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.
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 :
n is 0 or 1;
R1 is thienyl or phenyl, said thienyl or phenyl substituted with 2 or 3 of the
same or different halo atoms;
R2 is at each occurrence independently hydrogen, C1-C5 alkyl, C 3
cycloalkyl, or C - C 5 haloalkyl;
p is at each occurrence independently 0 or 1;
R4 is C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 cyanoalkyl, C1-C5 alkylthio,
C3-C6 cycloalkyl optionally substituted with hydroxy, halo, or C - C 5 alkyl: C3-C5
cycloheteroalkyl optionally substituted with C - C 5 alkyl, C3-C6 cycloalkyl, or C - C 5
R5
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;
R5 is hydroxy, -0-(d-C alkyl), or
R6 is hydrogen, C1-C5 alkyl, C1-C5 haloalkyl, C - C 5 cyanoalkyl, C - C 5
alkylthio, or C2-C5 alkynyl;
or R2 and R combine to form, with the nitrogen to which they are attached,
—f O ;
Yi, Y2, and Y3 are carbon or nitrogen with at most only one of Yi, Y2, and
Y3 being nitrogen, and when Yi, Y2, or Y3 is a carbon, each may be substituted by C - C 5
alkyl;
R7 is hydrogen, halo, C - C 5 alkyl, or
R8 ( H2) ^/'
-
O
R is hydroxy, -0-(d-C alkyl), or
R is C1-C5 alkyl,
R10 is hydrogen, C - C 5 alkyl, C1-C5 haloalkyl, C1-C5 cyanoalkyl, C1-C5
alkylthio, or C2-C5 alkynyl.
The invention provides a formulation, including a pharmaceutical
formulation, comprising a compound or salt of formula I and one or more acceptable
carriers. The formulation may further comprise at least one additional active ingredient.
A pharmaceutical formulation of the invention may be a human pharmaceutical
formulation or a veterinary pharmaceutical formulation.
The invention provides a method of controlling ecto- and endoparasite
infestations of an animal in need thereof comprising administering an effective amount of a
compound or salt of formula I to said animal. The method may further provide
administering at least one other active ingredient to said animal. The animal may be a
mammal, and may be a human or a companion animal, for example, a dog or cat.
The present invention provides a method for preventing and treating
diseases transmitted through parasites comprising administering at least one compound of
the invention to an animal in need thereof.
The invention provides a method for controlling parasites, characterized in
that a compound of formula I is allowed to act on the pests and/or their habitat. The
invention provides the use of compounds or salts thereof of formula I for controlling pests.
The invention provides a compound or salt of formula I for use in therapy.
The invention further provides a compound or salt of formula I for use in controlling ectoand
endoparasite infestations. The invention also provides use of a compound or salt of
formula I for the manufacture of a formulation or medicament for controlling ecto- and
endoparasite infestations.
The invention provides compounds of Formula II, or a salt thereof, of the
formula
II
wherein n is 0 or 1;
R1 is thienyl or phenyl, said thienyl or phenyl substituted with 2 or 3 of the
same or different halo atoms; and
R11 is hydroxy, -0-(d-C 4 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.
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, Tfichonema, 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, etal, 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., 19th ed., Mack Publishing Co., 1995). Formulations can be administered
through various means, including oral administration, parenteral administration such as
injection (intramuscular, subcutaneous, intravenous, intraperitoneal) or the like; topical
application with or without transdermal penetration such as dipping, spray, bathing,
washing, pouring-on and spotting-on, and dusting, or the like. Additional active
ingredients may be included in the formulation containing a compound of the invention or a
salt thereof.
Carrier is used herein to describe any ingredient other than the active
component(s) in a formulation. The choice of carrier will to a large extent depend on
factors such as the particular mode of administration or application, the effect of the carrier
on solubility and stability, and the nature of the dosage form.
C1-C5 alkyl refers to straight chain and branched alkyls having one to five
carbon atoms, and includes methyl, ethyl, propyl, n-butyl, iso-butyl, pentyl, isopentyl, and
neopentyl.
C2-C5 alkynyl refers to straight chain and branched alkynyls having two to
five carbon atoms, and includes ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,
3-methyl- 1-butynyl, pentynyl, isopentynyl, and neopentynyl.
Halogen or halo refers to fluorine, bromine, chlorine, and iodine.
Haloalkyl as used herein refers to an alkyl (as noted above) substituted with
one or more halo atoms. Such groups include trifluoromethyl, 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 -C6 cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, and
cyclohexyl.
C3-C5 cycloheteroalkyl refers to a saturated ring which has 3 to 5 carbons
and a hetero atom. The hetero atom may be sulfur, oxygen, nitrogen, or a sulfonyl group.
Diseases transmitted through parasites, particularly ectoparasites, are, for
example bacterial, viral, rickettsial and protozoal vector-borne diseases. Examples of viral
diseases transmitted through arboviruses, i.e. arthropod borne viruses, are Crimean-Congo
Hemorhagic Fever (CCHF), Febrile illness, Papataci fever, Encephalitis, Meningitis, which
are caused by Bunyaviridae such as Bunyavirus, Nairovirus or Phlebovirus; Bluetongue,
meningoencephalits, Febrile illness, hemorhagic fever, which are caused by Reoviridae,
such as Orbivirus, Colitivirus; Febrile illness, rash, encephalitis, polyarthritis,
lymphadenitis, which are caused by Togaviridae, such as Sindbisvirus, Chikungunya
Virus; tick-borne meningoencephalitis, Dengue hemorhagic fever, encephalitis, Febrile
illness, Yellow fever, which are caused by Flaviviridae, such as Flavivirus (including
diverse sub-groups). Examples of bacterial diseases transmitted through parasites are
Rickettsiosis, such as Rocky Mountain spotted fever, tick typhus caused by infection
through Rickettsia ssp; Tularemia caused by infection through Francisella tularensis;
Borreliosis or Spirochaetosis, such as Lyme disease, or relapsing fever, caused, by
infection through Borrelia ssp.; Ehrllichiosis caused by infection through Ehrlichia ssp.;
Plague, caused by infection through Yersinia ssp. Examples of protozoal or rickettsial
borne diseases are Babesiosis, such as Texas fever, red water disease, Q-fever caused by
infection through Babesia ssp.; Theileriosis, such as east coast fever, Mediterranean coast
fever, caused by infection through Theileria ssp. ;Nagana disease, Sleeping sickness caused
by infection through Trypanosoma ssp., Anaplasmosis caused by infection through
Anaplasma ssp.; Malaria caused by infection through Plasmodium ssp.; Leishmaniasis
caused by infection through Leishmania ssp.
Given their activity, certain of the compounds of the invention are suitable
as soil insecticides against pests in the soil, as well as insecticides for plants, such as
cereals, cotton, rice, maize, soya, potatoes, vegetables, fruit, tobacco, hops, citrus, and
avocados. Certain compounds according to the invention are suitable for protecting
plants and plant organs, for increasing the harvest yields, and for improving the quality of
the harvested material which are encountered in agriculture, in horticulture, in forests, in
gardens, and leisure facilities, and in the protection of stored products and of materials.
They may be employed as plant protection agents.
All plants and plant parts can be treated in accordance with the invention.
Plants are to be understood as meaning in the present context all plants and plant
populations such as desired and undesired wild plants or crop plants (including naturally
occurring crop plants). Crop plants can be plants which can be obtained by conventional
plant breeding and optimization methods or by biotechnological and genetic engineering
methods or by combinations of these methods, including the transgenic plants and
including the plant cultivars protectable or not protectable by plant breeders' rights. Plant
parts are to be understood as meaning all parts and organs of plants above and below the
ground, such as shoot, leaf, flower and root, examples which may be mentioned being
leaves, needles, stalks, stems, flowers, fruit bodies, fruits, seeds, roots, tubers and
rhizomes. The plant parts also include harvested material, and vegetative and generative
propagation material, for example cuttings, tubers, rhizomes, offshoots and seeds.
Treatment according to the invention of the plants and plant parts with the
active compounds is carried out by conventional and known means, including directly
acting on, or by allowing the compounds to act on, the surroundings, habitat or storage
space by the customary treatment methods, for example by immersion, spraying,
evaporation, fogging, scattering, painting on, injection and, in the case of propagation
material, in particular in the case of seeds, also by applying one or more coats.
The compounds can be converted to the customary formulations, such as
solutions, emulsions, wettable powders, water- and oil-based suspensions, powders, dusts,
pastes, soluble powders, soluble granules, granules for broadcasting, suspension-emulsion
concentrates, natural materials impregnated with active compound, synthetic materials
impregnated with active compound, fertilizers and microencapsulations in polymeric
substances.
These formulations are produced in a known manner, for example by
mixing the active compounds with extenders, that is liquid solvents and/or solid carriers,
optionally with the use of surfactants, that is emulsifiers and/or dispersants and/or
foam-formers. The formulations are prepared either in suitable plants or else before or
during the application.
Suitable for use as auxiliaries are substances which are suitable for
imparting to the composition itself and/or to preparations derived therefrom (for example
spray liquors, seed dressings) particular properties such as certain technical properties
and/or also particular biological properties. Typical suitable auxiliaries are extenders,
solvents, and carriers.
Following are Schemes A- 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
Preparation 1
Methyl 2,2,2-trifluoro-l-(3,4,5-trichlorothiophen-2-yl)ethanone
Add a solution of n-BuLi (21.6 mL, 2.5 M in hexane, 54.0 mmol) to a solution of
2,3,4,5-tetrachloro-thiophene (10 g, 45.0 mmol) in dry THF (160 mL) at -78 °C and stir
the mixture for 2 hours. Add a solution of trifluoro-acetic acid ethyl ester (9.59 g, 67.6
mmol) in THF (15 mL) and stir at -78 °C for additional 2.5 hours. Quench the reaction
with saturated NH4C 1 solution (100 mL). Extract the aqueous mixture with EtOAc (100
mL X 3). The combined organic layers are washed with brine, dried over anhydrous
Na2S0 4, and evaporate under vacuum. Purify the residue by a flash column on silica gel
eluting with PE:EtOAc (10: 1 to 5:1) to afford 2,2,2-trifluoro-l-(3,4,5-trichlorothiophen-
2-yl)-ethanone as a brown oil (10.4 g, 81.9%). 1 F NMR (400 MHz, CDC13)
d -73.38 (s, 3F).
Preparation 2
Methyl 3-acetyl-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxylate
Add methyl 2-(2-oxopropylthio)acetate (35.4 g, 183.2 mmol) to a freshly prepared
solution of solid sodium (8.78 g, 381.5 mmol) in dry MeOH (300 mL) at 0 °C, followed
by addition of a solution of cyclohexane-l,2-dione (20 g, 152.6 mmol) in MeOH (30 mL).
Stir the mixture at 0° C for 30 min and then at 50-60 °C for additional 1.5 hour. Remove
the solvent under vacuum and dilute the residue with water (100 mL). Extract the aqueous
mixture with ethyl acetate (100 mL X 3). The combined organic layers are washed with
brine, dried over anhydrous Na2S0 4, and evaporated under vacuum. Purify the residue by
a flash column on silica gel eluting with PE:EtOAc (50: 1 to 30: 1) to afford methyl
3-acetyl-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxylate as a white solid (10 g,
27.6%). MS (m/z): 239 (M+l).
Preparation 3
Methyl 3-acetyl-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxylate
Stir a mixture of Cyclopentane-l,2-dione (2.00 g, 20.4 mmol), methyl
2-(2-oxopropylthio)acetate ( 3.3 1 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-lcarboxylic
acid methyl ester as a pale yellow solid (206mg, 4.5 %). MS (m/z): 225
(M+l).
