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 of ion channels 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 depressive disorder, 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. Kv7 channel openers have already been disclosed in the prior art, for instance <NPL>)).

<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.

<NPL>, discloses "N-<NUM>-(<NUM>-difluoromethoxyphenyl) ethyl-<NUM>-cyclohexane acetamide".

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. Accordingly, the present invention provides novel compounds suitable as medicaments for the treatment of disorders which are modulated by the KCNQ potassium channels.

The present invention relates to the subject matter of claims <NUM> to <NUM>.

In particular,the present invention relates to a compound of Formula I
<CHM>
wherein.

According to another aspect of the invention, the invention relates to novel compounds as of the present invention.

The invention also concerns a pharmaceutical composition comprising a compound according to the invention and a pharmaceutically acceptable carrier or excipient.

According to an embodiment, the compound of Formula I may have an R4 group which is OCF<NUM> or OCHF<NUM>.

According to another embodiment the compound according to Formula I may have an R3 group is selected from the group comprising CH2-O-CF<NUM> and CH2-C≡N.

According to a further embodiment, the compound according to Formula I may have an R1 group which is C<NUM>-C<NUM> cycloalkyl, optionally substituted with <NUM> or <NUM> C<NUM>-C<NUM> alkyl, F, CHF<NUM> or CF<NUM>.

In yet another embodiment the compound according to any Formula I may have an R1 group and an R2 group, which combine to form cyclobutyl optionally substituted with <NUM> or <NUM> F, and R4 is OCF<NUM> or OCHF<NUM>.

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

or a pharmaceutically acceptable salt of any of these compounds.

Another aspect of the invention relates to a compound selected from the group consisting of:.

and (S)-<NUM>-(<NUM>-fluorocyclopropyl)-<NUM>-hydroxy-N-((R)-<NUM>-methoxy-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethyl)butanamide or a pharmaceutically acceptable salt of any of these compounds.

Reference to compounds encompassed by the present invention includes racemic mixtures as well as optically pure isomers of the compounds for which this is relevant, as well as tautomeric forms the compounds for which this is relevant. Furthermore, the compounds of the present invention may potentially exist in polymorphic and amorphic forms, or as unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like.

The present invention also includes isotopelabeled forms of the compounds of the invention, such as Deuterium. The compound may also incorporate positron-emitting isotopes for medical imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors. Suitable positron-emitting isotopes that can be incorporated in compounds of the invention are 11C, 13N, <NUM>, and 18F. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically-labeled reagent in place of non-isotopically-labeled reagent.

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

The compounds of the invention are suitable for use in therapy.

The compounds according to the invention are suitable 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 depressive disorder, anxiety, panic attacks, social phobia, sleep disturbances, ADHD, PTSD, OCD, impulsivity disorders, personality disorders, schizotypical disorder, aggression, chronic pain, neuropathy, autism spectrum disorders, Huntington's chorea, sclerosis, multiple sclerosis, Alzheimer's disease.

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

Pharmaceutical compositions comprising a compound of 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, for instance 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 according to the invention, such as one of the compounds disclosed in the Experimental Section herein. The present invention also provides a process for making a pharmaceutical composition comprising a compound according to the invention. The pharmaceutical compositions 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, 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, 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, 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 a 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 of 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 of the 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 of the present invention.

When compounds of the present invention contain one or more chiral atoms, reference to 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 of the 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 of the 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.

The compounds according to the invention are suitable for use in the treatment of epilepsy, including the use in the treatment of Focal (partial) epilepsy with simple partial seizures, Focal (partial) epilepsy with complex partial seizures, Generalized idiopathic epilepsy, Grand mal seizures, Status epilepticus, neonatal seizures, KCNQ epileptic encephalopathy (KCNQ2EE) and Benign Familial Neonatal Convulsions and other epileptic syndromes (such as severe myoclonic epilepsy in infancy, epilepsy with continuous spike waves during slow-wave sleep, West syndrome, Lennox-Gastaut syndrome, Dravet syndrome and Early myoclonic encephalopathy Ohtahara syndrome), or seizures related to stress, hormonal changes, drugs, alcohol, infection, traumatic brain injury, stroke, brain cancers, autism spectrum disorders or metabolic disturbances (such as hyponatraemia), or for use in the epileptic symptoms as part of neurogenerative disorders, such as Alzheimer's disease, Lewy body disease, Huntington's disease juvenile form, fronto-temporal lobar degeneration.

The classification of epilepsy can be based on ICD-<NUM> (<NUM>, published by WHO) and is described in section G40 and G41, and is included in the treatment of epilepsy according to the invention.

A seizure is a sudden, uncontrolled electrical disturbance in the brain. It can cause changes in behavior, movements or feelings, and in levels of consciousness. If a person has two or more seizures or a tendency to have recurrent seizures this is diagnosed as epilepsy.

There are many types of seizures, which range in severity. Seizure types vary by where and how they arise in the brain. Most seizures last from <NUM> seconds to two minutes.

Focal seizures result from abnormal electrical activity in one area of the brain. Focal seizures can occur with or without loss of consciousness:.

Seizures that appear to involve all areas of the brain are called generalized seizures. Different types of generalized seizures include:.

Many times, siezures may be associated or caused by:.

Headings and sub-headings are used herein for convenience only and should not be construed as limiting the invention in any way.

The use of any and all examples, or exemplary language (including "for instance", "for example", "e.g.", and "as such") in the present specification is intended merely to better illustrate the invention and does not pose a limitation on the scope of invention unless otherwise indicated.

