Patent Description:
Voltage-dependent potassium (Kv) channels conduct potassium ions (K+) across cell membranes in response to changes in the membrane potential and can thereby regulate cellular excitability by modulating (increasing or decreasing) the electrical activity of the cell. Functional Kv channels exist as multimeric structures formed by the association of four alpha and four beta subunits. The alpha subunits comprise six transmembrane domains, a pore-forming loop and a voltage-sensor and are arranged symmetrically around a central pore. The beta or auxiliary subunits interact with the alpha subunits and can modify the properties of the channel complex to include, but not be limited to, alterations in the channel's electrophysiological or biophysical properties, expression levels or expression patterns.

Nine Kv channel alpha subunit families have been identified and are termed Kv1-Kv9. As such, there is an enormous diversity in Kv channel function that arises as a consequence of the multiplicity of sub-families, the formation of both homomeric and heteromeric subunits within sub-families and the additional effects of association with beta subunits (<NPL>).

The Kv7 channel family consists of at least five members which include one or more of the following mammalian channels: Kv7. <NUM>, Kv7. <NUM>, Kv7. <NUM>, Kv7. <NUM>, Kv7. <NUM> and any mammalian or non-mammalian equivalent or variant (including splice variants) thereof. Alternatively, the members of this family are termed by the gene name KCNQ1, KCNQ2, KCNQ3, KCNQ4 and KCNQ5 respectively (<NPL>).

As mentioned above, the neuronal Kv7 potassium channels play roles in controlling neuronal excitation. Kv7 channels, in particular Kv7. <NUM> heterodimers, underlie the M-current (<NPL>). The M-current has a characteristic time- and voltage-dependence that results in stabilisation of the membrane potential in response to multiple excitatory stimuli.

In this way, the M-current is involved in controlling neuronal excitability (<NPL>). The M-current is a non-inactivating potassium current found in many neuronal cell types. In each cell type, it is dominant in controlling membrane excitability by being the only sustained current in the range of action potential initiation (<NPL>).

Retigabine (N-(<NUM>-amino-<NUM>-(<NUM>-fluorobenzylamino)-phenyl) carbamic acid ethyl ester) is a compound which binds to the Kv7 potassium channels (<NPL>). Retigabine activates K+ current in neuronal cells and the pharmacology of this induced current displays concordance with the published pharmacology of the M-channel that has been correlated to the Kv7. <NUM>/<NUM>+ channel heteromultimer which suggests that activation of Kv7. <NUM>/<NUM> channels is responsible for at least some of the anticonvulsant activity of this agent (<NPL>). Retigabine is effective in reducing the incidence of seizures in epileptic patients (<NPL>). Retigabine has a broad spectrum and potent anticonvulsant properties. It is active after oral and intraperitoneal administration in rats and mice in a range of anticonvulsant tests (<NPL>).

The five members of this family differ in their expression patterns. The expression of Kv7. <NUM> is restricted to the heart, peripheral epithelial and smooth muscle, whereas the expression of Kv7. <NUM>, Kv7. <NUM>, Kv7. <NUM> and Kv7. <NUM> appear to be dominant in the nervous system which includes the hippocampus, cortex, ventral tegmental area, and dorsal root ganglion neurons (for a review see <NPL>).

The KCNQ2 and KCNQ3 genes appear to be mutated in an inherited form of epilepsy known as benign familial neonatal convulsions (<NPL>). The proteins encoded by the KCNQ2 and KCNQ3 genes are localised in the pyramidal neurons of the human cortex and hippocampus, regions of the brain associated with seizure generation and propagation (<NPL>).

Furthermore, mRNA for Kv7. <NUM> and <NUM>, in addition to that for Kv7. <NUM>, are expressed in astrocytes and glial cells. <NUM>, Kv7. <NUM> and Kv7. <NUM> channels may help modulate synaptic activity in the CNS and contribute to the neuroprotective effects of KCNQ channel openers (<NPL>), which would be relevant for the treatment of neurodegenerative disorders such as but not limited to Alzheimer's disease, Parkinson's disease and Huntington's chorea.

mRNA for Kv7. <NUM> and Kv7. <NUM> subunits are found in brain regions associated with anxiety and emotional behaviours such as depression and bipolar disorder e.g. hippocampus, ventral tegmental area and amygdala (<NPL>; <NPL>. ), and retigabine is reportedly active in animal models of anxiety-like behaviour (<NPL>. As such Kv7 channels are relevant for the treatment of emotional related disorders such as but not limited to bipolar depression, major depression, anxiety, suicide, panic attacks, social phobia.

<NUM>/<NUM> channels have also been reported to be upregulated in models of neuropathic pain (<NPL>), and potassium channel modulators have been hypothesised to be active in both neuropathic pain and epilepsy (<NPL>). In addition to a role in neuropathic pain, the expression of mRNA for Kv7. <NUM>-<NUM> in the trigeminal and dorsal root ganglia and in the trigeminal nucleus caudalis implies that openers of these channels may also affect the sensory processing of migraine pain (<NPL>). Taken together, this evidence points to the relevance of KCNQ channel openers for the treatment of chronic pain and neuropathy related disorders.

<CIT> relates to the use of Kv7 channel openers for the treatment of schizophrenia. Kv7 channel openers modulate the function of the dopaminergic system (<NPL>; <NPL>; <NPL>; <NPL>. ; <NPL>) which would be relevant for the treatment of psychiatric disorders such as but not limited to psychosis, mania, stress-related disorders, acute stress reactions, attention deficit/hyperactivity disorder, posttraumatic stress disorder, obsessive compulsive disorder, impulsivity disorders, personality disorders, schizotypical disorder, aggression, autism spectrum disorders. <CIT> discloses the use of modulators of the M-current formed by expression of KCNQ2 and KCNQ3 genes for insomnia, while <CIT> discloses that modulators of Kv7. <NUM> can be utilized for the treatment of sleep disorders. <CIT> discloses the use of Kv7 openers in the treatment of sexual dysfunction.

<CIT> relates to <NUM>-morpholino-<NUM>-amido-pyridine derivatives and discloses their use as modulators of voltage gated Kv7 channels.

<CIT> relates to quinazolinone derivatives and discloses their use as activators of Kv7 channels.

<CIT> relates to benzoimidazol-<NUM>,<NUM>-yl amides and discloses their ability to potentiate K-currents in Kv7. <NUM>/<NUM> containing HEK cells.

<CIT> relates to imidazo(<NUM>,<NUM>-B) pyridin-<NUM>-yl amides and discloses their ability to potentiate K-currents in Kv7. <NUM>/<NUM> containing HEK cells.

<CIT> relates to <NUM>-(<NUM>,<NUM>-Diazepane-<NUM>-sulfonyl) isoquinoline and discloses its use as a selective Kv7. <NUM> and Kv7. <NUM>/<NUM> ion channel activator.

Although patients suffering from the above mentioned disorders may have available treatment options, many of these options lack the desired efficacy and are accompanied by undesired side effects. Therefore, an unmet need exists for novel therapies for the treatment of said disorders.

In an attempt to identify new therapies, the inventors have identified a series of novel compounds as represented by Formula I which act as Kv7. <NUM>, Kv7. <NUM>, Kv7. <NUM> and Kv7. <NUM> channel openers. Accordingly, the present invention provides novel compounds as medicaments for use in the treatment of disorders which are modulated by the KCNQ potassium channels.

Any subject matter falling outside the scope of the claims is provided for information purpose only.

The present invention relates to a compound of Formula I
<CHM>
wherein.

for use in the treatment of epilepsy, bipolar disorder, migraine or schizophrenia, or for use in the treatment of psychosis, mania, stress-related disorders, acute stress reactions, bipolar depression, major depression, anxiety, panic attacks, social phobia, sleep distrubances, ADHD, PTSD, OCD, impulsivity disorders, personality disorders, schizotypical disorder, aggression, chronic pain, neuropathy, autism spectrum disorders, Huntingtons chorea, sclerosis, multiple sclerosis, alzhiemers disease, respectively.

R4 is according to an embodiment of the invention OCF<NUM> or OCHF<NUM> and R2 is accorording to another embodiment H or CH<NUM>.

In one embodiement R1 is C<NUM>-C<NUM> cycloalkyl optionally substituted with <NUM> or <NUM> F, CHF<NUM> or CF<NUM>.

According to a specific embodiment R1 is t-butyl and R2 is H and R4 is one of OCF<NUM>, OCH<NUM>CF<NUM> or OCHF<NUM>.

According to another specific embodiment R1 and R2 combine to form cyclobutyl optionally substituted with <NUM> or <NUM> F and R4 is one of OCF<NUM>, OCH<NUM>CF<NUM> or OCHF<NUM>.

According to a specific embodiment of the invention the compound used according to the invention is selected from the group consisting of:.

Reference to compounds used according to the present invention includes racemic mixtures of the compounds, optical isomer of the compounds for which this is relevant, and polymorphic and amorphic forms of compounds used according tothe present invention, as well as tautomeric forms the compounds for which this is relevant. Furthermore, the compounds used according to the present invention may potentially exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. Both the use of solvated and unsolvated forms of the compounds are encompassed by the present invention.

The compound used according to the invention may be in a pharmaceutical composition comprising the compound and a pharmaceutically acceptable excipient or carrier.

In one embodiment, the invention relates to a compound for use in treating a patient in the need thereof suffering from epilepsy, bipolar disorder, migraine or schizophrenia comprising administering to the subject a therapeutically effective amount of the compound.