Preparation 4
Methyl
3-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-4,5,6,7-tetrahydrobenzo[c]t
hiophene- 1-carboxylate
Add a solution of LDA (2M in THF, 19.5 mL, 3.89 mmol) to a suspension of
3-acetyl-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxylate (7.4 g, 3.1 1 mmol) in dry
THF (80 mL) at -78°C under N2. After stirring for 1.5 h, add l-(3,5-Dichloro-phenyl)-
2,2,2-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 NH4C 1 aqueous solution. Extract the aqueous mixture with EtOAc (100 mL><3).
The combined organic layers are washed with brine, dried over anhydrous Na2S0 4 and
concentrated under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc
50:1) to afford methyl 3-(3-(3,5-dichlorophenyl)- 4,4,4-trifluoro-3-hydroxybutanoyl)
-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxylate as an orange solid (9.1 g, 60.4 %).
MS (m/z): 481 (M+l).
The following compounds are prepared essentially by the method of
Preparation 4.
Prep.
Chemical name Structure Physical data
No.
3-[4,4,4-Trifluoro-3
-hydroxy-3-(3,4,5-tr
ichloro-phenyl)-but
7 yryl]-4,5,6,7-tetrah MS (m/z): 515 (M+1)
ydro-benzo[c]thiop
hene- 1-carboxylic
acid methyl ester
3-[3-(3,5-Dichloro-
4-fluoro-phenyl)-4,
4,4-trifluoro-3-hydr o
oxy-butyryl]-4,5,6,
8 MS (m/z): 499 (M+1)
7-tetrahydro-benzo [
c]thiophene- 1-carbo
xylic acid methyl
ester
3-[4,4,4-Trifluoro-3
-hydroxy-3-(3,4,5-tr
ichloro-phenyl)-but
9 yryl]-5,6-dihydro-4 MS (m/z): 501 (M+1)
H-cyclopenta[c]thio
phene- 1-carboxylic
acid methyl ester
Preparation 11
3-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-4,5,6,7-tetrahydro-benzo[c]thioph
ene-l-carboxylic acid methyl ester
Stir a mixture of methyl 3-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro -3- hydroxyl
butanoyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxylate (9.1 g, 18.9 mmol), SOCI 2
(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
N H4CI aqueous solution. Extract the aqueous mixture with DCM (100 mL><3). The
combined organic layers are washed with brine, dried over anhydrous Na2S0 4 and
concentrated under vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc
50:1) to afford 3-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-4,5,6,7-
tetrahydro-benzo[c]thiophene-l-carboxylic acid methyl ester as an orange solid (8.75 g,
100 %). (m/z): 463 (M+l).
The following compounds are prepared essentially by the method of
Preparation 1 1.
Prep.
Chemical name Structure Physical data
No.
3-[4,4,4-Trifluoro-3
-(3 ,4,5 -trichloro-ph
enyl)-but-2-enoyl] -
14 4,5,6,7-tetrahydro-b MS (m/z): 497 (M+1).
enzo[c]thiophene- 1-
carboxylic acid
methyl ester
3-[3-(3,5-Dichloro-
4-fluoro-phenyl)-4,
4,4-trifluoro-but-2-
15 enoyl]-4,5,6,7-tetra MS (m/z): 481 (M+1).
hydro-benzo [c]thio
phene- 1-carboxylic
acid methyl ester
3-[4,4,4-Trifluoro-3
-(3 ,4,5 -trichloro-ph
enyl)-but-2-enoyl] - F3C
16 5,6-dihydro-4H-cyc MS (m/z): 483 (M+1).
lopenta[c]thiophene
° L
- 1-carboxylic acid
methyl ester
Prep.
Chemical name Structure Physical data
No.
3-[3-(3,5-Dichloro-
4-fluoro-phenyl)-4,
4,4-trifluoro-but-2-
17 enoyl]-5,6-dihydro- MS (m/z): 467 (M+l).
4H-cyclopenta[c]thi
ophene- 1-carboxyli
c acid methyl ester
Preparation 18
3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]
-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid methyl ester
Stir a mixture of 3-[3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]- 4,5,6,7-
tetrahydro-benzo[c]thiophene-l-carboxylic acid methyl ester (8.75 g, 18.9 mmol), NaOH
(2.65 g, 66. 1 mmol) and NH20H-HC1 (2.6 g, 37.8 mmol) in MeOH (60 mL) and water
(15 mL) at room temperature for 2.5 hour. After removal of solvent under vacuum, dilute
the residue with ice water (50 mL). Acidify the aqueous mixture with cone. HC1 to pH =
1 and extract the resultant mixture with EtOAc (50 ml_x3). The combined organic layers
are washed with brine, dried over anhydrous Na2S0 4 and concentrated under vacuum.
Purify the residue by silica gel chromatograph (PE:EtOAc 50:1) to afford
3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahyd
ro-benzo[c]thiophene-l-carboxylic acid methyl ester as an orange solid (8.1 g, 93.1%).
MS (m/z): 478 (M+l).
The following compounds are prepared essentially by the method of
Preparation 18.
Prep.
Chemical name Structure Physical data
No.
3-[5-(3 ,5-Dichloro-phe
nyl)-5-trifluoromethyl-
4,5-dihydro-isoxazol-3
19 -yl]-5,6-dihydro-4H-cy MS (m/z): 464 (M+1).
clopenta[c]thiophene- 1 c i —'
-carboxylic acid
methyl ester
3-[5-(3,4,5-Trichloro-t
hiophen-2-yl)-5 -trifluo
romethyl-4,5-dihydro-i
20 soxazol-3-yl]-4,5,6,7-t MS (m/z): 516 (M-1).
etrahydro-benzo[c]thio
phene- 1-carboxylic
acid methyl ester
3-[5-(3,4,5-Trichloro-t
hiophen-2-yl)-5 -trifluo
romethyl-4,5-dihydro-i
2 1 soxazol-3-yl]-4,5,6,7-t MS (m/z): 512 (M+1).
etrahydro-benzo[c]thio
phene- 1-carboxylic
acid methyl ester
Prep.
Chemical name Structure Physical data
No.
3-[5-(3,5-Dichloro-4-fl
uoro-phenyl)-5 -trifluor
omethyl-4,5-dihydro-is
22 oxazol-3-yl]-4,5,6,7-te MS (m/z): 496 (M+1).
trahydro-benzo[c]thiop
hene-l-carboxylic acid
methyl ester
3-[5-(3,4,5-Trichloro-p
henyl)-5-trifluorometh
yl-4,5-dihydro-isoxazo
23 l-3-yl]-5,6-dihydro-4H MS (m/z): 498 (M+1).
-cyclopenta[c]thiophen c i —'
e-l-carboxylic acid
methyl ester
3-[5-(3,5-Dichloro-4-fl
uoro-phenyl)-5 -trifluor
omethyl-4,5-dihydro-is o
24 oxazol-3 -yl] -5,6-dihyd MS (m/z): 482 (M+1).
ro-4H-cyclopenta[c]thi
ophene- 1-carboxylic
acid methyl ester
Preparation 25
3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]
-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid
Stir a mixture of 3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-
3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid methyl ester (8.1 g,
17.0 mmol) and LiOH-H20 (3.57 g, 84.9 mmol) in MeOH (64 mL) and water (16 mL) at
room temperature overnight. After removal of organic solvent under vacuum, dilute the
residue with ice water (80 mL). Acidify the aqueous mixture with cone. HC1 to pH = 1,
and extract the resultant mixture with EtOAc (100 ml_x3).The combined organic layers
are washed brine, dried over anhydrous Na2S0 4 and concentrated under vacuum. Purify
the residue by silica gel chromatograph (PE:EtOAc 1:1) to afford 3-[5-(3,5-Dichlorophenyl)-
5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophe
ne-l-carboxylic acid as pale yellow solid (6.8 g, 86.4 %). MS (m/z): 464 (M+l).
The following compounds may be prepared essentially by the method of
Preparation 25.
Prep.
Chemical name Structure Physical data
No.
3-[5-(3,4,5-Trichloro-t
hiophen-2-yl)-5 -trifluo
romethyl-4,5-dihydro-i
27 soxazol-3-yl]-4,5,6,7-t MS (m/z): 502 (M-1).
etrahydro-benzo[c]thio
phene- 1-carboxylic
acid
3-[5-(3,4,5-Trichloro-p
henyl)-5 -trifluorometh
O
yl-4,5-dihydro-isoxazo
28 MS (m/z): 496 (M-1).
l-3-yl]-4,5,6,7-tetrahyd
ro-benzo[c]thiophene-
1-carboxylic acid
3-[5-(3,5-Dichloro-4-fl
uoro-phenyl)-5 -trifluor o
omethyl-4,5-dihydro-is
29 MS (m/z): 480 (M-1).
oxazol-3-yl]-4,5,6,7-te
trahydro-benzo[c]thiop
hene-1 -carboxylic acid
3-[5-(3,5-Dichloro-4-fl
uoro-phenyl)-5 -trifluor
omethyl-4,5-dihydro-is
30 oxazol-3 -yl] -5,6-dihyd MS (m/z): 466 (M-1).
ro-4H-cyclopenta[c]thi
ophene- 1-carboxylic
acid
Prep.
Chemical name Structure Physical data
No.
3-[5-(3,4,5-Trichloro-p
henyl)-5 -trifluorometh
yl-4,5-dihydro-isoxazo C I
3 1 MS (m/z): 482 (M-l).
l-3-yl]-5,6-dihydro-4H
-cyclopenta[c]thiophen
e-l-carboxylic acid
Example 32
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((R)-2-oxopyr
rolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide
Stir a mixture of
3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]
-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid (850 mg, 1.84 mmol), HATU
(837 mg, 2.20 mmol) and DIEA (539 mg, 0.8 mL, 4.6 mmol) in DCM (8 mL) at room
temperature for 15 min, followed by addition of (R)-3-aminopyrrolidin-2-one
hydrochloride (3 15 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
Na2S0 4 and concentrated under vacuum. Purify the residue by preparative HPLC to
afford 3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-
dihydroisoxazol-3-yl)-N-((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-
1-carboxamide as a white solid (730 mg, 73.0 %). MS (m/z): 546 (M+l); H NMR (400
MHz, CDC13) d 7.52-7.46 (m, 3H), 6.49 (s, IH), 5.83 (s, IH), 4.51-4.48 (m, IH), 4.22 (d,
J=17.2, IH), 3.85 (d, J=17.2, IH), 3.52-3.47 (m, 2H), 3.09-2.87 (m, 5H), 2.12-2.03 (m,
IH), 1.89-1.73 (m, 4H).
The following compounds may be prepared essentially by the method of
Example 32.
Ex.
Chemical name Structure Physical data
No.
N,N-Dimethyl-2-(4-{3 MS (m/z): 659 (M+l); ¾
-[5-(3,4,5-trichloro-thi NMR (400 MHz, CDC13) d
ophen-2-yl)-5-trifluoro 4.07-4.02 (m, 2H), 3.68-3.80
methy 1-4,5 -dihydro-is (m, 4H), 3.49-3.41 (m, 2H),
33
oxazol-3-yl]-4,5,6,7-te 3.09-3.01 (s, 3H), 3.01-2.95
trahydro-benzo[c]thio (s, 3H), 2.91-2.85 (m, 2H),
phene- 1-carbonyl} -pip 2.84-2.78 (m, 4H), 2.69-2.63
erazin- 1-yl)-acetamide (m, 2H), 1.87-1.72 (m, 4H).
({3-[5-(3,5-Dichloro-p
henyl)-5-trifluorometh
Prep yl-4,5-dihydro-isoxazo
No. l-3-yl]-4,5,6,7-tetrahyd MS (m/z): 535 (M+l).
34 ro-benzo[c]thiophene-
1-carbonyl} -amino)-ac
etic acid methyl ester

Ex.
Chemical name Structure Physical data
No.
