Isooxazoline compounds as antiparasitic agents

Abstract

Compounds of formula (I) and pharmaceutically acceptable salts thereof, useful as treatments for parasitic diseases are provided. Also provided are pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts and methods of using the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions in the treatment of various disorders, including parasitic disease or infection.

Description

Attorney Docket No.78045-422677 ISOOXAZOLINE COMPOUNDS AND USES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 663,992, filed June 25, 2024; the entire contents of this application are hereby incorporated by reference herein. BACKGROUND

[0002] A number of parasites are known to infest mammals and cause irritation, disease, and health conditions. Parasites and pests such as fleas, ticks, mites, and lice can infest animals such as dogs and cats and cause health issues for the animals and those who come in contact with them. In many applications, long lasting effect against pests is desirable. Long lasting protection is particularly important with companion animals, such as dogs and cats and also mice, guinea pigs, ferrets, and rabbits; and with ranched animals such as cattle, sheep, pigs, and fish, in particular salmon and sea bass.

[0003] Aryl isoxazolines are used in agriculture, forestry, turf, household, wood products, nursery crops protection, and veterinary fields. Within the veterinary field, aryl isoxazolines are used in treatments of companion animals and livestock, including fish. For example, such inhibitors are disclosed in WO 2005 / 085216, WO 2007 / 079162, US 2007 / 066617, US20130131017, WO 2009 / 002809, WO 2009 / 112275, WO 2010 / 003923, WO 2010 / 070068, WO 2012 / 120399, WO 2013 / 079407, and WO 2021 / 127188.

[0004] Notwithstanding the availability of anti-parasitic agents available, there remains a need to improve the efficacy of bioavailable parasitic treatments in a manner that is long-lasting and safe for animal use. SUMMARY

[0005] In some embodiments, the disclosure relates to a compound of formula (I): or an is 0 or 1; each of Y1, Y2, Y3, and Y4is independently selected from the group consisting of –H, –CN, –CH3, –CH2F, –CHF2, –CF3, and halo; and each of X1, X2, and X3is independently C, N, or N+-O-.

[0006] In some aspects, at least two of Y1, Y2, Y3, and Y4are not –H. In some aspects, at least three of Y1, Y2, Y3, and Y4are not –H.

[0007] In some aspects, at least two of X1, X2, and X3are C. In some aspects, the disclosure relates to a compound of formula (I), wherein each of X1, X2, and X3are C.

[0008] In some aspects, at least one of Y1, Y2, Y3, and Y4is a halo. In some aspects, the halo is –Cl. In some aspects, the halo is –F.

[0009] In some aspects, at least two of Y1, Y2, Y3, and Y4is each independently a halo. In some aspects, the at least two of Y1, Y2, Y3, and Y4is –Cl or –F. In some aspects, one of Y1, Y2, Y3, and Y4is –Cl and one of Y1. Y2, Y3, and Y4is –F.

[0010] In some aspects, n is 0. In some aspects, n is 1.

[0011] In some embodiments, the disclosure relates to a compound of formula (I-A): A) or an is 0 or 1; each of X1, X2, and X3is independently C or N; and each of Y1, Y3, and Y4is independently selected from the group consisting of –CN, –CH3, –CH2F, –CHF2, –CF3, and halo.

[0012] In some aspects, at least two of X1, X2, and X3are C. In some aspects, each of X1, X2, and X3are C.

[0013] In some aspects, at least one of Y1, Y3, and Y4is a halo. In some aspects, the halo is –Cl. In some aspects, the halo is –F.

[0014] In some aspects, at least two of Y1, Y3, and Y4is a halo. In some aspects, the at least two of Y1, Y3, and Y4is –Cl or –F. In some aspects, one of Y1, Y3, and Y4is –Cl and one of Y1, Y3, and Y4is F.

[0015] In some aspects, at least one of Y1, Y3, and Y4is –CF3. In some aspects, one of Y1, Y3, and Y4is –CF3, one of Y1, Y3, and Y4is –Cl, and one of Y1, Y3, and Y4is –F.

[0016] In some aspects, n is 0. In some aspects, n is 1.

[0017] In some embodiments, the disclosure relates to a compound selected from Table A, or a pharmaceutically acceptable salt thereof.

[0018] In some aspects, the disclosure relates to a compound that is an (S)-enantiomer.

[0019] In some aspects, the disclosure relates to a compound of the disclosure, wherein the compound is in a non-salt form.

[0020] In some embodiments, the disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

[0021] In some embodiments, the disclosure relates to a method of treating a parasitic disease in a subject comprising administering to the subject a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0022] In some embodiments, the disclosure relates to a method of treating or lessening the severity in a subject of a parasitic infection comprising administering to the subject an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, the compound of claim 35 or a pharmaceutical composition of the disclosure.

[0023] In some aspects, the subject is a non-human animal.

[0024] In some embodiments, the disclosure relates to the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure, as a medicament.

[0025] In some embodiments, the disclosure relates to the use of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure in the manufacture of a medicament for the treatment of a parasitic disease.

[0026] In one aspect, the invention relates to a compound described herein, or a pharmaceutically acceptable salt thereof.

[0027] In another aspect, the invention relates to a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

[0028] In still another aspect, the invention relates to a method of treating a parasitic infection or disease in a subject by administering the compound, pharmaceutically acceptable salt, or pharmaceutical composition to the subject.

[0029] In yet another aspect, the invention relates to a method of treating a flea or tick infestation in a subject by administering the compound, pharmaceutically acceptable salt, or pharmaceutical composition to the subject. DETAILED DESCRIPTION

[0030] In one aspect, the invention relates to a compound of formula (I): (I) or an is 0 or 1; each of Y1, Y2, Y3, and Y4is independently selected from the group consisting of –H, –CN, –CH3, –CH2F, –CHF2, –CF3, and halo; and A is selected from the group consisting,the point of attachment to the adjacent amide carbonyl and ** indicates the point of attachment to the adjacent oxazole moiety; and each of X1, X2, and X3is independently C, N, or N+-O-.

[0031] For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry,” 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0032] As used herein, the term “compounds of the invention” refers to the compounds of formulas (I), and all of the embodiments thereof (e.g., formulas (I-A), etc.), as described herein, and to the compounds identified in Table A.

[0033] As described herein, the compounds of the invention comprise multiple variable groups (e.g., halo, -H, etc.). As one of ordinary skill in the art will recognize, combinations of groups envisioned by this invention are those combinations that result in the formation of stable or chemically feasible compounds. The term “stable,” in this context, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

[0034] As used herein, the term “halo” means F, Cl, Br or I.

[0035] As used herein, the term “alkyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having the specified number of carbon atoms, which is attached to the rest of the molecule by a single bond. For example, a “C1-C6 alkyl” group is an alkyl group having between one and six carbon atoms.

[0036] Unless otherwise specified, the compounds of the invention, whether identified by chemical name or chemical structure, include all stereoisomers (e.g., enantiomers and diastereomers), double bond isomers (e.g., (Z) and (E)), conformational isomers, and tautomers of the compounds identified by the chemical names and chemical structures provided herein. In addition, single stereoisomers, double bond isomers, conformational isomers, and tautomers as well as mixtures of stereoisomers, double bond isomers, conformational isomers, and tautomers are within the scope of the invention.

[0037] As used herein, in any chemical structure or formula, a non-bold, straight bond attached to a stereocenter of a compound, such as in , denotes that the compoundat the stereocenter.

[0038] As used herein, in any chemical structure or formula, a non-bold, wavy bond attached to a stereocenter of a compound, such as in , denotes that the compound but the exact configuration ofthe stereocenter is unspecified. For example, the compound may have either an (S)- or an (R)- configuration but is not a mixture of (S)- and (R)- configurations.

[0039] As used herein, the prefix “rac-,” when used in connection with a chiral compound, refers to a racemic mixture of the compound.

[0040] As used herein, the prefix “rel-,” when used in connection with a chiral compound, refers to a single enantiomer of unknown absolute configuration. In a compound bearing the “rel-” prefix, the (R)- and (S)- designators in the chemical name reflect the relative stereochemistry of the compound, but do not necessarily reflect the absolute stereochemistry of the compound. Where the relative stereochemistry of a given stereocenter is unknown, no stereochemical designator is provided.

[0041] As used herein, the term “compound,” when referring to the compounds of the invention, refers to a collection of molecules having identical chemical structures, except that there may be isotopic variation among the constituent atoms of the molecules. The term “compound” includes such a collection of molecules without regard to the purity of a given sample containing the collection of molecules. Thus, the term “compound” includes such a collection of molecules in pure form, in a mixture (e.g., solution, suspension, colloid, or pharmaceutical composition, or dosage form) with one or more other substances, or in the form of a hydrate, solvate, or co-crystal.

[0042] As used herein, “infestation” or “disease” refers to the presence of parasites that pose a risk of nuisance or harm to humans or animals. The presence can be in the environment (e.g., in animal bedding), on the skin or fur of an animal, in an orifice of the animal, etc. When the infestation is within an animal (e.g., in the blood or other internal tissues), the term infestation or disease is intended to be synonymous with the term, “infection,” as that term is generally understood in the art.

[0043] In some embodiments, the invention relates to a compound of formula (I),(I) or a pharmaceutically n is 0 or 1; each of Y1, Y2, Y3, and Y4is independently selected from the group consisting of –H, –CN, –CH3, –CH2F, –CHF2, –CF3, and halo; and each of X1, X2, and X3is independently C, N, N+-O-.

[0044] In some embodiments, X1, X2, and X3are C. In certain embodiments, one of X1, X2, and X3is N. In some embodiments, X1is N and X2and X3are C. In some embodiments, X2is N and X1and X3are C. In some embodiments, X3is N and X1and X2are C.

[0045] In certain embodiments, one of X1, X2, and X3is N+-O-. In some embodiments, X1is N+-O- and X2and X3are C. In some embodiments, X2is N+-O- and X1and X3are C. In some embodiments, X3is N+-O- and X1and X2are C.

[0046] In some embodiments, n is 0. In certain embodiments, n is 1.

[0047] In certain embodiments, Y2is –H. In some embodiments, at least one of Y1, Y2, Y3, and Y4is a halo. In certain embodiments, the halo is –Cl or –F. In some embodiments, at least one of Y1, Y2, Y3, and Y4is CHF2. In some embodiments, at least one of Y1, Y2, Y3, and Y4is –CF3. In some embodiments, at least one of Y1, Y2, Y3, and Y4is –Cl, one of Y1, Y2, Y3, and Y4is –F, and one of Y1, Y2, Y3, and Y4is –CF3.

[0048] In some embodiments, the invention relates to a compound of formula (I-i), i) or an is 0 or 1; each of Y1, Y2, Y3, and Y4is independently selected from the group consisting of –H, –CN, –CH3, –CH2F, –CHF2, –CF3, and halo; and each of X1, X2, and X3is independently C or N.

[0049] In some embodiments, X1, X2, and X3are C. In certain embodiments, one of X1, X2, and X3is N. In some embodiments, X1is N and X2and X3are C. In some embodiments, X2is N and X1and X3are C. In some embodiments, X3is N and X1and X2are C.

[0050] In some embodiments, n is 0. In certain embodiments, n is 1.

[0051] In certain embodiments, Y2is –H. In some embodiments, at least one of Y1, Y2, Y3, and Y4is a halo. In certain embodiments, the halo is –Cl or –F. In some embodiments, at least one of Y1, Y2, Y3, and Y4is CHF2. In some embodiments, at least one of Y1, Y2, Y3, and Y4is –CF3. In some embodiments, at least one of Y1, Y2, Y3, and Y4is –Cl, one of Y1, Y2, Y3, and Y4is –F, and one of Y1, Y2, Y3, and Y4is –CF3.

[0052] In some embodiments, the invention relates to a compound of formula (I-A): A) or an is 0 or 1; each of X1, X2, and X3is independently C or N; and each of Y1, Y3, and Y4is independently selected from the group consisting of –CN, –CH3, –CH2F, –CHF2, –CF3, and halo.

[0053] In some embodiments, the invention relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein X1, X2, and X3are C. In certain embodiments, one of X1, X2, and X3is N. In some embodiments, X1is N and X2and X3are C. In some embodiments, X2is N and X1and X3are C. In some embodiments, X3is N and X1and X2are C. In some embodiments, n is 0. In certain embodiments, n is 1. In some embodiments, at least one of Y1, Y3, and Y4is a halo. In certain embodiments, the halo is –Cl or –F. In some embodiments, at least one of Y1, Y3, and Y4is –CF3. In certain embodiments, one of Y1, Y3, and Y4is –CF3, one of Y1, Y3, and Y4is –Cl, and one of Y1, Y3, and Y4is –F.

[0054] In some embodiments, the invention relates to a compound of formula (I-B): B) or a pharmaceutically n is 0 or 1;X2is independently N or N+-O-.

[0055] In some embodiments, the invention relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein X2is N or N+-O-. In some embodiments, X2is N. In some embodiments, wherein X2is N+-O-.

[0056] In some embodiments, n is 0. In certain embodiments, n is 1.

[0057] In some embodiments, the invention relates to a compound selected from Table A, or a pharmaceutically acceptable salt thereof. In other embodiments, the invention relates to a compound selected from Table A, i.e., the compound in non-salt form. Table A. Compound Structures and Names. Compound Structure Compound Name - de(S)-4-(5-(5-chloro-2-fluoro-3- - - - - - - - 5-- )- 5- )- - 5- -5- - 5- - 5-- - - 5- - - - -N-(33-difluorocclobutl)-3-methl-5-[rel-(5S)-5- 5- - 5- o- - o- -4N-(3,3-difluorocyclobutyl)-3-methyl-5-[rel-(5S)-5- )- 5- )- 5- 5- 5- 5- -55- 3- 3- 5- 5- 5- 5-5- 5- 5- 5- 5- 5- - - - -- - -

[0058] In some embodiments, a compound is selected as a salt form from those listed in Table A. In other embodiments, a compound is selected from those listed in Table A in non-salt form. Such compounds are considered to be a “compound of the invention,” as that term is used herein. Salts, Compositions, Uses, Formulation, Administration and Additional Agents Pharmaceutically acceptable salts and compositions

[0059] As discussed herein, the invention provides compounds, and pharmaceutically acceptable salts thereof, that are treatments of parasitic diseases and infections and thus the present compounds, andpharmaceutically acceptable salts thereof, are useful for the treatment of diseases, disorders, and conditions including, but not limited to parasitic diseases, flea infestations, tick infestations, mange, or ear mites. Accordingly, in another aspect of the invention, pharmaceutical compositions are provided, wherein these compositions comprise a compound as described herein, or a pharmaceutically acceptable salt thereof, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle

[0060] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. A “pharmaceutically acceptable salt” of a compound of this invention includes any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. The salt may be in pure form, in a mixture (e.g., solution, suspension, or colloid) with one or more other substances, or in the form of a hydrate, solvate, or co-crystal.

[0061] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compound of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0062] As described herein, the pharmaceutically acceptable compositions of the invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington’s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0063] In another aspect, the invention features a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0064] In another aspect, the invention features a pharmaceutical composition comprising a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.Uses of Compounds and Pharmaceutically Acceptable Salts and Compositions

[0065] In another aspect, the invention features a method of treating a parasitic disease comprising administering to the subject a compound of the invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0066] In yet another aspect, the invention features a method of treating or lessening the severity of a parasitic infection in the subject comprising administering an effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof.

[0067] In some embodiments, the subject is a non-human animal. In certain embodiments, the subject is a dog. In certain embodiments, the subject is a cat. In some embodiments, the parasitic disease or infection is ticks. In some embodiments, the parasitic disease or infection is fleas. In some embodiments, the parasitic disease or infection is a worm. Compounds, Pharmaceutically Acceptable Salts, and Compositions for Use

[0068] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use as a medicament.

[0069] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in the treatment of a parasitic disease.

[0070] In another aspect, the invention features a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a parasitic disease or infection.

[0071] In some embodiments, the parasitic disease or infection is treated in a non-human animal. In certain embodiments, the parasitic disease or infection is treated in a dog. In certain embodiments, the parasitic disease or infection is treated in a cat. In some embodiments, the parasitic disease or infection is ticks. In some embodiments, the parasitic disease or infection is fleas. In some embodiments, the parasitic disease or infection is a worm. Manufacture of Medicaments

[0072] In another aspect, the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament.

[0073] In another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in the treatment of a parasitic infection or disease.

[0074] In yet another aspect, the invention provides the use of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating a parasitic infection or disease. Administration of Compounds, Pharmaceutically Acceptable Salts, and Compositions

[0075] In certain embodiments of the invention, an “effective amount” of a compound of the invention, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is that amount effective for treating or lessening the severity of one or more of the conditions recited above.

[0076] The compounds, salts, and compositions, according to the method of the invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the parasitic infections or diseases recited herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition, the particular agent, its mode of administration, and the like. The compounds, salts, and compositions of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compounds, salts, and compositions of the invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound or salt employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound or salt employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound or salt employed, and like factors well known in the medical arts. The term “subject” or “patient,” as used herein, means an animal, preferably a mammal.

[0077] The pharmaceutically acceptable compositions of this invention can be administered to subjects orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the condition being treated. In certain embodiments, the compound, salts, and compositions of the invention may be administered orally or parenterally at dosage levels of about 0.001 mg / kg to about 1000 mg / kg, one or more times a day, effective to obtain the desired therapeutic effect.

[0078] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound or salt, the liquid dosage forms may contain inert diluents commonly used in the artsuch as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0079] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0080] The injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0081] In order to prolong the effect of the compounds of the invention, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0082] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compound or salt of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambienttemperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0083] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound or salt is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0084] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0085] The active compound or salt can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release-controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound or salt may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only,or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0086] Dosage forms for topical or transdermal administration of a compound or salt of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0087] As described generally above, the compounds of the invention are useful as treatments for parasitic infections and diseases. In one embodiment, the compounds are preventatives of flea and tick infestations. Accordingly, in another aspect, the invention provides a method for treating or lessening the severity of a disease, condition, or disorder where a parasite is implicated in the disease state. Synthesis of the Compounds of the Invention

[0088] The compounds of the invention can be prepared from known materials by the methods described in the Examples, other similar methods, and other methods known to one skilled in the art. As one skilled in the art would appreciate, the functional groups of the intermediate compounds in the methods described below may need to be protected by suitable protecting groups. Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art. The use of protecting groups is described in detail in T.G.M. Wuts et al., Greene’s Protective Groups in Organic Synthesis (4th ed.2006). EXAMPLES

[0089] General methods.

[0090] All solvents used were commercially available and were used without further purification. Reactions were typically run using anhydrous solvents under an inert atmosphere of nitrogen.

[0091] Proton NMR spectra were recorded using a Bruker plus 400 NMR Spectrometer unless stated otherwise. All deuterated solvents contained typically 0.03% to 0.05% v / v tetramethylsilane, which was used as the reference signal (set at δ = 0.00 for both1H and13C).

[0092] Unless otherwise specified, the conditions described hereafter were used for Prep-HPLC, Prep Chiral HPLC, Prep Achiral SFC, and Prep Chiral SFC purification.

[0093] Preparative reverse-phase HPLC was performed using Varian HPLC system. The column used was XBridge Prep C18 OBD Column, 5 µm, 19 x 150 mm. The instrument using reverse-phase conditions (CH3CN / H2O, containing 0.1% Ammonium hydrogen carbonate or formic acid).

[0094] Preparative chiral HPLC was performed using Trilution LC system. The column used was CHIRALPAK IH Column, 5 µm, 20 x 250 mm. The instrument using normal-phase conditions (Mobile Phase A: hexane, Mobile Phase B: iPrOH or EtOH or MeOH and CH2Cl2, containing 0.1% DEA or 1% NH3-MeOH(2M) or 0.1% FA).

[0095] Preparative chiral SFC was performed using Waters ChromScope system. The column used was R,R-Whelk-O1 Column, 5 µm, 30 x 250 mm. The instrument using normal-phase conditions (Mobile Phase A: CO2, Mobile Phase B: iPrOH or MeOH, containing 0.1% FA or 1% NH3-MeOH(2M)).

[0096] Preparative achiral SFC was performed using LabSolutions system. The column used was DAICEL DCpack P4VP Column, 3 µm, 46 x 250 mm. The instrument using normal-phase conditions (Mobile Phase A: CO2, Mobile Phase B: iPrOH or MeOH or AcCN / MeO = (4 / 1), containing 1% NH3- MeOH (2M) or 0.1% FA).

