluoro-ethylcarbamoyl)-methyl]-amide is separated by SFC separation to give desired product (40 mg, 80 %). 1H NMR (CDCl , 400 MHz): δ 7.49 (d, J=6.0, 2 H), 6.64 (brs, 1 H), 6.34 (brs, 1 H), 4.52 (t, J=4.8, 1 H), 4.40 (t, J=4.8, 1 H), 4.06 (d, J=4.4, 2 H), 3.94 (d, J=17.2, 1 H), 3.63-3.52 (m, 3 H), 2.90 (t, J=7.6, 2 H), 2. 81 (t, J=7.6, 2 H), 2.47 (m, 2 H).

SFC conditions are as follows: Instrument: Thar SFC 80 Column: AD 250mm*20mm, 20um Mobile phase: A: Supercritical CO2 , B: EtOH （0.05%DEA ）, A:B =45:55 at 80ml/min Column Temp: 38 ℃ Nozzle Pressure: 100Bar Nozzle Temp: 60 ℃ Evaporator Temp: 20 ℃ Trimmer Temp: 25 ℃ Wavelength: 220nm Scheme J D DIIEA EA,, H HA AT TU U SF SFC C s se ep pa ara rattiio on n Example 248 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5- dihydroisoxazolyl)-N-(2-oxo(propynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[ c]thiophenecarboxamide Stir a mixture of 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5- dihydroisoxazolyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid (0.8 g, 1.7 mmol), N,N-diisopropylethylamine (663 mg, 5.1 mmol), 2-amino-N-(propynyl) acetamide hydrochloride (305 mg, 2.0 mmol) and HATU (974 g, 2.6 mmol) in CH Cl (10 mL) at room temperature for 2 hours. The reaction mixture is diluted with CH Cl (40 mL) and is washed with water (10 mLx3) and brine. Then the organic layer is dried over anhydrous Na SO and concentrated under vacuum. Purify the residue by preparative HPLC to afford 3-(5-(3,5-dichloro fluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N-(2-oxo(propynyla mino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxamide as a white solid (850 mg, 88.4 %). MS (m/z): 584.1 (M+Na).

Example 249 (S)(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N-( 2-oxo(propynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene carboxamide F C H Cl 850 mg of 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5- dihydroisoxazolyl)-N-(2-oxo(propynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[ c]thiophenecarboxamide is separated by SFC to give (S)(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N-( 2-oxo(propynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxamid e (400 mg, 94 % yield, 99.7% ee).

H NMR (400 MHz, CDCl ) δ 7.58 (d, J=6.0, 2 H), 6.76 (t, J=4.8, 1 H), 6.46 (t, J=4.8, 1 H), 4.14 (m, 4 H), 4.03 (d, J=17.2, 1 H), 3.64 (d, J=17.2, 1 H), 2.99 (t, J=7.6, 2 H), 2.90 (t, J=7.6, 2 H), 2.56 (m, 2 H), 2.29 (t, J=2.8, 1 H). MS (m/z): 584.1 (M+Na).

SFC analysis condition: Column: Chiralcel AS-H 150×4.6mm I.D., 5um.

Mobile phase: EtOH in CO from 5% to 40% over 8 minutes. Flow rate: 3 mL/min.

Wavelength: 220 nm. The S-isomer elutes at 4.00 minutes.

Instrument: Thar SFC 200; Column : AS 250mm*50mm,10um; Mobile phase: A: Supercritical CO , B: EtOH, A:B =45:55 at 200ml/min; Column Temp: 38 C; Nozzle Pressure: 100Bar; Nozzle Temp: 60 C; Evaporator Temp: 20 C; Trimmer Temp: C; Wavelength: 220nm.

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 al., 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 10mM. Using 96-well microtiter plates, an aliquot of the 10mM 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 (Amblyomma 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 as follows: % Efficacy = (# dead larvae)/(# total larvae) X 100.

The following of the Examples exhibited efficacy, and at the level of ≥ 80% efficacy when tested in this assay at 300 micromolar: 32, 36, 37, 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, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87b, 94, 95, 96, 230, 231, 232, 233, 236, 237, 240, 241, 243, 244, 245, 246, 247, and 249.

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 al., J. Med. Entomol. 43(3): 526-532(2006). The assay may be modified by using a different tick species (the reference describes Amblyomma 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, 87b, 95, 96, 234, 235, 240, 241, 243, 244, 245, 246, 247, and 249.