3-(5-(3,5-dichloro-4-fl MS (m/z): 576(M+1); ¾
uorophenyl)-5-(trifluor NMPv (CDOD , 400 MHz) d
omethyl)-4,5-dihydroi 7.76 (d, J=6.4, 2H), 4.24 (d,
soxazol-3 -yl)-N-(2-ox J=17.6, 1H), 4.03-3.99 (m,
5 1
o-2-(prop-2-ynylamin 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,
e-l-carboxamide 4H).
N-(2-oxo-2-(2,2,2-trifl MS (m/z): 622 (M+l); ¾
uoroethylamino)ethyl) NMPv (CDC13, 400 MHz) d
-3-(5-(3,4,5-trichlorop 7.64 (s, 2 H), 6.81 (brs, 1 H),
henyl)-5 -(trifluoromet 6.73 (brs, 1 H), 4.22 (d,
52
hyl)-4,5-dihydroisoxaz J=4.8, 2 H), 3.99 (m, 3 H),
ol-3-yl)-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
ene- 1-carboxamide H), 2.55 (m, 2 H).
N-((R)-2-oxopyrrolidi MS (m/z): 566 (M+l); ¾
n-3-yl)-3-(5-(3,4,5-tric NMPv (CDC13, 400 MHz) d
hlorophenyl)-5-(trifluo 7. 62 (s, 2 H), 6.46 (brs, 1
romethyl)-4,5-dihydroi H), 6.16 (brs, 1 H), 4.47 (m,
53
soxazol-3-yl)-5,6-dihy 1 H), 3.99 (d, J=17.2, 1 H),
a
dro-4H-cyclopenta[c]t 3.61 (d, J=17.2, 1 H), 3.47
hiophene- 1-carboxami (m, 2 H), 2. 93 (m, 5 H), 2.53
de (m, 2 H), 2.09 (m, 1 H).

Ex.
Chemical name Structure Physical data
No.
MS (m/z): 548 (M+l); 1H
NMR (CDC13, 400 MHz)
3-(5 -(3 ,5-dichlorophen
yl)-5-(trifluoromethyl)
MHz) d 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),
-2-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,
hene- 1-carboxamide
2H), 2.92-2.90(m, 2H), 1.79
(s, 4H), 1.26-1.17 (m, 3H).
MS (m/z): 547 (M+l); 1H
NMR (CDC13, 400 MHz)
3-(5 -(3 ,5-dichlorophen 57.48 (s, 2H), 7.42 (s, 1H),
yl)-5-(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
n-2-yl)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),
ophene- 1-carboxamide 2.06-1.98 (m, 1H), 1.96-1.89
(m, 2H), 1.79-1.77 (m, 4H),
1.64-1.59 (m, 1H).
Ex.
Chemical name Structure Physical data
No.
MS (m/z): 537 (M+l); 1H
3-(5 -(3 ,5-dichlorophen NMR (CDC13, 400 MHz) d
yl)-5-(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 c i 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+l); 1H
3-(5 -(3 ,5-dichlorophen
NMR (CDC13, 400 MHz) d
yl)-5-(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
(d, J=16 Hz, 1H), 3.72-3.64
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+l); 1H
3-(5 -(3 ,5-dichlorophen
NMR (CDC13, 400 MHz) d
yl)-5-(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 -hydroxy cycl
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).
Ex.
Chemical name Structure Physical data
No.
MS (m/z): 558 (M+l); IH
3-(5 -(3 ,5-dichlorophen NMR (CDC13, 400 MHz) d
yl)-5-(trifluoromethyl) 8.36 (s, IH), 8.32-8.29 (m,
-4,5-dihydroisoxazol-3 IH), 8.16 (d, J=2.4 Hz, IH),
68 -yl)-N-(5 -fluoropyridi 7.51-7.44 (m, 3H), 7.43 (s,
n-2-yl)-4,5,6,7-tetrahy IH), 4.09-4.05 (d, J=16 Hz,
drobenzo[c]thiophene- IH), 3.71-3.67 (d, J=16 Hz,
1-carboxamide IH), 3.09 (s, 2H), 2.94-2.93
(m, 2H), 1.83 (s, 4H)
MS (m/z): 547 (M+l); IH
3-(5 -(3 ,5-dichlorophen NMR (CDC13, 400 MHz) d
yl)-5-(trifluoromethyl) 7.49 (s, 2H), 7.40 (s, IH),
-4,5-dihydroisoxazol-3 6.23 (d, J=9.6 Hz, IH),
69 -yl)-N-(tetrahydro-2H- 4.18-4.16 (s, IH), 4.07-4.03
pyran-3-yl)-4,5,6,7-tet (d, J=16 Hz, IH), 3.83-3.77
rahydrobenzo [c]thioph (m, 2H), 3.69-3.57 (m, 3H),
ene- 1-carboxamide 2.98-2.90 (m, 4H), 1.90-1.75
(m, 8H).
Ex.
Chemical name Structure Physical data
No.
MS (m/z): 535 (M+l); IH
3-(5 -(3 ,5-dichlorophen NMR (CDC13, 400 MHz) d
yl)-5-(trifluoromethyl) 7.49 (s, 2H), 7.44 (s, IH),
-4,5-dihydroisoxazol-3 6.18 (d, J = 7.6 Hz, IH),
70 -yl)-N-(thietan-3-yl)-4, 5.40-5.34 (m, IH), 4.06 (d, J
5,6,7-tetrahydrobenzo[ = 17.2 Hz, IH), 3.66 (d, J =
c]thiophene- 1-carboxa 17.2 Hz, IH), 3.46-3.36 (m,
mide 4H), 2.97-2.90 (m, 4H),
1.81-1.78 (m, 4H).
MS (m/z): 547 (M+l); IH
NMR (CDC13, 400 MHz) d
3-(5 -(3 ,5-dichlorophen 7.47 (s, 2H), 7.41 (s, IH),
yl)-5-(trifluoromethyl) 5.74-5.72 (d, J=7.6 Hz, IH),
-4,5-dihydroisoxazol-3 4.19-4.11 (m, IH), 4.10-4.06
7 1 -yl)-N-(tetrahydro-2H- (d, J=16 Hz, IH), 4.04-3.96
pyran-4-yl)-4,5,6,7-tet (m, 2H), 3.69-3.65 (d, J=16
rahydrobenzo [c]thioph Hz, IH), 3.53-3.43 (m, 2H),
ene- 1-carboxamide 2.94-2.88 (m, 4H), 2.00-1.97
(m, 2H), 1.77 (s, 4H),
1.60-1.50 (m, 2H).
N-( 1-cyclopropyl-2-ox MS (m/z): 586 (M+l); IH
opyrrolidin-3-yl)-3-(5- NMR (CDC13, 400 MHz) d
(3,5-dichlorophenyl)-5 7.49 (s, 2 H), 7.43 (s, IH),
72 -(trifluoromethyl)-4,5- 6.50 (brs, 1 H), 4.43-4.40 (m,
dihydroisoxazol-3-yl)- 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]thiophene-l-carbo 3.42-3.30 (m, 2 H), 2.99-2.82
Ex.
Chemical name Structure Physical data
No.
xamide (m, 5 H), 1.91-1.80 (m, 5 H),
0.83-0.763 (m, 4 H)
N-(2-oxo-2-(prop-2-yn
ylamino)ethyl)-3-(5-(3 MS (m/z): 600 (M+l); 1H
,4,5-trichlorothiophen- NMR (CDC13, 400 MHz) d
2-yl)-5-(trifluorometh 6.92-6.77 (m, 2H), 4.21-4.09
74
yl)-4,5-dihydroisoxazo (m, 4H), 4.08-4.04 (m, 2H),
l-3-yl)-4,5,6,7-tetrahyd 3.09-2.88 (m, 4H), 1.87-1.71
robenzo [c]thiophene- 1 (m, 4H).
-carboxamide
Ex.
Chemical name Structure Physical data
No.
MS (m/z): 631 (M+l); 1H
3-[5-(3,4,5-Trichloro- NMR (CDC13, 400 MHz) d
phenyl)-5-trifluoromet 7.62 (s, 2H), 5.89-5.87 (m,
hyl-4,5-dihydro-isoxaz 1H), 4.28-4.20 (m, 1H),
ol-3-yl]-4,5,6,7-tetrahy
75
4.07-4.03 (d, J=16 Hz, 1H),
dro-benzo[c]thiophene 3.70-3.66 (d, J=16 Hz, 1H),
-1-carboxylic acid 3.20-3.12 (m, 4H), 2.94-2.89
(1,1 -dioxo-hexahydro- (m, 4H), 2.42-2.39 (m, 2H),
thiopyran-4-yl)-amide 2.27-2.17 (m, 2H), 1.79 (s,
4H).
N-(2-oxo-l-(2,2,2-trifl
MS (m/z): 664 (M+l); 1H
uoroethyl)pyrrolidin-3
NMR (CDC13, 400 MHz) d
-yl)-3-(5-(3,4,5-trichlo
7.63 (s, 2 H), 6.45 (brs, 1 H),
rophenyl)-5 -(trifluoro
76 4.53 (brs, 1 H), 4.09 (m, 2
methyl)-4,5-dihydrois
H), 3.85 (m, 1 H), 3.58 (m, 3
oxazol-3-yl)-4,5,6,7-te
H), 2.95 (m, 4 H), 2.02 (m, 1
trahydrobenzo[c]thiop
H), 1.79 (m, 4 H).
hene- 1-carboxamide

Ex.
Chemical name Structure Physical data
No.
3-[5-(3,5-Dichloro-4-fl MS (m/z): 585 (M+l); 1H
uoro-phenyl)-5-trifluor NMR (CDC13, 400 MHz) d
omethyl-4,5-dihydro-i 7.76 (d, J =6.0, 2H),
soxazol-3-yl]-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,
phene- 1-carboxylic 3H), 4.02 (d, J =17.6, 1H),
acid 2.97 (t, J =6.0, 2H), 2.90 (t,
(1,1 -dioxo-thietan-3 -yl J =6.0, 2H), 1.80-1.76 (m,
)-amide 4H).
3-[5-(3,5-Dichloro-4-fl
MS (m/z): 613 (M+l); 1H
uoro-phenyl)-5-trifluor
NMR (CDC13, 400 MHz) d
omethyl-4,5-dihydro-i
7.56 (d, J =6.0, 2 H), 5.75 (d,
soxazol-3-yl]-4,5,6,7-t
J =7.2, 1 H), 4.06 (d, J =16.8,
80 etrahydro-benzo[c]thio
1 H), 3.65 (d, J =16.8, 1 H),
phene- 1-carboxylic
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).
thiopyran-4-yl)-amide
3-(5-(3,5-dichloro-4-fl MS (m/z): 577 (M+l); 1H
uorophenyl)-5-(trifluor NMR (CDC13, 400 MHz) d
omethyl)-4,5-dihydroi 7.48(d , J =6.0, 2H), 5.67 (d,
8 1 soxazol-3 -yl)-N-(4-ox J =6.8, 1H), 4.33 (m, 1H),
ocyclohexyl)-4,5,6,7-t 0
3.98(d , J =16.8, 1H), 3.58 (d,
etrahydrobenzo[c]thio J =16.8, 1H), 2.82 (m, 4H),
phene- 1-carboxamide 2.40 (m, 6H), 1.65 (m, 6H)
Ex.
Chemical name Structure Physical data
No.