The citation and incorporation of patent documents herein is done for convenience only, and does not reflect any view of the validity, patentability and/or enforceability of such patent documents.

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. A 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 of the invention had the following biological activity:.

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. Within the scope of the present invention are variations of the described procedures, which are known to a person skilled in the art.

The compounds of 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.

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 (<NUM>-[bis(dimethylamino)methylene]-<NUM>-<NUM>,<NUM>,<NUM>-triazolo[<NUM>,<NUM>-b]pyridinium <NUM>-oxid hexafluorophosphate (HATU) and a suitable base such as diisopropylethylamine (DIPEA), in a solvent such as dichloromethane (DCM).

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 <NUM>-dimethylamino pyridine (DMAP).

The optically active amines of general Formula II can be prepared as outlined in Scheme 2a:
<CHM>
<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 XV 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.

In variations of this procedure, an R<NUM> substituent bearing a functional group can be further modified, by standard functional group conversion methodology known to the chemist skilled in the art. Examples of such manipulations for the preparation of chiral amines are illustrated in Scheme 2b. An intermediate of general Formula VII in which R<NUM> = allyl can be formed from XV and allyl-MgBr, and can undergo catalytic reduction to R<NUM> = n-propyl, using H<NUM>(g) in the presence of a suitable catalyst such as Pd/C, in a suitable solvent such as ethyl acetate. Alternatively, the intermediate of general Formula VII in which R<NUM> = allyl can undergo di-hydroxylation followed by oxidative cleavage to yield an intermediate VII in which R<NUM> = acetaldehyde, by treatment with suitable catalysts such as K<NUM>OsO<NUM> and NaIO<NUM>, in the presence of a suitable base such as <NUM>,<NUM>-lutidine, and in a suitable solvent such as dioxane/H<NUM>O. The obtained aldehyde can undergo additional transformations; for example exchange of oxygen for two fluorine atoms by treatment with a suitable reagent such as (diethylamino)sulfur triflouride (DAST), in a suitable solvent such as DCM. In a final step, chiral amines can be obtained by hydrolysis as described above.

As another example, an intermediate of general Formula XVI in which R<NUM> is an acetic acid ester, can be formed from XV in a reaction with ethyl <NUM>-bromo acetate, in the presence of CuCl and activated Zn, in a suitable solvent such as THF. The ester group can be further derivatized by transformations known to the skilled chemist. For example, the ester can be reduced to a primary alcohol, by treatment with a suitable reducing agent such as LiAlH<NUM>, in a suitable solvent, such as THF. The alcohol obtained may also be further derivatized through transformations known to the skilled practitioner. For example, the alcohol may be transformed into a leaving group through activation with a reagent such as mesyl chloride in the presence of a suitable base such as triethyalmine (TEA), in a suitable solvent such as DCM. The resulting mesylates can be reacted with a suitable nucleophile, such as potassium cyanide, in a suitable solvent such as DMSO.

Aldehydes of general Formula VI can also be transformed into chiral amines of general Formula II via an alternative strategy, as illustrated in Scheme 2c:
<CHM>.

Following this procedure, suitably substituted benzaldehydes VI can be transformed into corresponding suitably substituted styrenes, using Wittig methodology known to the skilled chemist. These intermediates can undergo an alkylation-oxidation reaction to form ketointermediates XVII. Intermediates of general Formula XVII can be condensed with (R)-<NUM>-methylpropane-<NUM>-sulfinamide in a suitable solvent such as dichloroethane, in the presence of a suitable drying agent, such as titanium(IV)ethoxide. The formed sulfinyl imine can be reduced with a suitable reducing agent such as L-Selectride, in a suitable inert solvent such as THF, to yield the corresponding suitably substituted (R)-<NUM>-methyl-N-((S)-<NUM>-aryl-alkyl)propane-<NUM>-sulfinamide, which can be converted to chiral amines of general Formula II by treatment with an appropriate acid in an appropriate solvent, such as HCl in MeOH.

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

The aldehydes of Formula VI, used to prepare the compounds of the invention, are commercially available, or may be prepared as described in the literature, see <NPL>.

In another procedure, the chiral amines of Formula II can be obtained from an aryl ketone, through hydride reduction of the intermediate sulfinyl imine obtained from reaction with (R)-<NUM>-methylpropane-<NUM>-sulfinamide, with a reagent such as L-Selectride; as shown in Scheme 3a.

A variation of this procedure is illustrated in Scheme 3b. In this procedure, further R<NUM> substituents which are ethers, can be installed from a common alpha bromoacetophenone intermediate XI, obtained by bromination of a suitably substituted acetophenone. Examples include, but are not limited to introduction of fluoroalkyl methylene ether groups as R<NUM>. Thus, using this methodology, suitably substituted bromoacetophenone can be reacted with a fluoroalkoxy donor, such as trifluoromethyl trifluoromethanesulfonate and KF under Finkelstein conditions, in a suitable solvent such as dimethylacetamide (DMA), to give intermediate XII, which can be further transformed into chiral amines as described above. Other examples include, but are not limited to introduction of alkyl methylene ethers as R<NUM>. Thus, suitably substituted bromoacetophenone can be transformed into acyl diazo intermediate XIII, by reaction with <NUM>-methyl-N'-(p-tolylsulfonyl)benzenesulfonohydrazide in the presence of a suitable base, such as <NUM>,<NUM>-diazabicyclo[<NUM>. <NUM>]undec-<NUM>-ene (DBU), and in a suitable solvent such as THF. The intermediate XIII can undergo a carbene formation reaction, by treatment with a suitable catalyst such as Indium triflate, in a suitable solvent such as toluene. The formed carbene can be trapped in situ by a suitable alcohol, to yield alkoxy keto intermediates XIV. From intermediate XIV, chiral amines of Formula II can be obtained through standard manipulations as described above.