[0097] Analyses were performed using a Shimadzu HPLC Liquid Chromatography (LC) system, coupled to a Shimadzu LCMS-2020 single quadrupole MS detector. The UV (DAD) acquisition was performed with a scan range of 190-400 nm. The MS was operated with an electro-spray ionization source (ESI) in both positive & negative ion mode. Capillary voltage 0.85 (kV), and desolvation temperature of 250 ºC. Desolvation gas flow 15 (L / min), Cone gas flow 1.5 (L / min). The MS acquisition range was set to 90-900 m / z. MS scan cycle time was 0.4 s. Data acquisition was performed with Shimadzu Lab Solution.

[0098] Method A: Column: HALO C182.0 µm, 30 x 3.0 mm; eluent A: H2O + 0.1 vol % TFA, eluent B: CH3CN + 0.05 vol % TFA; gradient: assigned for each compound; flow 1.5 mL / min; temperature: 40°C; PDA scan: 190 - 400 nm.

[0099] Method B: Column: Shim-pack Scepter C18-1202.0 µm, 33 x 3.0 mm; eluent A: H2O + 0.05 vol % NH4HCO3, eluent B: CH3CN; gradient: assigned for each compound; flow 1.2 mL / min; temperature: 40°C; PDA scan: 190 - 400 nm.

[0100] Method C: Column: Shim‐pack Scepter C18‐1203.0 µm, 33 x 3.0 mm; eluent A: H2O + 0.05% NH4HCO3, eluent B: CH3CN; gradient: assigned for each compound; flow 1.5 mL / min; temperature: 40°C; PDA scan: 190 - 400 nm.

[0101] Method D: Column: HALO 90A C182.0 µm, 30 x 3.0 mm; eluent A: H2O + 0.1vol % FA, eluent B: CH3CN + 0.1vol % FA; gradient: assigned for each compound; flow 1.2 mL / min; temperature: 40°C; PDA scan: 190 - 400 nm.

[0102] Method E: Column: Luna Omega PS C183.0 µm, 50 x 2.1 mm; eluent A: H2O + 0.1 vol % FA, eluent B: CH3CN + 0.10 vol % FA; gradient: assigned for each compound; flow 1.2 mL / min; temperature: 40°C; PDA scan: 190 - 400 nm.

[0103] Method F: Column: Ascentis Express C182.7 µm, 50 x 3.0 mm; eluent A: H2O + 0.05 vol % TFA, eluent B: CH3CN + 0.05 vol % TFA; gradient: assigned for each compound; flow 1.2 mL / min; temperature: 40°C; PDA scan: 190 - 400 nm.

[0104] Method G: Column: Kinetex XB-C181.7 µm, 30 x 2.1 mm; eluent A: H2O / 0.05%TFA, eluent B: CH3CN / 0.05%TFA; gradient: assigned for each compound; flow 1.5 mL / min; temperature: 40°C; PDA scan: 190 - 400 nm.

[0105] Method H: Column: Kinetex XB-C181.7 µm, 30 x 2.1 mm; eluent A: H2O / 0.1% FA, eluent B: CH3CN / 0.1% FA; gradient: assigned for each compound; flow 1.5 mL / min; temperature: 40°C; PDA scan: 190 – 400 nm.

[0106] Method I: Column: Kinetex XB-C182.6 µm, 50 x 3.0 mm; eluent A: H2O + 0.1 vol % FA, eluent B: CH3CN + 0.1 vol % FA; gradient: assigned for each compound; flow 1.2 mL / min; temperature: 40°C; PDA scan: 190 – 400 nm.

[0107] Method J: Column: Kinetex EVO C182.6 µm, 50 x 3.0 mm; eluent A: H2O + 0.05 vol % NH4HCO3, eluent B: CH3CN; gradient: assigned for each compound; flow 1.5 mL / min; temperature: 40°C; PDA scan: 190 – 400 nm.

[0108] Method K: Column: CORTECS C182.7 µm, 50 x 2.1 mm; eluent A: H2O + 0.1 vol % FA, eluent B: CH3CN + 0.10 vol % FA; gradient: assigned for each compound; flow 1.2 mL / min; temperature: 40°C; PDA scan: 190 – 400 nm.

[0109] Method L: Column: Shim‐pack Scepter C18‐1203.0 µm, 33 x 3.0 mm; eluent A: 5mM NH4HCO3 in H2O / CH3CN (95:5, v:v), eluent B: CH3CN; gradient: assigned for each compound; flow 1.5 mL / min; temperature: 40°C; PDA scan: 190 - 400 nm. Abbreviations

[0110] Unless otherwise noted, or where the context dictates otherwise, the following abbreviations shall be understood to have the following meanings: Abbreviation Meaning NMR Nuclear magnetic resonance GC Gas chromatographyESI-MS Electrospray mass spectrometry LC / MS Liquid chromatography-mass spectrometry UPLC Ultra performance liquid chromatography HPLC / MS / MS High performance liquid chromatography / tandem mass spectrometry IS internal standard HPLC High performance liquid chromatography SFC Supercritical fluid chromatography ESI Electrospray ionization m / z mass-to-charge ratio T temperature rt room temperature Kg kilogram G grams Mg milligrams L liter(s) mL milliliters μL microliters nL nanoliters Mol mole M molarity Mmol millimoles h hour(s) min minutes ms millisecond mm millimetersµmmicrometers nm nanometer MHz megahertz Hz hertz J coupling constant S singlet D doublet M multiplet T triplet δ chemical shift Rt retention time N normal (concentration) M molar (concentration) mM millimolar (concentration) μM micromolar (concentration) ppm parts per million % w / v weight-volume concentration % w / w weight-weight concentration DAST (diethylamino)sulfur trifluoride DEA diethylamine DIPEA N-diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethylsulfoxide EtOAc ethyl acetate EtOH ethanol FA formic acidHATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate iPrOH isopropanol MeOH methanol NCS N-chlorosuccinimide PE petroleum ether TFA trifluoroacetic acid THF tetrahydrofuran Example 1 4-[rel-(5S)-5-[5-chloro-3-(difluoromethyl)-2-fluoro-phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N- (3,3-difluorocyclobutyl)-2-methyl-benzamide (Example 1a) and 4-[rel-(5R)-5-[5-chloro-3-(difluoromethyl)-2-fluoro-phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N- (3,3-difluorocyclobutyl)-2-methyl-benzamide (Example 1b)Step 1: 1-bromo-5-chloro-3- -

[0111] To a solution of 3-bromanyl-5-chloranyl-2-fluoranyl-benzaldehyde (1.00 g, 4.21 mmol) in CH2Cl2 (15 mL) was added DAST (2.04 g, 12.6 mmol, 1.67 mL) at 0°C. The mixture was stirred for 2 h at rt. Then the reaction was quenched with aqueous saturated NaHCO3-solution and the resulting mixture was extracted with CH2Cl2. The organic layer was washed with saturated NaHCO3-solution and brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to afford the desired compound (91% yield). GC-MS: Rt= 3.6 min; MS (ESI+): m / z = 259.9 (M)+. Step 2: 5-chloro-1-(difluoromethyl)-2-fluoro-3-(3,3,3-trifluoroprop-1-en-2-yl)benzene.

[0112] To a solution of 1-bromo-5-chloro-3-(difluoromethyl)-2-fluorobenzene (1.00 g, 3.85 mmol) in H2O (8 mL) and THF (2 mL) was added 4,4,6-tri(methyl)-2-[1- [tris(fluoranyl)methyl]vinyl]-1,3,2-dioxaborinane (941 mg, 4.24 mmol), Pd(dppf)Cl2(315 mg, 385 μmol) and Cs2CO3(2.51 g, 7.71 mmol). The resulting mixture was stirred at 80°C for 16 h under nitrogen atmosphere. The reaction was allowed to cool down to rt and H2O was added. The layers were separated, and the aqueous layer was extracted with PE. The organic layer was concentrated under reduced pressure to afford a yellowish oil, which was used in the next step without further purification. GC-MS: Rt= 3.3 min; MS (ESI+): m / z = 274 (M+H)+.Step 3: methyl 4-(5-(5-chloro-3-(difluoromethyl)-2-fluorophenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-2-methylbenzoate.

[0113] To a solution of methyl 2-methyl-4-[oxidanyliminomethyl]benzoate (1.10 g, 5.68 mmol) in DMF (10 mL) was added NCS (948 mg, 7.10 mmol) at 0°C. The mixture stirred nitrogen atmosphere for 2 h at 0°C. Then, 1-[bis(fluoranyl)-tritio-methyl]-5-chloranyl-2-fluoranyl-3-[1- [tris(fluoranyl)methyl]vinyl]benzene (1.3g, 4.73 mmol) and DIPEA (1.22 g, 9.47 mmol) were added at 0°C. The resulting mixture was stirred under nitrogen atmosphere for 16 h at rt. After completion of the reaction, the mixture was diluted with H2O (10 mL) and extracted with EtOAc. The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc 20:1) to afford the desired product (82% yield). GC-MS: Rt = 7.4 min; MS (ESI+): m / z = 465 (M)+. Step 4: 4-(5-(5-chloro-3-(difluoromethyl)-2-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3- yl)-2-methylbenzoic acid.

[0114] To a solution of methyl 4-[5-[3-[bis(fluoranyl)-tritio-methyl]-5-chloranyl-2-fluoranyl- phenyl]-5-[tris(fluoranyl)methyl]-4H-isoxazol-3-yl]-2-methyl-benzoate (1.80 g, 3.86 mmol) in THF (10 mL) and H2O (10 mL) was added LiOH (463 mg, 19.3 mmol). The mixture was stirred for 2 h at rt, before it was neutralized with HCl (1 M) and then extracted with EtOAc. The organic layer was dried over anhydrous NaSO4. After filtration, the filtrate was concentrated under reduced pressure to yield the desired compound (76% yield). LC-MS (method A, 0.01-1.10 min 5-100% B, 1.40-1.42 min 5%B): Rt = 1.0 min; MS (ESI+): m / z = 452 (M+H)+. Step 5: 4-[rel-(5S)-5-[5-chloro-3-(difluoromethyl)-2-fluoro-phenyl]-5-(trifluoromethyl)-4H-isoxazol- 3-yl]-N-(3,3-difluorocyclobutyl)-2-methyl-benzamide (Example 1a) and 4-[rel-(5R)-5-[5-chloro-3- (difluoromethyl)-2-fluoro-phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N-(3,3-difluorocyclobutyl)- 2-methyl-benzamid (Example 1b).

[0115] To a solution of 4-[5-[3-[bis(fluoranyl)-tritio-methyl]-5-chloranyl-2-fluoranyl-phenyl]-5- [tris(fluoranyl)methyl]-4H-isoxazol-3-yl]-2-methyl-benzoic acid (300 mg, 578 μmol) in DMF (5 mL) was added HATU (264 mg, 693 μmol), 3,3-bis(fluoranyl)cyclobutanamine (93 mg, 867 μmol) and DIPEA (373 mg, 2.89 mmol). The mixture was allowed to stir for 2 h at rt. The residue was concentrated under reduced pressure. H2O was added and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0-20% EtOAc in PE) to afford the desired racemic product. The two isomers were separated by prep-Chiral HPLC [column: Lux 5um Amylose-1, 5*25 cm, 10 μm; mobile phase A: hexane (0.1% DEA), mobile phase B: iPrOH; flow rate: 20 mL / min;gradient: 10% B to 10% B in 17 min; wave length: 220 / 254 nm; Rt1= 10.8 min; Rt2= 15.2 min] to afford 4-[rel-(5S)-5-[5-chloro-3-(difluoromethyl)-2-fluoro-phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]- N-(3,3-difluorocyclobutyl)-2-methyl-benzamide (39% yield) as a colorless solid and 4-[rel-(5R)-5-[5- chloro-3-(difluoromethyl)-2-fluoro-phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N-(3,3- difluorocyclobutyl)-2-methyl-benzamide (83% yield) as a colorless solid.

[0116] (Isomer 1) Example 1a:1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.81 (d, 1H), 7.93-7.86 (m, 2H), 7.67-7.65 (m, 2H), 7.45 (d, 1H), 7.27 (t, 1H), 4.52 (d, 1H), 4.32 (d, 1H), 4.31-4.19 (m, 1H) 3.02- 2.92 (m, 2H), 2.75-2.62 (m, 2H), 2.49 (s, 3H). LC-MS (method B, 0.01-1.70 min 50-80% B, 1.70-2.30 min 80-95% B, 2.30-2.80 min 95% B): Rt = 1.3 min; MS (ESI+): m / z = 582 (M+H)+.

[0117] (Isomer 2) Example 1b:1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.81 (d, 1H), 7.93-7.86 (m, 2H), 7.67-7.65 (m, 2H), 7.46 (d, 1H), 7.27 (t, 1H), 4.52 (d, 1H), 4.32 (d, 1H), 4.29-4.20 (m, 1H) 3.01- 2.93 (m, 2H), 2.73-2.66 (m, 2H), 2.49 (s, 3H). LC-MS (method B, 0.01-1.70 min 50-80% B, 1.70-2.30 min 80-95% B, 2.30-2.80 min 95% B): Rt = 1.3 min; MS (ESI+): m / z = 582 (M+H)+. Example 2 (S)-4-(5-(5-chloro-2-fluoro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- N-(3,3-difluorocyclobutyl)-2-methylbenzamide (Example 2) Step 1: 1-chloro-2-fluoro-5-vinyl] benzene.

[0118] To a solution of 3-bromo-4-fluoro-5-(trifluoromethyl)aniline (16.0 g, 62.0 mmol) and 4,4,6- trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (16.5 g, 74.4 mmol) in THF (20 mL) was added Pd(dppf)Cl2 (5.06 g, 6.20 mmol) and the resulting mixture was stirred for 2 h at 80°C under nitrogen atmosphere . The resulting mixture was extracted with EtOAc (3 x). The combined organic layers were dried over anhydrous Na2SO4. The residue was purified by column chromatography on silica gel (40-50% EtOAc in PE) to afford the desired product (88% yield) as a yellowish solid. Step 2: methyl 2-cyano-4-hydroxyiminomethyl benzoate.

[0119] A mixture of methyl 2-cyano-4-formyl-benzoate (3.13 g, 16.6 mmol), hydroxylamine hydrochloride (1.38 g, 19.89 mmol, 827 μL) and sodium acetate trihydrate (2.70 g, 19.9 mmol) in EtOH (15 mL) was stirred for 1 h at 60°C. The mixture was allowed to cool down to rt. The resulting mixturewas filtered and the filter cake was washed with EtOH. The filtrate was concentrated under reduced pressure to afford methyl 2-cyano-4-(hydroxyiminomethyl) benzoate (88% yield). Step 3: methyl 4-(C-chloro-N-hydroxy-carbonimidoyl]-2-methyl-benzoate.

[0120] A solution of methyl 4-(hydroxyiminomethyl)-2-methyl-benzoate (10.1 g, 52.3 mmol) in DMF (15 mL) was treated with NCS (6.98 g, 52.3 mmol, 4.23 mL) for 1 h at rt. The resulting mixture was concentrated under reduced pressure to afford methyl 4-(C-chloro-N-hydroxy- carbonimidoyl)-2-methyl-benzoate as a brownish oil. Step 4: methyl 2-methyl-4-[rac-(5R)-5-[5-amino-2-fluoro-3-(trifluoromethyl)phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]benzoate.

[0121] To a solution of methyl 4-(C-chloro-N-hydroxy-carbonimidoyl)-2-methyl-benzoate (18.4 g, 80.8 mmol) and 4-fluoro-3-(trifluoromethyl)-5-[1-(trifluoromethyl) vinyl] aniline (26.5, 97.0 mmol) in DMF (30 mL) was added DIPEA (20.9 g, 162 mmol) and the resulting mixture was stirred for 2 h at rt. After completion of the reaction, the mixture was concentrated under reduced pressure to afford methyl 2- methyl-4-[rac-(5R)-5-[5-amino-2-fluoro-3-(trifluoromethyl) phenyl]-5-(trifluoromethyl)-4H-isoxazol-3- yl] benzoate (37% yield). Step 5: 2-methyl-4-[rac-(5R)-5-[5-amino-2-fluoro-3-(trifluoromethyl) phenyl]-5-(trifluoromethyl)- 4H-isoxazol-3-yl] benzoic acid.

[0122] A solution of methyl 2-methyl-4-[rac-(5R)-5-[5-amino-2-fluoro-3-(trifluoromethyl) phenyl]- 5-(trifluoromethyl)-4H-isoxazol-3-yl] benzoate (8.50 g, 18.3 mmol) in THF (15 mL) was treated with LiOH (438 mg, 18.3 mmol) in H2O (15 mL) for 4 h at 60°C. The mixture was neutralized to pH 6 with HCl (1 M). The resulting mixture was extracted with EtOAc (3 x 70 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the desired compound (91% yield) as a colorless solid. Step 6: 2-methyl-4-[rac-(5R)-5-[5-chloro-2-fluoro-3-(trifluoromethyl) phenyl]-5-(trifluoromethyl)- 4H-isoxazol-3-yl] benzoic acid.

[0123] To a solution of 2-methyl-4-[rac-(5R)-5-[5-amino-2-fluoro-3-(trifluoromethyl)phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]benzoic acid (13.7 g, 30.4 mmol) in AcOH (120 mL) was added with HCl (15.0 g, 411 mmol). The resulting mixture was allowed to stir for 5 min at 0°C, before NaNO2(2.73 g, 39.6 mmol, 1.26 mL) was added in portions at 0°C over 5 min. Then, CuCl (6.02 g, 60.9 mmol) was added in portions over 5 min at 0°C and the resulting mixture was stirred for additional 2 h at rt. After completion of the reaction, the resulting mixture was diluted with H2O (200 mL). The precipitate was collected by filtration and washed with H2O (3 x 100 mL) to afford 2-methyl-4-[rac-(5R)-5-[5-chloro-2-fluoro-3-(trifluoromethyl)- phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl] benzoic acid (29% yield). Step 7: (S)-4-(5-(5-chloro-2-fluoro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-2-methylbenzoic acid and (R)-4-(5-(5-chloro-2-fluoro-3- (trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid.

[0124] Racemic 4-(5-(5-chloro-2-fluoro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-2-methylbenzoic acid was separated via prep-chiral-SFC [column: CHIRAL ART Cellulose-SJ, 2*25 cm, 5 µm; mobile phase A: CO2, mobile phase B: iPrOH (0.1% 2M NH3-MeOH); flow rate: 120 mL / min; gradient: isocratic 20% B; column temperature: 35°C; back pressure: 100 bar; wave length: 220 nm; Rt1= 7.3 min; Rt2= 9.4 min; sample solvent: CH3CN] to get 4-[(5S)-5-[5-chloro-2- fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid and 4- [(5R)-5-[5-chloro-2-fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl- benzoic acid. Step 8: N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5S)-5-[5-chloro-2-fluoro-3-(trifluoromethyl) phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl] benzamide.

[0125] A mixture of 4-[(5S)-5-[5-chloro-2-fluoro-3-(trifluoromethyl) phenyl]-5-(trifluoromethyl)- 4H-isoxazol-3-yl]-2-methyl-benzoic acid (600 mg, 1.28 mmol), 3,3-difluorocyclobutanamine (164 mg, 1.53 mmol) in DMF (10 mL) was stirred for 2 h at 25°C. The resulting mixture was poured into H2O and then extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and then concentrated under reduced pressure. The crude product was isolated via prep-HPLC [column: XselectCSH Prep OBD C18 Column, 30*150 mm, 5 μm; mobile phase A: H2O (0.1% FA), mobile phase B: CH3CN; flow rate: 60 mL / min mL / min; gradient: 57% B to 87% B in 8 min; wave length: 254 nm / 220nm nm; Rt = 6.1 min] to get N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5S)-5-[5-chloro-2- fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide (43% yield) as a colorless solid.

[0126] Example 2:1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.82(d, 1H), 8.15-8.14 (m, 1H), 8.03-8.01 (m, 1H), 7.68-7.65 (d, 2H), 7.46 (d, 1H), 4.57-4.41 (m, 2H), 3.01-2.95 (m, 2H), 2.72-2.66 (m, 2H), 2.41 (s, 3H). LC-MS (method D, 0.01-1.75 min 30-95% B, 1.75-2.80 min 95% B): Rt = 1.6 min; MS (ESI+): m / z = 559 (M+H)+. Example 3 (S)-4-(5-(3-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- N-(3,3-difluorocyclobutyl)-2-methylbenzamide (Example 3)

[0127] To a solution of yl)phenyl]-5-(trifluoromethyl)- 4H-isoxazol-3-yl]-2-methyl-benzoic acid (50.0 mg, 101 μmol) in DMF (1 mL) was added 3,3- difluorocyclobutan-1-amine hydrochloride (19.0 mg, 131 μmol) , HATU (57.7 mg, 152 μmol) and DIPEA (65.0 mg, 506 μmol). The mixture was stirred for 1 h at rt. The resulting mixture was poured into H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by prep-HPLC [column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: H2O (10 mmol / L NH4HCO3), mobile phase B: CH3CN; gradient: 26% B to 45% B in 9 min] to afford 4-[(5S)- 5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N-(3,3- difluorocyclobutyl)-2-methyl-benzamide (86% yield) as a colorless solid.