In yet another embodiement the invention relates to a compound for use in treating a patient in the need thereof suffering from psychosis, mania, stress-related disorders, acute stress reactions, bipolar depression, major depression, anxiety, panic attacks, social phobia, sleep distrubances, ADHD, PTSD, OCD, impulsivity disorders, personality disorders, schizotypical disorder, aggression, chronic pain, neuropathy, autism spectrum disorders, Huntingtons chorea, sclerosis, multiple sclerosis, alzhiemers disease comprising administering to the subject a therapeutically effective amount of the compound.

In the present context, "optionally substituted" means that the indicated moiety may or may not be substituted, and when substituted is mono- or disubstituted. It is understood that where no substituents are indicated for an "optionally substituted" moiety, then the position is held by a hydrogen atom.

A given range may interchangeably be indicated with "-"(dash) or "to", e.g. the term "C<NUM>-<NUM> alkyl" is equivalent to "C<NUM> to C<NUM> alkyl".

The terms "C<NUM>- C<NUM> alkyl" and "C<NUM>- C<NUM> alkyl" refer to an unbranched or branched saturated hydrocarbon having from one up to six carbon atoms, inclusive. Examples of such groups include, but are not limited to, methyl, ethyl, <NUM>-propyl, <NUM>-propyl, <NUM>-butyl, <NUM>-butyl and t-butyl.

The term "C<NUM>- C<NUM> alkoxy" refers to a moiety of the formula -OR, wherein R indicates C<NUM>-C<NUM> alkyl as defined above.

The terms "C<NUM>-C<NUM> cycloalkyl"," C<NUM>- C<NUM> cycloalkyl" or "C<NUM>-C<NUM> cycloalkyl" refers to a saturated monocylic ring. Examples of such groups includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

Pharmaceutical compositions comprising a compound used according to the present invention defined above, may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, buccal, sublingual, transdermal and parenteral (e.g. subcutaneous, intramuscular, and intravenous) route; the oral route being preferred.

It will be appreciated that the route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient.

In the following, the term, "excipient" or "pharmaceutically acceptable excipient" refers to pharmaceutical excipients including, but not limited to, fillers, antiadherents, binders, coatings, colours, disintegrants, flavours, glidants, lubricants, preservatives, sorbents, sweeteners, solvents, vehicles and adjuvants.

The present invention also provides a pharmaceutical composition comprising a compound used according to the invention, such as one of the compounds disclosed in the Experimental Section herein. Also described herein is a process for making a pharmaceutical composition comprising a compound used according to the invention. The pharmaceutical compositions used according to the invention may be formulated with pharmaceutically acceptable excipients in accordance with conventional techniques such as those disclosed in <NPL>.

Pharmaceutical compositions for oral administration include solid oral dosage forms such as tablets, capsules, powders and granules; and liquid oral dosage forms such as solutions, emulsions, suspensions and syrups as well as powders and granules to be dissolved or suspended in an appropriate liquid.

Solid oral dosage forms may be presented as discrete units (e.g. tablets or hard or soft capsules), each containing a predetermined amount of the active ingredient, and preferably one or more suitable excipients. Where appropriate, the solid dosage forms may be prepared with coatings such as enteric coatings or they may be formulated so as to provide modified release of the active ingredient such as delayed or extended release according to methods well known in the art. Where appropriate, the solid dosage form may be a dosage form disintegrating in the saliva, such as for example an orodispersible tablet.

Examples of excipients suitable for solid oral formulation include, but are not limited to, microcrystalline cellulose, corn starch, lactose, mannitol, povidone, croscarmellose sodium, sucrose, cyclodextrin, talcum, gelatin, pectin, magnesium stearate, stearic acid and lower alkyl ethers of cellulose. Similarly, the solid formulation may include excipients for delayed or extended release formulations known in the art, such as glyceryl monostearate or hypromellose. If solid material is used for oral administration, the formulation may for example be prepared by mixing the active ingredient with solid excipients and subsequently compressing the mixture in a conventional tableting machine; or the formulation may for example be placed in a hard capsule e.g. in powder, pellet or mini tablet form. The amount of solid excipient will vary widely but will typically range from about <NUM> to about <NUM> per dosage unit.

Liquid oral dosage forms may be presented as for example elixirs, syrups, oral drops or a liquid filled capsule. Liquid oral dosage forms may also be presented as powders for a solution or suspension in an aqueous or non-aqueous liquid. Examples of excipients suitable for liquid oral formulation include, but are not limited to, ethanol, propylene glycol, glycerol, polyethylenglycols, poloxamers, sorbitol, poly-sorbate, mono and di-glycerides, cyclodextrins, coconut oil, palm oil, and water. Liquid oral dosage forms may for example be prepared by dissolving or suspending the active ingredient in an aqueous or non-aqueous liquid, or by incorporating the active ingredient into an oil-in-water or water-in-oil liquid emulsion.

Further excipients may be used in solid and liquid oral formulations, such as colourings, flavourings and preservatives etc..

Pharmaceutical compositions for parenteral administration include sterile aqueous and nonaqueous solutions, dispersions, suspensions or emulsions for injection or infusion, concentrates for injection or infusion as well as sterile powders to be reconstituted in sterile solutions or dispersions for injection or infusion prior to use. Examples of excipients suitable for parenteral formulation include, but are not limited to water, coconut oil, palm oil and solutions of cyclodextrins. Aqueous formulations should be suitably buffered if necessary and rendered isotonic with sufficient saline or glucose.

Other types of pharmaceutical compositions include suppositories, inhalants, creams, gels, dermal patches, implants and formulations for buccal or sublingual administration.

It is requisite that the excipients used for any pharmaceutical formulation comply with the intended route of administration and are compatible with the active ingredients.

In one embodiment, the compound used according to the present invention is administered in an amount from about <NUM>/kg body weight to about <NUM>/kg body weight per day. In particular, daily dosages may be in the range of <NUM>/kg body weight to about <NUM>/kg body weight per day. The exact dosages will depend upon the frequency and mode of administration, the gender, the age, the weight, and the general condition of the subject to be treated, the nature and the severity of the condition to be treated, any concomitant diseases to be treated, the desired effect of the treatment and other factors known to those skilled in the art.

A typical oral dosage for adults will be in the range of <NUM>-<NUM>/day of a compound of the present invention, such as <NUM>-<NUM>/day, such as <NUM>-<NUM>/day or <NUM>-<NUM>/day. Conveniently, the compounds used according tothe invention are administered in a unit dosage form containing said compounds in an amount of about <NUM> to <NUM>, such as <NUM>, <NUM> <NUM>, <NUM>, <NUM> or <NUM> of a compound used according tothe present invention.

When compounds used according tothe present invention contain one or more chiral centers reference to any of the compounds will, unless otherwise specified, cover the enantiomerically or diastereomerically pure compound as well as mixtures of the enantiomers or diastereomers in any ratio.

MDL Enhanced Stereo representation is used to describe unknown stereochemistry of the compounds used according tothe invention. Hence, the label "or1" on a chiral carbon atom is used to indicate that the absolute stereoconformation at this atom is not known; e.g. the stereoconformation at this carbon atom is either (S) or (R).

Furthermore, the chiral bond from a carbon atom labelled "or1", using upward wedge or downward wedge, are equal representations; e.g. the two drawings have the same meaning, the meaning being that the absolute stereoconformation at the "or1" labelled carbon atom is not known and can be (S) or (R).

Thus, the use of upward wedge bonds and downward wedge bonds from atoms labelled "or1", are merely intended to provide a visual cue that the drawings represent different stereoisomers, in which the conformation at the "or1" labelled carbon atom is not known.

Furthermore, some of the compounds used according tothe present invention may exist in different tautomeric forms and it is intended that any tautomeric forms that the compounds are able to form are included within the scope of the present invention.

In the present context, the term "therapeutically effective amount" of a compound means an amount sufficient to alleviate, arrest, partly arrest, remove or delay the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of said compound. An amount adequate to accomplish this is defined as "therapeutically effective amount". Effective amounts for each purpose will depend on the severity of the disease or injury as well as the weight and general state of the subject. It will be understood that determining an appropriate dosage may be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician.

In the present context, "treatment" or "treating" is intended to indicate the management and care of a patient for the purpose of alleviating, arresting, partly arresting, removing or delaying progress of the clinical manifestation of the disease. The patient to be treated is preferably a mammal, in particular a human being.

A synthesized cDNA fragment encoding human Kv7. <NUM> and human Kv7. <NUM> separated by a P2A sequence was inserted into the pcDNA5/FRT/TO vector using the BamHI and XhoI restriction sites. The construct was then transfected into HEK Flp-In <NUM> cells using Lipofectamine2000. The transfected cells were grown for <NUM> hours in DMEM containing <NUM>% (v/v) FBS and <NUM>% PenStrep and subsequently maintained under selection in DMEM containing <NUM>% (v/v) FBS, <NUM> % PenStrep and <NUM> ug/mL Hygromycin B at <NUM> in a humidified atmosphere of <NUM>% CO<NUM>. The resultant stable hKv7. <NUM>/hKv7. <NUM> cell line (HEK-hKv7. <NUM>/hKv7. <NUM>) was functionally tested with automated whole cell patch-clamp and displayed a typical Kv7-current which was sensitive to XE991 and potentiated by Retigabine.

The thallium influx assay for potassium channel activation was performed analogously to a published procedure (<NPL>) using the FLIPR Potassium Assay kit (Molecular Devices). <NUM>/hKv7. <NUM> cells were plated onto <NUM>-well, black-walled, clear-bottomed culture plates (Corning, Acton, MA, USA) at a density of <NUM>,<NUM> cells/well (<NUM>µl/well) if the cells were assayed the following day, or <NUM>,<NUM> cells/well (<NUM>µl/well) if the cells were assayed two days after seeding.