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

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

Another procedure suited for accessing chiral amines of general Formula II, in which R<NUM> is an ether, 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, re-protected with a suitable protecting group such as Boc under standard conditions, and subjected to ester reduction under suitable conditions such as LiAlH<NUM> in THF, to yield alcohol intermediates of general Formula IX. Intermediates of Formula IX may be further derivatised to access the desired R<NUM> substituent. For example, the alcohol group in intermediates IX may be difluoromethylated using a suitable reagent such as <NUM>,<NUM>-difluoro-<NUM>-(fluorosulfonyl) acetic acid under conditions such as CuI activation, in a suitable solvent such as acetonitrile, or; the alcohol group in IX may be alkylated using simple alkyl halides, such as methyl iodide, in the presence of a suitable base such as NaH in a suitable solvent such as THF. Alternatively, the alcohol of intermediates IX may be transformed into a leaving group through activation with a reagent such as mesyl chloride in the presence of a suitable base such as TEA, in a suitable solvent such as DCM. The resulting mesylates can be reacted with a suitable nucleophile, such as potassium cyanide, in a suitable solvent such as DMSO.

A 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 (trimethylsilyl chloride). 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.

Carboxylic acid ester of general Formula IV (R = Me, Et) are commercially available, or may be prepared as outlined in Scheme <NUM>:
<CHM>.

Suitably substituted carboxylic acids can be activated using a suitable reagent such as CDI and condensed with potassium <NUM>-ethoxy-<NUM>-oxo-propanoate in the presence of MgCl<NUM>, to yield intermediates of general Formula IV.

<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 an 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.

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 (2R)-<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>) in THF (<NUM>), and Boc<NUM>O (<NUM>), NaHCO<NUM> (<NUM>) was added and stirred at <NUM> for <NUM> hours. The mixture was concentrated and purified by chromatography on silica (petroleum ether:ethyl acetate=<NUM>:<NUM>) to afford the product (<NUM>).

To a suspension of LiAlH<NUM> (<NUM>) in THF (<NUM>) was added ethyl (R)-<NUM>-((tert-butoxycarbonyl)amino)-<NUM>-(<NUM>-(difluoromethoxy)phenyl)acetate (<NUM>) in THF (<NUM>), with ice-cooling. 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 (petroleum ether:ethyl acetate=<NUM>:<NUM>) (<NUM>).

To a solution of tert-butyl (R)-(<NUM>-(<NUM>-(difluoromethoxy)phenyl)-<NUM>-hydroxyethyl)carbamate (<NUM>) in MeCN (<NUM>), CuI (<NUM>) was added and stirred at <NUM> under N<NUM> atmosphere for <NUM> minutes. A solution of <NUM>,<NUM>-difluoro-<NUM>-fluorosulfonyl-acetic acid (<NUM>) in MeCN (<NUM>) was added at <NUM> over <NUM> minutes, and the reaction was stirred at <NUM> for <NUM> hour. The 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 (R)-(<NUM>-(difluoromethoxy)-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethyl)carbamate (<NUM>) in MeOH (<NUM>), was added HCl/MeOH (<NUM> in MeOH, <NUM>) at <NUM>, and the reaction was stirred at <NUM> for <NUM> minutes. Ammonium hydroxide (<NUM>%) was added to pH=<NUM>, the solution was concentrated and purified by chromatography on silica (petroleum ether: ethyl acetate = <NUM>:<NUM>) to afford (R)-<NUM>-(difluoromethoxy)-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethan-<NUM>-amine (<NUM>).

To a mixture of <NUM>-methylbenzenesulfonohydrazide (<NUM>) and <NUM>-methylbenzenesulfonyl chloride (<NUM>) DCM (<NUM>) was added. The mixture was cooled to <NUM> and pyridine (<NUM>) was added dropwise, and the reaction mixture was stirred at <NUM> for <NUM> hour and <NUM> for <NUM> hours. The mixture was added water (<NUM>) and methyl-tert-butyl ether (METB) (<NUM>) and filtered. The filter cake was washed with METB (<NUM>) and dried to give <NUM>-methyl-N'-(p-tolylsulfonyl)benzenesulfonohydrazide (<NUM>).

<NUM> NMR (DMSO-d6 <NUM>): δ <NUM> (s, <NUM>), <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>).

To a solution of <NUM>-[<NUM>-(difluoromethoxy)phenyl]ethanone (<NUM>) in dioxane (<NUM>) was added a solution of Br<NUM> (<NUM>) in dioxane (<NUM>). The resulting mixture was stirred at <NUM> for <NUM> hours. NaHCO<NUM> solution (<NUM>) and H<NUM>O (<NUM>) were added, and the aqueous phase was extracted with EtOAc (<NUM>×<NUM>). The organic phase was washed with brine (<NUM>), dried over Na<NUM>SO<NUM> and concentrated to give <NUM>-bromo-<NUM>-[<NUM>-(difluoromethoxy)phenyl]ethanone (<NUM>).

<NUM> NMR (CDCl3 <NUM>): δ <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM> (t, <NUM>), <NUM> (d, <NUM>), <NUM> (t, <NUM>), <NUM> (s, <NUM>).