[0128] Example 3:1H-NMR (400 MHz, DMSO-D6): δ [ppm] = 8.84 (d, 1H), 8.40-8.36 (m, 1H), 7.93-7.89 (m, 1H), 7.69-7.63 (m, 2H), 7.48-7.44 (m, 1H), 4.62-4.38 (m, 2H), 4.29-4.18 (m, 1H), 3.05- 2.91 (m, 2H), 2.76-2.61 (m, 2H), 2.38 (s, 3H). LC-MS (method E, 0.01-1.90 min 50-80% B, 1.90-2.00 min 80-100% B): Rt = 1.4 min; MS (ESI+): m / z = 559 (M+H)+. Example 4 (S)-4-(5-(5-cyano-2-fluoro-3-(trifluoromethyl) phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3- yl)-N-(3,3-difluorocyclobutyl)-2-methylbenzamide (Example 4)Step 1. (S)-4-(5-(5-chloro- - -4,5- dihydroisoxazol-3-yl)-N-(3,3-difluorocyclobutyl)-2-methylbenzamide.

[0129] To a solution of 4-[(5S)-5-[5-chloro-2-fluoro-3-(trifluoromethyl) phenyl]-5-(trifluoromethyl)- 4H-isoxazol-3-yl]-2-methyl-benzoic acid (360 mg, 766 μmol) in DMF (5 mL) were added HATU (379 mg, 996 μmol), DIPEA (396 mg, 3.07 mmol) and 3,3-difluorocyclobutanamine (90.3 mg, 843 μmol). The reaction mixture was stirred for 1 h at rt . The mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by trituration with PE / EtOAc (5:1) for 16 h at rt. The solid was collected by filtration to yield the desired product (79% yield) as a yellowish solid. LC-MS (method F, 0.01-1.50 min 5-100% B): Rt = 1.1 min; MS (ESI+): m / z =559 (M+H)+. Step 2. (S)-4-(5-(5-cyano-2-fluoro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-N-(3,3-difluorocyclobutyl)-2-methylbenzamide.

[0130] To a solution of 4-[(5S)-5-[5-chloro-2-fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)- 4H-isoxazol-3-yl]-N-(3,3-difluorocyclobutyl)-2-methyl-benzamide (320 mg, 573 μmol) in 1,4-dioxane (6 mL) and H2O (1.2 mL) were added K4Fe(CN)6 (1.27 g, 3.44 mmol), potassium acetate (169 mg, 1.72 mmol, 107 μL), Xphos (54.6 mg, 114 μmol) and Pd2(dba)3 (105 mg, 114 μmol). The resulting mixture was stirred for 16 h at 80°C under nitrogen atmosphere. Then, the mixture was allowed to cool down to rt and H2O was added. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-TLC (PE / EtOAc 3:1), and further purified by prep-HPLC [column: Xbridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: H2O (10 nmol / L NH4HCO3), mobile phase B: CH3CN; gradient: 49% B to 74% B in 13 min] to afford 4-[(5S)-5-[5-cyano- 2-fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N-(3,3-difluorocyclobutyl)-2- methyl-benzamide (33% yield) as a colorless solid.

[0131] Example 4:1H NMR (400 MHz, DMSO-d6) δ [ppm] = 8.82-8.81 (d,1H), 8.65-8.64 (m, 1H), 8.53-8.52 (m, 1H), 7.67-7.65 (m, 2H), 7.48-7.46 (d, 1H), 4.58-4.54 (m, 1H), 4.46-4.41 (m, 1H), 4.25-4.21 (m, 1H), 3.01-2.95 (m, 2H), 2.75-2.67 (m, 2H), 2.38 (s, 3H). LC-MS (method D, 0.01-2.00 min 5-100% B): Rt =6.6 min; MS (ESI+): m / z =550 (M+H)+. Example 5 N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H- isoxazol-3-yl]benzamide (Example 5a) and N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5R)-5-(3,5- dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide (Example 5b).Step 1: 1,3-dichloro-5-[1-(trifluoromethyl)vinyl]benzene.

[0132] To a solution of 1-bromo-3,5-dichloro-benzene (5.00 g, 22.1 mmol) and 4,4,6-trimethyl-2-[1- (trifluoromethyl)vinyl]-1,3,2-dioxaborinane (4.91 g, 22.1 mmol) in THF (50 mL) and H2O (12.5 mL) were added Cs2CO3(7.22 g, 22.1 mmol) and Pd(dppf)Cl2(1.81 g, 2.21 mmol). The resulting mixture was stirred for 16 h at 60°C under nitrogen atmosphere. After completion of the reaction, the mixture was allowed to cool down to rt. The mixture was extracted with PE and the combined extracts were concentrate under recued pressure to afford 1,3-dichloro-5-[1-(trifluoromethyl)vinyl]benzene as a yellowish oil. GC-MS: Rt= 3.6 min; MS (ESI+): m / z = 240 (M)+. Step 2: methyl 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoate.

[0133] To a stirred solution of methyl 4-[hydroxyiminomethyl]-2-methyl-benzoate (1.29 g, 6.66 mmol) in DMF (10 mL) was added NCS (593 mg, 4.44 mmol, 359 μL) in portions at 0°C. The resulting reaction mixture was stirred for 2 h at rt. Then 1,3-dichloro-5-[1-(trifluoromethyl)vinyl]benzene (1.07 g, 4.44 mmol) and DIPEA (2.86 g, 22.2 mmol) were added dropwise at 0°C. The resulting mixture was stirred for an additional 1 h at rt. After completion of the reaction, the mixture was treated with H2O and extracted with EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, filtered and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc 10:1) to afford methyl 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2- methyl-benzoate (58% yield) as a yellowish gum. Step 3: 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoic acid.

[0134] A solution of methyl 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2- methyl-benzoate (1.20 g, 2.78 mmol) and LiOH (332 mg, 13.9 mmol) in THF (6 mL) and H2O (6 mL) was stirred for 8 h at 50°C. After this time, the mixture was acidified to pH ~ 6 with HCl (4 M). The aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product (91% yield) as a yellowish solid.Step 4: N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)- 4H-isoxazol-3-yl]benzamide (Example 5a) and N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5R)-5- (3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide (Example 5b).

[0135] To a solution of 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl- benzoic acid (400 mg, 957 μmol) in DMF (5 mL), were added HATU (546 mg, 1.43 mmol), 3,3- difluorocyclobutanamine (113 mg, 1.05 mmol), and DIPEA (617 mg, 4.78 mmol). The resulting reaction mixture was stirred for 1 h at rt. After completion of the reaction, H2O was added, and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC [column: Xbridge Prep OBD C18 column, 50*250 mm, 10 μm; mobile phase A: H2O (10 nmol / L NH4HCO3), mobile phase B: CH3CN; flow rate: 60 mL / min; gradient: 55% B to 85% B in 30 min] to afford a mixture of two isomers. The two isomers were separated by chiral-SFC [column: CHIRALPAK IH 3*25 cm, 5 µm; mobile phase A: CO2, mobile phase B: MeOH (1%-2 M-NH3-MeOH); flow rate: 90 mL / min; gradient: isocratic 15% B; column temperature: 35°C; wave length: 220 nm; Rt1= 4.7 min; Rt2= 6.3 min] to afford N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5R)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol- 3-yl]benzamide (12% yield) as an off-white solid and N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5S)-5- (3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide as an off-white solid.

[0136] (Isomer 1) Example 5a:1H NMR (400 MHz, DMSO-d6): δ [ppm] = 8.81 (d, 1H), 7.82 (s, 1H), 7.63-7.60 (m, 4H), 7.47 (d, 1H), 4.41-4.27 (m, 2H), 4.24-4.20 (m, 1H), 3.00-2.93 (m, 2H), 2.75-2.70 (m, 2H), 2.37 (s, 3H). LC-MS (method C, 0-1.20 min 40-90% B; 1.20-1.80 min 90% B): Rt = 1.1 min; MS (ESI+): m / z = 507 [M+H]+.

[0137] (Isomer 2) Example 5b:1H NMR (400 MHz, DMSO-d6): δ [ppm] = 8.81 (d, 1H), 7.82 (s, 1H), 7.63-7.60 (m, 4H), 7.47 (d, 1H), 4.41-4.27 (m, 2H), 4.24-4.20 (m, 1H), 3.02-2.92 (m, 2H), 2.76-2.63 (m, 2H), 2.37 (s, 3H). LC-MS (method C, 0-1.20 min 40-90% B; 1.20-1.80 min 90% B): Rt = 1.1 min; MS (ESI+): m / z = 507 [M+H]+. Example 6 N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5S)-5-(3,5-dichloro-2-fluoro-phenyl)-5- (trifluoromethyl)-4H-isoxazol-3-yl]benzamide (Example 6a) and N-(3,3-difluorocyclobutyl)-2- methyl-4-[rel-(5R)-5-(3,5-dichloro-2-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide (Example 6b).Step 1: 1,5-dichloro-2-fluoro-3-(3,3,3-trifluoroprop-1-en-2-yl) benzene.

[0138] To a solution of 1-bromo-3,5-dichloro-2-fluoro-benzene (2.00 g, 8.20 mmol) in THF (20 mL) and H2O (5 mL), were added 4,4,6-trimethyl-2-[1-(trifluoromethyl) vinyl]-1,3,2-dioxaborinane (2.00 g, 9.02 mmol), Cs2CO3(8.02 g, 24.6 mmol) and Pd(dppf)Cl2(665 mg, 820 μmol). The resulting mixture was stirred for 16 h at 60°C under nitrogen atmosphere. Then, the mixture was allowed to cool down to rt, diluted with H2O, and extracted with PE. The combined organic layers were dried over anhydrous NaSO4, filtered, and concentrated under reduced pressure in an ice bath to afford the desired compound as brownish oil. GC-MS: Rt= 3.4 min; MS (ESI+): m / z = 258 (M)+. Step 2: methyl 4-(5-(3,5-dichloro-2-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2- methylbenzoate.

[0139] To a solution of methyl 4-[hydroxyiminomethyl]-2-methyl-benzoate (1.56 g, 8.07 mmol) in DMF (20 mL) was added NCS (1.08 g, 8.07 mmol, 653 μL). The reaction mixture was stirred for 1 h at rt. After completion of the reaction, the mixture was added slowly to a solution of 5-dichloro-2-fluoro-3-[1- (trifluoromethyl) vinyl] benzene (1.90 g, 7.34 mmol) in DMF (20 mL) at 0°C. The resulting mixture was stirred for 10 min at 0° C, before DIPEA (1.90 g, 14.7 mmol) was added. Finally, the reaction mixture was stirred for 1 h at rt. The reaction was quenched by the addition of H2O. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc 5:1) to afford the desired product (30% yield) as yellowish oil. LC-MS (method I, 0.01-1.50 min 5-95% B): Rt = 1.0 min; MS (ESI+): m / z = 450 (M+H)+. Step 3.4-(5-(3,5-dichloro-2-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methyl benzoic acid.

[0140] To a solution of methyl 4-[5-(3,5-dichloro-2-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol- 3-yl]-2-methyl-benzoate (300 mg, 666 μmol) in THF (4 mL) was added LiOH (80.0 mg, 3.33 mmol) and H2O (4 mL). The reaction mixture was stirred for 16 h at rt. Then, the mixture was diluted with H2O, neutralized with HCl (1 M), and extracted with EtOAc. The combined organic layers were driedover anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude product as a yellowish oil. LC-MS (method C, 0.01-1.50 min 5-100% B): Rt=0.6 min; MS (ESI+): m / z = 436 (M+H)+. Step 4. N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5S)-5-(3,5-dichloro-2-fluoro-phenyl)-5- (trifluoromethyl)-4H-isoxazol-3-yl]benzamide (Example 6a) and N-(3,3-difluorocyclobutyl)-2- methyl-4-[rel-(5R)-5-(3,5-dichloro-2-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide (Example 6b).

[0141] To a solution of 4-[5-(3,5-dichloro-2-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2- methyl-benzoic acid (180 mg, 413 μmol) in DMF (4 mL) were added HATU (204 mg, 536 μmol), DIPEA (213 mg, 1.65 mmol) and 3,3-difluorocyclobutanamine (49.0 mg, 454 μmol) . The reaction mixture was stirred for 1 h at rt. Then, the reaction was quenched by addition of H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC [column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: H2O (10 mmol / L NH4HCO3), mobile phase B: CH3CN; gradient: 59% B to 80% B in 7 min]. Then the two isomers were separated by prep-chiral-HPLC [column: CHIRALPAK IH, 2*25 cm, 5 μm; mobile phase A: hexane (0.1% FA), mobile phase B: MeOH:CH2Cl2 = 1:1; flow rate: 20 mL / min; gradient: isocratic; wave length: 254 / 220nm nm; Rt1 = 13.2 min; Rt2 = 16.6 min] to afford N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5R)-5-(3,5-dichloro- 2-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl] benzamide (30% yield) as a colorless solid and N- (3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5S)-5-(3,5-dichloro-2-fluoro-phenyl)-5-(trifluoromethyl)-4H- isoxazol-3-yl] benzamide (42% yield) as a colorless solid.

[0142] (Isomer 1) Example 6a:1H NMR (400 MHz, DMSO-d6) δ [ppm] = 8.83-8.82 (d, 1H), 8.05- 8.03 (m, 1H), 7.67-7.65 (m, 3H), 7.47-7.45 (m, 1H), 4.53-4.49 (m, 1H), 4.36-4.32 (m, 1H), 4.25-4.20 (m, 1H), 3.03-2.93 (m, 2H), 2.76-2.63 (m, 2H), 2.38 (s, 3H). LC-MS (method C, 0.00-1.20 min 50-90% B, 1.20-1.80 min 90% B): Rt = 1.0 min; MS (ESI+): m / z = 525 (M+H)+.

[0143] (Isomer 2) Example 6b:1H NMR (400 MHz, DMSO-d6) δ [ppm] = 8.83-8.81 (d, 1H), 8.05- 8.03 (m, 1H), 7.67-7.64 (m, 3H), 7.47-7.45 (m, 1H), 4.53-4.49 (m, 1H), 4.36-4.32 (m, 1H), 4.25-4.22 (m, 1H), 3.01-2.92 (m, 2H), 2.76-2.67 (m, 2H), 2.38 (s, 3H). LC-MS (method C, 0.00-1.20 min 50-90% B, 1.20-1.80 min 90% B): Rt= 1.0 min; MS (ESI+): m / z = 525 (M+H)+. Example 7 N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5S)-5-[3-chloro-5-(trifluoromethyl)phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]benzamide (Example 7a) and N-(3,3-difluorocyclobutyl)-2- methyl-4-[rel-(5R)-5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3- yl]benzamide (Example 7b).Step 1: 1-chloro-3-(trifluoromethyl)-5-[1-(trifluoromethyl)vinyl]benzene.

[0144] To a solution of 4,4,6-trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (1.71 g, 7.71 mmol) in H2O (4 mL) and THF (16 mL), were added 1-bromo-3-chloro-5-(trifluoromethyl)benzene (2.00 g, 7.71 mmol), Pd(dppf)Cl2(629 mg, 771 μmol) and Cs2CO3(7.54 g, 23.1 mmol). The resulting mixture was stirred for 16 h at 60°C under nitrogen atmosphere. After this time, the mixture was treated with H2O and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product (95 % yield)oil. Step 2: methyl 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2- methyl-benzoate.

[0145] To a stirred solution of methyl 4-[hydroxyiminomethyl]-2-methyl-benzoate (1.93 g, 9.96 mmol) in DMF (20 mL) was added NCS (1.33 g, 9.96 mmol) in portions at 0°C. The resulting mixture was stirred for 2 h at rt. Then 1-chloro-3-(trifluoromethyl)-5-[1-(trifluoromethyl)vinyl]benzene (2.00 g, 7.28 mmol) was added slowly. The resulting mixture was stirred for 2 h, before DIPEA (1.88 g, 14.6 mmol) was added at 0°C. The mixture was further stirred for 2 h at rt. Then, the mixture was treated with H2O and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc 1:2) to afford the desired product (15% yield) as yellowish oil. LC-MS (method G, 0.01-1.10 min 5-100% B, 1.40-1.42 min 100-5% B): Rt = 1.1 min; MS (ESI+): m / z = 466 (M+H)+. Step 3: 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl- benzoic acid.

[0146] To a solution of methyl 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H- isoxazol-3-yl]-2-methyl-benzoate (500 mg, 1.07 mmol) in THF (2.50 mL) was added LiOH (129 mg, 5.37 mmol) and H2O (5 mL). The resulting reaction mixture was stirred for 1 h at rt. After this time, the mixture was neutralized with HCl (1 N) and then extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford thedesired compound (93% yield) as a yellowish solid. LC-MS (method H, 0.01-1.00 min 5-95% B, 1.40- 1.42 min 95-5% B): Rt= 0.9 min; MS (ESI+): m / z = 450 (M-H)-. Step 4: N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5S)-5-[3-chloro-5-(trifluoromethyl)phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]benzamide (Example 7a) and N-(3,3-difluorocyclobutyl)-2- methyl-4-[rel-(5R)-5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3- yl]benzamide (Example 7b).

[0147] To a solution of 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol- 3-yl]-2-methyl-benzoic acid (540 mg, 1.20 mmol) in DMF (10 mL) were added HATU (455 mg, 1.20 mmol), DIPEA (463 mg, 3.59 mmol) and 3,3-difluorocyclobutanamine (128 mg, 1.20 mmol). The resulting reaction mixture was stirred for 1 h at rt. After this time, the mixture was treated with H2O and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by prep-HPLC [column: XBridge Prep Shield RP C18 column, 30*150 mm, 5 μm; mobile phase A: H2O (10 mmol / L NH4HCO3), mobile phase B: CH3CN; gradient: 57% B to 78% B in 7 min]. Then the two isomers were separated by prep- chiral-HPLC [column: CHIRALPAK IH, 2*25 cm, 5 μm; mobile phase A: hexane, mobile phase B: MeOH:EtOH = 1:1; flow rate: 20 mL / min; gradient: isocratic; wave length: 254 / 220nm nm; Rt1 = 11.3 min; Rt2 = 14.0 min] to afford afford N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5R)-5-[3- chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide (8.9% yield) as a colorless solid and N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5S)-5-[3-chloro-5- (trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide (7.6% yield) as a colorless solid.

[0148] (Isomer 1) Example 7a:1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.82 (d, 1H), 8.10 (s, 1H), 7.98 (s, 1H), 7.86 (m, 1H), 7.63-7.61 (m, 2H), 7.47 (d, 1H), 4.47-4.34 (m, 2H), 4.25-4.21 (m, 1H), 3.03-2.94(m, 2H), 2.74-2.66 (m, 2H), 2.37 (s, 3H). LC-MS (method C, 0.01-1.20 min 40-90% B, 1.20- 1.80 min 90-90% B, 1.80-1.82 min 90-5% B): Rt = 1.2 min; MS (ESI+): m / z = 540 (M+H)+.

[0149] (Isomer 2) Example 7b:1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.81 (d, 1H), 8.09 (s, 1H), 7.98 (s, 1H), 7.86 (m, 1H), 7.63-7.61 (m, 2H), 7.47 (d, 1H), 4.47-4.34 (m, 2H), 4.25-4.20 (m, 1H), 3.03-2.94(m, 2H), 2.74-2.63 (m, 2H), 2.37 (s, 3H). LC-MS (method C, 0.01-1.20 min 40-90% B, 1.20- 1.80 min 90% B,): Rt= 1.2 min; MS (ESI+): m / z = 541 (M+H)+. Example 8 N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5S)-5-(3-chloro-5-cyano-2-fluoro-phenyl)-5- (trifluoromethyl)-4H-isoxazol-3-yl]benzamide (Example 8a) and N-(3,3-difluorocyclobutyl)-2- methyl-4-[rel-(5R)-5-(3-chloro-5-cyano-2-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3- yl]benzamide (Example 8b).Step 1: 3-chloro-4-fluoro-5-[1-(trifluoromethyl)vinyl]benzonitrile.