On the assay day, the medium was removed after which <NUM> uL/well of test compound diluted to 2x final concentration in HBSS containing <NUM> HEPES, and <NUM> uL/well of 2x dye load buffer were added. The cells were then incubated for <NUM> at room temperature in the dark. Chloride-free stimulation buffer containing Tl+ and K+ at 5x final concentration (5x concentration: <NUM> in both cases) and test compound at 1x final concentration, were prepared during the incubation. The cells were then assayed in a FDSS7000EX Functional Drug Screening System (Hamamatsu). Following <NUM> sec of baseline fluorescence signal reading at <NUM>, and <NUM> sec at <NUM>, <NUM> uL/well of stimulation buffer were added and the fluorescence continuously measured for <NUM> sec at <NUM> followed, by <NUM> at <NUM>. Compound effect was quantified using AUC as readout and normalized to a reference compound, which was included on each plate.

In the assay described above, the compounds used according tothe invention had the following biological activity:.

<NUM>H NMR spectra were recorded at <NUM> on a Bruker Avance III <NUM> instrument or at <NUM> on a Bruker Avance <NUM> instrument. Deuterated dimethyl sulfoxide or deuterated chloroform was used as solvent.

Tetramethylsilane was used as internal reference standard. Chemical shift values are expressed in ppm-values relative to tetramethylsilane. The following abbreviations are used for multiplicity of NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, qui = quintet, h = heptet, dd = double doublet, ddd = double double doublet, dt = double triplet, dq = double quartet, tt = triplet of triplets, m = multiplet and brs = broad singlet.

Chromatographic systems and methods to evaluate chemical purity (LCMS methods) and chiral purity (SFC and HPLC methods) are described below.

General procedures for synthesis of intermediates and the compounds of general Formula I are described in reaction Scheme <NUM>, and are specifically illustrated in the preparations and Examples.

The compounds used according to the invention are prepared as described in Scheme <NUM>. Several of the compounds of general Formula I contain two chiral carbon atoms, and are formed as a mixture of diastereomers. When this is the case, the diastereomers may be separated, to yield the single stereoisomers Ia and Ib. <CHM>
<CHM>.

Scheme I depicts the preparation of the compounds of general Formula I by two general routes. The first route is the synthesis of compounds of Formula I by reaction of an enantiomerically pure amine of general Formula II, and an acid of general Formula III, through methodology well known in the art for the conversion of an acid and an amine into an amide. This methodology includes the formation of reactive derivatives of the acid of Formula III, including, but not limited to, activated esters and reactive mixed anhydrides, followed by condensation with amines of general Formula II. One such methodology is performing the condensation in the presence of HATU ((<NUM>-[bis(dimethylamino)methylene]-<NUM>-<NUM>,<NUM>,<NUM>-triazolo[<NUM>,<NUM>-b]pyridinium <NUM>-oxid hexafluorophosphate) and a suitable base such as DIPEA (diisopropylethylamine), in a solvent such as dichloromethane.

Alternatively, when R<NUM> is H, the compounds of general Formula I can be prepared via a second general route, in which intermediates of general formula V, are treated with a suitable reducing agent such as NaBH<NUM>, in a suitable solvent such as methanol. The intermediates of formula V can be obtained from enantiomerically pure amines of general Formula II, and a carboxylic acid of general Formula IV (R = H). This transformation can be effected using similar reaction conditions as described above for the condensation of II and III to form I.

A variation of this procedure is the direct coupling reaction between a chiral amine of general Formula II and a carboxylic acid ester of general Formula IV (R = Me, Et). This reaction can be performed by heating the reactants to reflux in a suitable solvent such as toluene, in the presence of a suitable base such as DIPEA, and in the presence of a catalytic amount of a suitable catalyst such as DMAP (<NUM>-dimethylamino pyridine).

The optically active amines of general Formula II can be prepared as outlined in Scheme <NUM>:
<CHM>.

Aldehydes of general formula VI can be condensed with (R)-<NUM>-methylpropane-<NUM>-sulfinamide in a suitable solvent such as dichloroethane, in the presence of a drying agent, such as titanium(IV)isopropoxide, or cupric sulfate. The formed sulfinyl imine is treated with R<NUM>MgBr in a suitable inert solvent such as THF, to yield the corresponding substituted (R)-<NUM>-methyl-N-((S)-<NUM>-aryl-alkyl)propane-<NUM>-sulfinamides VII, which are converted to the compounds of general Formula II by treatment with an appropriate acid in an appropriate solvent, such as HCl in MeOH.

The aldehydes of formula VI, used to prepare the compounds used according to the invention, are commercially available, or may be prepared as described in the literature, see fx.

In a variation of this procedure, the chiral amines of Formula II can be obtained from an aryl ketone, through hydride reduction of the intermediate sulfinyl imine with a reagent such as L-Selectride; as shown in Scheme <NUM>.

The ketones used to prepare the compounds used according to the invention, are commercially available, or may be prepared by methods known to the person skilled in the art.

Another variation of this procedure, particularly suited for accessing chiral amines of general Formula II, in which R<NUM> is a hydroxymethylene derivative, is outlined in Scheme <NUM>.

In this procedure, glyoxylate sulfinyl imine, formed in a condensation reaction between a glyoxylic ester and (R)-<NUM>-methylpropane-<NUM>-sulfinamide, can be reacted with a suitably substituted boronic acid using a suitable catalyst such as bis(acetonitrile) (<NUM>,<NUM>-cyclooctadiene)rhodium(I) tetra-fluoroborate, in a suitable solvent such as dioxane, as described in <CIT>. The resulting intermediates VIII can be hydrolysed and re-protected to yield intermediates of general Formula IX, which may be further derivatised to access the desired R<NUM> substituent. In the compounds used according to the invention, the carboxylic ester group of IX can be reduced to hydroxymethylene using LAH (lithium aluminium hydride), and difluoromethylated using a suitable reagent such as <NUM>,<NUM>-difluoro-<NUM>-(fluorosulfonyl) acetic acid under conditions such as CuI catalysis, in a suitable solvent such as acetonitrile.

The skilled artisan will recognise that other transformations are possible from intermediates of general Formula IX; the present invention is intended to include such alternative transformations.

The carboxylic acids of general Formula III can be prepared as outlined in Scheme <NUM>:
<CHM>
Ketones of general formula X are reacted with an alkyl ester of bromoacetic acid activated with for example Zn and iodine, to yield the corresponding aldol adduct. In an alternative procedure, the bromoacetic acid ester can be activated using Zn and TMSCl (trimethylsilylchloride). In a final step, hydrolysis of the alkyl ester is accomplished by treatment with an appropriate base such as NaOH or LiOH in an appropriate solvent, such as water, or an alcohol in water, and followed by acidification with an appropriate acid to yield the compounds of Formula III.

A mixture of <NUM>-(trifluoromethoxy)benzaldehyde (<NUM>, <NUM> mmol), (R)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>, <NUM> mmol) and CuSO<NUM> (<NUM>, <NUM> mmol) in DCE (<NUM>,<NUM>-dichloroethane) (<NUM>) was stirred at <NUM> for <NUM> hours. The mixture was filtered and the filter cake was washed with DCM (dichloromethane) (<NUM>). The organic phases were combined and concentrated. The residue was purified by flash silica gel chromatography with an eluent of <NUM>~<NUM>% ethyl acetate/petroleum ether (gradient) to yield the product (<NUM>, <NUM>% yield).

<NUM>H NMR (CDCl<NUM> <NUM>): δ <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>).

To a solution of (R)-<NUM>-methyl-N-[[<NUM>-(trifluoromethoxy)phenyl] methylene]propane-<NUM>-sulfinamide (<NUM>, <NUM> mmol) in DCM (<NUM>) was added MeMgBr (<NUM> in Et<NUM>O, <NUM>) dropwise at <NUM>. The resulting mixture was stirred at <NUM> for <NUM> hour and <NUM> for <NUM> hours. The mixture was cooled to <NUM>, and sat. NH<NUM>Cl solution was added. The resulting mixture was extracted with DCM (<NUM> × <NUM>). The organic phases were washed with brine (<NUM>), dried over Na<NUM>SO<NUM> and concentrated. The residue was purified by flash silica gel chromatography with an eluent of <NUM>~<NUM>% ethyl acetate/petroleum ether (gradient) to give the product (<NUM>, <NUM>% yield).

<NUM>H NMR (CDCl<NUM> <NUM>): δ <NUM> (t, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>).

(R)-<NUM>-methyl-N-[(<NUM>)-<NUM>-[<NUM>-(trifluoromethoxy)phenyl]ethyl] propane-<NUM>-sulfinamide (<NUM>, <NUM> mmol) in MeOH (<NUM>) was treated with HCl/MeOH (<NUM>) and stirred at <NUM> for <NUM> hours. The mixture was concentrated to give (S)-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethanamine hydrochloride (<NUM>, crude) which was used directly without further purification.

A mixture of <NUM>-hydroxybenzaldehyde (<NUM>, <NUM> mmol), <NUM>,<NUM>,<NUM>-trifluoroethyl trifluoromethanesulfonate (<NUM>, <NUM> mmol) and Cs<NUM>CO<NUM> (<NUM>, <NUM> mmol) in DMF (<NUM>) was stirred at <NUM> for <NUM> hours. The mixture was filtered and the filter cake was washed with ethyl acetate (<NUM>). The filtrate was washed with water (<NUM> x2) and brine (<NUM> x2), dried over Na<NUM>SO<NUM> and concentrated. The crude was purified by column chromatograph on silica gel (<NUM>% ethyl acetate in petroleum ether) to give the product (<NUM>, <NUM>% yield).