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

The following are embodiments of the invention, or are described herein, and are non-limiting. 1. A compound, or a salt thereof, of formula I wherein A is or 1 ; n is 0 or 1; R is thienyl or phenyl, said thienyl or phenyl substituted with 2 or 3 of the same or different halo atoms; R is at each occurrence independently hydrogen, C –C alkyl, C –C 1 5 3 6 cycloalkyl, or C –C haloalkyl; (CH ) R R is ; p is at each occurrence independently 0 or 1; R is C –C alkyl, C –C haloalkyl, C –C cyanoalkyl, C –C alkylthio, 1 5 1 5 1 5 1 5 C –C cycloalkyl optionally substituted with hydroxy, halo, or C –C alkyl: C –C 3 6 1 5 3 5 cycloheteroalkyl optionally substituted with C –C alkyl, C –C cycloalkyl, or C –C 1 5 3 6 1 5 (CH ) haloalkyl: phenyl, thienyl, 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; R is hydroxy, -O-(C –C alkyl), or R ; R is hydrogen, C –C alkyl, C –C haloalkyl, C –C cyanoalkyl, C –C 1 5 1 5 1 5 1 5 alkylthio, or C –C alkynyl; or R and R combine to form, with the nitrogen to which they are attached, O ; Y , Y , and Y are carbon or nitrogen with at most only one of Y , Y , and 1 2 3 1 2 Y being nitrogen, and when Y , Y , or Y is a carbon, each may be substituted by C –C 3 1 2 3 1 5 alkyl; R is hydrogen, halo, C –C alkyl, or (CH ) ; R is hydroxy, -O-(C –C alkyl), or (CH ) R is C –C alkyl, N N R or O ; and R is hydrogen, C –C alkyl, C –C haloalkyl, C –C cyanoalkyl, C –C 1 5 1 5 1 5 1 5 alkylthio, or C –C alkynyl. 2. A compound of clause 1 wherein A is 3. A compound according to any of clauses 1-2 wherein R is hydrogen and n is 1. 4. A compound of according to any of clauses 1-3 wherein R is CF or O OH C CH O .