To a solution of <NUM>-bromo-<NUM>-[<NUM>-(difluoromethoxy)phenyl]ethanone (<NUM>) and <NUM>-methyl-N'-(p-tolylsulfonyl)benzenesulfonohydrazide (<NUM>) in THF (<NUM>), DBU (<NUM>) was added dropwise at <NUM>. The reaction mixture was stirred at <NUM> for <NUM> hour and <NUM> for <NUM> hours. The mixture was quenched by sat. NaHCO<NUM> (<NUM>) and diluted with water (<NUM>), then extracted with EtOAc (<NUM>×<NUM>). The organic layer was washed with brine (<NUM>), dried over Na<NUM>SO<NUM> and concentrated. The crude was purified by column chromatograph on silica gel (<NUM>% EtOAc in Petroleum ether) to give <NUM>-(<NUM>-(difluoromethoxy)phenyl)-<NUM>-iminoethan-<NUM>-one (<NUM>).

<NUM> NMR (CDCl<NUM>, <NUM>): δ <NUM> (dt, <NUM>), <NUM> (s, <NUM>), <NUM> (t, <NUM>), <NUM> (dd, <NUM>), <NUM> (t, <NUM>), <NUM> (s, <NUM>).

To a solution of cyclopropanol (<NUM>) and <NUM>-diazo-<NUM>-[<NUM>-(difluoromethoxy) phenyl]ethanone (<NUM>) in toluene (<NUM>) was added indium(III) triflate (<NUM>) under N<NUM>. The resulting mixture was stirred at <NUM> for <NUM> hours. The mixture was quenched by sat. NaHCO<NUM> (<NUM>) and diluted with H<NUM>O (<NUM>), and then extracted with EtOAc (<NUM>×<NUM>). The organic layer was washed with brine (<NUM>×<NUM>), dried over Na<NUM>SO<NUM> and concentrated. The crude was purified by column chromatograph on silica gel (<NUM>% EtOAc in Petroleum ether) to give <NUM>-cyclopropoxy-<NUM>-(<NUM>-(difluoromethoxy)phenyl)ethan-<NUM>-one (<NUM>).

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

To a solution of <NUM>-(cyclopropoxy)-<NUM>-[<NUM>-(difluoromethoxy)phenyl]ethanone (<NUM>) and (R)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>) in THF (<NUM>) was added Ti(OEt)<NUM> (<NUM>). The resulting mixture was stirred at <NUM> for <NUM> hours and then used directly in the next step.

To the solution of (R,Z)-N-(<NUM>-cyclopropoxy-<NUM>-(<NUM>-(difluoromethoxy)phenyl)ethylidene)-<NUM>-methylpropane-<NUM>-sulfinamide in THF (<NUM>) from the previous step, was added a solution of L-selectride (<NUM> in THF, <NUM>) dropwise at -<NUM>. The mixture was stirred at -<NUM> for <NUM> hour, and was quenched by MeOH (<NUM>) and H<NUM>O (<NUM>), and filtered on celite. The filtrate was extracted with EtOAc (<NUM>×<NUM>), the organic layer was washed with brine (<NUM>×<NUM>), dried over Na<NUM>SO<NUM> and concentrated. The crude was purified by column chromatograph on silica gel (<NUM>~<NUM>% EtOAc in Petroleum ether) to give (R)-N-((R)-<NUM>-cyclopropoxy-<NUM>-(<NUM>-(difluoromethoxy)phenyl)ethyl)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>).

To a solution of (R)-N-((R)-<NUM>-cyclopropoxy-<NUM>-(<NUM>-(difluoromethoxy)phenyl)ethyl)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>) in MeOH (<NUM>) was added HCl/MeOH (<NUM>). The resulting mixture was stirred at <NUM> for <NUM> hour and concentrated to give (1R)-<NUM>-(cyclopropoxy)-<NUM>-[<NUM>-(difluoromethoxy)phenyl]ethanamine hydrochloride (<NUM>, crude).

Prepared as described for IIc using <NUM>-[<NUM>-(trifluoromethoxy)phenyl] ethanone as starting material.

To a solution of <NUM>-[<NUM>-(difluoromethoxy)phenyl]ethanone (<NUM>) in dioxane (<NUM>) was added a solution of Br2 (<NUM>) in dioxane (<NUM>) at <NUM>. This mixture was stirred at <NUM> for <NUM> hour, then diluted by EtOAc (<NUM>) and washed by water (<NUM>×<NUM>). The organic phase was dried over anhydrous Na<NUM>SO<NUM> and concentrated. The residue was purified by column of chromatography on silica gel (Petroleum ether: EtOAc = <NUM>:<NUM>) to afford <NUM>-bromo-<NUM>-[<NUM>-(difluoromethoxy)phenyl]ethanone (<NUM>).

To a solution of KF (<NUM>) in DMA (<NUM>) was added trifluoromethyl trifluoromethanesulfonate (<NUM>) at <NUM>. The reaction mixture was stirred in a sealed tube for <NUM> hour, then <NUM>-bromo-<NUM>-[<NUM>-(difluoromethoxy)phenyl]ethanone (<NUM>, <NUM> mmol) and KI (<NUM>) were added to this solution at <NUM> and was taken to <NUM> and stirred for <NUM> hours. The mixture was diluted with EtAOc (<NUM>) and washed with water (<NUM>×<NUM>). The organic phase was concentrated to yield the product, which was purified by acidic preparative HPLC (<NUM>).

<NUM> NMR (CDCl<NUM> <NUM>): δ <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM> (t, <NUM>), <NUM> (d, <NUM>), <NUM> (t1H), <NUM> (s, <NUM>). 19F NMR (CDCl3 <NUM>): δ -<NUM>, -<NUM>,-<NUM>.