3-(5-(3,5-dichloro-4-fl
MS (m/z): 646 (M+l); 1H
uorophenyl)-5-(trifluor
NMR (CDC13, 400 MHz) d
omethyl)-4,5-dihydroi
7. 50 (dd, J ;=2.4, J =6.0, 2
soxazol-3 -yl)-N-(2-ox
82 o-l-(2,2,2-trifluoroeth
1 H), 4.46 (m, 1 H), 3.98 (m,
yl)pyrrolidin-3 -yl)-4,5 ,
2 H), 3.78 (m, 1 H), 3.55 (m,
6,7 -tetrahy drobenzo [c]
3 H), 2.83 (m, 5 H), 1.963
thiophene- 1-carboxam
(m, 1 H), 1.71 (m, 4 H).
ide
MS (m/z): 565 (M+l); 1H
3-(5-(3,5-dichloro-4-fl
NMR (CDC13, 400 MHz) d
uorophenyl)-5-(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),
soxazol-3 -yl)-N-(tetra
83 3.98 (d, J=16.8, 1 H), 3.91
hydro-2H-pyran-4-yl)-
o 0 a (m, 2 H), 3.58 (d, J=l 6.8, 1
4,5,6,7-tetrahydrobenz
H), 3.45 (m, 2 H), 2.84 (m, 4
o[c]thiophene-l-carbo
H), 1.95 (m, 2 H), 1.72 (m, 4
xamide
H), 1.49 (m, 3 H).
Ex.
Chemical name Structure Physical data
No.
MS (m/z): 604 (M+l); 1H
NMR (CDC13, 400 MHz) d
N-( 1-cyclopropyl-2-ox
7.77 (d, J=6.0, 2H), 4.62 (t,
opyrrolidin-3-yl)-3-(5-
J=9.6, 1H), 4.24 (d, J=17.6,
(3,5-dichloro-4-fluoro
1H), 4.02 (d, J=17.6, 1H),
phenyl)-5-(trifluorome
84 3.43-3.39 (m, 2H), 2.99-2.96
thyl)-4,5-dihydroisoxa o (m, 2H), 2.90-2.88 (m, 2H),
zol-3-yl)-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),
e-l-carboxamide
1.81-1.78 (m, 4H), 0.85-0.82
(m, 4H).
MS (m/z): 545 (M+l); 1H
3-(5 -(3 ,5-dichlorophen NMR (CDC13, 400 MHz) d
yl)-5-(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 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).
Ex.
Chemical name Structure Physical data
No.
MS (m/z): 614 (M+l); 1H
3-(5 -(3 ,5-dichlorophen NMR (CDC13, 400 MHz)
yl)-5-(trifluoromethyl) 57.52-7.44 (m, 3H),
-4,5-dihydroisoxazol-3 6.43-6.38 (s, 1H), 4.52-4.48
-yl)-N-(2-oxo-l -(2,2,2 (m, 1H), 4.17-4.05 (m, 2H),
86
-trifluoroethyl)pyrrolid - 4.04-3.97 (d, J=17.2, 1H),
in-3-yl)-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),
ene- 1-carboxamide 2.58-2.46 (m, 2H), 2.08-1.97
(m, 1H).
Example 87
(A)
3-((R)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((R)-2-
oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l -carboxamide and
(B)
3-((S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((R)-2-
oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide
Separate 3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)
-N-((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide (6.2 g
11.29 mmol) by SFC (Column: Chiralcel OD 250x30mm ID., 5um. Mobile phase:
Supercritical C V MeOH=60/40, Flow rate:200 ml/min) to afford two diastereoisomers
3-((R)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((R)-2-ox
o pyrrolidin-3-yl)- 4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide (2.7 g, 4.92 mmol)
and
3-((S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-((R)-2-ox
opyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide (2.6 g, 4.74 mmol)
as a white solid.
(A) MS (m/z): 619.1 (M+73). ¾ NMR (CDC13, 400 MHz) d 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 NM (CDCI 3, 400 MHz) d 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).
Preparation 88
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-
4,5,6,7-tetrahydrobenzo[c]thiophene- 1-carbonyl chloride
Stir a mixture of
3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahyd
ro-benzo[c]thiophene-l-carboxylic acid (600 mg, 1.2 mmol), 2 drops DMF in oxalyl
dichloride (5 mL) at ambient temperature for 3 hours. Remove the solvent under vacuum to
afford 3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-
4,5,6,7-tetrahydrobenzo[c]thiophene-l -carbonyl chloride as a yellow solid (615 mg, 98%).
The following compound is prepared essentially by the method of Preparation 88.
Prep.
Chemical name Structure Physical data
No.
3-[5-(3,4,5-Trichloro-t
hiophen-2-yl)-5 -trifluo
romethyl-4,5-dihydro-
89 isoxazol-3-yl]-4,5,6,7-t
etrahydro-benzo[c]thio
phene- 1-carbonyl
chloride
Example 90
N-(4-carbamoylphenyl)-3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-
dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide
Stir a mixture of
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydr
obenzo[c]thiophene-l-carbonyl chloride (48 mg, 0.1 mmol) and 4-aminobenzamide (27
mg, 0.2 mmo) in pyridine (3 mL) at ambient temperature overnight. After removal solvent
under vacuum, purify the residue by preparative HPLC to afford
N-(4-carbamoylphenyl)-3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxaz
ol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide as a white solid (36 mg,
62.0%). MS (m/z): 582.1 (M+1). ¾ NMR (CDC13, 400 MHz) d 7.84 (d, J=8.4 Hz, 2H),
7.65-7.63 (m, 3H), 7.49 (s, 2H), 7.44 (s, IH), 6.03 (s, IH), 5.61 (s, IH), 4.09-4.05 (d, J=16
Hz, IH), 3.72-3.68 (d, J=16 Hz, IH), 3.07 (s, 2H), 2.94 (s, 2H), 1.76 (s, 4H).
The following compound is prepared essentially by the method of
Example 90.
Ex.
Chemical name Structure Physical data
o.
3-[5-(3,4,5-Trichloro-thio MS (m/z): 628 (M+l);
phen-2-yl)-5-trifluoromet H NMR (400 MHz,
hyl-4,5-dihydro-isoxazol- DMSO-i/6,) d 8.08-8.02
3-yl] -4,5 ,6,7-tetrahydro-b (m, 1H), 7.81-7.78 (m,
9 1 enzo[c]thiophene-l-carbo 1H), 4.58-4.43 (t, 2H),
xylic acid 3.13-2.84 (m, 4H),
(3-carbamoyl-thiophen 1.79-1.64 (m, 4H).
-2-yl)-amide
Scheme C
Preparation 92
2-(3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-
4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamido)acetic acid
Stir a mixture of methyl 2-(3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-
dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamido)acetate (534
mg, 1.0 mmol) and LiOH-H20 (168 mg, 4.0 mmol) in MeOH (20 mL) and water (5 mL)
at room temperature for overnight. After removal of organic solvent under vacuum, dilute
the residue with ice water (10 mL). Acidify the aqueous mixture with cone. HC1 to pH =
1, and extract the resultant mixture with EtOAc (15 ml_x3).The combined organic layers
are washed brine, dried over anhydrous Na2S0 4 and concentrated under vacuum. Purify
the residue by silica gel chromatograph (PE:EtOAc 1:1) to afford
2-(3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrah
ydrobenzo[c]thiophene-l-carboxamido)acetic acid as a pale yellow solid (427 mg,
82.0 %). MS (m/z): 521(M+1).
The following compound is prepared essentially by the method of Preparation 92.
Prep.
Chemical name Structure Physical data
No.
({3-[5-(3,4,5-Trichloro
-thiophen-2-yl)-5-triflu
oromethyl-4,5-dihydro
93 -isoxazol-3-yl]-4,5,6,7 MS (m/z): 561 (M+1).
-tetrahydro-benzo[c]thi
ophene- 1-carbonyl} -a
mino)-acetic acid
Example 94
N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichlorophenyl)-5-
(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-lcarboxamide
Stir a mixture of 2-(3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-
dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene- 1-carboxamido)acetic acid
(230 mg, 0.44 mmol), HATU (251 mg, 0.66 mmol) and NEt 3 (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 Na2S0 4 and concentrated under vacuum. Purify the residue by preparative
HPLC to afford N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-
dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]
thiophene-1 -carboxamide as a white solid (110 mg, 44.7 %). MS (m/z): 559.1 (M+l). ¾
NMR (DMSO-i/ 6, 400 MHz) d 8.64 (t, J=5.6 Hz, 1H), 8.22 (t, J=5.6 Hz, 1H ), 7.81-7.80
(m 1H), 7.68 (s, 2H), 4.35-4.22 (m, 2H), 4.16-4.15 (m, 2H), 3.88-3.86 (m, 2H), 2.94-2.86
(m, 4H), 1.70-1.69 (m, 4H).
The following compounds are prepared essentially by the method of Example 94.
Ex.
Chemical name Structure Physical data
o.
3-(5-(3,5-dichlorophen
MS (m/z): 558 (M+l); ¾
yl)-5-(trifluoromethyl)
NMR (CDC13, 400 MHz) d
-4,5-dihydroisoxazol-3
7.49-7.42 (m, 3H), 6.85 (br,
-yl)-N-(2-oxo-2-(prop-
95 1H), 6.72 (br, 1H), 4.17-4.03
2-ynylamino)ethyl)-4,
(m, 5H), 3.68 (d = 17.2
5,6,7-tetrahydrobenzo[
Hz, 1H), 3.00-2.90 (m, 4H),
c]thiophene- 1-carboxa
2.25 (s, 1H), 1.79 (br, 4H).
mide
N-(2-(cyanomethylami
no)-2-oxoethyl)-3-(5-(
MS (m/z): 599 (M+l); ¾
3,4,5 -trichlorothiophen
NMR (CDCI 3, 400 MHz) d
-2-yl)-5-(trifluorometh
96 4.28-4.18 (m, 4H), 4.10-4.07
yl)-4,5-dihydroisoxazo
(m, 2H), 3.04-2.87 (m, 4H),
l-3-yl)-4,5,6,7-tetrahyd
1.88-1.73 (m, 4H).
robenzo[c]thiophene- 1
-carboxamide
Preparation 20 1
4-chlorobenzo[b]thiophene-2-carboxylic
Stir a mixture of methyl 4-chlorobenzo[b]thiophene-2-carboxylate (1.0 g, 4.44 mmol) and
LiOH-H 20 (0.56 g, 13.3 mmol) in MeOH (30 mL) and water (10 mL) at room
temperature overnight. Concentrate the reaction mixture under vacuum and then dilute the
residue with ice water (20 mL). Acidify the aqueous mixture with cone. HC1 solution to
pH = 1. Extract the resultant mixture with EtOAc (15 mLx3). The combined organic
layers are washed with brine, dried over anhydrous Na2S0 4 and evaporate under vacuum
to afford 4-chlorobenzo[b]thiophene-2-carboxylic acid as a white solid (0.94 g, 100 %).
H NMR (400 MHz, CDC13) d 8.10-8.02 (m, 2H), 7.61-7.51 (m, 2H)
The following compounds are prepared essentially by the method of
Preparation 20 1.
Preparation 204
4-chloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide
Stir a mixture of 4-chlorobenzo[b]thiophene-2-carboxylic 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
a2S0 4 and concentrated under vacuum. Purify the residue by column chromatography on
silica gel eluting with PE: EtOAc (5:1 to 3:1) to afford
4-chloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide as white solid (0.85 g,
75.2 %). 1HNMR(400 MHz, CDC13) d 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.
Preparation 207
l-(4-chlorobenzo[b]thiophen-2-yl)ethanone
Add a solution of CH3MgBr (3 M in THF, 1.7 ml, 4.99 mmol) to a suspension of
4-chloro-N-methoxy-N-methylbenzo[b]thiophene-2-carboxamide (0.85 g, 3.33 mmol) in
dry THF (10 mL) at 0 °C. Then stir the mixture for overnight at ambient temperature.
Quench the reaction with saturated NH4C 1 aqueous solution (15 mL) and extract the
aqueous mixture with EtOAc (10 mLx3). The combined organic layers are washed with
brine, dried over anhydrous a2S0 4 and concentrated under vacuum. Purify the residue by
silica gel chromatograph (PE:EtOAc = 6:1) to afford
1-(4-chlorobenzo[b]thiophen-2-yl)ethanone as white solid (0.6 g, 86.9 %). H NMR (400
MHz, CDCI3) d 8.10-8.07 (s, IH), 7.75 (d, J=5.2, IH), 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):
208
2-yl-ethanone 178 (M+l).