<NUM>HNMR (CDCl<NUM> <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (q, J =<NUM>, J =<NUM>, <NUM>).

A mixture of <NUM>-(<NUM>,<NUM>,<NUM>-trifluoroethoxy)benzaldehyde (<NUM>, <NUM> mmol), (R)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>, <NUM> mmol) and CuSO<NUM> (<NUM>, <NUM> mmol) in DCE (<NUM>) was stirred at <NUM> for <NUM> hours. The mixture was filtered and the filter cake was washed with DCM (<NUM>). The organic phases were concentrated and purified by column chromatograph on silica gel (<NUM>% ethyl acetate in petroleum ether) to yield the product (<NUM>, <NUM>% yield).

<NUM>H NMR (CDCl<NUM> <NUM>): δ <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J =<NUM>, <NUM>), <NUM> (q, J =<NUM>, J =<NUM>, <NUM>), <NUM> (s, <NUM>).

To a solution of (R)-<NUM>-methyl-N-[[<NUM>-(<NUM>,<NUM>,<NUM>-trifluoroethoxy) phenyl] methylene]propane-<NUM>-sulfinamide (<NUM>, <NUM> mmol) in DCM (<NUM>) at <NUM> was added MeMgBr (<NUM>, <NUM>) dropwise. The resulting mixture was stirred at <NUM> for <NUM> hour and <NUM> for <NUM> hours. The mixture was cooled to <NUM>, and sat. NH<NUM>Cl solution was added. The resulting mixture was extracted with DCM (<NUM> x2). The organic phases were washed with brine (<NUM>), dried over Na<NUM>SO<NUM> and concentrated. The crude was purified by column chromatograph on silica gel (petroleum ether:ethyl acetate=<NUM>:<NUM>) to give the product (<NUM>, <NUM>% yield).

<NUM>H NMR (CDCl<NUM> <NUM>): δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, J = <NUM>, J = <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>). NH is not observed.

To a solution of (R)-<NUM>-methyl-N-[(<NUM>)-<NUM>-[<NUM>-(<NUM>,<NUM>,<NUM>-trifluoroethoxy)phenyl]ethyl]propane-<NUM>-sulfinamide (<NUM>, <NUM> mmol) in MeOH (<NUM>) was added HCl/MeOH (<NUM>, <NUM>). The resulting mixture was stirred at <NUM> for <NUM> hours, and was concentrated to give the crude product (<NUM>), which was used directly without further purification.

To a mixture of <NUM>-(difluoromethoxy)benzaldehyde (<NUM>, <NUM> mmol) and <NUM>-methylpropane-<NUM>-sulfinamide (<NUM>, <NUM> mmol) in DCE (<NUM>) was added CuSO<NUM> (<NUM>, <NUM> mmol) at <NUM> under N2. The mixture was stirred at <NUM> for <NUM> hours, filtered and the filtrate was concentrated. The crude product was purified by silica gel column eluted with petroleum ether/Ethyl acetate = <NUM>:<NUM>-<NUM>:<NUM> to give (R)-N-(<NUM>-(difluoromethoxy)benzylidene)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>, <NUM>% yield).

To a solution of (R)-N-(<NUM>-(difluoromethoxy)benzylidene)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>, <NUM> mmol) in DCM (<NUM>) was added bromo(methyl)magnesium (<NUM> in Et<NUM>O, <NUM>) dropwise at <NUM>. The resulting mixture was stirred at <NUM> for <NUM> hour and <NUM> for <NUM> hours. The reaction was quenched with NH<NUM>Cl (sat. aq, <NUM>), and aqueous phase was extracted with ethyl acetate (<NUM> ×<NUM>). The combined organic phase was washed with brine (<NUM> ×<NUM>), dried with anhydrous Na<NUM>SO<NUM>, filtered, concentrated and purified by silica gel chromatography (petroleum ether/Ethyl acetate = <NUM>:<NUM>-<NUM>:<NUM>) to afford (R)-N-((S)-<NUM>-(<NUM>-(difluoromethoxy) phenyl))-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>, <NUM>% yield).

To a solution of (R)-N-((S)-<NUM>-(<NUM>-(difluoromethoxy)phenyl) ethyl)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>, <NUM> mmol) in MeOH (<NUM>) was added HCl/MeOH (<NUM>, <NUM>). The resulting mixture was stirred at <NUM> for <NUM> hours, and the reaction was concentrated to afford (S)-<NUM>-(<NUM>-(difluoromethoxy)phenyl)ethan amine in <NUM> crude yield, which was used directly without further purification.

A mixture of <NUM>-(trifluoromethyl)benzaldehyde (<NUM>, <NUM> mmol), (R)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>, <NUM> mmol) and CuSO<NUM> (<NUM>, <NUM> mmol) in DCE (<NUM>) was stirred at <NUM> for <NUM> hours. The mixture was filtered and filter was washed with DCM (<NUM>). The filtrate was concentrated, and the residue was purified by column chromatography (SiO<NUM>, petroleum ether/Ethyl acetate) to afford the product in <NUM> yield (<NUM>%). <NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (s, <NUM>).

To a solution of (R)-<NUM>-methyl-N-(<NUM>-(trifluoromethyl)benzyli-dene)propane-<NUM>-sulfinamide (<NUM>, <NUM> mmol) in DCM (<NUM>) at <NUM> MeMgBr (<NUM> in Et<NUM>O, <NUM>) was added dropwise. The resulting mixture was stirred at <NUM> for <NUM> hour and <NUM> for <NUM> hours. The reaction mixture was cooled to <NUM>, and sat. NH<NUM>Cl solution was added. The mixture was extracted with DCM (<NUM> × <NUM>). The combined organic phases were washed with brine (<NUM> × <NUM>), dried over Na<NUM>SO<NUM> and concentrated. The residue was purified by column chromatography (SiO<NUM>, petroleum ether/Ethyl acetate) to afford the desired product (<NUM>, <NUM>% yield).

<NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM>-<NUM> (<NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>). NH not observed.

To a solution of (R)-<NUM>-methyl-N-((S)-<NUM>-(<NUM>-(trifluoromethyl) phenyl)ethyl)propane-<NUM>-sulfonamide (<NUM>, <NUM> mmol) in MeOH (<NUM>) was added HCl/MeOH (<NUM>, <NUM>). The resulting mixture was stirred at <NUM> for <NUM> hours, and then concentrated to afford the product in <NUM> yield. The crude was used directly without further purification.

A mixture of <NUM>-(trifluoromethoxy)benzaldehyde (<NUM>, <NUM> mmol), (R)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>, <NUM> mmol) and CuSO4 (<NUM>, <NUM> mmol) in DCE (<NUM>) was stirred at <NUM> for <NUM> hours. The mixture was filtered and the filter cake was washed with DCM (<NUM>). The filtrate was concentrated. The residue was purified by flash chromatography on silica gel (Eluent of <NUM>~<NUM>% Ethylacetate/petroleum ether gradient) to give (R)-<NUM>-methyl-N-[[<NUM>-(trifluoromethoxy)phenyl]methylene]propane-<NUM>-sulfinamide in a yield of <NUM>, (<NUM>%).

To a solution of (R)-<NUM>-methyl-N-(<NUM>-(trifluoromethoxy) benzylidene)propane-<NUM>-sulfinamide (<NUM>, <NUM> mmol) in DCM (<NUM>) at <NUM> EtMgBr (<NUM> in Et<NUM>O, <NUM>) was added drop-wise. The resulting mixture was stirred at <NUM> for <NUM> hour and <NUM> for <NUM> hours. The mixture was cooled to <NUM> and sat. aq NH<NUM>Cl (<NUM>) was added. The mixture was extracted with DCM (<NUM> × <NUM>), the phases were separated, and the organic layer was washed with brine (<NUM>), dried over Na<NUM>SO<NUM> and concentrated. The residue was purified by flash silica gel chromatography (Eluent of <NUM>~<NUM>% Ethyl acetate/petroleum ether gradient) to yield the product (<NUM>, <NUM>% yield).

To a solution of (R)-<NUM>-methyl-N-((S)-<NUM>-(<NUM>-(trifluoromethoxy) phenyl)propyl)propane-<NUM>-sulfin amide (<NUM>, <NUM> mmol) in MeOH (<NUM>) was added HCl/MeOH (<NUM>, <NUM>). The resulting mixture was stirred at <NUM> for <NUM> hours and then concentrated to yield the crude (S)-<NUM>-[<NUM>-(trifluoromethoxy)phenyl]propan-<NUM>-amine hydrochloride, which was used without further purification (<NUM>).

To a solution of <NUM>-bromo-<NUM>-(<NUM>-(trifluoromethoxy)phenyl) ethanone (<NUM>, <NUM> mmol) in MeOH (<NUM>) was added Ag<NUM>CO<NUM> (<NUM>, <NUM> mmol) and BF<NUM>. Et<NUM>O (<NUM>, <NUM> mmol). The mixture was stirred at <NUM> for <NUM> hours under N<NUM>. The reaction mixture was filtered and concentrated. The residue was purified by column chromatography (SiO<NUM>, eluent of <NUM>~<NUM>% Ethyl acetate/petroleum ether) to give <NUM>-methoxy-<NUM>-(<NUM>-(trifluoro-methoxy)phenyl)ethanone (<NUM>, <NUM>% yield). <NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

To a solution of <NUM>-methoxy-<NUM>-(<NUM>-(trifluoromethoxy)phenyl) ethanone (<NUM>, <NUM> mmol) in THF (<NUM>) was added titanium(IV)isopropoxide (<NUM>, <NUM> mmol) and (R)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>, <NUM> mmol). The mixture was stirred at <NUM> for <NUM> hour under N<NUM>. The reaction mixture was quenched with brine (<NUM>) and extracted with ethyl acetate (<NUM> × <NUM>). The combined organic phases were dried over MgSO<NUM>, filtered and concentrated. The residue was purified by column chromatography (SiO<NUM>, eluent of <NUM>~<NUM>% Ethyl acetate/petroleum ether) to give (R)-N-(<NUM>-methoxy-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethylidene)-<NUM>-methylpropane-<NUM>-sulfin amide (<NUM>, <NUM>% yield).