A mixture of <NUM>-(<NUM>-(difluoromethoxy)phenyl)-<NUM>-(trifluoromethoxy)ethan-<NUM>-one (<NUM>), (R)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>) and Ti(OEt)<NUM> (<NUM>) in THF (<NUM>) was stirred at <NUM> under N<NUM> for <NUM> hours. The product (<NUM>, crude) in THF (<NUM>) was obtained and used directly in the next step.

To a solution of (R)-N-(<NUM>-(<NUM>-(difluoromethoxy)phenyl)-<NUM>-(trifluoromethoxy) ethylidene)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>) in THF (<NUM>) was added L-selectride (<NUM> in THF, <NUM>) at -<NUM>. The mixture was stirred at -<NUM> for <NUM> hour and then diluted with EtOAc (<NUM>) and washed with water (<NUM>×<NUM>). The organic phase was dried, filtered and concentrated. The crude product was purified by chromatography on silica gel (Petroleum ether/Ethyl acetate = <NUM>:<NUM>) to afford (R)-N-((R)-<NUM>-(<NUM>-(difluoromethoxy)phenyl)-<NUM>-(trifluoromethoxy)ethyl)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>).

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

To a solution of (R)-N-((R)-<NUM>-(<NUM>-(difluoromethoxy)phenyl)-<NUM>-(trifluoromethoxy)ethyl)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>) in MeOH (<NUM>) was added HCl/MeOH (<NUM> in MeOH, <NUM>). This mixture was stirred at <NUM> for <NUM> hour, and then concentrated to afford ((R)-<NUM>-(<NUM>-(difluoromethoxy)phenyl)-<NUM>-(trifluoromethoxy)ethan-<NUM>-amine hydrochloride (<NUM>, crude).

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

Prepared as described for IIe using <NUM>-[<NUM>-(trifluoromethoxy)phenyl]ethanone as starting material. <NUM>H NMR (CDCl<NUM> <NUM>): δ <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>).

To a solution of <NUM>-(difluoromethoxy)benzaldehyde (<NUM>) and(R)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>) in DCE (<NUM>) was added CuSO<NUM> (<NUM>). The mixture was stirred at <NUM> for <NUM> hours. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (SiO<NUM>, Petroleum ether/Ethyl acetate = <NUM>/<NUM> to <NUM>:<NUM>) to afford the product (<NUM>).

To a solution of (R)-N-(<NUM>-(difluoromethoxy) benzylidene)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>) in DCM (<NUM>) was slowly added allyl(bromo)magnesium (<NUM> solution in THF, <NUM>) at <NUM>. The resulting mixture was stirred at <NUM> for <NUM> hour and <NUM> for <NUM> hours. The reaction mixture was quenched by addition of saturated NH<NUM>Cl (<NUM>) at <NUM>, then diluted with H<NUM>O (<NUM>) and extracted with DCM (<NUM>×<NUM>). The combined organic phases were washed with H<NUM>O (<NUM>), dried over Na<NUM>SO<NUM>, filtered and concentrated. The residue was purified by column chromatography (SiO<NUM>, Petroleum ether/Ethyl acetate = <NUM>/<NUM> to <NUM>:<NUM>) to afford (R)-N-((S)-<NUM>-(<NUM>-(difluoromethoxy)phenyl)but-<NUM>-en-<NUM>-yl)-<NUM>-methylpropane-<NUM>-sulfinamide(<NUM>).

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

To a solution of (R)-N-((S)-<NUM>-(<NUM>-(difluoromethoxy)phenyl)but-<NUM>-en-<NUM>-yl)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>) in EtOAc (<NUM>) was added Pd/C (<NUM>, <NUM>% purity) under N<NUM>. The suspension was degassed under vacuum and purged with H<NUM> several times. The mixture was stirred under H<NUM> (18psi) at <NUM> for <NUM> hour. The reaction mixture was filtered and concentrated to afford (R)-N-((S)-<NUM>-(<NUM>-(difluoromethoxy)phenyl)butyl)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>).

To a solution of (R)-N-((S)-<NUM>-(<NUM>-(difluoromethoxy) phenyl)butyl)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>) in MeOH (<NUM>) was added HCl/MeOH (<NUM>, <NUM>). The mixture was stirred at <NUM> for <NUM> hours and then concentrated to afford (<NUM>)-<NUM>-[<NUM>-(difluoromethoxy) phenyl] butan-<NUM>-amine hydrochloride (<NUM>).

To a solution of methyl triphenylphosphonium iodide (<NUM>) in DME (<NUM>) was added K<NUM>CO<NUM> (<NUM>). The resulting mixture was stirred at <NUM> for <NUM> hour, then <NUM>-(difluoromethoxy)benzaldehyde (<NUM>) was added and stirred continued at <NUM> for <NUM> hours. The mixture was filtered, and filtercake was washed with petroleum ether (<NUM>). The filtrate was concentrated and purified by column chromatography (SiO<NUM>, Petroleum ether/Ethyl acetate = <NUM>/<NUM> to <NUM>/<NUM>) to afford <NUM>-(difluoromethoxy)-<NUM>-vinyl-benzene (<NUM>).

<NUM>H NMR (CDCl3 <NUM>): δ <NUM> (t, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM> (d, <NUM>), <NUM> (t, <NUM>), <NUM> (t, <NUM>), <NUM> (d, <NUM>), <NUM> (d, <NUM>).