. A compound according to any of clauses 1 to 4, or salt thereof, being 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N-( (R)oxopyrrolidinyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; N,N-Dimethyl(4-{3-[5-(3,4,5-trichloro-thiophenyl)trifluoromethyl- 4,5-dihydro-isoxazolyl]-4,5,6,7-tetrahydro-benzo[c]thiophenecarbonyl}-piperaziny l)-acetamide; ({3-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl] -4,5,6,7-tetrahydro-benzo[c]thiophenecarbonyl}-amino)-acetic acid methyl ester; ({3-[5-(3,4,5-Trichloro-thiophenyl)trifluoromethyl-4,5-dihydro-isoxa zolyl]-4,5,6,7-tetrahydro-benzo[c]thiophenecarbonyl}-amino)-acetic acid methyl ester; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(2-oxo(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecar boxamide; 3-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-4 ,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid (1,1-dioxo-thietanyl)-amide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(3-oxocyclohexyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; 3-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-4 ,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid (1,1-dioxo-hexahydro-1l6-thiopyranyl)-amide; 3-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-4 ,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid [2-oxo(2,2,2-trifluoro-ethyl)-pyrrolidin- 3-yl]-amide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -((R)oxopyrrolidinyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxamide; N-(2-(cyanomethylamino)oxoethyl)(5-(3,5-dichlorophenyl)(triflu oromethyl)-4,5-dihydroisoxazolyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxa mide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(2-oxo(propynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxam ide; N-(2-oxo(2,2,2-trifluoroethylamino)ethyl)(5-(3,4,5-trichlorophenyl)- -(trifluoromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarb oxamide; N-((R)oxopyrrolidinyl)(5-(3,4,5-trichlorophenyl)(trifluorometh yl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; N-(2-(cyanomethylamino)oxoethyl)(5-(3,4,5-trichlorophenyl)(trifl uoromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxami N-(2-oxo(propynylamino)ethyl)(5-(3,4,5-trichlorophenyl)(trifl uoromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxami de; 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazo lyl)-N-(2-oxo(2,2,2-trifluoroethylamino)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene carboxamide; 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazo lyl)-N-((R)oxopyrrolidinyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide N-(2-(cyanomethylamino)oxoethyl)(5-(3,5-dichlorofluorophenyl) (trifluoromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecar boxamide; 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazo lyl)-N-(2-oxo(propynylamino)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarb oxamide; N-(2-oxo(2,2,2-trifluoroethylamino)ethyl)(5-(3,4,5-trichlorophenyl)- -(trifluoromethyl)-4,5-dihydroisoxazolyl)-5,6-dihydro-4H-cyclopenta[c]thiophene carboxamide; N-((R)oxopyrrolidinyl)(5-(3,4,5-trichlorophenyl)(trifluorometh yl)-4,5-dihydroisoxazolyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxamide; N-(2-(cyanomethylamino)oxoethyl)(5-(3,4,5-trichlorophenyl)(trifl uoromethyl)-4,5-dihydroisoxazolyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecarbox amide; N-(2-oxo(propynylamino)ethyl)(5-(3,4,5-trichlorophenyl)(trifl uoromethyl)-4,5-dihydroisoxazolyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecarbox amide; N-(2-oxo(2,2,2-trifluoroethyl)pyrrolidinyl)(5-(3,4,5-trichlorophen yl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-5,6-dihydro-4H-cyclopenta[c]thiophene carboxamide; 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazo lyl)-N-(2-oxo(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thioph enecarboxamide; 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazo lyl)-N-((R)oxopyrrolidinyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxam ide; N-(2-(cyanomethylamino)oxoethyl)(5-(3,5-dichlorofluorophenyl) (trifluoromethyl)-4,5-dihydroisoxazolyl)-5,6-dihydro-4H-cyclopenta[c]thiophene carboxamide; 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazo lyl)-N-(2-oxo(2,2,2-trifluoroethyl)pyrrolidinyl)-5,6-dihydro-4H-cyclopenta[c]thi ophenecarboxamide; 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazo lyl)-N-(2-oxo(propynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophenec arboxamide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(2-oxo(2,2,2-trifluoroethylamino)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarbo xamide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(2-(ethylamino)oxoethyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -((tetrahydrofuranyl)methyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(2-(methylthio)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(3-hydroxycyclohexyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(5-fluoropyridinyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(tetrahydro-2H-pyranyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(thietanyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(tetrahydro-2H-pyranyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; N-(1-cyclopropyloxopyrrolidinyl)(5-(3,5-dichlorophenyl)(triflu oromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamid N-(2-oxo(propynylamino)ethyl)(5-(3,4,5-trichlorothiophenyl)- -(trifluoromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarb oxamide; 3-[5-(3,4,5-Trichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl] -4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid (1,1-dioxo-hexahydro-thiopyranyl)-amide; N-(2-oxo(2,2,2-trifluoroethyl)pyrrolidinyl)(5-(3,4,5-trichlorophen