[0150] To a solution of 3,5-dichloro-4-fluoro-benzonitrile (1.00 g, 5.26 mmol) and 4,4,6-trimethyl-2- [1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (1.17 g, 5.26 mmol) in THF (10 mL) and H2O (2.5 mL) were added Cs2CO3 (5.15 g, 15.8 mmol) and Pd(dppf)Cl2 (429 mg, 526 μmol). The resulting mixture was stirred for 8 h at 80°C under nitrogen atmosphere. Then, the mixture was allowed to cool down to rt and was extracted with PE to afford the crude product as a yellowish liquid, which was used in the next step without further purification. GC-MS: Rt= 3.9 min; MS (ESI+): m / z = 249 (M)+. Step 2: methyl 4-[5-(3-chloro-5-cyano-2-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2- methyl-benzoate.

[0151] To a stirred mixture of methyl 4-[hydroxyiminomethyl]-2-methyl-benzoate (929 mg, 4.81 mmol) in DMF (15 mL) was added NCS (963 mg, 7.21 mmol, 583.63 μL) in portions at 0°C. The resulting mixture was stirred for 2 h at rt. To the above mixture was added 3-chloro-4-fluoro-5-[1- (trifluoromethyl)vinyl]benzonitrile (1.20 g, 4.81 mmol) and DIEA (3.10 g, 24.04 mmol) dropwise at 0 °C. The resulting mixture was further stirred for 1 h at rt. After completion of the reaction, the mixture was treated with H2O and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc / PE 1:10) to afford methyl 4-[5-(3-chloro-5-cyano-2-fluoro-phenyl)- 5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoate (27% yield) as a yellowish solid. GC-MS: Rt= 7.9 min; MS (ESI+): m / z = 440 (M)+. Step 3: 4-[5-(3-chloro-5-cyano-2-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl- benzoic acid.

[0152] To a solution of methyl 4-[5-(3-chloro-5-cyano-2-fluoro-phenyl)-5-(trifluoromethyl)-4H- isoxazol-3-yl]-2-methyl-benzoate (550 mg, 1.25 mmol) in THF (3 mL) and H2O (3 mL) was added LiOH (149 mg, 6.24 mmol). The resulting reaction mixture was stirred for 16 h at rt. After completion of the reaction, the mixture was acidified to pH ~ 6 by addition of HCl (2 M). The mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered andconcentrated under reduced pressure. The desired product was obtained (50% yield) as a yellowish solid. LC-MS (method D, 0.01-1.20 min 5-100% B, 1.10-1.40 min 100% B): Rt= 0.8 min; MS (ESI+): m / z = 427 (M+H)+. Step 4: N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5S)-5-(3-chloro-5-cyano-2-fluoro-phenyl)-5- (trifluoromethyl)-4H-isoxazol-3-yl]benzamide (Example 8a) and N-(3,3-difluorocyclobutyl)-2- methyl-4-[rel-(5R)-5-(3-chloro-5-cyano-2-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3- yl]benzamide (Example 8b).

[0153] To a solution of 4-[5-(3-chloro-5-cyano-2-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3- yl]-2-methyl-benzoic acid (500 mg, 1.17 mmol) in DMF (3 mL) were added 3,3-difluorocyclobutanamine (138 mg, 1.29 mmol), HATU (668 mg, 1.76 mmol) and DIEA (756 mg, 5.86 mmol). The reaction mixture was stirred for 1 h at rt. After this time, H2O was added. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by achiral-SFC [column: DAICEL DCpak P4VP 5*25 cm, 5um; mobile phase A: CO2, mobile phase B: iPrOH; flow rate: 65 mL / min; gradient: isocratic 34% B; Column temperature: 35°C; back pressure: 100 bar; wave length: 220 nm; Rt1 = 7.49 min; sample solvent: CAN + CH2Cl2] to afford a mixture of two enantiomers. The two enantiomers were separated by prep-chiral-HPLC [column: CHIRALPAK IH, 2*25 cm, 5 μm; mobile phase A: hexane, mobile phase B: EtOH: CH2Cl2 =1: 1; flow rate: 20 mL / min; gradient: isocratic 20; wave length: 254 / 220 nm; Rt1 = 7.6 min; Rt2 = 9.6 min] to afford N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5R)-5-(3-chloro- 5-cyano-2-fluoro-phenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide (8.6% yield) as a colorless solid and N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5S)-5-(3-chloro-5-cyano-2-fluoro-phenyl)-5- (trifluoromethyl)-4H-isoxazol-3-yl]benzamide (9.2% yield) as a colorless solid.

[0154] (Isomer 1) Example 8a: LC-MS (method L, 0.01-1.20 min 40-90% B; 1.20-1.80 min 90% B): Rt = 0.9 min; MS (ESI+): m / z = 516 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ [ppm] = 8.82 (d, 1H), 8.50-8.49 (m, 1H), 8.16-8.15 (m, 1H), 7.67-7.64 (m, 2H), 7.46 (d, 1H), 4.56-4.36 (m, 2H), 4.26-4.19 (m, 1H), 3.03-2.92 (m, 2H), 2.76-2.63 (m, 2H), 2.37 (s, 3H).

[0155] (Isomer 2) Example 8b: LC-MS (method L, 0.01-1.20 min 40-90% B; 1.80-1.82 min 90% - 5% B): Rt= 0.9 min; MS (ESI+): m / z = 516 [M+H]+.1H NMR (400 MHz, DMSO-d6): δ [ppm] = 8.82 (d, 1H), 8.50-8.48 (m, 1H), 8.16-8.14 (m, 1H), 7.67-7.64 (m, 2H), 7.46 (d, 1H), 4.56-4.36 (m, 2H), 4.26-4.19 (m, 1H), 3.03-2.92 (m, 2H), 2.76-2.63 (m, 2H), 2.38 (s, 3H). Example 9 N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5S)-5-[3,5-dichloro-4-(trifluoromethyl)phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]benzamide (Example 9a) and rel-(R)-4-(5-(3,5-dichloro-4-(trifluoromethyl) phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(3,3-difluorocyclobutyl)- 2-methylbenzamide (Example 9b).

[0156] A solution of 4-bromo-2,6-dichloro-aniline (5.00 g, 20.8 mmol) in H2SO4 (70 mL, 6 M) was stirred for 20 min at rt, before it was cooled to 0 °C in an ice bath. NaNO2 (1.58 g, 22.8 mmol, 727 μL) in H2O (30 mL) was added dropwise at 0 °C, and the resulting mixture was stirred for 2.5 h at 0 °C. Then, KI (4.13 g, 24.9 mmol, 1.33 mL) in H2O (15 mL) was added dropwise at 0 °C. The reaction mixture was allowed to warm slowly to rt, and was then further stirred for 1 h at rt. The precipitate was collected by filtration, washed with H2O, and dried under reduced pressure. The desired product was obtained (44% yield) as a yellowish solid. GC-MS: Rt = 5.3 min; MS (ESI+): m / z = 352 (M)+. Step 2: 5-bromo-1,3-dichloro-2-(trifluoromethyl)benzene.

[0157] To a solution of 5-bromo-1,3-dichloro-2-iodo-benzene (2.00 g, 5.69 mmol) in DMF (30 mL) was added methyl 2,2-difluoro-2-fluorosulfonyl-acetate (4.37 g, 22.7 mmol, 2.87 mL) and CuI (2.71 g, 14.2 mmol, 482 μL). The resulting reaction mixture was stirred for 16 h at 90 °C under nitrogen atmosphere. After this time, H2O was added, and the aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product as a brownish oil. GC-MS: Rt = 3.9 min; MS (ESI+): m / z = 294 (M)+. Step 3: 1,3-dichloro-2-(trifluoromethyl)-5-(3,3,3-trifluoroprop-1-en-2-yl) benzene.

[0158] To a solution of 5-bromo-1,3-dichloro-2-(trifluoromethyl)benzene (1.90 g, 6.46 mmol) in THF (30 mL) and H2O (6 mL) were added 4,4,6-trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2- dioxaborinane (1.58 g, 7.11 mmol), Cs2CO3(6.32 g, 19.4 mmol) and Pd(dppf)Cl2(524 mg, 646 μmol). The resulting reaction mixture was stirred for 16 h at 60 °C under nitrogen atmosphere. After this time, H2O was added, and the aqueous layer was separated and extracted with PE. The combined organic layers were dried over anhydrous NaSO4, filtered, and concentrated under reduced pressure (at 10 °C).1,3- Dichloro-2-(trifluoromethyl)-5-[1-(trifluoromethyl)vinyl]benzene was isolated (1.9 g, crude, in 15 mL PE). GC-MS: Rt= 3.7 min; MS (ESI+): m / z = 308 (M)+.Step 4: methyl 4-(5-(3,5-dichloro-4-(trifluoro methyl) phenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-2-methylbenzoate.

[0159] To a solution of methyl 4-[hydroxyiminomethyl]-2-methyl-benzoate (688 mg, 3.56 mmol) in DMF (20 mL) was added NCS (475 mg, 3.56 mmol) and the mixture was stirred for 1 h at rt (solution A). Then, 1,3-dichloro-2-(trifluoromethyl)-5-[1-(trifluoromethyl)vinyl]benzene (1.00 g, 3.24 mmol) in DMF (20 mL) was cooled to 0 °C, and solution A was added dropwise at 0 °C. The resulting mixture was stirred for 10 min at 0 °C, before DIEA (836 mg, 6.47 mmol) was added slowly at 0 °C. The reaction mixture was further stirred for 1 h at rt. The reaction was quenched by the addition of H2O. The aqueous layer was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc 0 - 20%) to afford the desired product (20% yield) as a yellowish oil. LC-MS (method D, 0.00-1.50 min, 5-100% B): Rt = 1.1 min; MS (ESI+): m / z =498 (M- H)-. Step 5: 4-(5-(3,5-dichloro-4-(trifluoro methyl) phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- 2-methylbenzoic acid.

[0160] To a solution of methyl 4-[5-[3,5-dichloro-4-(trifluoromethyl)phenyl]-5-(trifluoromethyl)- 4H-isoxazol-3-yl]-2-methyl-benzoate (300 mg, 600 μmol) in THF (3 mL), was added LiOH (72.0 mg, 3.00 mmol) in H2O (3 mL). The reaction mixture was stirred for 16 h at rt. Then, the mixture was diluted with H2O, acidified to pH ~ 5 by the addition of HCl (1 M) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The desired product was obtained as a yellowish oil. LC-MS (method D, 0.00-1.50 min, 5-100% B): Rt = 1.0 min; MS (ESI+): m / z =484 (M-H)-. Step 6: N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5S)-5-[3,5-dichloro-4-(trifluoromethyl)phenyl]- 5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide (Example 9a) and N-(3,3-difluorocyclobutyl)-2- methyl-4-[rel-(5R)-5-[3,5-dichloro-4-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3- yl]benzamide (Example 9b).

[0161] To a solution of 4-[5-[3,5-dichloro-4-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H- isoxazol-3-yl]-2-methyl-benzoic acid (180 mg, 370 μmol) in DMF (3 mL) were added HATU (183 mg, 481 μmol), DIEA (191 mg, 1.48 mmol) and 3,3-difluorocyclobutanamine (44 mg, 407 μmol). The reaction mixture was stirred for 1 h at rt. Then, the reaction was quenched by the addition of H2O and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep-HPLC [column: XBridge Prep Shield RP C18 column, 30*150 mm, 5 μm; mobile phase A: H2O(10 mmol / L NH4HCO3), mobile phase B: CH3CN; gradient: 60% B to 81% B in 7 min; wavelength: 254nm / 220nm nm; Rt1= 6.68 min]. The two isomers were separated by prep-chiral HPLC [column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; mobile phase A: hexane, mobile phase B: iPrOH: CH2Cl2= 1: 1; flow rate: 20 mL / min; gradient: isocratic 15; wave length: 254 / 220 nm; Rt1= 12.6 min; Rt2 = 14.7 min] to afford N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5R)-5-[3,5-dichloro-4- (trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide (47% yield) as a colorless solid and N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5S)-5-[3,5-dichloro-4-(trifluoromethyl)phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]benzamide (55% yield) as a colorless solid.

[0162] (Isomer 1) Example 9a: LC-MS (method D, 0.01-1.20 min 40-100% B; 1.20-1.80 min 100% B): Rt = 1.0 min; MS (ESIp+): m / z =575 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ [ppm] = 8.82 (d, 1H), 7.89 (s, 2H), 7.62-7.60 (m, 2H), 7.48 (d, 1H), 4.46-4.33 (m, 2H), 4.27-4.20 (m, 1H), 3.00-2.96 (m, 2H), 2.73-2.67 (m, 2H), 2.38 (s, 3H).

[0163] (Isomer 2) Example 9b: LC-MS (method D, 0.01-1.20 min 40- 100% B; 1.20-1.80 min 100% B): Rt = 1.0 min; MS (ESI+): m / z =575 (M+H)+.1H NMR (400 MHz, DMSO-d6) δ [ppm] = 8.82 (d, 1H), 7.89 (s, 2H), 7.62-7.60 (m, 2H), 7.48 (d, 1H), 4.46-4.33 (m, 2H), 4.25-4.22 (m, 1H), 2.99-2.95 (m, 2H), 2.73-2.67 (m, 2H), 2.38 (s, 3H). Example 10 N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5S)-5-[3-chloro-4-fluoro-5-(trifluoromethyl)phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]benzamide (Example 10a) and N-(3,3-difluorocyclobutyl)-2- methyl-4-[rel-(5R)-5-[3-chloro-4-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol- 3-yl]benzamide (Example 10b).Step 1: 1-chloro-2-fluoro-3-(trifluoromethyl)-5-[1-(trifluoromethyl)vinyl]benzene.

[0164] To a solution of 5-bromo-1-chloro-2-fluoro-3-(trifluoromethyl)benzene (2.00 g, 7.21 mmol) and 4,4,6-trimethyl-2-[1-(trifluoromethyl)vinyl]-1,3,2-dioxaborinane (1.60 g, 7.21 mmol) in THF (16 mL) and H2O (4 mL) were added Pd(dppf)Cl2 (588 mg, 721 μmol) and Cs2CO3 (7.05 g, 21.6 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 60°C for 16 h. After completion of thereaction, the mixture was allowed to cool down to rt, before it was extracted with PE to afford the desired product as a yellowish liquid. The crude product was used in the next step without further purification. Step 2: methyl 4-[5-[3-chloro-4-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol- 3-yl]-2-methyl-benzoate.

[0165] To a solution of methyl 4-[hydroxyiminomethyl]-2-methyl-benzoate (727 mg, 3.76 mmol) in DMF (10 mL), was added NCS (609 μL, 7.53 mmol). The mixture was stirred for 1 h at rt, before it was added dropwise to a solution of 1-chloro-2-fluoro-3-(trifluoromethyl)-5-[1-(trifluoromethyl)vinyl]benzene (1.00 g, 3.42 mmol) in DMF (10 mL) at 0°C. The resulting reaction mixture was stirred at 0°C for 10 min. Then, DIEA (883 mg, 6.84 mmol) was added at 0°C and the reaction was further stirred at rt for 2 h. Then, the mixture was treated with H2O and extracted with EtOAc (3 x). The combined organic layers were dried over anhydrous Na2SO4, filtered was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc / PE 10 :1) to afford methyl 4-[5-[3-chloro-4- fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-methyl-benzoate (92% yield) as a yellow solid. LC-MS (method G, 0.01-1.10 min 5-100% B, 1.40-1.42 min 5% B): Rt = 0.1 min; MS (ESI+): m / z = 484 (M+H)+. Step 3: 4-[5-[3-chloro-4-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2- methyl-benzoic acid.

[0166] A solution of methyl 4-[5-[3-chloro-4-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)- 4H-isoxazol-3-yl] -2-methyl-benzoate (1.50 g, 3.10 mmol) and LiOH (371 mg, 15.5 mmol) in THF (15 mL) and H2O (15 mL) was stirred for 8 h at rt. After this time, the pH of the solution was adjusted to 4 by adding aqueous HCl (6 M). Then, H2O was added and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 4-[5-[3-chloro-4-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3- yl]-2-methyl-benzoic acid (93% yield) as a yellowish solid. LC-MS (method L, 0.01-1.00 min 10-90% B, 1.40-1.42 min 90-10% B): Rt = 0.8 min; MS (ESI+): m / z = 468 (M-H)+. Step 4: N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5S)-5-[3-chloro-4-fluoro-5- (trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide (Example 10a) and N- (3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5R)-5-[3-chloro-4-fluoro-5-(trifluoromethyl)phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]benzamide (Example 10a).

[0167] To a solution of 4-[5-[3-chloro-4-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H- isoxazol-3-yl]-2-methyl-benzoic acid (150 mg, 319 μmol) in DMF (5 mL), were added DIEA (206 mg, 1.60 mmol) and HATU (182 mg, 479 μmol). The reaction mixture was stirred for 0.5 h at rt. Then, 3,3- difluorocyclobutanamine hydrochloride (55.0 mg, 383 μmol) was added dropwise at rt. After 1 h thereaction was complete, and the resulting mixture was treated with H2O and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC [column: Xselect CSH Prep C18 OBD Column, 30*150 mm, 5 μm; mobile phase A: H2O (10 mmol / L NH4HCO3), mobile phase B: CH3CN; flow rate: 60 mL / min; gradient: 52% B to 82% B in 10 min; wave length: 254 nm / 220 nm]. The two isomers were separated by prep-chiral-HPLC [column: CHIRALPAK IH, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2 M NH3·MeOH), mobile phase B: MeOH:CH2Cl2= 1: 1; flow rate: 20 mL / min; gradient: isocratic 8; wave length: 254 / 220nm nm; Rt1 = 9.0 min; Rt2 = 11.6 min ] to afford N-(3,3-difluorocyclobutyl)-2- methyl-4-[rel-(5S)-5-[3-chloro-4-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3- yl]benzamide (23% yield) as a colorless solid and N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5R)-5-[3- chloro-4-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]benzamide (25% yield) as a colorless solid.

[0168] (Isomer 1) Example 10b: LC-MS (method L, 0.01-1.20 min 40-90% B, 1.20-1.80 min 90% B, 1.80-1.82 min 90-50% B): Rt = 1.2 min; MS (ESI+): m / z = 557 (M-H)+.1H-NMR (400 MHz, DMSO- d6): δ [ppm] = 8.81 (d, 1H), 8.20-8.18 (m, 1H), 7.89-7.88 (m, 1H), 7.62-7.60 (m, 2H), 7.47 (d, 1H), 4.46- 4.35 (m, 2H), 4.28-4.18 (m, 1H), 3.03-2.92 (m, 2H), 2.76-2.71 (m, 2H), 2.374 (s, 3H).

[0169] (Isomer 2) Example 10a: LC-MS (method L, 0.01-1.20 min 40-90% B, 1.20-1.80 min 90- 90% B, 1.80-1.82 min 90-50% B): Rt = 1.2 min; MS (ESI+): m / z = 557 (M-H)+.1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.81 (d, 1H), 8.20-8.18 (m, 1H), 7.89-7.88 (m, 1H), 7.62-7.60 (m, 2H), 7.47 (d, 1H), 4.46-4.34 (m, 2H), 4.24-4.20 (m, 1H), 3.03-2.92 (m, 2H), 2.76-2.71 (m, 2H), 2.374 (s, 3H). Example 11 (S)-4-(5-(5-chloro-2-fluoro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)- N-((3,3-difluorocyclobutyl)methyl)-2-methylbenzamide (Compound 11).

[0170] To a solution ofphenyl]-5-(trifluoromethyl)- 4H-isoxazol-3-yl]-2-methyl-benzoic acid (150 mg, 319 μmol) in DMF (1.5 mL) were added HATU (146 mg, 383 μmol), [3,3-bis(fluoranyl)cyclobutyl]methanamine hydrochloride (60.0 mg, 383 μmol) and DIPEA (206 mg, 1.60 mmol, 278 μL). The mixture was stirred for 1 h at rt. After this time, H2O wasadded and the mixture was extracted with EtOAc. The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc 5:1). The crude product was purified by prep-HPLC [column: XBridge Prep OBD C18 column, 30*150 mm, 5 μm; mobile phase A: H2O (10 mmol / L NH4HCO3), mobile phase B: CH3CN; gradient: 57% B to 87% B in 7 min] to afford 4-[(5S)-5-[5-chloro- 2-fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N-[(3,3- difluorocyclobutyl)methyl]-2-methyl-benzamide (67% yield) as an off-white solid.