To a solution of (R)-N-(<NUM>-methoxy-<NUM>-(<NUM>-(trifluoromethoxy) phenyl)ethylidene)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>, <NUM> mmol) in THF (<NUM>) was added L-selectride (<NUM> in THF, <NUM> mmol, <NUM>) at <NUM>. The mixture was stirred at <NUM> for <NUM> hours. The reaction mixture was diluted with methanol (<NUM>), and then filtered and concentrated. The residue was purified by column chromatography (SiO<NUM>, eluent of <NUM>~<NUM>% Ethyl acetate/ petroleum ether) to give the desired product (<NUM>, <NUM>% yield).

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

(R)-N-((R)-<NUM>-methoxy-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethyl)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>, <NUM> mmol) in HCl/MeOH (<NUM>, <NUM>) was stirred at <NUM> for <NUM> hours. The reaction mixture was concentrated, and the residue diluted with water (<NUM>), added ammonium hydroxide to pH=<NUM>~<NUM> and extracted with ethyl acetate (<NUM> × <NUM>). The combined organic extracts were dried over MgSO<NUM>, filtered and concentrated to give the product as a yellow oil (<NUM>, <NUM>% yield). The product was used directly without further purification.

To a solution of ethyl <NUM>-oxoacetate (<NUM>, <NUM> mmol) and (R)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>, <NUM> mmol) in DCM (<NUM>) was added CuSO<NUM> (<NUM>, <NUM> mmol), and the reaction mixture was stirred at <NUM> for <NUM> hours. The solid was filtered off, washed with ethyl acetate (<NUM>) and the organic phases were combined and concentrated. The resulting residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate, <NUM>/<NUM>) to yield the desired product (<NUM>, <NUM>% yield).

To a solution of ethyl-<NUM>-[(R)-tert-butylsulfinyl]iminoacetate (<NUM>, <NUM> mmol) and [<NUM>-(trifluoromethoxy)phenyl]boronic acid (<NUM>, <NUM> mmol) in dioxane (<NUM>) was added [Rh(COD)(MeCN)<NUM>]BF<NUM> (<NUM>, <NUM> mmol) and this mixture was stirred at <NUM> for <NUM> hours. The product was purified by silica gel chromatography (petroleum ether: ethyl acetate=<NUM>:<NUM>) to yield <NUM> (<NUM>%).

To a solution of ethyl (<NUM>R)-<NUM>-[[(R)-tert-butylsulfinyl]amino]-<NUM>-[<NUM>-(trifluoromethoxy)phenyl] acetate (<NUM>, <NUM> mmol) in MeOH (<NUM>), was added HCl/MeOH (<NUM>, <NUM>) and this mixture was stirred at <NUM> for <NUM> hours, and then concentrated to afford ethyl (<NUM>R)-<NUM>-amino-<NUM>-[<NUM>-(trifluoromethoxy)phenyl] acetate (<NUM>, crude).

To a mixture of ethyl (<NUM>R)-<NUM>-amino-<NUM>-[<NUM>-(trifluoromethoxy) phenyl]acetate hydrochloride (<NUM>, <NUM> mmol) in THF (<NUM>), was added Boc<NUM>O (<NUM>, <NUM> mmol). Then NaHCO<NUM> (<NUM>, <NUM> mmol) was added to this solution and stirred at <NUM> for <NUM> hours. This mixture was concentrated and purified by chromatography on silica (petroleum ether:ethyl acetate=<NUM>:<NUM>) to afford the product (<NUM>, <NUM>% yield).

To a suspension of LiAlH<NUM> (<NUM>, <NUM> mmol) in THF (<NUM>) was added ethyl (<NUM>R)-<NUM>-(tert-butoxycarbonylamino)-<NUM>-[<NUM>-(trifluoro-methoxy)phenyl]acetate (<NUM>, <NUM> mmol) in THF (<NUM>), with ice-cooling. Following addition, the reaction was allowed to warm to <NUM> and was stirred for <NUM> hours. Anhydrous magnesium sulfate was added and then one drop of water and ethyl acetate were successively added. Insoluble substances were filtered off through a pad of celite. The filtrate was concentrated and purified by chromatography on silica (SiO<NUM>; petroleum ether:ethyl acetate=<NUM>:<NUM>) (<NUM>, <NUM>% yield).

To a solution of tert-butyl N-[(<NUM>R)-<NUM>-hydroxy-<NUM>-[<NUM>-(trifluoro-methoxy)phenyl]ethyl] carbamate (<NUM>, <NUM> mmol) in MeCN (<NUM>), CuI (<NUM>, <NUM> mmol) was added and stirred at <NUM> under N<NUM> atmosphere for <NUM> minutes. Subsequently, a solution of <NUM>,<NUM>-difluoro-<NUM>-fluorosulfonyl-acetic acid (<NUM>, <NUM> mmol) in MeCN (<NUM>) was added at <NUM> over <NUM> minutes, and the reaction was stirred at <NUM> for <NUM> hour. This mixture was concentrated and then diluted by ethyl acetate (<NUM>), filtered and concentrated to afford the desired product (<NUM>, crude).

To a solution of tert-butyl N-[(<NUM>R)-<NUM>-(difluoromethoxy)-<NUM>-[<NUM>-(trifluoromethoxy)phenyl]ethyl]carbamate (<NUM>, <NUM> mmol) in MeOH (<NUM>), was added HCl/MeOH (<NUM> in MeOH, <NUM>) at <NUM>, and the reaction was stirred at <NUM> for <NUM> minuters. Ammonium hydroxide (<NUM>%) was added to pH=<NUM>, and this solution was concentrated and purified by chromatography on silica (SiO<NUM>; petroleum ether: ethyl acetate = <NUM>:<NUM>) to afford (<NUM>R)-<NUM>-(difluoromethoxy)-<NUM>-[<NUM>-(trifluoromethoxy)phenyl]ethanamine (<NUM> , <NUM>% yield).

Zn (<NUM>, <NUM> mmol) in THF (<NUM>) was added TMSCl (<NUM>, <NUM> mmol) in portions. The resulting mixture was stirred at <NUM> for <NUM> and then refluxed. The reaction mixture was cooled to room temperature, and ethyl <NUM>-bromoacetate (<NUM>, <NUM> mmol) was added dropwise at such a rate that the reaction boiled gently. The resulting mixture was stirred at <NUM> for <NUM> hour and then at <NUM> for <NUM> hour, then a solution of cyclobutanone (<NUM>, <NUM> mmol) in THF (<NUM>) was added. The mixture was stirred at <NUM> for another <NUM> hours. The mixture was poured into NH<NUM>. H<NUM>O (<NUM>, <NUM>%) on ice and extracted with ethyl acetate (<NUM> x2). The organic layer was washed with water (<NUM> x2) and brine (<NUM> x2), dried over Na<NUM>SO<NUM> and concentrated to give the product (<NUM>, crude).

<NUM>H NMR (CDCl<NUM> <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (t, J =<NUM>, <NUM>).

NaOH (<NUM>, <NUM> mmol) was dissolved in MeOH (<NUM>) and H<NUM>O (<NUM>), and ethyl <NUM>-(<NUM>-hydroxycyclobutyl)acetate (<NUM>, <NUM> mmol) was added. The mixture was stirred at <NUM> for <NUM> hours and then concentrated, and the residue was acidified by 2N HCl solution to pH = <NUM>-<NUM> and extracted with ethyl acetate (<NUM> x2). The organic extract was washed with water (<NUM> x2) and brine (<NUM> x2), dried over Na<NUM>SO<NUM> and concentrated to give the crude product (<NUM>, crude).

<NUM>H NMR (CDCl<NUM> <NUM>): δ <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>).

To a solution of <NUM>,<NUM>-difluorocyclobutanone (<NUM>, <NUM> mmol), Zn (<NUM>, <NUM> mmol) and I<NUM> (<NUM>, <NUM> mmol) in THF (<NUM>) under N<NUM>, ethyl <NUM>-bromoacetate (<NUM>, <NUM> mmol) was added dropwise. The mixture was stirred at <NUM> for <NUM> hours. H<NUM>SO<NUM> (<NUM>%, <NUM>) was carefully added to the reaction mixture at <NUM>, and the mixture was extracted with ethyl acetate (<NUM> ×<NUM>). The organic extract was washed with NaHCO<NUM> (sat. aq, <NUM>), dried over Na<NUM>SO<NUM> and concentrated. The crude product (<NUM>) was used directly without further purification.

To a solution of ethyl <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-hydroxy-cyclobutyl) acetate (<NUM>, <NUM> mmol) in MeOH (<NUM>) and H<NUM>O (<NUM>), NaOH (<NUM>, <NUM> mmol) was added at <NUM>° C. The mixture was stirred at <NUM> for <NUM> hours. The reaction solution was cooled to <NUM> and 1N HCl was added to the solution until pH reached <NUM>-<NUM>. The residue was diluted with brine (<NUM>) and extracted with methyl-tert-butyl ether (<NUM> × <NUM>). The combined organic extracts were dried over Na<NUM>SO<NUM>, filtered and concentrated. The crude product (<NUM>) was used without further purification.