yl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophene carboxamide; N-(tetrahydro-2H-pyranyl)(5-(3,4,5-trichlorophenyl)(trifluoromet hyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; N-(1-cyclopropyloxopyrrolidinyl)(5-(3,4,5-trichlorophenyl)(tri fluoromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxa mide; 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro-isoxaz olyl]-4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid (1,1-dioxo-thietanyl)-amide; 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro-isoxaz olyl]-4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid (1,1-dioxo-hexahydro-thiopyranyl)-amide; 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazo lyl)-N-(4-oxocyclohexyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazo lyl)-N-(2-oxo(2,2,2-trifluoroethyl)pyrrolidinyl)-4,5,6,7-tetrahydrobenzo[c]thioph enecarboxamide; 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazo lyl)-N-(tetrahydro-2H-pyranyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide ; N-(1-cyclopropyloxopyrrolidinyl)(5-(3,5-dichlorofluorophenyl )(trifluoromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiopheneca rboxamide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(4-oxocyclohexyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxamide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(2-oxo(2,2,2-trifluoroethyl)pyrrolidinyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1 -carboxamide; 3-((R)(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazoly l)-N-((R)oxopyrrolidinyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; 3-((S)(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl )-N-((R)oxopyrrolidinyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; N-(4-carbamoylphenyl)(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5- dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; 3-[5-(3,4,5-Trichloro-thiophenyl)trifluoromethyl-4,5-dihydro-isoxaz olyl]-4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid (3-carbamoyl-thiophenyl)-amide; 2-(3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl) - 4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamido)acetic acid; ({3-[5-(3,4,5-Trichloro-thiophenyl)trifluoromethyl-4,5-dihydro-isoxa zolyl]-4,5,6,7-tetrahydro-benzo[c]thiophenecarbonyl}-amino)-acetic acid; N-(2-(cyanomethylamino)oxoethyl)(5-(3,5-dichlorophenyl) (trifluoromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarbo xamide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(2-oxo(propynylamino)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; or N-(2-(cyanomethylamino)oxoethyl)(5-(3,4,5-trichlorothiophenyl)- -(trifluoromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarb oxamide. 6. A compound of clause 1 wherein A is 7. A compound of clause 1 or 6 wherein Y is nitrogen. 8. A compound according to any of clauses 1, 6, or 7, wherein R is 9. A compound according to any of clauses 6-8, or salt therof, being 3-(4-chlorobenzo[b]thiophenyl)(3,5-dichlorophenyl)(trifluoromet hyl)-4,5-dihydroisoxazole; 2-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-t hieno[2,3-c]pyridine; 5-Bromo[5-(3,5-dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxaz olyl]-thieno[2,3-b]pyridine; 2-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-t hieno[2,3-b]pyridine; 3-(benzo[b]thiophenyl)(3,5-dichlorophenyl)(trifluoromethyl)-4,5- dihydroisoxazole; 3-(benzo[d]thiazolyl)(3,5-dichlorophenyl)(trifluoromethyl)-4,5-di hydroisoxazole; -(3,5-dichlorophenyl)(3-methylbenzo[b]thiophenyl)(trifluoromet hyl)-4,5-dihydroisoxazole; 5-(3,5-dichlorophenyl)(5-methylbenzo[b]thiophenyl)(trifluoromet hyl)-4,5-dihydroisoxazole; 3-(5-chlorobenzo[b]thiophenyl)(3,5-dichlorophenyl)(trifluoromet hyl)-4,5-dihydroisoxazole; methyl 2-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)thieno[2,3-b]pyri dinecarboxylate; 2-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-t hieno[2,3-b]pyridinecarboxylic acid; 2-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(2-oxo(2,2,2-trifluoroethylamino)ethyl)thieno[2,3-b]pyridinecarboxamide; or 2-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -((R)oxopyrrolidinyl)thieno[2,3-b]pyridinecarboxamide. 10. A compound, or salt thereof, being (S)(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisox azolyl)-N-(2-oxo(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thi ophenecarboxamide; 3-[5-(3,5-dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro- isoxazolyl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid [(2,2-difluoro-ethylcarbamoyl)-methyl]-amide; (S)[5-(3,5-dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro- isoxazolyl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid [(2,2-difluoro-ethylcarbamoyl)-methyl]-amid); 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro-isoxaz olyl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid [(2-fluoro-ethylcarbamoyl)-methyl]-amide; (S)- 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro -isoxazolyl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid [(2-fluoro-ethylcarbamoyl) -methyl]-amide; 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5- dihydroisoxazolyl)-N-(2-oxo(propynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[ c]thiophenecarboxamide; or (S)(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisox azolyl)-N-(2-oxo(propynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene- 1-carboxamide. 11. A formulation comprising a compound or salt of any of clauses 1-10 and one or more acceptable carriers. 12. The formulation of clause 11 wherein it further comprises at least one additional active ingredient. 13. The formulation of clause 11 or clause 12 wherein it is a human pharmaceutical formulation. 14. The formulation of clause 11 or clause 12 wherein it is a veterinary pharmaceutical formulation.