[0171] Example 11:1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.09-8.02 (m, 1H), 7.74-7.69 (m, 1H), 7.58-7.58 (m, 2H), 7.42 (d, 1H), 5.92-5.88 (t, 1H), 4.23-4.17 (m, 1H), 3.93-3.88 (m, 1H), 3.85 (t, 2H), 2.82-2.69 (m, 2H) , 2.62-2.48 (m, 4H) , 2.48-2.32 (m, 2H) . LC-MS (method B, 0.01-1.70 min 60- 80% B, 1.70-2.30 min 80-95% B, 2.30-2.80 min 95% B): Rt = 1.2 min; MS (ESI+): m / z = 573 (M+H)+. Example 12 (S)-4-(5-(3-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3- yl)-N-((3,3-difluorocyclobutyl)methyl)-2-methylbenzamide (Example 12).

[0172] To a solutionphenyl]-5-(trifluoromethyl)- 4H-isoxazol-3-yl]-2-methyl-benzoic acid (100 mg, 202 μmol) in DMF (1 mL) were added (3,3- difluorocyclobutyl)methanamine (32.0 mg, 202 μmol), HATU (92.8 mg, 243 μmol) and DIPEA (157 mg, 1.21 mmol, 211 μL). The resulting mixture was stirred for 1 h at rt. After this time, H2O was added and the mixture was extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified prep-HPLC [column: XBridge Prep C18 OBD column, 19*150 mm, 5μm; mobile phase A: H2O (10 mmol / L NH4HCO3), mobile phase B: CH3CN; gradient: 60% B to 80% B in 6 min] to afford 4-[(5S)- 5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N-[(3,3- difluorocyclobutyl)methyl]-2-methyl-benzamide (29% yield) as a colorless solid.

[0173] Example 12:1H-NMR (400 MHz, DMSO-D6): δ [ppm] = 8.04-8.03 (m, 1H), 7.82-7.80 (m, 1H), 7.54-7.53 (m, 2H), 7.40 (d, 1H), 5.92-5.89 (m, 1H), 4.22 (d, 1H), 3.88 (d, 1H), 3.57 (t, 2H), 2.72- 2.63 (m, 2H), 2.40-2.47 (s, 4H), 2.42-2.30 (m, 2H). LC-MS (method C, 0.01-1.70 min 50-80% B, 1.70- 2.30 min 80-95% B, 2.30-2.80 min 95% B): Rt = 1.5 min; MS (ESI+): m / z = 573 (M+H)+.Example 13 N-(3,3-difluorocyclobutyl)-3-methyl-5-[rel-(5S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H- isoxazol-3-yl]thiophene-2-carboxamide (Example 13a) and N-(3,3-difluorocyclobutyl)-3-methyl-5- [rel-(5R)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxamide (Example 13b).

[0174] To a solution of 5-bromo-4-methyl-thiophene-2-carbaldehyde (4.00 g, 19.5 mmol) in EtOH (40 mL) was added NH2OH·HCl (1.63 g, 23.4 mmol, 974 μL) and sodium acetate (1.92 g, 23.4 mmol, 1.26 mL). The reaction mixture was stirred for 1 h at 60°C. After this time, H2O was added and the mixture was further stirred for 30 min. The precipitate was collected by filtration and washed with H2O to afford 5-bromo-4-methyl-thiophene-2-carbaldehyde oxime (99% yield) as a colorless solid. LC-MS (method C, 0.01-1.10 min 10-95% B, 1.40-1.42 min 95-10% B): Rt = 0.9 min; MS (ESI+): m / z = 220 (M+H)+. Step 2: 5-bromo-N-hydroxy-4-methyl-thiophene-2-carboximidoyl chloride.

[0175] To a solution of 5-bromo-4-methyl-thiophene-2-carbaldehyde oxime (2.74 g, 12.5 mmol) in DMF (30 mL) was added NCS (1.66 g, 12.5 mmol, 1.01 mL). The mixture was stirred for 1 h at rt, and was used in the next step without further purification. Step 3: 3-(5-bromo-4-methyl-2-thienyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazole.

[0176] To a solution of 5-bromo-N-hydroxy-4-methyl-thiophene-2-carboximidoyl chloride (2.11 g, 8.30 mmol) in DMF was added dropwise to a solution of 1,3-dichloro-5-[1-(trifluoromethyl) vinyl] benzene (2.00 g, 8.30 mmol) in DMF (15 mL) at 0°C. The resulting mixture was stirred at 0°C for 10 min. Then, DIPEA (2.14 g, 16.6 mmol) was added at 0°C and the mixture was further stirred at rt for 1 h. After this time, H2O was added and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc / PE 1:10) to afford the desired product (34% yield) as a yellowish solid. LC-MS (method G, 0.01-1.10 min 5-100% B, 1.40-1.42 min 100-5% B): Rt= 1.2 min; MS (ESI+): m / z = 459 (M+H)+. Step 4: 5-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-3-methyl-thiophene-2- carboxylic acid.

[0177] To a solution of 3-(5-bromo-4-methyl-2-thienyl)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)- 4H-isoxazole (1.40 g, 3.05 mmol) in THF (17 mL) was added i-PrMgCl (7.63 mL, 2 M in THF, 15.3 mmol) dropwise at 0°C under nitrogen atmosphere. The mixture was stirred at rt for 30 min, before crushed dry ice was added. The mixture was further stirred for 1 h at rt. Then, H2O was added and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product (53% yield) as a yellowish solid. LC-MS (method G, 0.01-1.80 min 5-100% B, 1.80-1.82 min 5% B): Rt= 1.0 min; MS(ESI+): m / z = 424 (M+H)+. Step 5: N-(3,3-difluorocyclobutyl)-3-methyl-5-[rel-(5S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)- 4H-isoxazol-3-yl]thiophene-2-carboxamide (Example 13a) and N-(3,3-difluorocyclobutyl)-3-methyl- 5-[rel-(5R)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxamide (Example 13b).

[0178] To a solution of 5-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-3-methyl- thiophene-2-carboxylic acid (600 mg, 1.41 mmol) in DMF (20 mL) was added DIPEA (914 mg, 7.07 mmol) and HATU (807 mg, 2.12 mmol). The reaction mixture was stirred for 30 min at rt. To the above solution was then added 3,3-difluorocyclobutanamine hydrochloride (305 mg, 2.12 mmol) dropwise. The resulting mixture was stirred for 1 h at rt. After this time, H2O was added and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue product was purified by prep-HPLC [column: XBridge Prep OBD C18 column, 50*250 mm, 10 μm; mobile phase A: H2O (10 nmol / L NH4HCO3), mobile phase B: CH3CN; gradient: 66% B to 98% B in 20 min]. The two isomers were separated by chiral HPLC [column: CHIRALPAK IH, 2*25 cm, 5 μm; mobile phase A: hexane (0.1% FA), mobile phase B: MeOH:CH2Cl2 = 1:1; flow rate: 20 mL / min; gradient: isocratic; wave length: 254 / 220nm; Rt1 = 10.6 min; Rt2 = 13.5 min] to afford N-(3,3-difluorocyclobutyl)-3-methyl-5-[rel-(5S)-5-(3,5-dichlorophenyl)-5- (trifluoromethyl)-4H-isoxazol-3-yl] thiophene-2-carboxamide (8.4% yield) as a colorless solid and N- (3,3-difluorocyclobutyl)-3-methyl-5-[rel-(5R)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3- yl] thiophene-2-carboxamide (7.5% yield) as a colorless solid.

[0179] (Isomer 1) Example 13a:1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.61 (d, 1H), 7.83- 7.82 (m, 1H), 7.60 (s, 2H), 7.36 (s, 1H), 4.41-4.28(m, 2H), 4.25-4.15 (m, 1H), 2.95-2.91 (m, 2H), 2.76- 2.73 (m, 2H), 2.41 (s, 3H). LC-MS (method L, 0.01-1.20 min 50-90% B, 1.20-1.80 min 90% B, 1.80-1.82 min 90-5% B): Rt= 1.1 min; MS (ESI+): m / z = 513 (M+H)+.

[0180] (Isomer 2) Example 13b:1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.61 (d, 1H), 7.83- 7.82 (m, 1H), 7.60 (s, 2H), 7.36-7.35 (m, 1H), 4.41-4.28 (m, 2H), 4.25-4.18 (m, 1H), 2.94-2.91 (m, 2H),2.75-2.71 (m, 2H), 2.41 (s, 3H). LC-MS (method L, 0.01-1.20 min 50-90% B, 1.20-1.80 min 90% B, 1.80-1.82 min 90-5% B): Rt= 1.1 min; MS (ESI+): m / z = 513 (M+H)+. Example 14 rel-(S)-6-(5-(3-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol- 3-yl)-N-(3,3-difluorocyclobutyl)-4-methylnicotinamide, (Example 14a) and rel-(R)-6-(5-(3-chloro-2- fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(3,3- difluorocyclobutyl)-4-methylnicotinamide, (Example 14b).Step 1: methyl 6-formyl-4-methylnicotinate.

[0181] To a solution of 5-bromo-4-methyl-pyridine-2-carbaldehyde (1.80 g, 9.00 mmol) in MeOH (425 mL) were added triethylamine (4.55 g, 45.0 mmol, 6.27 mL) and Pd(dppf)Cl2 (734 mg, 900 μmol) in a pressure tank. The reaction vessel was purged with nitrogen (3 x) and was then pressurized to 5 atm with carbon monoxide. The mixture was stirred at 80 °C for 16 h. After this time, the reaction mixture was allowed to cool down to rt, filtered to remove insoluble solids and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc / PE 0 - 10%) to afford methyl 6-formyl-4-methyl-pyridine-3-carboxylate (99% yield) as a yellowish solid. LC-MS (method D, 0-1.1 min 5-100% B; 1.1- 1.4 min 100% B): Rt= 0.6 min; MS (ESI+): m / z = 180 [M+H]+. Step 2: methyl-6-((hydroxyimino)methyl)-4-methylnicotinate.

[0182] To a solution of methyl 6-formyl-4-methyl-pyridine-3-carboxylate (1.60 g, 8.93 mmol) in EtOH (20 mL) was added sodium acetate trihydrate (1.46 g, 10.7 mmol) and hydroxylamine hydrochloride (745 mg, 10.7 mmol, 446 μL). The reaction mixture was stirred at 80 °C for 2 h. Then, the mixture was allowed to cool down to rt, concentrated under vacuum, treated with H2O, and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product (99% yield). LC-MS (method D, 0-1.1 min 5-100% B; 1.1- 1.4 min 100% B): Rt= 0.6 min; MS (ESI+): m / z = 195 [M+H]+. Step 3: methyl-6-(bromo(hydroxyimino)methyl)-4-methylnicotinate.

[0183] To a solution of methyl 6-[hydroxyiminomethyl]-4-methyl-pyridine-3-carboxylate (1.90 g, 9.78 mmol) in DMF (20 mL) was added NBS (2.61 g, 14.68 mmol, 1.25 mL) at 0 °C. The reaction mixture was stirred for 1 h at rt. After completion of the reaction, the resulting mixture was used directly in the next step. Step 4: methyl 6-(5-(3-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-4-methylnicotinate.

[0184] 1-chloro-2-fluoro-5-(trifluoromethyl)-3-[1-(trifluoromethyl)vinyl]benzene (17 g, 58.10 mmol) and methyl 6-[C-bromo-N-hydroxy-carbonimidoyl]-4-methyl-pyridine-3-carboxylate (2.64 g, 9.68 mmol) were mixed in DMF at 0 °C. The mixture was stirred for 10 min at 0 °C, then DIEA (6.26 g, 48.4 mmol, 8.43 mL) was added at 0 °C, and the mixture was further stirred for 1 h at rt. The mixture was concentrated and residue was purified by prep-HPLC [column: XBridge Prep OBD C18 column, 30*150 mm, 5μm; mobile phase A: H2O (0.1% FA), mobile phase B: CH3CN; flow rate: 100 mL / min; gradient: 38% B to 39% B in 6 min] to afford the desired product (22% yield) as a brownish solid. LC-MS (method D, 0-1.1 min 5-100% B; 1.1- 1.4 min 100% B): Rt = 1.1 min; MS (ESI+): m / z = 485 [M+H]+. Step 5: 6-(5-(3-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol- 3-yl)-4-methylnicotinic acid.

[0185] To a solution of methyl 4-methyl-6-[5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]pyridine-3-carboxylate (1.06 g, 2.19 mmol) in H2O (5 mL) and THF (5 mL) was added LiOH (262 mg, 10.9 mmol). The resulting mixture was stirred for 16 h at rt. Then, the mixture was acidified to pH ~ 5 by the addition of HCl (1M), diluted with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to yield the desired product as a brownish solid. LC-MS (method D, 0-1.1 min 5-100% B; 1.1- 1.4 min 100% B): Rt = 1.0 min; MS (ESI+): m / z = 471 [M+H]+. Step 6: rel-(S)-6-(5-(3-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-N-(3,3-difluorocyclobutyl)-4-methylnicotinamide (Example 14a) and rel-(R)- 6-(5-(3-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N- (3,3-difluorocyclobutyl)-4-methylnicotinamide (Example 14b).

[0186] A solution of 6-[5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H- isoxazol-3-yl]-4-methyl-pyridine-3-carboxylic acid (200 mg, 425 μmol), 3,3-difluorocyclobutanamine hydrochloride (61 mg, 425 μmol), HATU (195 mg, 510 μmol) and DIEA (329 mg, 2.55 mmol, 444 μL) in DMF (2 mL) was stirred for 2 h at rt. After this time, the mixture was poured into H2O, the aqueous layer was separated and extracted with EtOAc. The combined organic layers were dried overanhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by prep-TLC (PE: EtOAc = 2: 1) to give a mixture of two isomers. The two isomers were separated via prep- chiral SFC [column: (R, R)-WHELK-O12.12*25 cm, 5 µm; mobile phase A: CO2, mobile phase B: iPrOH; flow rate: 60 mL / min; gradient: isocratic 15% B; temperature: 35°C; back pressure: 100 bar; wave length: 220 nm; Rt1= 5.2 min; Rt2= 6.1 min] to afford N-(3,3-difluorocyclobutyl)-4-methyl-6-[rel-(5S)-5- [3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyridine-3- carboxamide (19% yield) as a colorless solid and N-(3,3-difluorocyclobutyl)-4-methyl-6-[rel-(5R)-5-[3- chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyridine-3-carboxamide (20% yield) as a colorless solid.

[0187] (Isomer 1) Example 14a:1H-NMR (400 MHz, DMSO-D6): δ [ppm] =9.04 (d, 1H), 8.63 (s, 1H), 8.36 (d, 1H), 7.94-7.91(m, 2H), 4.48-4.37 (m, 2H), 4.28-4.21 (m, 1H), 3.05-2.95 (m, 2H), 2.77-2.64 (m, 2H), 2.42 (s, 3H). LC-MS (method J, 0.01-1.20 min 40-95% B, 1.2-1.80 min 95% B): Rt= 1.1 min; MS (ESI+): m / z = 560 (M+H)+.

[0188] (Isomer 2) Example 14b:1H-NMR (400 MHz, DMSO-D6): δ [ppm] =9.04 (d, 1H), 8.63 (s, 1H), 8.36 (d, 1H), 7.94-7.91(m, 2H), 4.48-4.37 (m, 2H), 4.28-4.21 (m, 1H), 3.05-2.95 (m, 2H), 2.77-2.64 (m, 2H), 2.42 (s, 3H). LC-MS (Analytical method J, 0.01-1.20 min 40-95% B, 1.2-1.80 min 95% B): Rt = 1.1 min; MS (ESI+): m / z = 560 (M+H)+. Example 15 N-(3,3-difluorocyclobutyl)-3-methyl-5-[rel-(5S)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]pyridine-2-carboxamide (Example 15a) and N-(3,3- difluorocyclobutyl)-3-methyl-5-[rel-(5R)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]pyridine-2-carboxamide (Example 15b).Step 1: methyl 3-methyl-5-vinylpicolinate.

[0189] A mixture of methyl 5-bromo-3-methyl-pyridine-2-carboxylate (1.50 g, 6.19 mmol), tributyl(vinyl)tin (2.36 g, 7.43 mmol) and Pd(PPh3)2Cl2 (436 mg, 619 μmol) in 1,4-dioxane (20 mL) was stirred for 2 h at 100°C under nitrogen atmosphere. Then, the mixture was allowed to cool down to rt, before it was concentrated under reduced pressure. The residue was purified by column chromatographyon silica gel (PE / EtOAc 10:1) to afford methyl 3-methyl-5-vinyl-pyridine-2-carboxylate (97% yield). LC- MS (method C, 0.01-1.00 min 5-100% B, 1.00-1.40 min 100% B): Rt= 0.8 min; MS (ESI+): m / z = 178 (M+H)+. Step 2: methyl 5-formyl-3-methylpicolinate.

[0190] A mixture of methyl 3-methyl-5-vinyl-pyridine-2-carboxylate (3.07 g, 15.6 mmol), NMO (2.37 g, 20.3 mmol), citric acid (3.89 g, 20.3 mmol) and KOsO4(485 mg, 1.56 mmol) in n-BuOH (30 mL) and H2O (30 mL) was stirred for 1 h at rt. To the above mixture was added NaIO4(6.67 g, 31.2 mmol) protionwise at rt. Then, the mixture was further stirred for 1 h at rt. H2O was added and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to the desired product (95% yield). LC-MS (method C, 0.01-1.00 min 5-100% B, 1.00-1.40 min 100% B): Rt = 0.6 min; MS (ESI+): m / z = 180 (M+H)+. Step 3: methyl 5-((hydroxyimino)methyl)-3-methylpicolinate.

[0191] A mixture of methyl 5-formyl-3-methyl-pyridine-2-carboxylate (3.12 g, 14.8 mmol), hydroxylamine hydrochloride (1.23 g, 17.8 mmol, 739 μL) and AcONa (1.46 g, 17.8 mmol, 954 μL) in EtOH (40 mL) was stirred for 2 h at 80°C. Then, the mixture was allowed to cool down to rt, before it was concentrated under reduced pressure. H2O was added and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc 5:1) to afford methyl 5-(hydroxyiminomethyl)-3-methyl-pyridine-2-carboxylate (47% yield). LC-MS (method K, 0.01-1.00 min 5-100% B, 1.00-1.40 min 100% B): Rt = 0.5 min; MS (ESI+): m / z = 195 (M+H)+. Step 4: methyl-5-(bromo(hydroxyimino)methyl)-3-methylpicolinate.

[0192] To a stirred solution of methyl 5-[hydroxyiminomethyl]-3-methyl-pyridine-2-carboxylate (1.50 g, 6.95 mmol) in DMF (15 mL) was added NBS (1.11 g, 8.34 mmol, 675 μL) portion wise at 0°C. The resulting mixture was stirred for 2 h at 50°C. The resulting solution was used in the next step without further purification. Step 5: methyl 5-(5-(3-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-3-methylpicolinate.

[0193] To a stirred solution of methyl 5-[C-bromo-N-hydroxy-carbonimidoyl]-3-methyl-pyridine-2- carboxylate (1.79 g, 6.56 mmol) in DMF (15 mL) was added 1-chloro-2-fluoro-5-(trifluoromethyl)-3-[1- (trifluoromethyl)vinyl]benzene (1.92 g, 6.56 mmol) and DIPEA (2.54 g, 19.7 mmol) dropwise at 0°C. The resulting mixture was stirred for 1 h at rt. H2O was added, and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography on silica gel (PE / EtOAc 10:1) to afford the desired compound (26% yield). LC-MS (method C, 0.01-1.00 min 5-100% B, 1.00-1.40 min 100% B): Rt= 1.2 min; MS (ESI+): m / z = 485 (M+H)+. Step 6: 5-(5-(3-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol- 3-yl)-3-methylpicolinic acid.

[0194] A mixture of methyl 5-[5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)- 4H-isoxazol-3-yl]-3-methyl-pyridine-2-carboxylate (910 mg, 1.69 mmol) and LiOH (202 mg, 8.45 mmol) in THF (8 mL) and H2O (8 mL) was stirred for 16 h at rt. After this time, the mixture was acidified to pH ~ 7 by the addition of HCl (1 M). The mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford the desired carboxylic acid (92% yield). LC-MS (method C, 0.01-1.00 min 5-100% B, 1.00- 1.40 min 100% B): Rt = 0.8 min; MS (ESI+): m / z = 471 (M+H)+. Step 7: N-(3,3-difluorocyclobutyl)-3-methyl-5-[rel-(5S)-5-[3-chloro-2-fluoro-5- (trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyridine-2-carboxamide (Example 15a) and N-(3,3-difluorocyclobutyl)-3-methyl-5-[rel-(5R)-5-[3-chloro-2-fluoro-5- (trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyridine-2-carboxamide (Example 15b).