To a mixture of Zn (<NUM>, <NUM> mmol), I<NUM> (<NUM>, <NUM> mmol) in THF (<NUM>) was added ethyl <NUM>-bromoacetate (<NUM>, <NUM> mmol) and <NUM>,<NUM>,<NUM>-trifluoro-<NUM>-methyl-butan-<NUM>-one (<NUM>, <NUM> mmol) at <NUM>. The mixture was stirred at <NUM> for <NUM> hours. H<NUM>SO<NUM> (<NUM>% aq, <NUM>) was added, and the mixture was extracted with ethyl acetate (<NUM> x4). The combined organic phases were washed with brine (<NUM>), dried over Na<NUM>SO<NUM>, filtered and concentrated to give ethyl <NUM>-hydroxy-<NUM>-methyl-<NUM>-(trifluoromethyl)pentanoate (<NUM>, crude).

A mixture of ethyl <NUM>-hydroxy-<NUM>-methyl-<NUM>-(trifluoromethyl)pentanoate (<NUM>, crude) and LiOH. H<NUM>O (<NUM>, <NUM> mmol) in THF (<NUM>) and H<NUM>O (<NUM>) was stirred at <NUM> for <NUM> hours. The pH was adjusted to ~<NUM> with <NUM> HCl, and the mixture extracted with ethyl acetate (<NUM> x4). The combined organic extract was washed with brine (<NUM>), dried over Na<NUM>SO<NUM>, filtered and concentrated to give <NUM>-hydroxy-<NUM>-methyl-<NUM>-(trifluoromethyl)pentanoic acid (<NUM>, crude) as a yellow solid, which was used directly in the next step without further purification.

To a solution <NUM>,<NUM>,<NUM>,<NUM>-tetrafluorobutan-<NUM>-one (<NUM>, <NUM> mmol), Zn (<NUM>, <NUM> mmol) and I<NUM> (<NUM>, <NUM> mmol) in THF (<NUM>), ethyl <NUM>-bromoacetate (<NUM>, <NUM> mmol) was added dropwise under N<NUM> at <NUM>. The mixture was stirred at <NUM> for <NUM> hours. The reaction mixture was cooled to <NUM>, and H<NUM>SO<NUM> (<NUM>, <NUM>% aq. ) was carefully added. The mixture was extracted with ethyl acetate (<NUM> × <NUM>), and the combined organic extract was washed with sat. aq NaHCO<NUM> (<NUM>), dried over Na<NUM>SO<NUM> and concentrated. The title compound (<NUM>, crude) was obtained and used in the next step without further purification.

To a solution of ethyl <NUM>,<NUM>,<NUM>,<NUM>-tetrafluoro-<NUM>-hydroxy-<NUM>-methyl-pentanoate (<NUM>, <NUM> mmol) in MeOH (<NUM>) and H<NUM>O (<NUM>), NaOH (<NUM>, <NUM> mmol) was added at <NUM>. The mixture was stirred at <NUM> for <NUM> hours and concentrated. The aqueous layer was acidified with 1N HCl aq. to pH = <NUM> - <NUM>, and extracted with methyl-tert-butyl ether (<NUM> × <NUM>). The combined organic extract was dried over Na<NUM>SO<NUM>, and concentrated. The title compound was obtained (<NUM>, crude) and used without further purification.

To a mixture of Zn (<NUM>, <NUM> mmol) and I<NUM> (<NUM>, <NUM> mmol) in THF (<NUM>) was added <NUM>,<NUM>,<NUM>-trifluorobutan-<NUM>-one (<NUM>, <NUM> mmol) and ethyl <NUM>-bromoacetate (<NUM>, <NUM> mmol) at <NUM>. The mixture was stirred at <NUM> for <NUM> hours. The reaction mixture was cooled to <NUM> and quenched with H<NUM>SO<NUM> (<NUM>, <NUM>% aq). The mixture was extracted with ethyl acetate (<NUM> × <NUM>). The combined organic extract was washed with brine (<NUM>) and dried over Na<NUM>SO<NUM>, filtered and concentrated. The product was obtained (<NUM>, crude) and was used directly without further purification.

A mixture of ethyl <NUM>,<NUM>,<NUM>-trifluoro-<NUM>-hydroxy-<NUM>-methyl-pentanoate (<NUM>, crude) and NaOH (<NUM>, <NUM> mmol) in H<NUM>O (<NUM>) was stirred at <NUM> for <NUM> hours. The pH was adjusted to ~<NUM> with sat. KHSO<NUM> at <NUM>, and the mixture extracted with ethyl acetate (<NUM> × <NUM>). The combined organic extract was washed with brine (<NUM>), dried over Na<NUM>SO<NUM>, filtered and concentrated to afford the product (<NUM>, crude).

To a mixture of <NUM>-(<NUM>-fluorocyclopropyl)ethanone (<NUM>, <NUM> mmol), Zn (<NUM>, <NUM> mmol) and I<NUM> (<NUM>, <NUM> mmol) in THF (<NUM>) was added ethyl <NUM>-bromoacetate (<NUM>, <NUM> mmol) dropwise at <NUM>. The mixture was stirred at <NUM> for <NUM> hours. The reaction mixture was cooled to <NUM>, and H<NUM>SO<NUM> (<NUM>% aq, <NUM>) was added dropwise. The mixture was added water (<NUM>) and was extracted with ethyl acetate (<NUM> × <NUM>). The combined organic extract was washed with brine (<NUM>), dried over Na<NUM>SO<NUM>, filtered and concentrated. The obtained product was used without further purification. Yield: <NUM>, crude.

A mixture of ethyl <NUM>-(<NUM>-fluorocyclopropyl)-<NUM>-hydroxybutanoate (<NUM>, crude) and NaOH (<NUM>, <NUM> mmol) in H<NUM>O (<NUM>) was stirred at <NUM> for <NUM> hours. The pH was adjusted with <NUM>% HCl (aq) to ~<NUM>. The mixture was extracted with ethyl acetate (<NUM> × <NUM>), and the combined organic extract was washed with brine (<NUM>), dried over Na<NUM>SO<NUM>, filtered and concentrated to yield the crude product, which was used directly without further purification. (<NUM>, crude.

Zn (<NUM>, <NUM> mmol) in THF (<NUM>) was added TMSCl (<NUM>, <NUM> mmol), and the resulting mixture was stirred at <NUM> for <NUM> minutes and then heated to <NUM>. The heating was stopped, and methyl <NUM>-bromoacetate (<NUM>, <NUM> mmol) was added in dropwise at such a rate that the ether boiled gently. The resulting mixture was stirred at <NUM> for <NUM> hour and <NUM> for <NUM> hour, and then a solution of <NUM>-cyclopropylethanone (<NUM>, <NUM> mmol) in THF (<NUM>) was added. The reaction was stirred at <NUM> for <NUM> hours. The mixture was poured onto NH<NUM>·H<NUM>O on ice (<NUM>, <NUM>%), and extracted with ethyl acetate (<NUM> x2). The organic extract was washed with water (<NUM>) and brine (<NUM>), dried over Na<NUM>SO<NUM> and concentrated to give the desrired product (<NUM>, crude).

A mixture of crude methyl <NUM>-cyclopropyl-<NUM>-hydroxybutanoate (<NUM>, <NUM> mmol) and LiOH·H<NUM>O (<NUM>, <NUM> mmol) in THF (<NUM>) and H<NUM>O (<NUM>) was stirred at <NUM> for <NUM> hours. H<NUM>O (<NUM>) was added and extracted with ethyl acetate (<NUM> x2). The organic extracts were discarded. The pH of the aqueous layer was adjusted to ~<NUM> with 2N HCl, extracted with ethyl acetate (<NUM> x3) and the combined organic fractions were washed with brine (<NUM> mLx10), dried over Na<NUM>SO<NUM>, filtered and concentrated to give the desired product in <NUM>% overall yield (<NUM>).

<NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>).

Et<NUM>N (<NUM>, <NUM> mmol) and MgCl<NUM> (<NUM>, <NUM> mmol) was added to a suspension of (<NUM>-ethoxy-<NUM>-oxo-propanoyl)oxy potassium salt (<NUM>, <NUM> mmol) in MeCN (<NUM>) and stirred at <NUM> for <NUM> hours. A pre-stirred mixture of CDI (carbonyl-diimidazole) (<NUM>, <NUM> mmol) and <NUM>-(difluoromethyl) cyclopropane carboxylic acid (<NUM>, <NUM> mmol) in MeCN (<NUM>) was added at <NUM> and stirred at <NUM> for <NUM> hours. The reaction mixture was diluted with H<NUM>O (<NUM>) and extracted with ethyl acetate (<NUM> × <NUM>). The combined organic extracts were washed with brine (<NUM>), dried over Na<NUM>SO<NUM>, filtered and concentrated. The residue was purified by flash chromatography on silica gel (Eluent of <NUM>~<NUM>% Ethyl acetate/petroleum ether gradient). The product was obtained in <NUM> (<NUM>%) yield.

Et<NUM>N (<NUM>, <NUM> mmol) and MgCl<NUM> (<NUM>, <NUM> mmol) was added to a suspension of potassium <NUM>-ethoxy-<NUM>-oxo-propanoate (<NUM>, <NUM> mmol) in CH<NUM>CN (<NUM>) and stirred at <NUM> for <NUM> hours. A pre-stirred mixture of carbonyl diimidazole (CDI) (<NUM>, <NUM> mmol) and <NUM>-(trifluoromethyl)cyclopropane carboxylic acid (<NUM>, <NUM> mmol) in CH<NUM>CN (<NUM>) was added at <NUM> and stirred at <NUM> for <NUM> hours. The mixture was poured into water (<NUM>). The aqueous phase was extracted with ethyl acetate (<NUM>×<NUM>). The combined organic phase was washed with brine (<NUM>×<NUM>), dried with anhydrous Na<NUM>SO<NUM>, filtered and concentrated. The residue was purified by column chromatography on silica gel (petroleum ether/Ethyl acetate = <NUM>:<NUM>-<NUM>:<NUM>) to afford the product in <NUM> (<NUM>%) yield.