. 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 clauses 1-10 to said animal. 16. The method of clause 15 wherein at least one other active ingredient is administered to said animal. 17. The method of clause 15 or clause 16 wherein said animal is a human. 18. The method of clause 15 or clause 16 wherein said animal is a companion animal. 19. The method of clause 17 or clause 18 wherein said companion animal is a dog or cat.

. The method oaccording to any of clauses 15-19 wherein said parasite is a tick. 21. The method of clause 15 wherein said animal is a livestock animal. 22. A method for preventing or treating diseases transmitted through parasites comprising administering an effective amount of a compound of any of clauses 1-10 to an animal in need thereof. 23. The method of clause 22 wherein at least one other active ingredient is administered to said animal. 24. The method of clause 22 or clause 23 wherein said animal is a human.

. The method of clause 22 wherein said animal is a companion animal. 26. The method of clause 25 wherein said companion animal is a dog or cat. 27. The method according to any of clauses 22-26 wherein said parasite is a tick. 28. The method of clause 22 or clause 23 wherein said animal is a livestock animal. 29. A method for controlling parasites, characterized in that a compound of any of clauses 1-10 is allowed to act on the pests or their habitat, or both.

. The method of clause 29 wherein the compound is placed on a plant or an animal. 31. Use of compounds or salts thereof of any of clauses 1-10 for controlling parasites. 32. A compound or salt according to any of clauses 1-10 for use in therapy. 33. A compound or salt according to any of clauses 1-10 for use in controlling an ectoparasite infestation. 34. A compound, or salt thereof, of Formula II II wherein n is 0 or 1; R is thienyl or phenyl, said thienyl or phenyl substituted with 2 or 3 of the same or different halo atoms; and R is hydroxy, -O-(C -C alkyl), or a halo atom. 35. The compound of 34 wherein R is phenyl substituted with 2 or 3 of the same or different halo atoms. 36. The compound according to clauses 34 or 35 wherein R is hydroxy. 37. The compound according to any of clauses 34-36 wherein it is 3-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl] -4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid methyl ester; 3-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-5 ,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid methyl ester; 3-[5-(3,4,5-Trichloro-thiophenyl)trifluoromethyl-4,5-dihydro-isoxaz olyl]-4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid methyl ester 3-[5-(3,4,5-Trichloro-thiophenyl)trifluoromethyl-4,5-dihydro-isoxaz olyl]-4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid methyl ester; 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro-isoxaz olyl]-4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid methyl ester; 3-[5-(3,4,5-Trichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl] -5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid methyl ester; 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro-isoxaz olyl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid methyl ester; 3-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl] -4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid; 3-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-5 ,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid; 3-[5-(3,4,5-Trichloro-thiophenyl)trifluoromethyl-4,5-dihydro-isoxaz olyl]-4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid; 3-[5-(3,4,5-Trichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl] -4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid; 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro-isoxaz olyl]-4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid; 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro-isoxaz olyl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid; 3-[5-(3,4,5-Trichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl] -5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)- 4,5,6,7-tetrahydrobenzo[c]thiophenecarbonyl chloride; or 3-[5-(3,4,5-Trichloro-thiophenyl)trifluoromethyl-4,5-dihydro-isoxaz olyl]-4,5,6,7-tetrahydro-benzo[c]thiophenecarbonyl chloride. 38. A compound according to clause 34 wherein it is 3-[5-(3,5-dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-5,6-dih ydro-4H-cyclopenta[c]thiophenecarboxylic acid. 39. A compound according to clause 34 wherein it is 3-[5-(3,4,5-Trichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-5,6-dihydro-4 H-cyclopenta[c]thiophenecarboxylic acid. 40. A compound according to clause 34 wherein it is 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-4,5,6,7 -tetrahydro-benzo[c]thiophenecarboxylic acid. 41. A compound according to clause 34 wherein it is 3-[5-(3,4,5-Trichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-4,5,6,7-tetrah ydro-benzo[c]thiophenecarboxylic acid. 42. A process for preparing a compound according to clauses 1-5 or 10, comprising synthetically modifying a compound according to any of clauses 34-41. 43. The process of clause 42 wherein a compound according to any of clauses 34-41 is reacted with a compound of the formula R NH .

Claims (29)

WHAT WE CLAIM IS:

1. A compound, or a salt thereof, of formula I wherein A is 10 O or ; n is 0 or 1; R is thienyl or phenyl, said thienyl or phenyl substituted with 2 or 3 of the same or different halo atoms; R is at each occurrence independently hydrogen, C –C alkyl, C –C 1 5 3 6 15 cycloalkyl, or C –C haloalkyl; (CH ) R 3 2 p R is ; p is at each occurrence independently 0 or 1; R is C –C alkyl, C –C haloalkyl, C –C cyanoalkyl, C –C alkylthio, 1 5 1 5 1 5 1 5 C –C cycloalkyl optionally substituted with hydroxy, halo, or C –C alkyl; C –C 3 6 1 5 3 5 20 cycloheteroalkyl optionally substituted with C –C alkyl, C –C cycloalkyl, or C –C 1 5 3 6 1 5 (CH ) 5 haloalkyl; phenyl, thienyl, pyridinyl, or , 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; R is hydroxy, -O-(C –C alkyl), or ; 10 R is hydrogen, C –C alkyl, C –C haloalkyl, C –C cyanoalkyl, C –C 1 5 1 5 1 5 1 5 alkylthio, or C –C alkynyl; or R and R combine to form, with the nitrogen to which they are attached, Y , Y , and Y are carbon or nitrogen with at most only one of Y , Y , and 1 2 3 1 2 15 Y being nitrogen, and when Y , Y , or Y is a carbon, each may be substituted by C –C 3 1 2 3 1 5 alkyl; R is hydrogen, halo, C –C alkyl, or (CH ) R is hydroxy, -O-(C –C alkyl), or (CH ) 20 R ; R is C –C alkyl, 2 10 R N R 5 or O ; and R is hydrogen, C –C alkyl, C –C haloalkyl, C –C cyanoalkyl, C –C 1 5 1 5 1 5 1 5 alkylthio, or C –C alkynyl.