To a solution of <NUM>,<NUM>-difluoro-<NUM>-iodo-ethane (<NUM>), <NUM>-(difluoromethoxy)-<NUM>-vinyl- benzene (<NUM>), bis[(Z)-<NUM>-methyl-<NUM>-oxo-but-<NUM>-enoxy]copper (<NUM>) and Ag<NUM>SO<NUM> (<NUM>) in ACN (<NUM>) was added Et<NUM>N (<NUM>) and tert-butyl hydroperoxide (TBHP) (<NUM>, <NUM>% in water). The resulting mixture was stirred at <NUM> for <NUM> hours. The reaction was quenched with saturated aq. Na<NUM>S<NUM>O<NUM> and extracted with DCM (<NUM>×<NUM>). The organic phases were combined, 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 = <NUM>/<NUM> to <NUM>/<NUM>) to afford <NUM>-(<NUM>-(difluoromethoxy)phenyl)-<NUM>,<NUM>-difluorobutan-<NUM>-one (<NUM>).

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

To a solution of <NUM>-(<NUM>-(difluoromethoxy)phenyl)-<NUM>,<NUM>-difluorobutan-<NUM>-one (<NUM>) and (R)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>) in THF (<NUM>) was added Ti(OEt)<NUM> (<NUM>). The mixture was stirred at <NUM> for <NUM> hours. The reaction mixture was used directly in the next step.

L-selectride (<NUM> in THF, <NUM>) was added to a solution of (S)-N-(<NUM>-(<NUM>-(difluoromethoxy)phenyl)-<NUM>,<NUM>-difluorobutylidene)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>) in THF at -<NUM>. The reaction mixture was stirred for <NUM> hour, then it was taken to <NUM> and H<NUM>O (~<NUM>) was added. The resulting mixture was extracted with EtOAc (<NUM>×<NUM>). The organic extracts were washed with brine (<NUM>), dried over Na<NUM>SO<NUM> and concentrated. The residue was purified by column chromatography (SiO<NUM>, Petroleum ether/Ethyl acetate = <NUM>/<NUM> to <NUM>/<NUM>) to afford N-[(<NUM>S)-<NUM>-[<NUM>-(difluoromethoxy)phenyl]-<NUM>,<NUM>-difluoro-butyl]-<NUM>-methyl- propane-<NUM>-sulfinamide (<NUM>).

N-[(<NUM>S)-<NUM>-[<NUM>-(difluoromethoxy)phenyl]-<NUM>,<NUM>-difluoro-butyl]-<NUM>-methyl-propane-<NUM>-sulfinamide (<NUM>) in MeOH (<NUM>) and HCl/MeOH (<NUM>, <NUM>) was stirred at <NUM> for <NUM> hour. The mixture was concentrated to afford (S)-<NUM>-(<NUM>-(difluoromethoxy)phenyl)-<NUM>,<NUM>-difluorobutan-<NUM>-amine hydrochloride (<NUM>).

To a solution of <NUM>-(difluoromethoxy)benzaldehyde (<NUM>) and (R)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>) in DCE (<NUM>) was added CuSO<NUM> (<NUM>). The reaction mixture was stirred at <NUM> for <NUM> hours, and then filtered and concentrated. The crude product was purified by chromatography on silica (SiO<NUM>, Petroleum ether/Ethyl acetate = <NUM>/<NUM> to <NUM>/<NUM>) to afford (S,E)-N-(<NUM>-(difluoromethoxy) benzylidene)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>).

<NUM>H NMR (CDCl<NUM> <NUM>): δ <NUM> (s, <NUM>), <NUM> (d, <NUM>), <NUM> (s, <NUM>), <NUM> (t, <NUM>), <NUM> (d, <NUM>), <NUM> (t, <NUM>), <NUM> (s, <NUM>).

To a solution of (S,E)-N-(<NUM>-(difluoromethoxy)benzylidene)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>) in DCM (<NUM>) was slowly added allyl(bromo)magnesium (<NUM> solution in THF, <NUM>) at <NUM>. The reaction mixture was stirred at <NUM> for <NUM> hour and <NUM> for <NUM> hours. The reaction was quenched by addition of sat. NH<NUM>Cl (<NUM>) at <NUM>, and then diluted with H<NUM>O (<NUM>) and extracted with DCM (<NUM>×<NUM>). The combined organic phases were washed with H<NUM>O (<NUM>), dried over Na<NUM>SO<NUM>, filtered and concentrated. The residue was purified by chromatography (SiO<NUM>, Petroleum ether/Ethyl acetate = <NUM>/<NUM> to <NUM>/<NUM>) to afford (S)-N-((S)-<NUM>-(<NUM>-(difluoromethoxy)phenyl)but-<NUM>-en-<NUM>-yl)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>).

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

Potassium dioxido(dioxo)osmium hydrate (<NUM>) was added in one portion to a stirred solution of S)-N-((S)-<NUM>-(<NUM>-(difluoromethoxy)phenyl)but-<NUM>-en-<NUM>-yl)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>), <NUM>,<NUM>-lutidine (<NUM>) and sodium periodate (<NUM>) in a mixture of dioxane (<NUM>) and H<NUM>O (<NUM>). The reaction mixture was stirred at <NUM> for <NUM> hour and then diluted with DCM (<NUM>) and water (<NUM>). The aqueous layer was extracted with DCM (<NUM>×<NUM>). The combined organic extracts were dried over Na<NUM>SO<NUM>. The crude reaction mixture was used directly in the next step.