1-(5-Bromo-thieno [2,3-
MS (m/z):
209 b]pyridin-2-yl)-ethanon
258 (M+l).
e
1-Thieno [2,3 -b]pyridin- MS (m/z):
210
2-yl-ethanone 178 (M+l)
Preparation 211
l-(4-chlorobenzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan
-1-one
Add a solution of LiHMDS ( 1 M in THF, 4.3 ml, 4.31 mmol) to a mixture of
l-(4-chlorobenzo[b]thiophen-2-yl)ethanone (0.6 g, 2.87 mmol) in dry THF (10 mL) at
-78 °C under N2. After stirring 1.5 hour at -78 °C, add
l-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone (836 mg, 3.44 mmol) to the reaction
mixture and stir the resultant mixture for additional 2 hours. Quench the reaction with
saturated NH4C 1 solution and extract the aqueous mixture with EtOAc (10 mLx3). The
combined organic layers are washed with brine, dried over anhydrous Na2S0 4 and
concentrated under vacuum afford crude
l-(4-chlorobenzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan
-1-one as brown solid (1.1 g, 84.6%). 'HNMR (400 MHz, CDC13) d 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 11.
Preparation 220
l-(4-chlorobenzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-en- 1-one
Stir a mixture of
l-(4-chlorobenzo[b]thiophen-2-yl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan
-1-one (1.1 g, crude, 2.43 mmol), SOCI2 (1.16 g, 0.7 mL, 9.43 mmol) and pyridine (384 mg,
0.4 mL, 4.86 mmol) in anhydrous DCM (10 mL) at ambient temperature for overnight.
Dilute the mixture with saturated NH4CI solution and extract the aqueous mixture with
DCM (10 mLx3). The combined organic layers are washed with brine, dried over
anhydrous Na2S0 4 and concentrated under vacuum to afford crude
1-(4-chlorobenzo[b]thiophen-2-yl)-3 -(3 ,5-dichlorophenyl)-4,4,4-trifluorobut-2-en- 1-one
as brown solid (1.05 g, 100%). 'HNMR (400 MHz, CDC13) 58.12-8.10 (s, 1H), 7.69-7.64
(m, 1H), 7.47-7.44 (m, 2H), 7.38-7.35 (m, 2H), 7.27-7.24 (m, 1H), 6.96 -6.92 (s, 1H).
The following compounds are prepared essentially by the method of
Preparation 220.
Prep.
Chemical name Structure Physical data
No.
3-(3 ,5-dichlorophenyl)
F3 0
-4,4,4-trifluoro- 1-(5-m MS (m/z): 413
227
ethylbenzo [b]thiophen
-2-yl)but-2-en- 1-one C I
1-(5 -chlorobenzo [b]thi
F3 0
ophen-2-yl)-3 -(3 ,5-die MS (m/z): 433
228
hlorophenyl)-4,4,4-trif
luorobut-2-en-l-one C I
Example 229
3-(4-chlorobenzo[b]thiophen-2-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydr
oisoxazole
Stir a mixture of
1-(4-chlorobenzo[b]thiophen-2-yl)-3 -(3 ,5-dichlorophenyl)-4,4,4-trifluorobut-2-en- 1-one
(1.05 g, crude, 2.43 mmol), NaOH (389 mg, 9.72 mmol) and NH2OH-HCl(335 mg, 4.8
mmol) in MeOH (8 mL) and water (8 mL) at ambient temperature for 4 hours. After
removal of solvent under vacuum, dilute the residue with ice water (20 mL). Extract the
aqueous mixture with EtOAc (15 mLx3). The combined organic layers are washed with
brine, dried over anhydrous Na2S0 4 and concentrated under vacuum. Purify the residue by
preparative HPLC to afford
3-(4-chlorobenzo[b]thiophen-2-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydr
oisoxazole as white solid (305 mg, 28. 1 %). MS (m/z): 450 (M+l). H NMR (400 MHz,
CDC13) dd 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.

Preparation 238
methyl
2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thieno [
dine-5-carboxylate
Stir a mixture of
5-bromo-2-[5-(3,5-dichloro-phenyl)-54rifluoromethyl-4,5-dihydro-isoxazol-3 - /]-thieno[
2,3-b]pyridine (494 mg, 1 mmol), Pd(dppf )Ci2 (100 mg) and triethyl amine ( 1 mL) in
anhydrous THF (10 mL) and methanol (5 mL) under carbon monoxide (50 psi) at 70 °C for
lOh. After removal of solvent under vacuum, purify the residue with silica gel
chromatography (eluting with 10% ethyl acetate in petroleum ether) to afford methyl
2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thieno[2,3-b]pyri
dine-5-carboxylate as a white solid (210 mg, 44.18%). MS (m/z): 475 (M+l).
Preparation 239
2-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-j/]-thieno[2,3-b]pyr
idine-5-carboxylic acid
Add a solution of LiOH-H20 (76 mg, 2 mmol) in water (0.5 mL) to a solution of methyl
2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thieno[2,3-b]pyri
dine-5-carboxylate (237 mg, 0.5 mmol) in THF(3 mL). Stir the mixture at temperature for
12 hours. After addition of 10 mL of water, acidify the mixture with concentrated HC1 to
PH = 6~7. Extract the resultant mixture with ethyl acetate (3 10 mL). The combined
organic layers are washed brine, dried over anhydrous Na2S0 4 and concentrated under
vacuum to afford
2-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-j/]-thieno[2,3-b]pyr
idine-5-carboxylic acid as pale yellow solid (170 mg, 73.9%), which is used in next step
without further purification. MS (m/z): 461 (M+l).
Example 240
2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(2,2,
2-trifluoroethylamino)ethyl)thieno[2,3-b]pyridine-5-carboxamide
Stir a mixture of 2-Amino-N-(2,2,2-trifluoro-ethyl)-acetamide (156 mg, 1 mmol),
2-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-thieno[2,3-b]pyri
dine-5-carboxylic acid (160 mg, 0.24 mmol), HATU (150 mg, 0.39 mmol) and DIPEA (0.2
mL) at room temperature for for 10 hours. After removal of solvent, purify the mixture by
preparetive-HPLC to afford
2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(2,2,
2-trifluoroethylamino)ethyl)thieno[2,3-b]pyridine-5-carboxamide as a white solid (50 mg,
34.78%). MS (m/z): 599 (M+l). 'HNMR (400 MHz, CDC13) d 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.
C ir al
Example 242
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-ox
o-2-(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxa
mide
Stir a mixture of
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-
dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic 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 ¾ ¾ (10 mL) at room temperature for 2 hours. The reaction
mixture is diluted with CH2CI2 (50 mL) and is washed with water (10 mLx 3) and brine.
Then the organic layer is dried over anhydrous Na2S0 4 and is concentrated under vacuum.
Purify the residue by preparative HPLC to afford 3-(5-(3,5-dichloro-
4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(2,2,2-trifluor
oethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxamide as a white
solid (1.1 g, 84.6 %). MS (m/z): 606.0 (M+l).
Example 243
(S)-3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)
-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-lcarboxamide
1 g of
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-
(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-car
boxamide is separated by SFC to give
(S)-3 -(5 -(3 ,5-dichloro-4-fluorophenyl)-5 -(trifluoromethyl)-4,5 -dihydroisoxazol-3 -yl)
-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-lcarboxamide
(400 mg, 80 % yield, 100% ee).
H NMR (400 MHz, CDC13) d 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+l).
SFC analysis condition: Column: Chiralcel AD-H 250x4.6mm I.D., 5um.
Mobile phase: ethanol in CO2 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 C0 2, B: MeOH (0.05% NH3H20), A:B =45:55 at 80ml/min; Column Temp:
38 °C; Nozzle Pressure: lOOBar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C; Trimmer
Temp: 25 °C; Wavelength: 220nm
Scheme G l
Preparation of l-chloro-l-oxopropan-2-yl acetate (3)
0 H AcOH, H2S04 0Ac 0Ac T toluene J (COCI)2
02H * - O H ^^COCI
92% 100%
3a 3b
Scheme G 2
Synthesis of 2-amino-N-(2,2-difluoro-ethyr) acetamide hydrochloride
Scheme G 3
Synthesis of 3-[5-r3,5-dichloro-4-fluoro-phenyl)-5-
trifluoromethyl-4,5-dihvdro-isoxazol-3-yll-5,6-dihydro-4H-cvclopenta[cl
thiophene-l-carboxylic acid [r2,2-difluoro-ethylcarbamoyl)-methyllamide
Example 244
3-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-
3-yl]-5,6-dihydro-4 H-cyclopenta[c]thiophene-l-carboxylic acid
[(2,2-difluoro-ethylcarbamoyl)-methyl]-amide
A) Synthesis of 2-acetoxy -propionic acid
OAc
C0 2H
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 (CDC13, 400 MHz): d
9.27 (brs, 1H), 5.10 (m, 1H), 2.13 (s, 3H), 1.53 (d, J =7.2, 3H).
B) Synthesis of l-chloro-l-oxopropan-2-yl acetate
OAc
^^COCI
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. 'HNMR (CDC13, 400 MHz): d 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 toluene-4-sulfonic 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-cyclopent-l-enyl-pyrrolidineas colorless oil (898g, 6.55 mol, 91.8%). H NMR (CDC13,
400 MHz): d 4.04 (m, 1H), 3.06 (m, 4H), 2.39 (m, 4H), 1.85 (m, 6H).
D) Synthesis of l-oxo-l-(2-(pyrrolidin-l-yl)cyclopent-l-enyl)propan-2-yl
acetate
Add dropwise a solution of l-chloro-l-oxopropan-2-yl acetate (600 g, 3.98
mol) in toluene (1200 mL) to a solution of 1-cyclopent-l-enyl-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
l-oxo-l-(2-(pyrrolidin-l-yl)cyclopent-l-enyl)propan-2-yl acetate (952 g), which is used in
next step without further purification. 1H NMR (CDC13, 400 MHz): d 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 l-oxo-l-(2-oxocyclopentyl)propan-2-yl acetate
Stir a mixture of l-oxo-l-(2-(pyrrolidin-l-yl) cyclopent-l-enyl)propan-2-yl
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 Na2S0 4 and concentrated under vacuum. Purify the residue by silica gel
chromatograph (eluting with 3% to 10% ethyl acetate in petroleum ether) to give
l-oxo-l-(2-oxocyclopentyl)propan-2-yl acetate as oil (573.4g, 2.89 mol, 72.6% for 2
steps).
F) Synthesis of l-chloro-l-(2-oxocyclopentylidene)propan-2-yl acetate
A mixture of l-oxo-l-(2-oxocyclopentyl)propan-2-yl acetate (8.0 g, 0.04
mol) and tributylphosphane (13.9 g, 0.069 mol) in CC14 (100 mL) at 60°C 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
l-chloro-l-(2-oxocyclopentylidene)propan-2-yl acetate and l-(2-chlorocyclopent-l-enyl)
-l-oxopropan-2-yl 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
°C~0 °C and stirred the mixture at -10 °C~0 °C for 1 hour. Then add a mixture of
l-chloro-l-(2-oxocyclopentylidene)propan-2-yl acetate and l-(2-chlorocyclopent-l-enyl)
-l-oxopropan-2-yl acetate (5.47 g, 0.025 mol, 6 :1) in tetrahydrofuran (15 mL) at 0 °C. After
stiring at 0 °C for overnight, dilute the reaction mixture with water and extract with ethyl
acetate. The combined organic layers are washed with brine, dried over anhydrous
Na2S0 4 and concentrated. The residue and K2CO (6.9 g, 0.05 mol) in MeOH (20 mL) is
heated at 50 °C 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]thiophene- 1-carboxylic acid methyl
ester (3.2 g, 14. 1 mmol, 35.6% for 2 steps) as yellow oil. 1H NMR (CDC13, 400 MHz): d
5.03 (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]thiophene-l-carboxylate
Reflux a mixture of 3-(l-Hydroxy-ethyl)-5,6-dihydro-4H-cyclopenta[c]
thiophene-l-carboxylic 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-4 H-cyclopenta[c]thiophene-l-carboxylic acid methyl ester as white
solid (3.0 g, 13.39 mmol, 94.5%). ¾ NMR (CDC13, 400 MHz): d 3.88 (s, 3H), 2.96 (m,
4H), 2.50 (s, 3H), 2.45 (m, 2H).