2. The compound of claim 1, or a salt thereof, wherein A is 10 wherein R is hydrogen, and n is 1.

3. The compound of claim 1 or 2, or a salt thereof, wherein R is

4. The compound of claim 1, or a salt thereof, wherein A is wherein Y is nitrogen.

5. The compound of claim 4, or a salt thereof, wherein R is

6. The compound of claim 1, or a salt thereof, being 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N-( (R)oxopyrrolidinyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; N,N-Dimethyl(4-{3-[5-(3,4,5-trichloro-thiophenyl)trifluoromethyl- 10 4,5-dihydro-isoxazolyl]-4,5,6,7-tetrahydro-benzo[c]thiophenecarbonyl}-piperaziny l)-acetamide; ({3-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl] -4,5,6,7-tetrahydro-benzo[c]thiophenecarbonyl}-amino)-acetic acid methyl ester; ({3-[5-(3,4,5-Trichloro-thiophenyl)trifluoromethyl-4,5-dihydro-isoxa 15 zolyl]-4,5,6,7-tetrahydro-benzo[c]thiophenecarbonyl}-amino)-acetic acid methyl ester; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(2-oxo(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecar boxamide; 20 3-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-4 ,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid (1,1-dioxo-thietanyl)-amide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(3-oxocyclohexyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; 5 3-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-4 ,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid (1,1-dioxo-hexahydro-1l6-thiopyranyl)-amide; 3-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-4 ,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid 10 [2-oxo(2,2,2-trifluoro-ethyl)-pyrrolidin- 3-yl]-amide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -((R)oxopyrrolidinyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxamide; N-(2-(cyanomethylamino)oxoethyl)(5-(3,5-dichlorophenyl)(triflu oromethyl)-4,5-dihydroisoxazolyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxa 15 mide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(2-oxo(propynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxam ide; N-(2-oxo(2,2,2-trifluoroethylamino)ethyl)(5-(3,4,5-trichlorophenyl)- 20 5-(trifluoromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarb oxamide; N-((R)oxopyrrolidinyl)(5-(3,4,5-trichlorophenyl)(trifluorometh yl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; N-(2-(cyanomethylamino)oxoethyl)(5-(3,4,5-trichlorophenyl)(trifl 25 uoromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxami N-(2-oxo(propynylamino)ethyl)(5-(3,4,5-trichlorophenyl)(trifl uoromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxami 30 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazo lyl)-N-(2-oxo(2,2,2-trifluoroethylamino)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene carboxamide; 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazo lyl)-N-((R)oxopyrrolidinyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide 35 ; 5 N-(2-(cyanomethylamino)oxoethyl)(5-(3,5-dichlorofluorophenyl) (trifluoromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecar boxamide; 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazo lyl)-N-(2-oxo(propynylamino)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarb 10 oxamide; N-(2-oxo(2,2,2-trifluoroethylamino)ethyl)(5-(3,4,5-trichlorophenyl)- 5-(trifluoromethyl)-4,5-dihydroisoxazolyl)-5,6-dihydro-4H-cyclopenta[c]thiophene carboxamide; N-((R)oxopyrrolidinyl)(5-(3,4,5-trichlorophenyl)(trifluorometh 15 yl)-4,5-dihydroisoxazolyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxamide; N-(2-(cyanomethylamino)oxoethyl)(5-(3,4,5-trichlorophenyl)(trifl uoromethyl)-4,5-dihydroisoxazolyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecarbox amide; N-(2-oxo(propynylamino)ethyl)(5-(3,4,5-trichlorophenyl)(trifl 20 uoromethyl)-4,5-dihydroisoxazolyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecarbox amide; N-(2-oxo(2,2,2-trifluoroethyl)pyrrolidinyl)(5-(3,4,5-trichlorophen yl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-5,6-dihydro-4H-cyclopenta[c]thiophene carboxamide; 25 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazo lyl)-N-(2-oxo(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thioph enecarboxamide; 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazo lyl)-N-((R)oxopyrrolidinyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxam 30 ide; N-(2-(cyanomethylamino)oxoethyl)(5-(3,5-dichlorofluorophenyl) (trifluoromethyl)-4,5-dihydroisoxazolyl)-5,6-dihydro-4H-cyclopenta[c]thiophene carboxamide; 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazo 35 lyl)-N-(2-oxo(2,2,2-trifluoroethyl)pyrrolidinyl)-5,6-dihydro-4H-cyclopenta[c]thi ophenecarboxamide; 5 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazo lyl)-N-(2-oxo(propynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophenec arboxamide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(2-oxo(2,2,2-trifluoroethylamino)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarbo 10 xamide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(2-(ethylamino)oxoethyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -((tetrahydrofuranyl)methyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; 15 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(2-(methylthio)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N 20 -(3-hydroxycyclohexyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(5-fluoropyridinyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(tetrahydro-2H-pyranyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; 25 