[0195] A mixture of 5-[5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H- isoxazol-3-yl]-3-methyl-pyridine-2-carboxylic acid (200 mg, 382 μmol), 3,3-difluorocyclobutanamine hydrochloride (66.0 mg, 459 μmol), HATU (218 mg, 574 μmol) and DIPEA (148 mg, 1.15 mmol) in DMF (3 mL) was stirred for 1 h at rt. After this time, H2O was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel (PE / EtOAc 3 :1) to afford the desired racemic product. The two isomers were separated by prep- chiral HPLC [column: CHIRAL ART Amylose-SA, 2*25 cm, 5 μm; mobile phase A: hexane:CH2Cl2 = 3:1(0.1% DEA), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: isocratic; wave length: 254 / 220 nm; Rt1 = 3.9 min; Rt2 = 5.0 min] to afford N-(3,3-difluorocyclobutyl)-3-methyl-5-[rel- (5S)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyridine-2- carboxamide (29% yield) as a colorless solid and N-(3,3-difluorocyclobutyl)-3-methyl-5-[rel-(5R)-5-[3- chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyridine-2-carboxamide (29% yield) as a colorless solid.

[0196] (Isomer 1) Example 15a:1H-NMR (400 MHz, DMSO-D6): δ [ppm] = 9.20 (d, 1H), 8.82- 8.81 (m, 1H), 8.39-8.37 (m, 1H), 8.17-8.14 (m, 1H), 7.94-7.90 (m, 1H), 4.72-4.66 (m, 1H), 4.48-4.42 (m,1H), 4.34-4.20 (m, 1H), 3.00-2.75 (m, 4H), 2.57 (s, 3H). LC-MS (method C, 0.01-1.20 min 50-95% B, 1.20-1.8 min 95% B): Rt= 1.1 min; MS (ESI+): m / z = 560 (M+H)+.

[0197] (Isomer 2) Example 15b:1H-NMR (400 MHz, DMSO-D6): δ [ppm] = 9.20 (d, 1H), 8.82- 8.81 (m, 1H), 8.39-8.37 (m, 1H), 8.16-8.15 (m, 1H), 7.93-7.91 (m, 1H), 4.72-4.66 (m, 1H), 4.47-4.43 (m, 1H), 4.32-4.25 (m, 1H), 2.99-2.76 (m, 4H), 2.57 (s, 3H). LC-MS (method C, 0.01-1.20 min 50-95% B, 1.20-1.8 min 95% B): Rt= 1.1 min; MS (ESI+): m / z = 560 (M+H)+. Example 16 N-(3,3-difluorocyclobutyl)-2-methyl-6-[rel-(5S)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]pyridine-3-carboxamide (Example 16a) and N-(3,3- difluorocyclobutyl)-2-methyl-6-[rel-(5R)-5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]pyridine-3-carboxamide (Example 16b).Step 1: methyl 2-methyl-6-vinylnicotinate.

[0198] To a solution of methyl 6-chloro-2-methyl-pyridine-3-carboxylate (3.00 g, 16.16 mmol) in 1,4-dioxane (30 mL) were added Pd(PPh3)2Cl2 (1.13 g, 1.62 mmol) and tributyl(vinyl)tin (6.15 g, 19.4 mmol). The reaction mixture was stirred for 16 h at 100°C under nitrogen atmosphere. After this time, the mixture was allowed to cool down to rt and concentrated under reduced pressure. H2O was added and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO4, filtered, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc 3:1) to afford methyl 2-methyl-6-vinyl-pyridine-3- carboxylate (99% yield) as a colorless oil. LC-MS (method D, 0-1.1 min 5-100% B; 1.1- 1.4 min 100% B): Rt= 0.6 min; MS (ESI+): m / z = 178 [M+H]+. Step 2: methyl 6-formyl-2-methylnicotinate.

[0199] To a solution of methyl 2-methyl-6-vinyl-pyridine-3-carboxylate (4.50 g, 25.4 mmol) in 1,4- dioxane (50 mL) and H2O (50 mL) was added potassium osmate(VI) dihydrate (9.82 g, 26.7 mmol). The mixture was stirred for 20 min at 30°C, before NaIO4(5.97 g, 27.9 mmol) was added. The resulting mixture was further stirred for 1 h at 30°C. After completion of the reaction, the mixture was concentrated under reduced pressure, diluted with H2O and extracted with EtOAc. The combined organic layers weredried over anhydrous NaSO4, filtered, and concentrated under reduced pressure to afford the desired product (99% yield) as a brownish oil. Step 3: methyl 6-((hydroxyimino)methyl)-2-methylnicotinate.

[0200] To a solution of methyl 6-formyl-2-methyl-pyridine-3-carboxylate (5.00 g, 27.9 mmol) in EtOH (50 mL) was added sodium acetate (2.75 g, 33.5 mmol, 1.80 mL). The reaction mixture was stirred for 16 h at 80°C. After this time, the mixture was concentrated under reduced pressure, diluted with H2O, and extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (PE / EtOAc 1:1) to afford methyl 6-[hydroxyiminomethyl]-2-methyl-pyridine-3-carboxylate (18% yield). LC-MS (method D, 0-1.1 min 5-100% B; 1.1- 1.4 min 100% B): Rt = 0.5 min; MS (ESI+): m / z = 195 (M+H)+. Step 4: methyl 6-(5-(3-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5- dihydroisoxazol-3-yl)-2-methylnicotinate.

[0201] To a solution of methyl 6-[hydroxyiminomethyl]-2-methyl-pyridine-3-carboxylate (1.00 g, 5.15 mmol) in DMF (10 mL) was added NCS (825 mg, 6.18 mmol) at 0°C. The mixture was stirred under nitrogen atmosphere for 2 h at 0°C. Then, 1-chloro-2-fluoro-5-(trifluoromethyl)-3-[1- (trifluoromethyl)vinyl]benzene (1.66 g, 5.66 mmol) and DIEA (1.33 g, 10.3 mmol) were added at 0 °C. The resulting reaction mixture was stirred under nitrogen atmosphere for 16 h at rt. After this time, H2O was added and the mixture was extracted with EtOAc. The combined organic layers were concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel (PE / EtOAc 3:1) to afford the desired product (48% yield). Step 5: 6-(5-(3-chloro-2-fluoro-5-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol- 3-yl)-2-methylnicotinic acid.

[0202] To a solution of methyl 2-methyl-6-[5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]pyridine-3-carboxylate (600 mg, 1.24 mmol) in THF (10 mL) and H2O(10 mL) was added LiOH (148 mg, 6.19 mmol). The mixture was stirred under nitrogen atmosphere for 16 h at 40 °C. After this time, the mixture was concentrated under reduced pressure. The residue was diluted with H2O, neutralized to pH 5-6 by the addition of HCl (1M) and then extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO4, filtered, and concentrated under reduced pressure to afford the desired carboxylic acid (41% yield). LC-MS (method D, 0-1.10 min 5-100% B, 1.10-1.40 min 100% B): Rt=1.1 min; MS (ESI+): m / z = 471 (M+H)+. Step 6: N-(3,3-difluorocyclobutyl)-2-methyl-6-[rel-(5S)-5-[3-chloro-2-fluoro-5- (trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyridine-3-carboxamide (Example16a) and N-(3,3-difluorocyclobutyl)-2-methyl-6-[rel-(5R)-5-[3-chloro-2-fluoro-5- (trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyridine-3-carboxamide (Example 16b).

[0203] To a solution of 6-[5-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H- isoxazol-3-yl]-2-methyl-pyridine-3-carboxylic acid (120 mg, 255 µmol) in DMF (1.5 mL) were added HATU (116 mg, 306 μmol), 3,3-difluorocyclobutanamine hydrochloride (44.0 mg, 306 μmol) and DIEA (165 mg, 1.27 mmol, 222 μL). The reaction mixture was stirred under nitrogen atmosphere for 1 h at rt. Then, H2O was added and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous NaSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc 3:1). The two isomers were separated via prep-chiral HPLC [column: CHIRALPAK AD-H, 2*25 cm, 5 μm; mobile phase A: hexane (0.1% DEA), mobile phase B: EtOH; flow rate: 20 mL / min; gradient: isocratic 10; wave length: 254 / 220 nm; Rt1 = 6.9 min; Rt2 = 15.5 min] to afford N-(3,3-difluorocyclobutyl)-2-methyl-6-[rel-(5S)-5-[3-chloro-2-fluoro-5- (trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyridine-3-carboxamide (21% yield) as an off-white solid and N-(3,3-difluorocyclobutyl)-2-methyl-6-[rel-(5R)-5-[3-chloro-2-fluoro-5- (trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyridine-3-carboxamide (18% yield) as an off-white solid.

[0204] (Isomer 1) Example 16a:1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.04-8.03 (m, 1H), 7.91 (d, 1H), 7.83-7.81 (m, 1H), 7.76 (d, 1H), 6.07-6.06 (m, 1H), 4.49-4.40 (m, 2H), 4.03 (d, 1H), 3.18- 3.12 (m, 2H), 2.70 (s, 3H), 2.67-2.59 (m, 2H). LC-MS (method C, 0.01-1.20 min 40-95% B, 1.20-1.80 min 95% B): Rt1 = 1.1 min; MS (ESI+): m / z = 560 (M+H)+.

[0205] (Isomer 2) Example 16b:1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.04-8.03 (m, 1H), 7.91 (d, 1H), 7.83-7.81 (m, 1H), 7.76 (d, 1H), 6.10 (br, 1H), 4.48-4.41 (m, 2H), 4.03 (d, 1H), 3.18-3.12 (m, 2H), 2.71 (s, 3H), 2.67-2.55 (m, 2H). LC-MS (method C, 0.01-1.20 min 40-95% B, 1.20-1.80 min 95% B): Rt1 = 1.1 min; MS (ESI+): m / z = 560 (M+H)+. Example 17 N-(3,3-difluorocyclobutyl)-4-[rel-(5S)-5-[5-chloro-2-fluoro-3-(trifluoromethyl)phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]naphthalene-1-carboxamide (Example 17a) and N-(3,3- difluorocyclobutyl)-4-[rel-(5R)-5-[5-chloro-2-fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)- 4H-isoxazol-3-yl]naphthalene-1-carboxamide (Example 17b).S

[0206] To a solution of methyl 4-formylnaphthalene-1-carboxylate (2.00 g, 9.34 mmol) in EtOH (38.9 mL) was added NH2OH·HCl (779 mg, 11.2 mmol) and AcONa (919 mg, 11.2 mmol) and the resulting mixture was stirred for 1 h at 60°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and treated with H2O. The precipitated solids were collected by filtration and the filter cake was washed with ice H2O and dried in vacuo to afford methyl 4- [hydroxyiminomethyl]naphthalene-1-carboxylate (84% yield) as a colorless solid. LC-MS (method G, 0.01-1.10 min 5-100% B, 1.40-1.42 min 100-5% B): Rt = 0.8 min; MS (ESI+): m / z = 230 (M+H)+. Step 2: methyl 4-[C-chloro-N-hydroxy-carbonimidoyl]naphthalene-1-carboxylate.

[0207] To a solution of methyl 4-[hydroxyiminomethyl]naphthalene-1-carboxylate (920 mg, 4.01 mmol) in DMF (9.68 mL) was added NCS (536 mg, 4.01 mmol). The reaction mixture was stirred 1h at rt and then used directly in the next step. Step 3: methyl 4-[5-[5-amino-2-fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol- 3-yl]naphthalene-1-carboxylate.

[0208] To a solution of 4-fluoro-3-(trifluoromethyl)-5-[1-(trifluoromethyl)vinyl]aniline (1.00 g, 3.66 mmol) in DMF (10 mL) was added methyl 4-[C-chloro-N-hydroxy-carbonimidoyl]naphthalene-1- carboxylate (966 mg, 3.66 mmol). The resulting reaction mixture was stirred for 10 min at 0°C. Then, DIEA (944 mg, 7.32 mmol) was added at 0°C and the mixture was allowed to further stir for 1 h at rt. Then, the mixture was treated with H2O and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EtOAc 1:1) to afford methyl 4-[5-[5-amino-2- fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]naphthalene-1-carboxylate (27% yield) as yellowish oil. LC-MS (method L, 0.01-1.00 min 10-90% B, 1.40-1.42 min 100-10% B): Rt = 1.0 min; MS (ESI+): m / z = 501 (M+H)+. Step 4: 4-[5-[5-amino-2-fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3- yl]naphthalene-1-carboxylic acid.

[0209] To a solution of methyl 4-[5-[5-amino-2-fluoro-3-(trifluoromethyl)phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]naphthalene-1-carboxylate (600 mg, 1.20 mmol) in THF (10 mL) was added a solution of LiOH (144 mg, 6.00 mmol) in H2O (10 mL). The reaction mixture was stirred 3 h at rt. Then, the mixture was concentrated under reduced pressure. The residue was diluted with H2O and aqueous HCl (1M) was added to adjust pH to 5-6. The aqueous layer was then extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 4-[5-[5-amino-2-fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3- yl]naphthalene-1-carboxylic acid (60% yield) as a yellowish solid. LC-MS (method L, 0.01-1.00 min 10- 90% B, 1.40-1.42 min 100-10% B): Rt = 0.6 min; MS (ESI+): m / z = 487 (M+H)+. Step 5: 4-[5-[5-chloro-2-fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3- yl]naphthalene-1-carboxylic acid.

[0210] A solution of 4-[5-[5-amino-2-fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H- isoxazol-3-yl]naphthalene-1-carboxylic acid (390 mg, 801 μmol) in AcOH (3.97 mL) and concentrated HCl (596 μL) was stirred for 5 min at 0°C, before CuCl (159 mg, 1.60 mmol) was added at 0°C. The resulting mixture was stirred 2 h at rt under nitrogen atmosphere. After this time, H2O was added and the precipitated solids were collected by filtration and dried in vacuo to give afford 4-[5-[5-chloro-2-fluoro-3- (trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]naphthalene-1-carboxylic acid (43% yield) as a yellowish solid. LC-MS (method L, 0.01-1.00 min 10-90% B, 1.40-1.42 min 100-10% B): Rt = 0.8 min; MS (ESI+): m / z = 375 (M+H)+. Step 6: N-(3,3-difluorocyclobutyl)-4-[rel-(5S)-5-[5-chloro-2-fluoro-3-(trifluoromethyl)phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]naphthalene-1-carboxamide (Example 17a) and N-(3,3- difluorocyclobutyl)-4-[rel-(5R)-5-[5-chloro-2-fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)- 4H-isoxazol-3-yl]naphthalene-1-carboxamide (Example 17b).

[0211] To a solution of 4-[5-[5-chloro-2-fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H- isoxazol-3-yl]naphthalene-1-carboxylic acid (270 mg, 534 μmol) in DMF were added HATU (304 mg, 801 μmol) and DIEA (344 mg, 2.67 mmol). The reaction mixture was stirred for 15 min at rt. Then, 3,3- difluorocyclobutanamine (114 mg, 1.07 mmol) was added and the mixture was further stirred for 2 h at rt. After this time, H2O was added and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC [mobile phase A: H2O (10 nmol / L NH4HCO3), mobile phase B: CH3CN; flow rate: 60 mL / min; gradient: 59% B to 89 % B in 10 min; UV detector: 254 nm / 220 nm; Rt= 8.5 min]. The two enantiomers were separated by prep-chiral-HPLC [column: CHIRAL ART Cellulose-SB, 2*25 cm, 5 μm; mobile phase A: hexane (0.5% 2 M NH3·MeOH), mobile phase B: MeOH: CH2Cl2=1: 1; flow rate:20 mL / min; gradient: isocratic 15; wave length: 254 / 220 nm; Rt1= 8.6 min; Rt2= 11.0 min] to afford N- (3,3-difluorocyclobutyl)-4-[rel-(5S)-5-[5-chloro-2-fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)- 4H-isoxazol-3-yl]naphthalene-1-carboxamide (13% yield) as an off-white solid and N-(3,3- difluorocyclobutyl)-4-[rel-(5R)-5-[5-chloro-2-fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H- isoxazol-3-yl]naphthalene-1-carboxamide (17% yield) as an off-white solid.

[0212] (Isomer 1) Example 17a: LC-MS (method L, 0.01-1.20 min 60-90% B, 1.80-1.80 min 90% B): Rt= 0.9 min; MS (ESI+): m / z = 595 (M+H)+.1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 9.14 (d, 1H), 8.80-8.78 (m, 1H), 8.22-8.17 (m, 2H), 8.11-8.09 (m, 1H), 7.97 (d, 1H), 7.75-7.67 (m, 3H), 4.73-4.63 (m, 2H), 4.40-4.33 (m, 1H), 3.10-3.00 (m, 2H).2.84-2.76 (m, 2H).

[0213] (Isomer 2) Example 17b: LC-MS (method L, 0.01-1.20 min 60-90% B, 1.20-1.80 min 90% B): Rt = 0.9 min; MS (ESI+): m / z = 595 (M+H)+.1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 9.14 (d, 1H), 8.80-8.78 (m, 1H), 8.27-8.20 (m, 1H), 8.18-8.17 (m, 1H), 8.11-8.09 (m, 1H), 7.97 (d, 1H), 7.75-7.67 (m, 3H), 4.74-4.63 (m, 2H), 4.39-4.33 (m, 1H), 3.09-3.03 (m, 2H).2.83-2.75 (m, 2H). Example 18 N-(3,3-difluorocyclobutyl)-3-methyl-5-[rel-(5S)-5-(3,5-dichloro-2-fluoro-phenyl)-5- (trifluoromethyl)-4H-isoxazol-3-yl] thiophene-2-carboxamide (Example 18a) and N-(3,3- difluorocyclobutyl)-3-methyl-5-[rel-(5R)-5-(3,5-dichloro-2-fluoro-phenyl)-5-(trifluoromethyl)-4H- isoxazol-3-yl] thiophene-2-carboxamide (Example 18b).13a and 13b.

[0215] (Isomer 1) Example 18a: LC-MS (method D, 0.01-2.00 min 5-100% B; 1.20-1.80 min 100% B): Rt = 0.9 min; MS (ESI+): m / z = 531 (M+H)+.1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.61 (d, 1H), 8.06-8.04 (m, 1H), 7.65-7.63 (m, 1H), 7.49 (s, 1H), 4.53-4.48 (m, 1H), 4.37-4.32 (m, 1H), 4.25-4.18 (m, 1H), 2.97-2.89 (m, 2H), 2.81-2.68 (m, 2H), 2.41 (s, 3H).

[0216] (Isomer 2) Example 18b: LC-MS (method D, 0.01-2.00 min 5-100% B; 1.20-1.80 min 100% B): Rt = 0.9 min; MS (ESI+): m / z = 531 (M+H)+.1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.61 (d, 1H), 8.06-8.04 (m, 1H), 7.65-7.63 (m, 1H), 7.49 (s, 1H), 4.53-4.48 (m, 1H), 4.37-4.33 (m, 1H), 4.25- 4.18 (m, 1H), 2.98-2.88 (m, 2H), 2.81-2.67 (m, 2H), 2.41 (s, 3H).Example 19 N-(3,3-difluorocyclobutyl)-3-methyl-5-[rel-(5S)-5-[3-chloro-5-(trifluoromethyl)phenyl] -5- (trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxamide (Example 19a) and N-(3,3- difluorocyclobutyl)-3-methyl-5-[rel-(5R)-5-[3-chloro-5-(trifluoromethyl)phenyl] -5- (trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxamide (Example 19b). 13a and

[0218] (Isomer 1) Example 19a: LC-MS (method C, 0.01-1.20 min 40-90% B, 1.20-1.80 min 90% B): Rt= 1.2 min; MS (ESI+): m / z = 547 (M+H)+.1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.61 (d, 1H), 8.10 (s, 1H), 7.95 (s, 1H), 7.82 (s, 1H), 7.36 (s, 1H), 4.47-4.34 (m, 2H), 4.25-4.15 (s, 1H), 2.95- 2.91 (m, 2H), 2.78- 2.71 (m, 2H).2.41 (s, 3H).

[0219] (Isomer 2) Example 19b: LC-MS (method C, 0.01-1.20 min 40-90% B, 1.20-1.80 min 90% B): Rt= 1.2 min; MS (ESI+): m / z = 547 (M+H)+.1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.61 (d, 1H), 8.10 (s, 1H), 7.95 (s, 1H), 7.82 (s, 1H), 7.36 (s, 1H), 4.47-4.434 (m, 2H), 4.25-4.15 (m, 1H), 2.95- 2.91 (m, 2H), 2.77-2.73 (m, 2H).2.41 (s, 3H). Example 20 N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5S)-5-[3-chloro-5-(1-fluoro-1-methyl-ethyl)phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]benzamide (Example 20a) and N-(3,3-difluorocyclobutyl)-2- methyl-4-[rel-(5R)-5-[3-chloro-5-(1-fluoro-1-methyl-ethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol- 3-yl]benzamide (Example 20b).7a and 7b.