I) Synthesis of
3-[3-(3,5-Dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-3-hydroxy-butyryl]-5,6-
dihydro-4H-cyclopenta[c]thiophene-l-carboxylic 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]thiophene-l-carboxylic acid methyl ester (14.0 g,
62.5 mmol) in dry THF (200 mL) at -78°C under N2. After stirring at room temperature for
1.5 h, add l-(3,5-dichloro-4-fluoro-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 NH4C 1 aqueous
solution. Extract the aqueous mixture with EtOAc (100 mL><3). The combined organic
layers are washed with brine, dried over anhydrous a2S0 4 and concentrated under
vacuum. Purify the residue by silica gel chromatograph (PE:EtOAc 15:1) to afford
3-[3-(3,5-
Dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-3-hydroxy-butyryl]-5,6-dihydro-4H-cyclopenta
[c]thiophene-l-carboxylic acid methyl ester as an orange solid (27 g, 89.3%). MS (m/z):
486 (M+l).
J) Synthesis of 3-[3-(3,5-Dichloro-4-fluorophenyl)-4,4,4-trifluorobut-2-enoyl]-5,6-
dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid methyl ester
Stir a mixture of 3-[3-(3,5-
Dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-3-hydroxylbutyryl]-
5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid methyl ester (26 g,
53.7 mmol), S0C12 (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-Dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-5,6-dihydro-4H-cyclope
nta[c]thiophene-l-carboxylic acid methyl ester as a pale yellow solid (25 g, 100 %). (m/z):
467 (M+l).
K) Synthesis of
3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-
3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid methyl
ester
Stir a mixture of 3-[3-(3,5-Dichloro-4-fluoro-phenyl)-4,4,4-trifluoro-but-2-
enoyl]-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid methyl ester (25 g, 53.6
mmol), NaOH (8.6 g, 0.214 mol) and NH2OH-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 Na2S04 and
concentrated by vacuum to afford 3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl
-4,5-dihydro-isoxazol-3-yl] -5,6- dihydro-4H-cyclopenta[c]thiophene- 1-carboxylic 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-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-
3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-l -carboxylic
Stir a mixture of
3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-
dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid methyl
ester (26 g, 54. 1 mmol) and LiOH-H20 (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 cone. HC1 to pH = 1,
and extract the resultant mixture with EtOAc (200 ml_x3). Purify the residue by silica gel
chromatograph (EtOAc:MeOH 6 : 1) to afford
3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-
4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H- cyclopenta[c]thiophene- 1-carboxylic acid as a
white solid (23 g, 91.7 % for 2 steps). MS (m/z): 468 (M+l).
M) Synthesis of [(2,2-difluoro-ethylcarbamoyl)-methyl]-carbamic acid r -butyl
ester
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 Na2S0 4, 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
P)
To a solution of compound
[(2,2-difluoro-ethylcarbamoyl)-methyl]-carbamic acid -butyl ester (30 g crude product,
0.13 mol) in acetic acid ethyl ester (100 mL) is added 4 M HC1 (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- , 400 MHz): d 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-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-
3-yl]-5,6-dihydro-4 H-cyclopenta[c]thiophene-l-carboxylic acid
[(2,2-difluoro-ethylcarbamoyl)-methyl]-amide
To a solution of compound
3-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl
-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4 H-cyclopenta[c]thiophene-l-carboxylic 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+l).
Scheme H
SFC Separation of Example 244 to provide S Form
Example 245
(5)-3-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-
3-yl]-5,6-dihydro-4 H-cyclopenta[c]thiophene-l-carboxylic acid
[(2,2-difluoro-ethylcarbamoyl)-methyl]-amide
3 g of 3-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-
3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid
[(2,2-difluoro-ethylcarbamoyl)-methyl]-amide is separated by SFC separation to give
desired product (1.4 g, 93 %).
1H NMR (CDC13, 400 MHz): d 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, lOum
Mobile phase: A: Supercritical C02, B: EtOH, A:B =60:40 at 240ml/min
Column Temp: 38 °C
Nozzle Pressure: lOOBar
Nozzle Temp: 60 °C
Evaporator Temp: 20 °C
Trimmer Temp: 25 °C
Wavelength: 220nm
Scheme I
Example 246
-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol
-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid
[(2-fluoro-ethylcarbamoyl)-methyl]-amide
A) Synthesis of
( {3 -[5-(3 ,5-Dichloro-4-fluoro-phenyl)-5 -trifluoromethyl-4,5 -dihydro-isoxazol-
3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carbonyl}-amino)-acetic acid
methyl ester
To a solution of compound
3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro
-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic 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 Na2S0 4, 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-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol
-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carbonyl}-amino)-acetic acid
Stir a mixture of
({3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol
-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carbonyl}-amino)-acetic acid methyl
ester ( 11 g, 18.6 mmol) and LiOH-H20 (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 HC1 to pH = 3, and extract the resultant mixture with EtOAc (100 ml_x3),
the combined organic layer is washed with brine, dried over anhydrous Na2S0 4 and
concentrated under vacuum, the residue is purified by silica gel chromatograph (PE :
EtOAc 1:1) to afford ({3-[5-(3,5-Dichloro-4-fluoro-phenyl)
-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-lcarbonyl}-
amino)-acetic acid as a white solid (10.2 g, 90.7 % for two steps). MS (m/z):
525 (M+l).
C) Synthesis of
3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro
-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid
[(2-fluoro-ethylcarbamoyl)-methyl]-amide
To a solution of compound
({3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl
-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carbonyl}-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+l).
Example 247
(S)- 3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro
-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid
[(2-fluoro-ethylcarbamoyl) -methyl] -amide
100 mg of
3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-
dihydro-4H-cyclopenta[c]thiophene- 1-carboxylic acid
[(2-fluoro-ethylcarbamoyl)-methyl]-amide is separated by SFC separation to give desired
product (40 mg, 80 %).
1H NMR (CDC13, 400 MHz): d 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. 8 1 (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 C02 , B: EtOH (0.05%DEA) , A:B =45:55
at 80ml/min
Column Temp: 38°C
Nozzle Pressure: lOOBar
Nozzle Temp: 60°C
Evaporator Temp: 20°C
Trimmer Temp: 25°C
Wavelength: 220nm
Scheme J
Chiral
Example 248
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-
dihydroisoxazol-3-yl)-N-(2-oxo-2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[
c]thiophene- 1-carboxamide
Stir a mixture of
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-
dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid (0.8 g,
1.7 mmol), N,N-diisopropylethylamine (663 mg, 5.1 mmol), 2-amino-N-(prop-2-yn-l-yl)
acetamide hydrochloride (305 mg, 2.0 mmol) and HATU (974 g, 2.6 mmol) in ¾ ¾ (10
mL) at room temperature for 2 hours. The reaction mixture is diluted with CH2CI2 (40 mL)
and is washed with water (10 mLx3) and brine. Then the organic layer is dried over
anhydrous Na2S0 4 and concentrated under vacuum. Purify the residue by preparative
HPLC to afford 3-(5-(3,5-dichloro
-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(2-oxo-2-(prop-2-ynyla
mino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxamide as a white solid (850
mg, 88.4 %). MS (m/z): 584.1 (M+Na).
Example 249
(S)-3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(
2-oxo-2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-lcarboxamide
850 mg of 3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-
dihydroisoxazol-3-yl)-N-(2-oxo-2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[
c]thiophene-l-carboxamide is separated by SFC to give
(S)-3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(
2-oxo-2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxamid
e (400 mg, 94 % yield, 99.7% ee).
H NMR (400 MHz, CDC13) d 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 150x4.6mm I.D., 5um.
Mobile phase: EtOH in CO2 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, lOum; Mobile
phase: A: Supercritical C0 2 , B: EtOH, A:B =45:55 at 200ml/min; Column Temp: 38 °C;
Nozzle Pressure: lOOBar; Nozzle Temp: 60 °C; Evaporator Temp: 20 °C; Trimmer Temp:
25 °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 ah, J . Med. Entomol. 41: 1034-1042 (2004). Briefly, experimental test articles are
formulated in dimethylsulfoxide (DMSO) to prepare a stock solution at a concentration of
lOmM. Using 96-well microtiter plates, an aliquot of the lOmM sample is subsequently
diluted in a water-based solution containing 1% ethanol and 0.2% Triton X-100, to obtain
the desired concentration (typically 0.3mM or lower) of experimental test article in a
volume of 0.1ml (minimum n=3 replicates per compound or concentration).
Approximately 30-50 Lone star tick larvae (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, 23 1,
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 ah, 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 and are non-limiting.
1. A compound, or a salt thereof, of formula I
I
wherein A is
n is 0 or 1;
R1 is thienyl or phenyl, said thienyl or phenyl substituted with 2 or 3 of the
same or different halo atoms;
R2 is at each occurrence independently hydrogen, C1-C5 alkyl, C3-C6
cycloalkyl, or C - C 5 haloalkyl;
p is at each occurrence independently 0 or 1;
R4 is C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 cyanoalkyl, C - C 5 alkylthio,
C3-C6 cycloalkyl optionally substituted with hydroxy, halo, or C - C 5 alkyl: C3-C5
cycloheteroalkyl optionally substituted with C1-C5 alkyl, C3-C6 cycloalkyl, or C1-C5
R5
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;
R5 is hydroxy, -0-(Ci-C alkyl), or
R6 is hydrogen, C1-C5 alkyl, C1-C5 haloalkyl, C - C 5 cyanoalkyl, C - C 5
alkylthio, or C2-C5 alkynyl;
or R2 and R combine to form, with the nitrogen to which they are attached,
Yi, Y2, and Y are carbon or nitrogen with at most only one of Yi, Y2, and
Y 3 being nitrogen, and when Yi, Y2, or Y3 is a carbon, each may be substituted by C - C 5
alkyl;
R7 is hydrogen, halo, C - C 5 alkyl, or
( H2) "
o
R is hydroxy, -0-(Ci-C alkyl), or
R is C1-C5 alkyl,
R10 is hydrogen, C - C 5 alkyl, C1-C5 haloalkyl, C1-C5 cyanoalkyl, C1-C5
alkylthio, or C2-C5 alkynyl.
2. A compound of clause 1 wherein A is
3. A compound according to any of clauses 1-2 wherein R2 is
hydrogen and n is 1.