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(thietanyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(tetrahydro-2H-pyranyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; N-(1-cyclopropyloxopyrrolidinyl)(5-(3,5-dichlorophenyl)(triflu 30 oromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamid N-(2-oxo(propynylamino)ethyl)(5-(3,4,5-trichlorothiophenyl)- 5-(trifluoromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarb oxamide; 5 3-[5-(3,4,5-Trichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl] -4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid (1,1-dioxo-hexahydro-thiopyranyl)-amide; N-(2-oxo(2,2,2-trifluoroethyl)pyrrolidinyl)(5-(3,4,5-trichlorophen yl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophene 10 carboxamide; N-(tetrahydro-2H-pyranyl)(5-(3,4,5-trichlorophenyl)(trifluoromet hyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; N-(1-cyclopropyloxopyrrolidinyl)(5-(3,4,5-trichlorophenyl)(tri fluoromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxa 15 mide; 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro-isoxaz olyl]-4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid (1,1-dioxo-thietanyl)-amide; 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro-isoxaz 20 olyl]-4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid (1,1-dioxo-hexahydro-thiopyranyl)-amide; 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazo lyl)-N-(4-oxocyclohexyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazo 25 lyl)-N-(2-oxo(2,2,2-trifluoroethyl)pyrrolidinyl)-4,5,6,7-tetrahydrobenzo[c]thioph enecarboxamide; 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazo lyl)-N-(tetrahydro-2H-pyranyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide 30 N-(1-cyclopropyloxopyrrolidinyl)(5-(3,5-dichlorofluorophenyl )(trifluoromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiopheneca rboxamide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(4-oxocyclohexyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxamide; 5 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(2-oxo(2,2,2-trifluoroethyl)pyrrolidinyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-1 -carboxamide; 3-((R)(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazoly l)-N-((R)oxopyrrolidinyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; 10 3-((S)(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl )-N-((R)oxopyrrolidinyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; N-(4-carbamoylphenyl)(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5- dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; 3-[5-(3,4,5-Trichloro-thiophenyl)trifluoromethyl-4,5-dihydro-isoxaz 15 olyl]-4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid (3-carbamoyl-thiophenyl)-amide; 2-(3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl) - 4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamido)acetic acid; ({3-[5-(3,4,5-Trichloro-thiophenyl)trifluoromethyl-4,5-dihydro-isoxa 20 zolyl]-4,5,6,7-tetrahydro-benzo[c]thiophenecarbonyl}-amino)-acetic acid; N-(2-(cyanomethylamino)oxoethyl)(5-(3,5-dichlorophenyl) (trifluoromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarbo xamide; 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N 25 -(2-oxo(propynylamino)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarboxamide; N-(2-(cyanomethylamino)oxoethyl)(5-(3,4,5-trichlorothiophenyl)- 5-(trifluoromethyl)-4,5-dihydroisoxazolyl)-4,5,6,7-tetrahydrobenzo[c]thiophenecarb oxamide; (S)(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisox 30 azolyl)-N-(2-oxo(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thi ophenecarboxamide; 3-[5-(3,5-dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro- isoxazolyl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid [(2,2-difluoro-ethylcarbamoyl)-methyl]-amide; 5 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro-isoxaz olyl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid [(2-fluoro-ethylcarbamoyl)-methyl]-amide; (S)- 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro -isoxazolyl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid 10 [(2-fluoro-ethylcarbamoyl) -methyl]-amide; 3-(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5- dihydroisoxazolyl)-N-(2-oxo(propynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[ c]thiophenecarboxamide; (S)(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisox 15 azolyl)-N-(2-oxo(propynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene- 1-carboxamide; 3-(4-chlorobenzo[b]thiophenyl)(3,5-dichlorophenyl)(trifluoromet hyl)-4,5-dihydroisoxazole; 2-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-t 20 hieno[2,3-c]pyridine; 5-Bromo[5-(3,5-dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxaz olyl]-thieno[2,3-b]pyridine; 2-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-t hieno[2,3-b]pyridine; 25 3-(benzo[b]thiophenyl)(3,5-dichlorophenyl)(trifluoromethyl)-4,5- dihydroisoxazole; 3-(benzo[d]thiazolyl)(3,5-dichlorophenyl)(trifluoromethyl)-4,5-di hydroisoxazole; 5-(3,5-dichlorophenyl)(3-methylbenzo[b]thiophenyl)(trifluoromet 30 hyl)-4,5-dihydroisoxazole; 5-(3,5-dichlorophenyl)(5-methylbenzo[b]thiophenyl)(trifluoromet hyl)-4,5-dihydroisoxazole; 3-(5-chlorobenzo[b]thiophenyl)(3,5-dichlorophenyl)(trifluoromet hyl)-4,5-dihydroisoxazole; 5 methyl 2-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)thieno[2,3-b]pyri dinecarboxylate; 2-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-t hieno[2,3-b]pyridinecarboxylic acid; 10 2-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -(2-oxo(2,2,2-trifluoroethylamino)ethyl)thieno[2,3-b]pyridinecarboxamide; or 2-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N -((R)oxopyrrolidinyl)thieno[2,3-b]pyridinecarboxamide.