To a solution of (S)-N-((S)-<NUM>-(<NUM>-(difluoromethoxy)phenyl)-<NUM>-oxopropyl)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>) in DCM (<NUM>) was added dropwise diethylaminosulfur trifluoride (DAST) (<NUM>) at - <NUM>. The reaction mixture was allowed to come to <NUM> and was stirred for <NUM> hours. The solution was poured into saturated aqueous NaHCO<NUM> (<NUM>) and the organic phase was separated. This solution was dried over anhydrous Na<NUM>SO<NUM> and concentrated. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate = <NUM>/<NUM> to <NUM>/<NUM>) to afford (S)-N-((S)-<NUM>-(<NUM>-(difluoromethoxy)phenyl)-<NUM>,<NUM>-difluoropropyl)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>).

To a solution of (S)-N-((S)-<NUM>-(<NUM>-(difluoromethoxy)phenyl)-<NUM>,<NUM>-difluoropropyl)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>) in MeOH (<NUM>) was added HCl/MeOH (<NUM>, <NUM>) at <NUM> and the reaction was stirred from for <NUM> hour, and was allowed to come to <NUM>. The reaction mixture was concentrated to afford (<NUM>)-<NUM>-[<NUM>-(difluoromethoxy)phenyl]-<NUM>,<NUM>-difluoro-propan- <NUM>-amine hydrochloride (<NUM>, crude, HCl salt). Used directly without further purification.

To a mixture of <NUM>-(difluoromethoxy)benzaldehyde (<NUM>) and (R)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>) in DCE (<NUM>) was added CuSO<NUM> (<NUM>) at <NUM> under N<NUM>. The reaction mixture was stirred at <NUM> for <NUM> hours, filtered and the filtrated was concentrated. The crude product was purified by chromatography on silica gel column (Petroleum ether/Ethyl acetate = <NUM>:<NUM>-<NUM>:<NUM>) to give ((S,E)-N-(<NUM>-(difluoro-methoxy)benzylidene)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>).

To a solution of ((S,E)-N-(<NUM>-(difluoro-methoxy)benzylidene)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>) 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 by aq. NH<NUM>Cl (<NUM>), and the aqueous phase was extracted with ethyl acetate (<NUM>×<NUM>). The combined organic extracts were washed with brine (<NUM>×<NUM>), dried with anhydrous Na<NUM>SO<NUM>, filtered, concentrated and purified by chromatography on silica gel (Petroleum ether/Ethyl acetate = <NUM>:<NUM>-<NUM>:<NUM>) to afford (S)-N-((S)-<NUM>-(<NUM>-(difluoromethoxy)phenyl)ethyl)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>).

To a solution of (S)-N-((S)-<NUM>-(<NUM>-(difluoromethoxy) phenyl)ethyl)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>) in MeOH (<NUM>) was added HCl/MeOH (<NUM>, <NUM>). The resulting mixture was stirred at <NUM> for <NUM> hours, and concentrated to afford (S)-<NUM>-(<NUM>-(difluoromethoxy) phenyl)ethan-<NUM>-amine hydrochloride
(<NUM>, crude).

To a solution of ethyl <NUM>-oxoacetate (<NUM>) and (R)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>) in DCM (<NUM>) under N<NUM> was added CuSO<NUM> (<NUM>) and the reaction mixture was stirred at <NUM> for <NUM> hours. The solid was filtered off, washed with ethyl acetate (<NUM>) and the organic layer was concentrated. The residue was purified by chromatography (SiO<NUM>, hexane/ethyl acetate, <NUM>/<NUM>) to yield ethyl (R,E)-<NUM>-((tert-butylsulfinyl)imino)acetate (<NUM>).

To a solution of ethyl (R,E)-<NUM>-((tert-butylsulfinyl)imino)acetate (<NUM>) and [<NUM>-(trifluoromethoxy)phenyl]boronic acid (<NUM>) in dioxane (<NUM>) was added bis(acetonitrile)(<NUM>,<NUM>-cyclooctadiene)rhodium(I)tetrafluoroborate (CAS:<NUM>-<NUM>-<NUM>) (<NUM>) and this mixture was stirred at <NUM> for <NUM> hours. The solution was filtered and the organic phase was concentrated. The residue was purified by chromatography (SiO<NUM>, Petroleum Ether:EtOAc=<NUM>:<NUM>) to afford ethyl (R)-<NUM>-(((S)-tert-butylsulfinyl)amino)-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)acetate (<NUM>).

To a solution of ethyl (R)-<NUM>-(((S)-tert-butylsulfinyl)amino)-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)acetate (<NUM>) in MeOH (<NUM>) was added HCl/MeOH (<NUM>, <NUM>) at <NUM>. The reaction mixture was stirred at <NUM> for <NUM> hour and concentrated to afford ethyl (R)-<NUM>-amino-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)acetate as a hydrochloride salt (<NUM>).

To a mixture of ethyl (R)-<NUM>-amino-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)acetate hydrochloride (<NUM>) in THF (<NUM>) was added Boc<NUM>O (<NUM>) and NaHCO<NUM> (<NUM>) and the reaction was stirred at <NUM> for <NUM> hours. The reaction mixture was concentrated and diluted with EtOAc (<NUM>), washed with water (<NUM>) and then concentrated. The residue was purified by chromatography (SiO<NUM>; Petroleum Ether:EtOAc=<NUM>:<NUM>) to afford ethyl (R)-<NUM>-((tert-butoxycarbonyl)amino)-<NUM>-(<NUM>-(trifluoromethoxy) phenyl)acetate (<NUM>).