A solution of (<NUM>)-<NUM>-[<NUM>-(trifluoromethoxy)phenyl]ethan amine hydrochloride (IIa) (<NUM>, <NUM> mmol), <NUM>,<NUM>-dimethyl-<NUM>-oxo-pentanoic acid (<NUM>, <NUM> mmol), HATU (<NUM>, <NUM> mmol) and DIPEA (<NUM>, <NUM> mmol) in DCM (<NUM>) was stirred at <NUM> for <NUM> hours. The resulting mixture was washed with water (<NUM>) and extracted with DCM (<NUM> ×<NUM>). The organic layer was washed with brine (<NUM> ×<NUM>), dried over Na<NUM>SO<NUM> and concentrated. The residue was purified by chromatography (SiO<NUM>, petroleum ether/Ethyl acetate = <NUM>:<NUM> to <NUM>:<NUM>) to afford <NUM>,<NUM>-dimethyl-<NUM>-oxo-N-[(<NUM>)-<NUM>-[<NUM>-(trifluoromethoxy)phenyl] ethyl]pentanamide (<NUM>, crude).

The following intermediates were prepared by simiar methodology as Va, using the relevant intermediates.

Prepared from IIb (<NUM>, <NUM> mmol) and <NUM>,<NUM>-dimethyl-<NUM>-oxo-pentanoic acid (<NUM>, <NUM> mmol).

Prepared from IIc (<NUM>, <NUM> mmol) and <NUM>,<NUM>-dimethyl-<NUM>-oxo-pentanoic acid (<NUM>, <NUM> mmol)
Yield: <NUM> crude.

Prepared from IId (<NUM>, <NUM> mmol) and <NUM>,<NUM>-dimethyl-<NUM>-oxo-pentanoic acid (<NUM>, <NUM> mmol).

Prepared from IIe (<NUM>, <NUM> mmol) and <NUM>,<NUM>-dimethyl-<NUM>-oxo-pentanoic acid (<NUM>, <NUM> mmol).

Prepared from IIb (<NUM>, <NUM> mmol) and <NUM>-methyl-<NUM>-oxo-pentanoic acid (<NUM>).

Prepared from IIa (<NUM>, <NUM> mmol) and <NUM>-methyl-<NUM>-oxo-pentanoic acid (<NUM>)
Yield: <NUM> (<NUM>%).

Prepared from IIg (<NUM>, <NUM> mmol) and <NUM>,<NUM>-dimethyl-<NUM>-oxo-pentanoic acid (<NUM>, <NUM> mmol)
Yield: <NUM> (<NUM>%).

Prepared from IIf (<NUM>, <NUM> mmol) and <NUM>,<NUM>-dimethyl-<NUM>-oxo-pentanoic acid (<NUM>, <NUM> mmol)
Yield: <NUM>, (<NUM>%).

A mixture of IIa (<NUM>, <NUM> mmol), IVa (<NUM>, <NUM> mmol), DMAP (<NUM>, <NUM> mmol) and Et<NUM>N (<NUM>, <NUM> mmol) in toluene (<NUM>) was degassed and purged with N<NUM> for <NUM> times, then the mixture was stirred at <NUM> for <NUM> hours under N<NUM>. The mixture was concentrated, and the residue was purified by flash chromatography on silica gel (Eluent of <NUM>~<NUM>% Ethyl acetate/petroleum ether gradient) to yield the desired product (<NUM>, <NUM>% yield).

The following were prepared by similar methodology as described for Vg, using the relevant intermediates.

Prepared from IVb (<NUM>, <NUM> mmol) and IIa (<NUM>, <NUM> mmol)
Yield: <NUM> (<NUM>%).

Prepared from methyl <NUM>-(<NUM>,<NUM>-difluorocyclobutyl)-<NUM>-oxopropanoate (<NUM>, <NUM> mmol) and IIa (<NUM>, <NUM> mmol).

<NUM>H NMR (CDCl<NUM>, <NUM>) δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

To a mixture of <NUM>,<NUM>-dimethyl-<NUM>-oxo-N-[(<NUM>)-<NUM>-[<NUM>-(trifluoro methoxy)phenyl]ethyl]pentanamide (Va) (<NUM>, <NUM> mmol) in MeOH (<NUM>) was added NaBH<NUM> (<NUM>, <NUM> mmol) in portions at <NUM>. The mixture was stirred at <NUM> for <NUM> hour. Water (<NUM>) was added portionwise at <NUM>. This reaction was repeated on the same scale twice, and the crude products from the three separate reactions were combined and worked up as follows:
The mixture was concentrated to remove MeOH, and then extracted with ethyl acetate (<NUM> ×<NUM>). The combined organic extracts were washed with brine (<NUM> ×<NUM>), dried over Na<NUM>SO<NUM>, filtered and concentrated to afford <NUM>-hydroxy-<NUM>,<NUM>-dimethyl-N-[(<NUM>S)-<NUM>-[<NUM>-(trifluoromethoxy) phenyl]ethyl] pentanamide (<NUM>, crude).

<CHM>
<NUM>-Hydroxy-<NUM>,<NUM>-dimethyl-N-[(<NUM>S)-<NUM>-[<NUM>-(trifluoromethoxy)phenyl] ethyl]pentanamide (<NUM>, <NUM> mmol) was separated by chromatography.

The following examples were prepared by similar methodology as described for 1a and 1b, using the relevant intermediates:.

<CHM>
<NUM>-Hydroxy-<NUM>,<NUM>-dimethyl-N-((S)-<NUM>-(<NUM>-(<NUM>,<NUM>,<NUM>-trifluoroethoxy) phenyl)ethyl)pentanamide was prepared from Vb, in <NUM>% yield.

<CHM>
N-((S)-<NUM>-(<NUM>-(Difluoromethoxy)phenyl)ethyl)-<NUM>-hydroxy-<NUM>,<NUM>-dimethylpentanamide (<NUM>) was separated by chiral SFC.

<CHM>
<NUM>-Hydroxy-<NUM>,<NUM>-dimethyl-N-((S)-<NUM>-(<NUM>-(trifluoromethyl)phenyl) ethyl)pentan amide was separated by chromatography on silica, (petroleum ether: Ethyl acetate = <NUM>:<NUM>).

<NUM>H NMR (CDCl<NUM> <NUM>): δ <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>).

LC-MS: tR = <NUM> (LCMS Method <NUM>), m/z = <NUM> [M + H]+.

SFC: tR = <NUM> (SFC Method <NUM>), de = <NUM>%, [α]D<NUM> = - <NUM> (c = <NUM>/<NUM>, MeOH).

<NUM>H NMR (CDCl<NUM> <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>).

<CHM>
<NUM>-Hydroxy-<NUM>,<NUM>-dimethyl-N-((S)-<NUM>-(<NUM>-(trifluoromethoxy)phenyl) propyl)pentanamide was separated by flash chromatography on silica gel (Eluent of <NUM>~<NUM>% Ethyl acetate/petroleum ether gradient).

<NUM>H NMR (CDCl<NUM> <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>).

SFC: tR = <NUM>. (SFC Method <NUM>), de = <NUM>%, [α]D<NUM> = -<NUM> (c = <NUM>/<NUM>, MeOH).

<NUM>H NMR (CDCl<NUM> <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>).

SFC: tR = <NUM>. (SFC Method <NUM>) de = <NUM>%, [α]D<NUM> = -<NUM> (c = <NUM>/<NUM>, MeOH).

Prepared from V1. Yield: <NUM>, (<NUM>%).

<NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

SFC: tR = <NUM>. (SFC method <NUM>), de = <NUM>%, [α]D<NUM> = -<NUM> (c = <NUM>/mL, MeOH).

<NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

SFC: tR = <NUM>. (SFC Method <NUM>), de = <NUM>%, [α]D<NUM> = -<NUM> (c = <NUM>/mL, MeOH).

<CHM>
<NUM>-Hydroxy-<NUM>-methyl-N-((S)-<NUM>-(<NUM>-(<NUM>,<NUM>,<NUM>-trifluoroethoxy)phenyl) ethyl)pentanamide was separated by chiral SFC.

<CHM>
<NUM>-(<NUM>-(difluoromethyl)cyclopropyl)-<NUM>-hydroxy-N-((S)-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethyl)propanamide was separated by flash silica gel chromatography (Eluent of <NUM>~<NUM>% Ethyl acetate/petroleum ether gradient).

<NUM>H NMR (CDCl<NUM> <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (quin, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>).

<NUM>H NMR (CDCl<NUM> <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (quin, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). LC-MS: tR = <NUM> (LCMS Method <NUM>), m/z = <NUM> [M + H]+.

SFC tR = <NUM>. (SFC Method <NUM>), de = <NUM>%, [α]D<NUM> = -<NUM> (c = <NUM>/<NUM>, MeOH).

Prepared from Vh and used directly in the next step.

The crude product from step <NUM> was separated by chiral SFC to yield the desired products.

<NUM>H NMR (DMSO-d<NUM> <NUM>): δ <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>).

<NUM>H NMR (DMSO-d<NUM> <NUM>): δ <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>).