7. A compound of claim 1, or a salt thereof, being 15 (S)[5-(3,5-dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro- isoxazolyl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid [(2,2-difluoro-ethylcarbamoyl)-methyl]-amide).

8. A compound of claim 1, or a salt thereof, being (S)(5-(3,5-dichlorofluorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)-N-( 20 2-oxo(propynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxamid

9. A formulation comprising a compound or a salt thereof of any one of claims 1-8, and one or more acceptable carriers.

10. A use of a compound or a salt thereof of any one of claims 1-8 in 25 the manufacture of a medicament.

11. A method of controlling a parasite infestation in or on a non-human mammal in need thereof comprising administering an effective amount of a compound of any one of claims 1-8 or a salt thereof to said mammal.

12. The method of claim 11, wherein said non-human mammal is a 30 livestock animal. 5

13. The method of claim 11 or 12, wherein said parasite is a flea, tick, or mite.

14. The method of any one of claims 11-13, wherein said non-human mammal is a companion animal, and said parasite is a tick.

15. The method of claim 14, wherein said companion animal is a dog 10 or cat.

16. A use of a compound or a salt thereof of any one of claims 1-8 in the manufacture of a medicament for controlling a parasite infestation in or on an animal in need thereof.

17. A compound, or salt thereof, of Formula II 15 O wherein n is 0 or 1; R is thienyl or phenyl, said thienyl or phenyl substituted with 2 or 3 of the same or different halo atoms; and 20 R is hydroxy, -O-(C -C alkyl), or a halo atom.

16. The compound of claim 15 wherein the compound is 3-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl] -4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid methyl ester; 5 3-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-5 ,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid methyl ester; 3-[5-(3,4,5-Trichloro-thiophenyl)trifluoromethyl-4,5-dihydro-isoxaz olyl]-4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid methyl ester; 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro-isoxaz 10 olyl]-4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid methyl ester; 3-[5-(3,4,5-Trichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl] -5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid methyl ester; 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro-isoxaz olyl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid methyl ester; 15 3-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl] -4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid; 3-[5-(3,5-Dichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl]-5 ,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid; 3-[5-(3,4,5-Trichloro-thiophenyl)trifluoromethyl-4,5-dihydro-isoxaz 20 olyl]-4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid; 3-[5-(3,4,5-Trichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl] -4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid; 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro-isoxaz olyl]-4,5,6,7-tetrahydro-benzo[c]thiophenecarboxylic acid; 25 3-[5-(3,5-Dichlorofluoro-phenyl)trifluoromethyl-4,5-dihydro-isoxaz olyl]-5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid; 3-[5-(3,4,5-Trichloro-phenyl)trifluoromethyl-4,5-dihydro-isoxazolyl] -5,6-dihydro-4H-cyclopenta[c]thiophenecarboxylic acid; 5 3-(5-(3,5-dichlorophenyl)(trifluoromethyl)-4,5-dihydroisoxazolyl)- 4,5,6,7-tetrahydrobenzo[c]thiophenecarbonyl chloride; or 3-[5-(3,4,5-Trichloro-thiophenyl)trifluoromethyl-4,5-dihydro-isoxaz olyl]-4,5,6,7-tetrahydro-benzo[c]thiophenecarbonyl chloride.

19. A process for preparing a compound of claim 1, comprising 10 reacting a compound of claim 17 or 18 with a compound of the formula R NH wherein R and R are as defined in claim 1.

20. A compound of claim 1 prepared by the process of claim 19.

21. A compound or salt thereof of any one of claims 1-8 for use in 15 therapy.

22. A compound or salt thereof of any one of claims 1-8 for controlling a parasite infestation in or on an animal.

23. A compound or salt thereof as claimed in claim 1 or 20, substantially as herein described with reference to any example thereof. 20

24. A formulation as claimed in claim 9, substantially as herein described with reference to any example thereof.

25. A method as claimed in claim 11, substantially as herein described with reference to any example thereof.

26. A use as claimed in claim 10 or 16, substantially as herein 25 described with reference to any example thereof.

27. A compound or salt thereof as claimed in claim 17, substantially as herein described with reference to any example thereof. 5

28. A process as claimed in claim 19, substantially as herein described with reference to any example thereof.

29. A compound or salt thereof of any one of claims 1-8 for use according to claim 21 or 22, substantially as herein described with reference to any example thereof.