4. A compound of according to any of clauses 1-3 wherein R is

3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(
(R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;
N,N-Dimethyl-2-(4-{3-[5-(3,4,5-trichloro-thiophen-2-yl)-5-trifluoromethyl-
4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carbonyl}-piperazin-l-y
l)-acetamide;
( {3-[5-(3 ,5-Dichloro-phenyl)-5 -trifluoromethyl-4,5-dihydro-isoxazol-3 -yl]
-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carbonyl}-amino)-acetic acid methyl ester;
({3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxa
zol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carbonyl}-amino)-acetic acid methyl
ester;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-car
boxamide;
3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4
,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid (l,l-dioxo-thietan-3-yl)-amide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(3-oxocyclohexyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;
3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4
,5,6,7-tetrahydro-benzo[c]thiophene- 1-carboxylic acid
(1,1 -dioxo-hexahydro- 116-thiopyran-4-yl)-amide;
3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4
,5,6,7-tetrahydro-benzo[c]thiophene- 1-carboxylic acid
[2-oxo- l-(2,2,2-trifluoro-ethyl)-pyrrolidin- 3-yl]-amide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-((R)-2-oxopyrrolidin-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxamide;
N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichlorophenyl)-5-(triflu
oromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxa
mide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(2-oxo-2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxam
ide;
N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-3-(5-(3,4,5-trichlorophenyl)-
5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carb
oxamide;
N-((R)-2-oxopyrrolidin-3-yl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluorometh
yl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;
N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifl
uoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxami
de;
N-(2-oxo-2-(prop-2-ynylamino)ethyl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifl
uoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxami
de;
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo
l-3-yl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene
-1-carboxamide;
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo
l-3-yl)-N-((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene- 1-carboxamide
N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichloro-4-fluorophenyl)
-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-car
boxamide;
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo
l-3-yl)-N-(2-oxo-2-(prop-2-ynylamino)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carb
oxamide;
N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-3-(5-(3,4,5-trichlorophenyl)-
5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-lcarboxamide;
N-((R)-2-oxopyrrolidin-3-yl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluorometh
yl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene- 1-carboxamide;
N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifl
uoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carbox
amide;
N-(2-oxo-2-(prop-2-ynylamino)ethyl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifl
uoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carbox
amide;
N-(2-oxo-l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(5-(3,4,5-trichlorophen
yl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene
-1-carboxamide;
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo
l-3-yl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thioph
ene- 1-carboxamide;
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo
l-3-yl)-N-((R )-2-oxopyrrolidin-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxam
ide;
N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichloro-4-fluorophenyl)
-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-lcarboxamide;
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo
l-3-yl)-N-(2-oxo-l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-5,6-dihydro-4H-cyclopenta[c]thi
ophene- 1-carboxamide;
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo
l-3-yl)-N-(2-oxo-2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-c
arboxamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carbo
xamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(2-(ethylamino)-2-oxoethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene- 1-carboxamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-((tetrahydrofuran-2-yl)methyl)-4,5,6,7-tetrahydrobenzo[c]thiophene- 1-carboxamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(2-(methylthio)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l -carboxamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l -carboxamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(3-hydroxycyclohexyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(5-fluoropyridin-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(tetrahydro-2H-pyran-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(thietan-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;
N-( 1-cyclopropyl-2-oxopyrrolidin-3 -yl)-3 -(5-(3 ,5-dichlorophenyl)-5-(triflu
oromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamid
e;
N-(2-oxo-2-(prop-2-ynylamino)ethyl)-3-(5-(3,4,5-trichlorothiophen-2-yl)-
5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carb
oxamide;
3-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]
-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid
(1,1 -dioxo-hexahydro-thiopyran-4-yl)-amide;
N-(2-oxo-l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(5-(3,4,5-trichlorophen
yl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene- 1-
carboxamide;
N-(tetrahydro-2H-pyran-4-yl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluoromet
hyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l -carboxamide;
N-(l-cyclopropyl-2-oxopyrrolidin-3-yl)-3-(5-(3,4,5-trichlorophenyl)-5-(tri
fluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxa
mide;
3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxaz
ol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid
(1,1 -dioxo-thietan-3 -yl)-amide;
3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxaz
ol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid
(1,1 -dioxo-hexahydro-thiopyran-4-yl)-amide;
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo
l-3-yl)-N-(4-oxocyclohexyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo
l-3-yl)-N-(2-oxo-l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thioph
ene- 1-carboxamide;
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo
l-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamid
e;
N-( 1-cyclopropyl-2-oxopyrrolidin-3 -yl)-3 -(5-(3 ,5-dichloro-4-fluorophenyl
)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-ca
rboxamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(4-oxocyclohexyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l -carboxamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(2-oxo- l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l
-carboxamide;
3-((R)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-y
l)-N-((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l -carboxamide;
3-((S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl
)-N-((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;
N-(4-carbamoylphenyl)-3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-
dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l -carboxamide;
3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxaz
ol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid
(3-carbamoyl-thiophen-2-yl)-amide;
2-(3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)
- 4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamido)acetic acid;
({3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxa
zol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carbonyl}-amino)-acetic acid;
N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichlorophenyl)-5-
(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carbo
xamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(2-oxo-2-(prop-2-ynylamino)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;
or
N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,4,5-trichlorothiophen-2-yl)-
5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carb
oxamide.
A compound of clause 1wherein A
7. A compound of clause 1 or 6 wherein Yi is nitrogen.
8. Acompound according to any of clauses 1, 6, or 7, wherein R is
.0
O
9. A compound according to any of clauses 6-8, or salt therof, being
3-(4-chlorobenzo[b]thiophen-2-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromet
hyl)-4,5-dihydroisoxazole;
2-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-t
hieno[2,3-c]pyridine;
5-Bromo-2-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxaz
ol-3 -yl] -thieno [2,3 -b]pyridine;
2-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-t
hieno[2,3-b]pyridine;
3-(benzo[b]thiophen-2-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-
dihydroisoxazole;
3-(benzo[d]thiazol-2-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-di
hydroisoxazole;
5-(3,5-dichlorophenyl)-3-(3-methylbenzo[b]thiophen-2-yl)-5-(trifluoromet
hyl)-4,5-dihydroisoxazole;
5-(3,5-dichlorophenyl)-3-(5-methylbenzo[b]thiophen-2-yl)-5-(trifluoromet
hyl)-4,5-dihydroisoxazole;
3-(5-chlorobenzo [b]thiophen-2-yl)-5-(3 ,5-dichlorophenyl)-5 -(trifluoromet
hyl)-4,5-dihydroisoxazole;
methyl
2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thieno[2,3-b]pyri
dine-5-carboxylate;
2-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-j/]-t
hieno [2,3 -b]pyridine-5 -carboxylic acid;
2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)thieno[2,3-b]pyridine-5-carboxamide; or
2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-((R)-2-oxopyrrolidin-3-yl)thieno[2,3-b]pyridine-5-carboxamide.
10. A compound, or salt thereof, being
(S)-3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisox
azol-3-yl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thi
ophene- 1-carboxamide;
3-[5 -(3 ,5-dichloro-4-fluoro-phenyl)-5 -trifluoromethyl-4,5 -dihydroisoxazol-
3-yl]-5,6-dihydro-4 H-cyclopenta[c]thiophene-l-carboxylic acid
[(2,2-difluoro-ethylcarbamoyl)-methyl]-amide;
(5)-3-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-
3-yl]-5,6-dihydro-4 H-cyclopenta[c]thiophene- 1-carboxylic acid
[(2,2-difluoro-ethylcarbamoyl)-methyl]-amid);
3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxaz
ol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-l -carboxylic acid
[(2-fluoro-ethylcarbamoyl)-methyl]-amide;
(S)- 3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro
-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid
[(2-fluoro-ethylcarbamoyl) -methyl]-amide;
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-
dihydroisoxazol-3-yl)-N-(2-oxo-2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[
c]thiophene- 1-carboxamide; or
(S)-3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisox
azol-3-yl)-N-(2-oxo-2-(prop-2-ynylamino)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.
15. 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.
20. 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.
25. 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.
30. 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;
R1 is thienyl or phenyl, said thienyl or phenyl substituted with 2 or 3 of the
same or different halo atoms; and
R11 is hydroxy, -0-(d-C 4 alkyl), or a halo atom.
35. The compound of 34 wherein R1 is phenyl substituted with 2 or 3
of the same or different halo atoms.
36. The compound according to clauses 34 or 35 wherein R11 is
hydroxy.
37. The compound according to any of clauses 34-36 wherein it is
3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]
-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid methyl ester;
3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5
,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid methyl ester;
3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxaz
ol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid methyl ester
3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxaz
ol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid methyl ester;
3-[5 -(3 ,5-Dichloro-4-fluoro-phenyl)-5 -trifluoromethyl-4,5 -dihydro-isoxaz
ol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid methyl ester;
3-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]
-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid methyl ester;
3-[5 -(3 ,5-Dichloro-4-fluoro-phenyl)-5 -trifluoromethyl-4,5 -dihydro-isoxaz
ol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid methyl ester;
3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]
-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid;
3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5
,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid;
3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxaz
ol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid;
3-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]
-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid;
3-[5 -(3 ,5-Dichloro-4-fluoro-phenyl)-5 -trifluoromethyl-4,5 -dihydro-isoxaz
ol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid;
3-[5 -(3 ,5-Dichloro-4-fluoro-phenyl)-5 -trifluoromethyl-4,5 -dihydro-isoxaz
ol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid;
3-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]
-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-
4,5,6,7-tetrahydrobenzo[c]thiophene-l-carbonyl chloride; or
3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxaz
ol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carbonyl chloride.
38. A compound according to clause 34 wherein it is
3-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dih
ydro-4H-cyclopenta[c]thiophene- 1-carboxylic acid.
39. A compound according to clause 34 wherein it is
3-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4
H-cyclopenta[c]thiophene- 1-carboxylic acid.
40. A compound according to clause 34 wherein it is
3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7
-tetrahydro-benzo[c]thiophene-l-carboxylic acid.
41. A compound according to clause 34 wherein it is
3-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrah
ydro-benzo[c]thiophene-l-carboxylic 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
R2
3 /
R3— H
We claim:
1. A compound, or a salt thereof, of formula I
wherein A is
n is 0 or 1;
R1 is thienyl or phenyl, said thienyl or phenyl substituted with 2 or 3 of the
same or different halo atoms;
R2 is at each occurrence independently hydrogen, C1-C5 alkyl, C3-C6
cycloalkyl, or C1-C5 haloalkyl;
R 3 i -|-(CH 2)p - R
p is at each occurrence independently 0 or 1;
R is C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 cyanoalkyl, C - C 5 alkylthio,
C3-C6 cycloalkyl optionally substituted with hydroxy, halo, or C - C 5 alkyl: C3-C5
cycloheteroalkyl optionally substituted with C - C 5 alkyl, C3-C6 cycloalkyl, or C1-C5
R5
( H2) /
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;
R5 is hydroxy, -0-(Ci-C alkyl), or
R6 is hydrogen, C1-C5 alkyl, C1-C5 haloalkyl, - C cyanoalkyl, - C
alkylthio, or C2-C5 alkynyl;
or R2 and R combine to form, with the nitrogen to which they are attached,
Yi, Y 2, and Y 3 are carbon or nitrogen with at most only one of Y l Y 2, and
Y 3 being nitrogen, and when Yi, Y 2, or Y is a carbon, each may be substituted by C - C 5
alkyl;
R7 is hydrogen, halo, C - C 5 alkyl, or
¾ (CH )
O ;
R8 is hydroxy, -0-(d-C alkyl), or
R is C1-C5 alkyl,
R10 is hydrogen, C1-C5 alkyl, C1-C5 haloalkyl, C1-C5 cyanoalkyl, C1-C5
alkylthio, or C2-C5 alkynyl.