<CHM>
<NUM>-Hydroxy-<NUM>-methyl-N-((S)-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethyl) pentan amide was separated by chromatography (SiO<NUM>, petroleum ether/ethyl acetate = <NUM>:<NUM> to <NUM>:<NUM>).

<NUM>H NMR (CDCl<NUM>, <NUM>) δ <NUM> (t, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM>(m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (quin, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

SFC: tR = <NUM> (SFC Method <NUM>), de = <NUM>%, [α]D<NUM> = -<NUM> (c = <NUM>/<NUM>, MeOH).

<NUM>H NMR (CDCl<NUM>, <NUM>) δ <NUM> (t, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s,<NUM>), <NUM>-<NUM>(m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (quin, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>),<NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>). LC-MS: tR = <NUM> (LCMS Method <NUM>), m/z = <NUM> [M + H]+.

Prepared from Vj. Yield = <NUM>, (<NUM>%).

<CHM>
N-((R)-<NUM>-(Difluoromethoxy)-<NUM>-(<NUM>-(trifluoromethoxy)phenyl) ethyl)-<NUM>-hydroxy-<NUM>,<NUM>-dimethyl pentanamide was separated by chiral SFC.

<NUM>H NMR (CDCl<NUM> <NUM>): δ <NUM> (t, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>).

LC-MS: tR = <NUM> (LCMS Method <NUM>), m/z =<NUM> [M + H]+.

SFC: tR = <NUM> (SFC Method <NUM>), de = <NUM>%, [α]D<NUM> = -<NUM> (c = <NUM>/<NUM>, MeCN).

<NUM>H NMR (DMSO-d<NUM> <NUM>): δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>).

Prepared from Vk. Yield: <NUM>, (<NUM>%).

<CHM>
<NUM>-Hydroxy-N-[(<NUM>R)-<NUM>-methoxy-<NUM>-[<NUM>-(trifluoromethoxy)phenyl] ethyl]-<NUM>,<NUM>-dimethyl-pentanamide was separated by chiral SFC.

<NUM>H NMR (CDCl<NUM> <NUM>): δ <NUM> (t, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>(s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>),<NUM> (s, <NUM>).

<NUM>H NMR (CDCl<NUM> <NUM>): δ <NUM> (t, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>),<NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>).

A mixture of (<NUM>S)-<NUM>-[<NUM>-(trifluoromethoxy)phenyl]ethanamine hydrochloride (IIa) (<NUM>, <NUM> mmol), <NUM>-(<NUM>,<NUM>-difluoro-<NUM>-hydroxy-cyclobutyl)acetic acid (IIIb) (<NUM>, <NUM> mmol), HATU (<NUM>, <NUM> mmol) and DIPEA (<NUM>, <NUM> mmol) in DCM (<NUM>) was stirred at <NUM> for <NUM> hours. The mixture was washed with water (<NUM> × <NUM>) and extracted with DCM (<NUM>). The organic layer was washed with brine (<NUM> × <NUM>), dried over Na<NUM>SO<NUM> and concentrated. The residue was purified by flash chromatography on silica gel (Eluent of <NUM>~<NUM>% Ethyl acetate/petroleum ether gradient) to give the product (<NUM>, <NUM>% yield).

<NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (quin, J = <NUM>, <NUM>), <NUM> (br s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

HPLC: tR = <NUM>. (Chiral HPLC Method <NUM>), de = <NUM>%. [α]<NUM>D = -<NUM> (c = <NUM>/<NUM>, MeOH).

The following examples were prepared by similar methodology to Example <NUM>, using the relevant staring materials:.

Prepared from IIb (<NUM>, <NUM> mmol), and IIIa (<NUM>, <NUM> mmol).

<NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM> (t, J =<NUM>, <NUM>), <NUM> (d, J =<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J =<NUM>, J =<NUM>, <NUM>), <NUM> (d, J =<NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (q, J =<NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM>(d, J =<NUM>, <NUM>).

SFC: tR = <NUM> (SFC Method <NUM>), de = <NUM>%, [α]D<NUM> = -<NUM> (c = <NUM>, MeOH).

Prepared from IIb and IIIc. Yield: <NUM>, (crude). The crude was used directly without purification.

Separated by by flash silica gel chromatography (Eluent of <NUM>~<NUM>% Ethyl acetate/petroleum ether gradient).

<NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>). <NUM> - <NUM> (m, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

<NUM>H NMR (CDCl<NUM>, <NUM>): δ <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

SFC: tR = <NUM>. (SFC Method <NUM>) de = <NUM>%, [α]D<NUM> = -<NUM> (c = <NUM>/mL, MeOH).

Prepared from IIa and <NUM>,<NUM>,<NUM>-trifluoro-<NUM>-hydroxy-<NUM>-(trifluoromethyl)butanoic acid. Yield: <NUM>, (<NUM>%) <NUM>H NMR (DMSO-d<NUM> <NUM>): δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>),<NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (d, J = <NUM>, <NUM>).

Chiral HPLC: tR = <NUM>, (HPLC Method <NUM>), de = <NUM>%, [α]D<NUM> = -<NUM> (c = <NUM>/<NUM>, MeOH).

Prepared from IIa and IIId. Yield: <NUM> (<NUM>%).

The diastereomers were separated by chiral SFC.

<NUM>H NMR (CDCl<NUM> <NUM>): δ <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (quin, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>).

Prepared from IIa and IIIe. Yield: <NUM>, (<NUM>%).

Separated by by flash chromatography on silica gel (Eluent of <NUM> ~ <NUM>% Ethyl acetate/petroleum ether gradient).

<NUM>H NMR (CDCl<NUM> <NUM>): δ <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (quin, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>).

<NUM>H NMR (CDCl<NUM> <NUM>): δ <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (quin, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>).

Prepared from IIa and IIIf. The crude was used directly in the next step.

Separated by flash chromatography on silica gel (Eluent of <NUM>~<NUM>% Ethyl acetate/petroleum ether gradient).

<NUM>H NMR (CDCl<NUM> <NUM>): δ <NUM> (t, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>).

<NUM>H NMR (CDCl<NUM> <NUM>): δ <NUM> (t, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>). LC-MS: tR = <NUM> (LCMS Method <NUM>), m/z = <NUM> [M + H]+.

Prepared from IIa and <NUM>-(<NUM>-hydroxycyclopentyl)acetic acid. Yield: <NUM>, (<NUM>%).

<NUM>H NMR (<NUM>, CDCl<NUM>) δ <NUM> (t, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>).

LC-MS: tR = <NUM> (LCMS Method <NUM>), m/z = <NUM> [M + H]+,
SFC: tR = <NUM>. (SFC Method <NUM>), de = <NUM>%, [α]D<NUM> = -<NUM>, (c = <NUM>/mL, MeOH).

Prepared from IIb and IIIg. Yield: <NUM>, (<NUM>%).

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>).

LC-MS: tR = <NUM> (LCMS Method <NUM>), m/z = <NUM> [M + H-<NUM>]+.

SFC: tR = <NUM> (SFC Method <NUM>), de = <NUM>%, [α]D<NUM> = -<NUM> (c = <NUM>/mL, MeOH).

<NUM>H NMR (<NUM>, DMSO-d<NUM>) δ <NUM> (br d, J = <NUM>, <NUM>), <NUM> (t, J = <NUM>, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>).

SFC: tR = <NUM>. (SFC Method <NUM>), de = <NUM>%, [α]D<NUM> = -<NUM> (c = <NUM>/mL, MeOH).

Prepared from IIb and <NUM>,<NUM>,<NUM>-trifluoro-<NUM>-hydroxy-<NUM>-methyl-butanoic acid. Yield: <NUM>, (<NUM>%).

<NUM>H NMR (CDCl<NUM>, <NUM>) δ <NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (br d, J = <NUM>, <NUM>), <NUM> (s, <NUM>), <NUM> (quin, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> (s, <NUM>); LC-MS: tR = <NUM> (LCMS Method <NUM>), m/z = <NUM> [M + H]+.

<NUM>H NMR (CDCl<NUM>, <NUM>) δ<NUM> (t, J = <NUM>, <NUM>), <NUM> (d, J = <NUM>, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> - <NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (quin, J = <NUM>, <NUM>), <NUM> (q, J = <NUM>, <NUM>), <NUM> (dd, J = <NUM>, <NUM>, <NUM>), <NUM> (d, J=<NUM>, <NUM>), <NUM> (s, <NUM>);
LC-MS: tR = <NUM> (LCMS Method <NUM>), m/z = <NUM> [M + H]+.

Claim 1:
A compound of Formula I
<CHM>
wherein
R1 is selected from the group consisting of C<NUM>-C<NUM> alkyl, CF<NUM>, CH<NUM>CF<NUM>, CF<NUM>CHF<NUM>, C<NUM>-C<NUM> cycloalkyl, wherein said C<NUM>-C<NUM> cycloalkyl may be substituted with <NUM> or <NUM> F, CHF<NUM> or CF<NUM>, and R2 is H, C<NUM>-C<NUM> alkyl or CF<NUM>;
or
R1 and R2 combine to form C<NUM>-C<NUM> cycloalkyl optionally substituted with <NUM> or <NUM> F, CHF<NUM> or CF<NUM>;
R3 is C<NUM>-C<NUM> alkyl or CH<NUM>O-C<NUM>-<NUM> alkyl, said C<NUM>-C<NUM> alkyl or CH<NUM>O-C<NUM>-<NUM> alkyl optionally substituted with <NUM> or <NUM> F; and
R4 is selected from the group consisting of OCF<NUM>, OCH<NUM>CF<NUM>, OCHF<NUM>, and CF<NUM>,
for use in the treatment of epilepsy, bipolar disorder, migraine or schizophrenia.