[0221] (Isomer 1) Example 20a: LC-MS (method C, 0.01-1.20 min 50-90% B; 1.20-1.80 min 90% B): Rt= 1.0 min; MS (ESI-): m / z = 531 [M-H]-.1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.81 (d, 1H),7.64-7.62(m, 3H), 7.58-7.57 (m, 2H), 7.46 (d, 1H), 4.41 (d, 1H), 4.28-4.21 (m, 2H), 3.02-2.92 (m, 2H), 2.76-2.63 (m, 2H), 2.37 (s, 3H), 1.71 (s, 3H), 1.66 (s, 3H).

[0222] (Isomer 2) Example 20b: LC-MS (method C, 0.01-1.20 min 50-90% B; 1.20-1.80 min 90% B): Rt= 1.0 min; MS (ESI-): m / z = 531 [M-H]-.1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.81 (d, 1H), 7.65-7.62(m, 3H), 7.59-7.57 (m, 2H), 7.46 (d, 1H), 4.41 (d, 1H), 4.28-4.19 (m, 2H), 3.02-2.92 (m, 2H), 2.76-2.63 (m, 2H), 2.38 (s, 3H), 1.71 (s, 3H), 1.65 (s, 3H). Example 21 N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5S)-5-[3-chloro-5-(1,1-difluoroethyl) phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]benzamide (Example 21a) and N-(3,3-difluorocyclobutyl)-2- methyl-4-[rel-(5R)-5-[3-chloro-5-(1,1-difluoroethyl) phenyl]-5-(trifluoromethyl)-4H-isoxazol-3- yl]benzamide (Example 21b).7a and 7b.

[0224] (Isomer 1) Example 21a: LC-MS (method C, 0.01-1.20 min 40-90% B; 1.20-1.80 min 90% B): Rt= 1.1 min; MS (ESI+): m / z = 537 [M+H]+.1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.81 (d, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 7.71(s, 1H), 7.64-7.62 (m, 2H), 7.47 (d, 1H), 4.44 (d, 1H), 4.32 (d, 1H), 4.25-4.22 (m, 1H), 3.03-2.92 (m, 2H), 2.76-2.65 (m, 2H), 2.38 (s, 3H), 2.04 (t, 3H).

[0225] (Isomer 2) Example 21b: LC-MS (method C, 0.01-1.20 min 40-90% B; 1.20-1.80 min 90% B): Rt= 1.1 min; MS (ESI+): m / z = 537 [M+H]+.1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.81 (d, 1H), 7.83 (s, 1H), 7.79 (s, 1H), 7.71(s, 1H), 7.64-7.62 (m, 2H), 7.47 (d, 1H), 4.44 (d, 1H), 4.32 (d, 1H), 4.25-4.22 (m, 1H), 3.03-2.93 (m, 2H), 2.76-2.63 (m, 2H), 2.38 (s, 3H), 2.04 (t, 3H). Example 22 N-(3,3-difluorocyclobutyl)-4-[rel-(5S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]- 2-(trifluoromethyl) benzamide (Example 22a) and N-(3,3-difluorocyclobutyl)-4-[rel-(5R)-5-(3,5- dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-(trifluoromethyl)benzamide (Example 22b).St

[0226] To a solution of 1-bromo-3,5-dichloro-benzene (10.0 g, 44.3 mmol) in THF (100 mL) and H2O (25 mL) were added 4,4,6-trimethyl-2-[1-(trifluoromethyl) vinyl]-1,3,2-dioxaborinane (11.8 g, 53.1 mmol), Cs2CO3 (28.9 g, 88.5 mmol) and Pd(dppf)Cl2 (3.62 g, 4.43 mmol). The resulting mixture was stirred at 80°C for 16 h. After this time, the mixture was concentrated under reduced pressure (30℃) and then extracted with PE. The combined organic layers were washed with H2O, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure (30℃). The crude product was used in the next step directly without further purification. LC-MS (method A): Rt = 1.0 min; MS (ESI+): m / z = 241 (M+H)+. Step 2: methyl 4-[(E)-hydroxyiminomethyl]-2-(trifluoromethyl) benzoate.

[0227] To a solution of methyl 4-formyl-2-(trifluoromethyl) benzoate (5.00 g, 21.54 mmol) in EtOH (50 mL) were added NH2OH·HCl (1.80 g, 25.8 mmol) and AcONa (2.12 g, 25.8 mmol). The resulting reaction mixture was stirred at 60°C for 2 h under nitrogen atmosphere. Upon completion of the reaction, the mixture was allowed to cool down to rt. The precipitated solids were collected by filtration, washed with H2O, and dried under reduced pressure to afford methyl 4-[(E)-hydroxyiminomethyl]-2- (trifluoromethyl) benzoate. LC-MS (method A): Rt= 0.7 min; MS (ESI+): m / z = 248 (M+H)+. Step 3: methyl 4-[(Z)-C-chloro-N-hydroxy-carbonimidoyl]-2-(trifluoromethyl)benzoate.

[0228] To a solution of methyl 4-[(E)-hydroxyiminomethyl]-2-(trifluoromethyl) benzoate (5.13 g, 20.8 mmol) in DMF (50 mL) was added NCS (3.33 g, 24.9 mmol) and the resulting mixture was stirred at rt for 1 h. The resulting mixture was used in the next step directly. Step 4: methyl 4-[rac-(5R)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2- (trifluoromethyl)benzoate.

[0229] To a stirred solution of methyl 4-[(Z)-C-chloro-N-hydroxy-carbonimidoyl]-2- (trifluoromethyl) benzoate (crude) in DMF (50 mL) were added 1,3-dichloro-5-[1-(trifluoromethyl) vinyl] benzene (crude) and DIEA (4.70 g, 36.4 mmol) dropwise at rt. Then the resulting mixture was stirred at rt for 2 h. Upon completion of the reaction, H2O (1 L) was added and the mixture was extracted with EtOAc(3 x). The combined organic layer were washed with H2O, brine, dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (EtOAc / PE 1:4) to afford methyl 4-[rac-(5R)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3- yl]-2-(trifluoromethyl)benzoate. LC-MS (method A): Rt= 1.1 min; MS (ESI+): m / z = 486 (M+H)+. Step 5: 4-[rac-(5R)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2- (trifluoromethyl)benzoic acid.

[0230] To a solution of methyl 4-[rac-(5R)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol- 3-yl]-2-(trifluoromethyl) benzoate (2.00 g, 4.11 mmol) in THF (16 mL) was added LiOH (493 mg, 20.6 mmol) in H2O (8 mL) and the resulting mixture was stirred at 60℃ for 16 h. Upon completion of the reaction, the solvent was evaporated under reduced pressure and the pH was adjusted to 4 by addition of aqueous HCl (2 M). The aqueous layer was then extracted with EtOAc (2 x). The combined organic layers were washed with H2O (3 x), brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford 4-[rac-(5R)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2- (trifluoromethyl) benzoic acid. LC-MS (method A): Rt = 1.0 min; MS (ESI+): m / z = 472 (M+H)+. Step 6: N-(3,3-difluorocyclobutyl)-4-[rel-(5S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H- isoxazol-3-yl]-2-(trifluoromethyl) benzamide (Example 22a) and N-(3,3-difluorocyclobutyl)-4-[rel- (5R)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-(trifluoromethyl)benzamide (Example 22b).

[0231] To a stirred solution of 4-[rac-(5R)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol- 3-yl]-2-(trifluoromethyl) benzoic acid (200 mg, 0.42 mmol) in DMF (2 mL) were added HATU (193 mg, 0.51 mmol), DIEA (273 mg, 2.12 mmol) and 3,3-difluorocyclobutanamine (54.0 mg, 0.51 mmol). The resulting reaction mixture was stirred at rt for 1 h. Upon completion of the reaction, H2O was added, and the resulting mixture was extracted with EtOAc (3 x). The combined organic layers were washed with H2O, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo (35 ℃). The residue was purified by prep-TLC (EA / PE 1:3). The two enantiomers were separated by prep-chiral-HPLC [column: CHIRAL ART Cellulose-SJ 3*25 cm, 5µm; mobile phase A: CO2, mobile phase B: MeOH (1%-2M- NH3·MeOH); flow rate: 90 mL / min; gradient: isocratic 14% B; column temperature(℃): 35; back pressure(bar): 100; wave length: 220 nm; Rt1 = 3.6 min; Rt2 =4.3 min] to afford N-(3,3- difluorocyclobutyl)-4-[rel-(5S)-5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2- (trifluoromethyl)benzamide (19% yield) and N-(3,3-difluorocyclobutyl)-4-[rel-(5R)-5-(3,5- dichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]-2-(trifluoromethyl)benzamide (21% yield).

[0232] (Isomer 1) Example 22a: LC-MS (method J, 0.01-1.20 min 50-90% B, 1.20-1.80 min 90% B): Rt = 1.0 min; MS (ESI+): m / z = 561 (M+H)+.1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 9.09 (d,1H), 8.13-8.08 (m, 1H), 8.05 (s, 1H), 7.84-7.83 (m, 1H), 7.72 (d, 1H), 7.64-7.63 (m, 2H), 4.56-4.38 (m, 2H), 4.24-4.18 (m, 1H), 3.04-2.97 (m, 2H), 2.72-2.59 (m, 2H).

[0233] (Isomer 2) Example 22b: LC-MS (method J, 0.01-1.20 min 50-90% B, 1.20-1.80 min 90% B): Rt= 1.0 min; MS (ESI+): m / z = 561 (M+H)+. 1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 9.09 (d, 1H), 8.13-8.08 (m, 1H), 8.05 (s, 1H), 7.84-7.83 (m, 1H), 7.72 (d, 1H), 7.64-7.63 (m, 2H), 4.56-4.38 (m, 2H), 4.24-4.18 (m, 1H), 3.06-2.95 (m, 2H), 2.72-2.59 (m, 2H). Example 23 N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5S)-5-[5-chloro-3-(1,1-difluoroethyl)-2-fluoro-phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]benzamide (Example 23a) and N-(3,3-difluorocyclobutyl)-2- methyl-4-[rel-(5R)-5-[5-chloro-3-(1,1-difluoroethyl)-2-fluoro-phenyl]-5-(trifluoromethyl)-4H- isoxazol-3-yl]benzamide (Example 23b).1a and 1b.

[0235] (Isomer 1) Example 23a: LC-MS (method D, 0.01-2.00 min 5-100% B): Rt= 1.2 min; MS (ESI+): m / z = 555 (M+H)+.1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.82 (d, 1H), 7.85-7.79 (m, 2H), 7.67-7.65 (m, 2H), 7.46 (d, 1H), 4.54-4.54 (m, 1H), 4.34 (d, 1H), 4.27-4.18 (m, 1H), 2.99-2.94 (m, 2H), 2.72-2.66 (m, 2H), 2.38 (s, 3H), 2.05 (t, 3H).

[0236] (Isomer 2) Example 23b: LC-MS (method D, 0.01-1.20 min 5-100% B; 1.20-1.80 min 100% B): Rt= 1.2 min; MS (ESI+): m / z = 555 (M+H)+.1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.82 (d, 1H), 7.85-7.79 (m, 2H), 7.68-7.65 (m, 2H), 7.46 (d, 1H), 4.54-4.53 (m, 1H), 4.34 (d, 1H), 4.27-4.18 (m, 1H), 3.01-2.94 (m, 2H), 2.74-2.66 (m, 2H), 2.38 (s, 3H), 2.05 (t, 3H). Example 24 N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5S)-5-[3-chloro-5-(1,1-difluoroethyl)-2-fluoro-phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl] benzamide (Example 24a) and N-(3,3-difluorocyclobutyl)-2- methyl-4-[rel-(5R)-5-[3-chloro-5-(1,1-difluoroethyl)-2-fluoro-phenyl]-5-(trifluoromethyl)-4H- isoxazol-3-yl]benzamide (Example 24b).[ s 1a and 1b.

[0238] (Isomer 1) Example 24a: LC-MS (method D, 0.01-1.20 min 5-100% B; 1.20-1.80 min 100% B): Rt= 1.2 min; MS (ESI+): m / z = 555 (M+H)+.1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.82 (d, 1H), 8.07-8.05 (m, 1H), 7.79-7.77 (m, 1H), 7.68-7.65 (m, 2H), 7.46 (d, 1H), 4.57-4.56 (m, 1H), 4.37 (d, 1H), 4.25-4.21 (m, 1H), 3.03-2.92 (m, 2H), 2.76-2.63 (m, 2H), 2.38 (s, 3H), 2.04 (t, 3H).

[0239] (Isomer 2) Example 24b: LC-MS (method D, 0.01-1.20 min 5-100% B; 1.20-1.80 min 100% B): Rt = 1.2 min; MS (ESI+): m / z = 555 (M+H)+.1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.82 (d, 1H), 8.07-8.05 (m, 1H), 7.79-7.77(m, 1H), 7.68-7.65 (m, 2H), 7.46 (d, 1H), 4.56-4.51 (m, 1H), 4.37 (d, 1H), 4.27-4.19 (m, 1H), 3.02-2.92 (m, 2H), 2.76-2.63 (m, 2H), 2.38 (s, 3H), 2.04 (t, 3H). Example 25 N-(3,3-difluorocyclobutyl)-2-methyl-4-[rel-(5S)-5-[3-chloro-5-(difluoromethyl) phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]benzamide (Example 25a) and N-(3,3-difluorocyclobutyl)-2- methyl-4-[rel-(5R)-5-[3-chloro-5-(difluoromethyl) phenyl]-5-(trifluoromethyl)-4H-isoxazol-3- yl]benzamide (Example 25b).7a and 7b.

[0241] (Isomer 1) Example 25a: LC-MS (method D, 0.01-1.20 min 5-100% B; 1.20-1.80 min 100% B): Rt= 1.1 min; MS (ESI+): m / z = 523 (M+H)+.1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.81 (d, 1H), 7.82 (s, 2H), 7.78 (s, 1H), 7.64-7.62 (m, 2H), 7.47 (d, 1H), 7.15 (t, 1H), 4.44 (d, 1H), 4.30 (d, 1H), 4.28-4.21 (m, 1H), 3.02-2.92 (m, 2H), 2.76-2.62 (m, 2H), 2.37 (s, 3H).

[0242] (Isomer 2) Example 25b: LC-MS (method D, 0.01-1.20 min 5-100% B; 1.20-1.80 min 100% B): Rt = 1.1 min; MS (ESI+): m / z = 523 (M+H)+.1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 8.81 (d,1H), 7.83 (s, 2H), 7.78 (s, 1H), 7.64-7.62 (m, 2H), 7.47 (d, 1H), 7.15 (t, 1H), 4.44 (d, 1H), 4.30 (d, 1H), 4.28-4.21 (m, 1H), 3.00-2.93 (m, 2H), 2.72-2.66 (m, 2H), 2.37 (s, 3H). Example 26 (S)-6-(5-(5-chloro-2-fluoro-3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3- yl)-N-(3,3-difluorocyclobutyl)-4-methylnicotinamide (Example 26a) and (R)-6-(5-(5-chloro-2-fluoro- 3-(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-N-(3,3- difluorocyclobutyl)-4-methylnicotinamide (Example 26b)

[0243] To a stirred solution of methyl 6-chloro-4-methyl-pyridine-3-carboxylate (5 g, 26.94 mmol) and potassium vinyltrifluoroborate (4.33 g, 32.33 mmol) in dioxane (1,4) (50 mL) and H2O (5 mL) was added Pd(dppf)Cl2(2.20 g, 2.69 mmol) and potassium carbonate (7.45 g, 53.88 mmol, 3.25 mL) at rt under nitrogen atmosphere. The reaction was stirred at 80°C for 3hr. The resulting mixture was extracted with EtOAc and H2O. The combined organic layers were washed with saturated NaCl solution, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with [PE: EtOAc =3:1] to afford methyl 4-methyl-6-vinyl-pyridine-3-carboxylate (4.2 g, 23.70 mmol, 87.99 % yield) as a yellow solid. Step 2: methyl 6-formyl-4-methyl-pyridine-3-carboxylate

[0244] To a stirred solution of methyl 4-methyl-6-vinyl-pyridine-3-carboxylate (4.2 g, 23.70 mmol) in THF (30 mL) and MeCN (60 mL) at rt under N2 atmosphere. To the above solution was added the mixture of NaIO4 (25.35 g, 118.51 mmol) and H2O (30 ml) and Potassium osmate (VI) dihydrate (873.33 mg, 2.37 mmol) and H2O (30 ml) in sequence. The reaction was stirred at rt for 2hr. The resulting mixture was filtered; the filter cake was washed with EtOAc. The filtrate was extracted with EtOAc and H2O. The combined organic layers were washed with NaCl saturated solution, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with [PE: EtOAc =3:1] to afford methyl 6-formyl-4-methyl- pyridine-3-carboxylate (960 mg, 5.36 mmol, 22.61 % yield) as a white solid.Step 3: Methyl 6-[(E)-hydroxyiminomethyl]-4-methyl-pyridine-3-carboxylate

[0245] To a stirred solution of methyl 6-formyl-4-methyl-pyridine-3-carboxylate (960 mg, 5.36 mmol) in EtOH (20.04 mL) was added Hydroxylamine hydrochloride (372.33 mg, 5.36 mmol, 222.95 μL) and Sodium acetate anhydrous (439.51 mg, 5.36 mmol, 287.64 μL) at rt for 3hr. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc and H2O. The combined organic layers were washed with NaCl saturated solution, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by trituration with n-Hexane:EtOAc=10:1 to get methyl 6-[(E)-hydroxyiminomethyl]-4-methyl-pyridine-3- carboxylate (840 mg, 4.33 mmol, 80.73 % yield) as an off-white solid. Step 4: 4-fluoro-3-(trifluoromethyl)-5-[1-(trifluoromethyl)vinyl]aniline

[0246] To a solution of 3-bromo-4-fluoro-5-(trifluoromethyl)aniline (2 g, 7.75 mmol)，4,4,6- trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane (1.72 g, 7.75 mmol) was added THF (10 mL), H2O (10 mL). The reaction mixture was stirred 2 h at 80 °C. The reaction mixture was partitioned between ethyl acetate and H2O. the aqueous layer was extracted with EA three times. The combined organic layers were washed with brine, dried over Na2SO4and then was concentrated under reduced pressure. The residue was purified with flash chromatography eluting with 0 to 25 EtOAc in PE to get 4- fluoro-3-(trifluoromethyl)-5-[1-(trifluoromethyl)vinyl]aniline (1.25 g, 4.58 mmol, 59.04% yield). Step 5: Methyl 6-[5-[5-amino-2-fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol- 3-yl]-4-methyl-pyridine-3-carboxylate

[0247] To a stirred solution of methyl 6-[(E)-hydroxyiminomethyl]-4-methyl-pyridine-3- carboxylate (760 mg, 3.91 mmol) in DMF (8 mL) was added NCS (627.14 mg, 4.70 mmol, 380.08 μL) at rt in dark under nitrogen atmosphere. Resulting reaction mixture was stirred at 40°C for 1hr. After chloro intermediate formation, to the above solution was slowly added 4-fluoro-3-(trifluoromethyl)-5-[1- (trifluoromethyl)vinyl]aniline (1.07 g, 3.91 mmol) (dissolved in 3 mL DMF) and DIEA (1.52 g, 11.74 mmol) (dissolved in 3 mL DMF) sequentially at 0°C in dark under nitrogen atmosphere. The reaction was stirred at rt in dark under nitrogen atmosphere. The resulting mixture was extracted with EtOAc and H2O. The combined organic layers were washed with NaCl saturated solution, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC (PE: EtOAc =4:1) to afford methyl 6-[5-[5-amino-2-fluoro-3-(trifluoromethyl)phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]-4-methyl-pyridine-3-carboxylate (630 mg, 1.35 mmol, 34.59 % yield) as a yellow solid. Step 6: 6-[5-[5-amino-2-fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-4- methyl-pyridine-3-carboxylic acid

[0248] 4H-isoxazol-3-yl]-4-methyl-pyridine-3-carboxylate (620.00 mg, 1.33 mmol) in THF (4 mL) and H2O (4 mL) was added LiOH (159.55 mg, 6.66 mmol) at rt for 2hr. The mixture was acidified to pH 6~7 with 1M HCl solution. The resulting mixture was extracted with EtOAc and H2O. The combined organic layers were washed with NaCl saturated solution, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to get 6-[5-[5-amino-2-fluoro-3- (trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-4-methyl-pyridine-3-carboxylic acid (560 mg, crude) as a yellow solid. Step 7: 6-[5-[5-chloro-2-fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-4- methyl-pyridine-3-carboxylic acid