2. A compound of claim 1 wherein A is
3. A compound of claim 1 wherein R2 is hydrogen and n is 1.
4. A compound of claim 1 wherein R is

3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(
(R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;
N,N-Dimethyl-2-(4-{3-[5-(3,4,5-trichloro-thiophen-2-yl)-5-trifluoromethyl-
4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carbonyl}-piperazin-l-y
l)-acetamide;
( {3-[5-(3 ,5-Dichloro-phenyl)-5 -trifluoromethyl-4,5-dihydro-isoxazol-3 -yl]
-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carbonyl}-amino)-acetic acid methyl ester;
({3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxa
zol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carbonyl}-amino)-acetic acid methyl
ester;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-car
boxamide;
3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4
,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid (l,l-dioxo-thietan-3-yl)-amide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(3-oxocyclohexyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;
3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4
,5,6,7-tetrahydro-benzo[c]thiophene- 1-carboxylic acid
(1,1 -dioxo-hexahydro- 116-thiopyran-4-yl)-amide;
3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4
,5,6,7-tetrahydro-benzo[c]thiophene- 1-carboxylic acid
[2-oxo- l-(2,2,2-trifluoro-ethyl)-pyrrolidin- 3-yl]-amide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-((R)-2-oxopyrrolidin-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxamide;
N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichlorophenyl)-5-(triflu
oromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxa
mide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(2-oxo-2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxam
ide;
N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-3-(5-(3,4,5-trichlorophenyl)-
5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carb
oxamide;
N-((R)-2-oxopyrrolidin-3-yl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluorometh
yl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;
N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifl
uoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxami
de;
N-(2-oxo-2-(prop-2-ynylamino)ethyl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifl
uoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxami
de;
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo
l-3-yl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene
-1-carboxamide;
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo
l-3-yl)-N-((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene- 1-carboxamide
N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichloro-4-fluorophenyl)
-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-car
boxamide;
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo
l-3-yl)-N-(2-oxo-2-(prop-2-ynylamino)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carb
oxamide;
N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-3-(5-(3,4,5-trichlorophenyl)-
5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-lcarboxamide;
N-((R)-2-oxopyrrolidin-3-yl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluorometh
yl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene- 1-carboxamide;
N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifl
uoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carbox
amide;
N-(2-oxo-2-(prop-2-ynylamino)ethyl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifl
uoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carbox
amide;
N-(2-oxo-l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(5-(3,4,5-trichlorophen
yl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene
-1-carboxamide;
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo
l-3-yl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thioph
ene- 1-carboxamide;
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo
l-3-yl)-N-((R )-2-oxopyrrolidin-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxam
ide;
N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichloro-4-fluorophenyl)
-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-lcarboxamide;
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo
l-3-yl)-N-(2-oxo-l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-5,6-dihydro-4H-cyclopenta[c]thi
ophene- 1-carboxamide;
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo
l-3-yl)-N-(2-oxo-2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l-c
arboxamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carbo
xamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(2-(ethylamino)-2-oxoethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene- 1-carboxamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-((tetrahydrofuran-2-yl)methyl)-4,5,6,7-tetrahydrobenzo[c]thiophene- 1-carboxamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(2-(methylthio)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l -carboxamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(3,3,3-trifluoropropyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l -carboxamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(3-hydroxycyclohexyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(5-fluoropyridin-2-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(tetrahydro-2H-pyran-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(thietan-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;
N-( 1-cyclopropyl-2-oxopyrrolidin-3 -yl)-3 -(5-(3 ,5-dichlorophenyl)-5-(triflu
oromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamid
e;
N-(2-oxo-2-(prop-2-ynylamino)ethyl)-3-(5-(3,4,5-trichlorothiophen-2-yl)-
5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carb
oxamide;
3-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]
-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid
(1,1 -dioxo-hexahydro-thiopyran-4-yl)-amide;
N-(2-oxo-l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(5-(3,4,5-trichlorophen
yl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene- 1-
carboxamide;
N-(tetrahydro-2H-pyran-4-yl)-3-(5-(3,4,5-trichlorophenyl)-5-(trifluoromet
hyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l -carboxamide;
N-(l-cyclopropyl-2-oxopyrrolidin-3-yl)-3-(5-(3,4,5-trichlorophenyl)-5-(tri
fluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxa
mide;
3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxaz
ol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid
(1,1 -dioxo-thietan-3 -yl)-amide;
3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxaz
ol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid
(1,1 -dioxo-hexahydro-thiopyran-4-yl)-amide;
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo
l-3-yl)-N-(4-oxocyclohexyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo
l-3-yl)-N-(2-oxo-l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thioph
ene- 1-carboxamide;
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazo
l-3-yl)-N-(tetrahydro-2H-pyran-4-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamid
e;
N-( 1-cyclopropyl-2-oxopyrrolidin-3 -yl)-3 -(5-(3 ,5-dichloro-4-fluorophenyl
)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-ca
rboxamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(4-oxocyclohexyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l -carboxamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(2-oxo- l-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-5,6-dihydro-4H-cyclopenta[c]thiophene-l
-carboxamide;
3-((R)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-y
l)-N-((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l -carboxamide;
3-((S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl
)-N-((R)-2-oxopyrrolidin-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;
N-(4-carbamoylphenyl)-3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-
dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l -carboxamide;
3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxaz
ol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid
(3-carbamoyl-thiophen-2-yl)-amide;
2-(3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)
- 4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamido)acetic acid;
({3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxa
zol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carbonyl}-amino)-acetic acid;
N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,5-dichlorophenyl)-5-
(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carbo
xamide;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(2-oxo-2-(prop-2-ynylamino)ethyl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carboxamide;
or
N-(2-(cyanomethylamino)-2-oxoethyl)-3-(5-(3,4,5-trichlorothiophen-2-yl)-
5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4,5,6,7-tetrahydrobenzo[c]thiophene-l-carb
oxamide.
Acompound of claim 1 wherein A
7. A compound of claim 6 wherein Yi is nitrogen.
8. A compound of claim 6 wherein R7 is
.0
O
9. A compound of claim 6, or salt therof, being
3-(4-chlorobenzo[b]thiophen-2-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromet
hyl)-4,5-dihydroisoxazole;
2-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-t
hieno[2,3-c]pyridine;
5-Bromo-2-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxaz
ol-3 -yl] -thieno [2,3 -b]pyridine;
2-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-t
hieno[2,3-b]pyridine;
3-(benzo[b]thiophen-2-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-
dihydroisoxazole;
3-(benzo[d]thiazol-2-yl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-di
hydroisoxazole;
5-(3,5-dichlorophenyl)-3-(3-methylbenzo[b]thiophen-2-yl)-5-(trifluoromet
hyl)-4,5-dihydroisoxazole;
5-(3,5-dichlorophenyl)-3-(5-methylbenzo[b]thiophen-2-yl)-5-(trifluoromet
hyl)-4,5-dihydroisoxazole;
3-(5-chlorobenzo [b]thiophen-2-yl)-5-(3 ,5-dichlorophenyl)-5 -(trifluoromet
hyl)-4,5-dihydroisoxazole;
methyl
2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)thieno[2,3-b]pyri
dine-5-carboxylate;
2-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-j/]-t
hieno [2,3 -b]pyridine-5 -carboxylic acid;
2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)thieno[2,3-b]pyridine-5-carboxamide; or
2-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N
-((R)-2-oxopyrrolidin-3-yl)thieno[2,3-b]pyridine-5-carboxamide.
11. A compound, or salt thereof, being
(S)-3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisox
azol-3-yl)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thi
ophene- 1-carboxamide;
3-[5 -(3 ,5-dichloro-4-fluoro-phenyl)-5 -trifluoromethyl-4,5-dihydroisoxazol-
3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid
[(2,2-difluoro-ethylcarbamoyl)-methyl]-amide;
(5)-3-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-
3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene- 1-carboxylic acid
[(2,2-difluoro-ethylcarbamoyl)-methyl]-amid);
3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxaz
ol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-l -carboxylic acid
[(2-fluoro-ethylcarbamoyl)-methyl]-amide;
(S)- 3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro
-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid
[(2-fluoro-ethylcarbamoyl) -methyl]-amide;
3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-
dihydroisoxazol-3-yl)-N-(2-oxo-2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[
c]thiophene- 1-carboxamide; or
(S)-3-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisox
azol-3-yl)-N-(2-oxo-2-(prop-2-ynylamino)ethyl)-5,6-dihydro-4H-cyclopenta[c]thiophene-
1-carboxamide.
11. A formulation comprising a compound or salt of claim 1 and one or
more acceptable carriers.
12. The formulation of claim 11wherein it further comprises at least
one additional active ingredient.
13. The formulation of claim 11wherein it is a human pharmaceutical
formulation.
14. The formulation of claim 1 1 wherein it is a veterinary
pharmaceutical formulation.
15. 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
claim 1 to said animal.
16. The method of claim 15 wherein at least one other active ingredient
is administered to said animal.
17. The method of claim 15 wherein said animal is a human.
18. The method of claim 15 wherein said animal is a companion
animal.
19. The method of claim 18 wherein said companion animal is a dog or
cat.
20. The method of claim 15 wherein said parasite is a tick.
21. The method of claim 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 claim 1 to an
animal in need thereof.
23. The method of claim 22 wherein at least one other active ingredient
is administered to said animal.
24. The method of claim 22 wherein said animal is a human.
25. The method of claim 22 wherein said animal is a companion
animal.
26. The method of claim 25 wherein said companion animal is a dog or
cat.
27. The method of claim 22 wherein said parasite is a tick.
28. The method of claim 22 wherein said animal is a livestock animal.
29. A method for controlling parasites, characterized in that a compound
of claim 1 is allowed to act on the pests or their habitat, or both.
30. The method of claim 29 wherein the compound is placed on a plant
or an animal.
31. Use of compounds, or salts thereof, of claim 1 for controlling
parasites.
32. A compound, or salt thereof, of claim 1 for use in therapy.
33. A compound, or salt thereof ,of claim 1 for use in controlling an
ectoparasite infestation.
34. A compound, or salt thereof, of Formula II
II
wherein n is 0 or 1;
R1 is thienyl or phenyl, said thienyl or phenyl substituted with 2 or 3 of the
same or different halo atoms; and
R11 is hydroxy, -0-(d-C 4 alkyl), or a halo atom.
35. The compound of 34 wherein R1 is phenyl substituted with 2 or 3
of the same or different halo atoms.
36. The compound according to claim 34 wherein R11 is hydroxy.
37. The compound of claim 34 wherein it is
3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]
-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid methyl ester;
3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5
,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid methyl ester;
3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxaz
ol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid methyl ester
3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxaz
ol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid methyl ester;
3-[5 -(3 ,5-Dichloro-4-fluoro-phenyl)-5 -trifluoromethyl-4,5 -dihydro-isoxaz
ol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid methyl ester;
3-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]
-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid methyl ester;
3-[5 -(3 ,5-Dichloro-4-fluoro-phenyl)-5 -trifluoromethyl-4,5 -dihydro-isoxaz
ol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid methyl ester;
3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]
-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid;
3-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5
,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid;
3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxaz
ol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid;
3-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]
-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid;
3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxaz
ol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carboxylic acid;
3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxaz
ol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid;
3-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]
-5,6-dihydro-4H-cyclopenta[c]thiophene-l-carboxylic acid;
3-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-
4,5,6,7-tetrahydrobenzo[c]thiophene-l-carbonyl chloride; or
3-[5-(3,4,5-Trichloro-thiophen-2-yl)-5-trifluoromethyl-4,5-dihydro-isoxaz
ol-3-yl]-4,5,6,7-tetrahydro-benzo[c]thiophene-l-carbonyl chloride.
38. A compound according to claim 34 wherein it is
3-[5-(3,5-dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dih
ydro-4H-cyclopenta[c]thiophene- 1-carboxylic acid.
39. A compound according to claim 34 wherein it is
3-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4
H-cyclopenta[c]thiophene- 1-carboxylic acid.
40. A compound according to claim 34 wherein it is
3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7
-tetrahydro-benzo[c]thiophene-l -carboxylic acid.
41. A compound according to claim 34 wherein it is
3-[5-(3,4,5-Trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-4,5,6,7-tetrah
ydro-benzo[c]thiophene-l -carboxylic acid.
42. A process for preparing a compound of claim , comprising
synthetically modifying a compound of claim 34.
43. The process of claim 42 wherein a compound of claim 34 is
with a compound of the formula
R2
3 /
R3— H