[0249] To a stirred solution of 6-[5-[5-amino-2-fluoro-3-(trifluoromethyl)phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]-4-methyl-pyridine-3-carboxylic acid (510.00 mg, 1.13 mmol) in AcOH (6 mL) and HCl (1.5 mL) was added NaNO2 (101.36 mg, 1.47 mmol, 46.75 μL) (dissolved in 0.1 mL H2O)at 0°C under N2. After a while, to the above solution was added CuCl (223.75 mg, 2.26 mmol) at 0°C under N2. The reaction was stirred at rt for 4 hr. The resulting mixture was extracted with EtOAc and H2O. The combined organic layers were washed with NaCl saturated solution, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE: EtOAc =1:1) to afford 6-[5-[5-chloro-2-fluoro-3- (trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-4-methyl-pyridine-3-carboxylic acid (212 mg, 450.37 μmol, 39.85 % yield) as a white solid. Step 8: 6-[5-[5-chloro-2-fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]-N- (3,3-difluorocyclobutyl)-4-methyl-pyridine-3-carboxamide

[0250] To a stirred solution of 6-[5-[5-chloro-2-fluoro-3-(trifluoromethyl)phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]-4-methyl-pyridine-3-carboxylic acid (106.00 mg, 225.18 μmol) 3,3- difluorocyclobutanamine (24.12 mg, 225.18 μmol) and HATU (102.75 mg, 270.22 μmol) in DMF (0.8 mL) was added DIEA (87.31 mg, 675.55 μmol) at rt for 2hr. The resulting mixture was extracted with EtOAc and H2O. The combined organic layers were washed with NaCl saturated solution, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE: EtOAc =4:1) to afford 6-[5-[5-chloro-2-fluoro-3-(trifluoromethyl)phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]-N-(3,3-difluorocyclobutyl)-4-methyl-pyridine-3-carboxamide (95 mg, 169.70 μmol, 75.36 % yield) as a white solid. Step 9:

[0251] The crude product 6-[5-[5-chloro-2-fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)- 4H-isoxazol-3-yl]-N-(3,3-difluorocyclobutyl)-4-methyl-pyridine-3-carboxamide (95.00 mg, 169.70μmol) was further purified by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.1% FA)--HPLC, Mobile Phase B: MeOH: DCM=1: 1-- HPLC; Flow rate: 20ML / MIN mL / min; Gradient (B%): isocratic 5; Wave Length: 254 / 220nm nm; RT1(min): 12.209; RT2(min): 15.387; Sample Solvent: EtOH--HPLC; Injection Volume: 0.4 mL; Number Of Runs: 9 to afford N-(3,3-difluorocyclobutyl)-4-methyl-6-[rel-(5S)-5-[5-chloro-2-fluoro-3- (trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyridine-3-carboxamide (26.5 mg, 47.10 μmol, 27.76 % yield, 99.5% purity) (Example 26a) as a white solid and N-(3,3-difluorocyclobutyl)-4- methyl-6-[rel-(5R)-5-[5-chloro-2-fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3- yl]pyridine-3-carboxamide (27.2 mg, 46.94 μmol, 27.66 % yield, 96.6 % purity) (Example 26b) as a white solid.

[0252] 1H NMR (400 MHz, DMSO) δ 9.04 (d, J = 6.4 Hz, 1H), 8.63 (s, 1H), 8.15 (dd, J = 6.0, 2.6 Hz, 1H), 8.05 (dd, J = 6.0, 2.7 Hz, 1H), 7.91 (s, 1H), 4.48 – 4.33 (m, 2H), 4.31 – 4.21 (m, 1H), 3.05 – 2.92 (m, 1H), 2.80 – 2.67 (m, 1H), 2.43 (s, 3H).

[0253] LC-MS (Method E): Rt = 2.653 and 3.129 min; MS (ESI+): m / z = 559.85 (M+H)+. Example 27 N-[(3,3-difluorocyclobutyl)methyl]-4-methyl-6-[rel-(5S)-5-[5-chloro-2-fluoro-3- (trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyridine-3-carboxamide (Example 27a) and N-[(3,3-difluorocyclobutyl)methyl]-4-methyl-6-[rel-(5R)-5-[5-chloro-2-fluoro-3- (trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyridine-3-carboxamide (Example 27b) O-N- [(3,3-difluorocyclobutyl)methyl]-4-methyl-pyridine-3-carboxamide

[0254] To a stirred solution of 6-[5-[5-chloro-2-fluoro-3-(trifluoromethyl)phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]-4-methyl-pyridine-3-carboxylic acid (110.00 mg, 233.68 μmol) ,(3,3- difluorocyclobutyl)methanamine (28.31 mg, 233.68 μmol) and HATU (106.62 mg, 280.42 μmol) in DMF (1.5 mL) was added DIEA (90.60 mg, 701.05 μmol) at 0°C. The reaction was stirred at rt for 1hr. The resulting mixture was extracted with EtOAc and H2O. The combined organic layers were washed with NaCl saturated solution, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated underreduced pressure. The residue was purified by silica gel column chromatography, eluted with [PE: EtOAc =2:1] to get 6-[5-[5-chloro-2-fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol- 3-yl]-N-[(3,3-difluorocyclobutyl)methyl]-4-methyl-pyridine-3-carboxamide (130 mg, crude) as a white solid. Step 2: Separation of enantiomers

[0255] The crude product 6-[5-[5-chloro-2-fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)- 4H-isoxazol-3-yl]-N-[(3,3-difluorocyclobutyl)methyl]-4-methyl-pyridine-3-carboxamide (130.00 mg, 226.54 μmol) was further purified by Chiral-HPLC with the following conditions：Column: CHIRALPAK IH, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL / min; Gradient (B%): isocratic 10; Wave Length: 254 / 220 nm; RT1(min): Rt: 1.793; RT2(min): Rt: 1.307; Sample Solvent: EtOH--HPLC; Injection Volume: 0.4 mL; Number Of Runs: 9 to afford N-[(3,3-difluorocyclobutyl)methyl]-4-methyl-6-[rel-(5S)-5-[5-chloro- 2-fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyridine-3-carboxamide (31.0 mg, 53.70 μmol, 23.70 % yield, 99.4% purity) (Example 27a) as a white solid and N-[(3,3- difluorocyclobutyl)methyl]-4-methyl-6-[rel-(5R)-5-[5-chloro-2-fluoro-3-(trifluoromethyl)phenyl]-5- (trifluoromethyl)-4H-isoxazol-3-yl]pyridine-3-carboxamide (32.2 mg, 55.27 μmol, 24.40 % yield, 98.5% purity) (Example 27B) as a white solid.

[0256] 1H NMR (400 MHz, DMSO) δ 8.72 (t, J = 5.8 Hz, 1H), 8.58 (s, 1H), 8.15 (dd, J = 5.7, 2.6 Hz, 1H), 8.05 (dd, J = 5.8, 2.7 Hz, 1H), 7.91 (s, 1H), 4.48 – 4.33 (m, 2H), 3.41 (t, J = 5.8 Hz, 2H), 2.64 – 2.60 (m, 2H), 2.48 – 2.32 (m, 6H).

[0257] LC-MS (Method A): Rt = 1.307 and 1.793 min; MS (ESI+): m / z = 571.05 (M+H)+. Example 28 N-(3,3-difluorocyclobutyl)-4-methyl-1-oxido-6-[rel-(5S)-5-[5-chloro-2-fluoro-3- (trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyridin-1-ium-3-carboxamide (Example 28a) and N-(3,3-difluorocyclobutyl)-4-methyl-1-oxido-6-[rel-(5R)-5-[5-chloro-2-fluoro-3- (trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyridin-1-ium-3-carboxamide (Example 28b) F O FStep 1:

[0258] To a solution of N-(3,3-difluorocyclobutyl)-4-methyl-6-[rel-(5S)-5-[5-chloro-2-fluoro-3- (trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyridine-3-carboxamide (20 mg, 35.73 μmol) (Example 1a) in DCM (5 mL) was added 3-chloroperoxybenzoic acid (61.65 mg, 357.26 μmol) at 0 °C. The reaction mixture was stirred for 48hr at rt. The resulting mixture was extracted with DCM and water. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 30 mg of crude product. The crude product was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water(10 mmol / LNH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 50% B to 80 % B in 10 min; Wave Length: 254 nm / 220 nm; RT1(min): 7.18 to afford N-(3,3-difluorocyclobutyl)-4-methyl-1-oxido-6-[rel-(5S)-5-[5-chloro-2-fluoro-3- (trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3-yl]pyridin-1-ium-3-carboxamide (8.9 mg, 15.41 μmol, 43.13 % yield, 99.7% purity) (Example 28a) as a white solid.

[0259] Synthesis similar to experiment described above, starting with of N-(3,3-difluorocyclobutyl)- 4-methyl-6-[rel-(5S)-5-[5-chloro-2-fluoro-3-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4H-isoxazol-3- yl]pyridine-3-carboxamide (Example 28b).

[0260] 1H NMR (400 MHz, DMSO) δ 9.12 (d, J = 6.0 Hz, 1H), 8.46 (s, 1H), 8.16 (d, J = 6.0 Hz, 1H), 8.03 (d, J = 6.0 Hz, 1H), 7.78 (s, 1H), 4.67 (d, J = 18.8 Hz, 1H), 4.62 (d, J = 18.8 Hz, 1H), 4.48 (s, 1H), 4.43 (s, 1H), 4.24 – 4.15 (m, 1H), 3.02 – 2.94 (m, 2H), 2.81 – 2.64 (m, 2H), 2.33 (s, 3H).

[0261] LCMS m / z: 576.10 (M+H)+ / Method A. Example 29

[0262] The activity of the compounds of the invention may be determined by a variety of methods, including in vitro and in vivo methods. Example A: In vitro evaluation of ingestion activity against adult cat fleas

[0263] To prepare the test blood mixture for feeding fleas, the test substance is dissolved in dimethyl sulphoxide and diluted with citrated cattle blood to the desired concentration. To assemble the test set-up, about 20 unfed adult male and female cat fleas (Ctenocephalides felis) are placed into a chamber which is closed at the top and bottom with gauze. A metal cylinder is sealed at one end with parafilm membrane, placed with the sealed base onto the chamber, and filled with the test blood mixture, which can be imbibed by the fleas through the parafilm membrane. The blood cylinder part of the assembled test set-up is contained at about 37 °C in an isolated air heated container above the isolating carrier plate holding the flea chambers. The flea chamber part is kept at rt. After 48 h, insecticidal activity against fleas is determined.100% means that all of the fleas have been killed or rendered moribund; 0% means that noneof the fleas have been affected at the dose administered. From a dose response curve the respective EC50was calculated (4-parameter logistic curve fitting). A substance shows good insecticidal activity against Ctenocephalides felis if the EC50is below an application rate of 20 ppm.

[0264] In this test for example, the following compounds from the preparation examples showed EC50 < 1 ppm: Examples 1a, 2, 3, 4, 5a, 6a, 7a, 8a, 9a, 10a, 11, 12, 13a, 14a, 15a 17a, 20a, 21a, 22b, 23a, 24a, 25a, 26a, 27a, and 28a.

[0265] In this test for example, the following compounds from the preparation examples showed EC50 < 20 ppm: Examples 1a, 2, 3, 4, 5a, 5b, 6a, 6b, 7a, 8a, 9a, 9b, 10a, 11, 12, 13a, 14a, 14b, 15a, 16a, 17a, 18b, 19a, 20a, 21a, 22a, 22b, 23a, 24a, 25a, 26a, 27a, 27b, 28a, and 28b.

[0266] For the data above, where single isomers were tested, without knowing the absolute configuration of the isomer, the data indicates that the test article is one isomer or another, for example, Example 1a or its enantiomer. Example B: In vitro evaluation of contact activity against adult Brown Dog ticks

[0267] In vitro contact tests with ticks are conducted with adult males and females of Rhipicephalus sanguineus. For the coating of the test vials, the test substance is dissolved and diluted in acetone p.a. to the desired concentration. The solution is then homogeneously applied to the inner walls and base of a glass vial by turning and rocking on an orbital shaker until complete evaporation of the solvent. For example, with 900 ppm solution of test substance an area-based dose of 5 µg / dm² is achieved. After the solvent is completely evaporated, 5 -10 adult ticks are applied to each coated test vial, which is then sealed with a perforated plastic lid and incubated in a horizontal position in the dark at rt and ambient humidity. Acaricidal activity is determined after 48 h. For this, ticks are moved to the base of the test vial by gentle knocking, and test vials are then incubated on a hotplate at 45-50°C for no longer than 5 min. Ticks which remain motionless on the base of the test vial or move uncoordinated without deliberately climbing up to avoid the heat are considered dead or moribund, respectively. An acaricidal activity of 100% means all ticks were dead or moribund. An acaricidal activity of 0% means none of the ticks was found dead or moribund. From a dose response curve, the respective EC50 was calculated (4-parameter logistic curve fitting). A substance shows good acaricidal activity against Rhipicephalus sanguineus if the EC50 is below an application rate of 5 µg / dm².

[0268] In this test for example, the following compounds from the preparation examples showed EC50 < 0.25 µg / dm2: Examples 1a, 11, 27a, and 28a.

[0269] In this test for example, the following compounds from the preparation examples showedEC50< 5µg / dm2: Examples 1a, 2, 3, 11, 26a, 27a, and 28a.

[0270] For the data above, where single isomers were tested, without knowing the absolute configuration of the isomer, the data indicates that the test article is one isomer or another, for example, Example 1a or its enantiomer. Example C: In vitro evaluation of systemic activity against female engorged Cattle ticks

[0271] To prepare the test compound mixture for injecting ticks, the test substance is dissolved in dimethyl sulphoxide and diluted with the same solvent to the desired concentration.1 µl of the test mixture is injected into each abdomen of 5 engorged adult female cattle ticks (Rhipicephalus (Boophilus) microplus). The ticks are individually transferred into the single compartments of 5x5 replica plates and kept in a climate-controlled chamber (28°C, 85% rel. hum.). Acaricidal activity against cattle ticks is assessed after 7 days by assessment of laid fertile eggs. Eggs which do not appear normal may be stored in a climate-controlled cabinet (28°C, 85% rel h.) until larval hatch after 42 days. An acaricidal activity of 100% means that none of the ticks has laid eggs or laid eggs were infertile; 0% means that all the eggs are fertile. From a dose response curve, the respective EC50 was calculated (4-parameter logistic curve fitting). A substance shows good systemic acaricidal activity against Rhipicephalus microplus if the EC50 is below an application rate of 10 µg / tick.

[0272] In this test for example, the following compounds from the preparation examples showed EC50 < 0.04 µg / tick: Examples 1a, 2, 3, 5a, 6a,7a, 8a, 9a, 10a, 17a, 19a, 20a, 21a, 22a, 22b, 23a, 24a, 25a, 26a, 27a, and 28a.

[0273] In this test for example, the following compounds from the preparation examples showed EC50< 0.5 µg / tick: Examples 1a, 2, 3, 5a, 6a, 7a, 8a, 9a,10a, 13a,17a, 18a, 19a, 20a, 21a, 22a, 22b, 23a, 24a, 25a, 26a, 27a, and 28a.

[0274] For the data above, where single isomers were tested, without knowing the absolute configuration of the isomer, the data indicates that the test article is one isomer or another, for example, Example 1a or its enantiomer. Example D: PK determination following administration to beagle dogs

[0275] Behavior of single oral or intravenous dose of the desired compound was assessed in beagle dogs. The animals (n = 3) received the compound by oral gavage (1 mg / kg) or intravenous dose (0.2 mg / kg). Blood samples were collected at (2, 5, 15), 30 minutes and 1, 2, 4, 8, 12, 24, 48, 72, 96, 168, 336, 504, 672, 1032, 1344, 1680, 2016, 2352, 2688, 3024 h post dose. A portion of each whole blood sample was processed to plasma. Test article concentrations in plasma and whole blood were determined using LC-MS / MS.

[0276] In this test for example, the following compounds from the preparation examples showed t1 / 2 > 50 d: Example 2.

[0277] Many modifications and variations of the embodiments described herein may be made without departing from the scope, as is apparent to those skilled in the art. The specific embodiments described herein are offered by way of example only.

Claims

1. CLAIMS What is claimed is:

1. A compound of formula (I): or an is 0 or 1; each of Y1, Y2, Y3, and Y4is independently selected from the group consisting of –H, –CN, –CH3, –CH2F, –CHF2, –CF3, and halo; and each of X1, X2, and X3is independently C, N, or N+-O-.

2. A compound of formula (I-i): or an is 0 or 1; each of Y1, Y2, Y3, and Y4is independently selected from the group consisting of –H, – CN, –CH3, –CH2F, –CHF2, –CF3, and halo; and each of X1, X2, and X3is independently C or N.

3. The compound of claim 1 or 2, wherein at least two of Y1, Y2, Y3, and Y4are not –H.

4. The compound of claim 1 or 2, wherein at least three of Y1, Y2, Y3, and Y4are not –H.

5. The compound of any one of claims 1-4, wherein at least two of X1, X2, and X3are C.

6. The compound of any one of claims 1-4, wherein each of X1, X2, and X3are C.

7. The compound of any one of claims 1-6, wherein at least one of Y1, Y2, Y3, and Y4is a halo.

8. The compound of claim 7, wherein the halo is –Cl.

9. The compound of claim 7, wherein the halo is –F.

10. The compound of any one of claims 1-6, wherein at least two of Y1, Y2, Y3, and Y4is each independently a halo.

11. The compound of claim 10, wherein the at least two of Y1, Y2, Y3, and Y4is –Cl or –F.

12. The compound of claim 10, wherein one of Y1, Y2, Y3, and Y4is –Cl and one of Y1. Y2, Y3, and Y4is –F.

13. The compound of any one of claims 1-12, wherein n is 0.

14. The compound of any one of claims 1-12, wherein n is 1.

15. The compound of claim 1 or 2, wherein the compound is of formula (I-A): A) or an is 0 or 1; each of X1, X2, and X3is independently C or N; and each of Y1, Y3, and Y4is independently selected from the group consisting of –CN, –CH3, –CH2F, –CHF2, –CF3, and halo.

16. The compound of claim 15, wherein at least two of X1, X2, and X3are C.

17. The compound of claim 15 or 16, wherein each of X1, X2, and X3are C.

18. The compound of any one of claims 15-17, wherein at least one of Y1, Y3, and Y4is a halo.

19. The compound of claim 18, wherein the halo is –Cl.

20. The compound of claim 18, wherein the halo is –F.

21. The compound of any one of claims 15-18, wherein at least two of Y1, Y3, and Y4is a halo.

22. The compound of claim 21, wherein the at least two of Y1, Y3, and Y4is –Cl or –F.

23. The compound of claim 21, wherein one of Y1, Y3, and Y4is –Cl and one of Y1, Y3, and Y4is –F.

24. The compound of any one of claims 15-23, wherein at least one of Y1, Y3, and Y4is –CF3.

25. The compound of any one of claims 15-24, wherein one of Y1, Y3, and Y4is –CF3, one of Y1, Y3, and Y4is –Cl, and one of Y1, Y3, and Y4is –F.

26. The compound of any one of claims 15-25, wherein n is 0.

27. The compound of any one of claims 15-25, wherein n is 1.

28. The compound of claim 1 or 2, wherein the compound is of formula (I-B): (I-B)or a pharmaceutically n is 0 or 1; X2is independently N or N+-O-.

29. The compound of claim 28, wherein X2is N.

30. The compound of any one of claims 28, wherein X2is N+-O-.

31. The compound of any one of claims 28-30, wherein n is 0.

32. The compound of any one of claims 28-30, wherein n is 1.

33. A compound selected from Table A, or a pharmaceutically acceptable salt thereof.

34. The compound of any one of claims 1 to 33, wherein the compound is an (S)-enantiomer.

35. The compound of any one of claims 1 to 34, wherein the compound is in a non-salt form.

36. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, or the compound of claim 35 and one or more pharmaceutically acceptable carriers or vehicles.

37. A method of treating a parasitic disease in a subject comprising administering to the subject the compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, the compound of claim 35 or the pharmaceutical composition of claim 36.

38. A method of treating or lessening the severity in a subject of a parasitic infection comprising administering to the subject an effective amount of the compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, the compound of claim 35 or the pharmaceutical composition of claim 36.

39. The method of claim 37, wherein the subject is a non-human animal.

40. Use of the compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, the compound of claim 35, or the pharmaceutical composition of claim 36, as a medicament.

41. Use of the compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt thereof, the compound of claim 35, or the pharmaceutical composition of claim 36 in the manufacture of a medicament for the treatment of a parasitic disease.

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