To a suspension of LiAlH<NUM> (<NUM>) in THF (<NUM>) was added ethyl (R)-<NUM>-((tert-butoxycarbonyl)amino)-<NUM>-(<NUM>-(trifluoromethoxy) phenyl)acetate (<NUM>) in THF (<NUM>) under ice-cooling, and the mixture was stirred at <NUM> to <NUM> for <NUM> hours. Anhydrous magnesium sulfate was added and then water (<NUM>) and ethyl acetate (<NUM>) were successively added, and the insoluble substances was filtered off using celite. The filtrate was concentrated. The crude product was purified by chromatography (SiO<NUM>, Petroleum Ether:EtOAc =<NUM>:<NUM>) to afford tert-butyl (R)-(<NUM>-hydroxy-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethyl)carbamate (<NUM>).

To a solution of tert-butyl (R)-(<NUM>-hydroxy-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethyl)carbamate (<NUM>) in hexane (<NUM>) was added diethyl sulfate (<NUM>), tetrabutyl ammonium chloride (TBAC) (<NUM>) and a solution of NaOH (<NUM>) in H<NUM>O (<NUM>). The resulting mixture was stirred at <NUM> for <NUM> hours. The reaction mixture was diluted with EtOAc (<NUM>), washed with water (<NUM>) and brine (<NUM>), dried over Na<NUM>SO<NUM> and concentrated. The crude was purified by chromatography (SiO2, <NUM>% EthylAcetate in Petroleum Ether) to give tert-butyl (R)-(<NUM>-ethoxy-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethyl)carbamate (<NUM>).

To a solution of tert-butyl (R)-(<NUM>-ethoxy-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethyl)carbamate (<NUM>) in MeOH (<NUM>) was added HCl/MeOH (<NUM>, <NUM>) at <NUM> and this mixture was stirred at <NUM> for <NUM> hours. The solution was concentrated to afford (R)-<NUM>-ethoxy-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethan-<NUM>-amine hydrochloride (<NUM>).

A mixture of <NUM>-(trifluoromethoxy)benzaldehyde (<NUM>), (R)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>) and CuSO<NUM> (<NUM>) 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 chromatography (SiO<NUM>, <NUM>-<NUM>% Ethylacetate/petroleum ether gradient) to give (S,E)-<NUM>-methyl-N-(<NUM>-(trifluoromethoxy)benzylidene)propane-<NUM>-sulfinamide (<NUM>).

To a solution of (S,E)-<NUM>-methyl-N-(<NUM>-(trifluoromethoxy)benzylidene)propane-<NUM>-sulfinamide (<NUM>) 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 chromatography (SiO<NUM>, <NUM>-<NUM>% ethyl acetate/petroleum ether gradient) to yield the product (<NUM>).

To a solution of (S)-<NUM>-methyl-N-((S)-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)propyl)propane-<NUM>-sulfinamide (<NUM>) 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 purifi-cation (<NUM>).

This intermediate was prepared as described for intermediate IIk, Step <NUM>-<NUM>.

To a solution of tert-butyl (R)-(<NUM>-hydroxy-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethyl)carbamate (<NUM>) in DCM (<NUM>) was added Et<NUM>N (<NUM>), then methanesulfonyl chloride (<NUM>) was added at <NUM>. The mixture was stirred at <NUM> for <NUM> hours. The reaction mixture was washed with saturated aqueous NH<NUM>Cl solution (<NUM>), dried over anhydrous Na<NUM>SO<NUM>, filtered and concentrated to afford (R)-<NUM>-((tert-butoxycarbonyl)amino)-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethyl methanesulfonate (<NUM>, crude) which was used in the next step without purification.

To a solution of (R)-<NUM>-((tert-butoxycarbonyl)amino)-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethyl methanesulfonate (<NUM>) in DMSO (<NUM>) was added KCN (<NUM>) at <NUM>. The mixture was stirred at <NUM> for <NUM> hours. The reaction mixture was diluted with <NUM>% Na<NUM>CO<NUM> solution (<NUM>) and extracted with EtOAc (<NUM>×<NUM>). The combined organic extracts were washed with water (<NUM>) and brine (<NUM>), then dried over Na<NUM>SO<NUM>, filtered and concentrated. The residue was purified by chromatography (SiO<NUM>, Petroleum ether/Ethyl acetate=<NUM>/<NUM> to <NUM>/<NUM>) to afford tert-butyl (S)-(<NUM>-cyano-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethyl)carbamate (<NUM>).

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

To a solution of tert-butyl (S)-(<NUM>-cyano-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethyl)carbamate (<NUM>) in MeOH (<NUM>) was added HCl/MeOH (<NUM>, <NUM>) at <NUM>. The mixture was stirred at <NUM> for <NUM> hours. Then the reaction mixture was concentrated to afford (S)-<NUM>-amino-<NUM>-(<NUM>-(trifluoromethoxy) phenyl)propanenitrile hydrochloride (<NUM>, crude).

To a solution of <NUM>-(trifluoromethoxy)benzaldehyde (<NUM>) and (R)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>) in DCE (<NUM>) was added CuSO<NUM> (<NUM>). The mixture was stirred at <NUM> for <NUM> hours and filtered. The filtercake was washed with DCM (<NUM>). The filtrates were combined and concentrated, and the residue was purified by chromatography (SiO<NUM>, Petroleum ether/Ethyl acetate = <NUM>/<NUM> to <NUM>:<NUM>) to afford (R,E)-<NUM>-methyl-N-(<NUM>-(trifluoro-methoxy)benzylidene)propane-<NUM>-sulfinamide (<NUM>).

A solution of (R,E)-<NUM>-methyl-N-(<NUM>-(trifluoro-methoxy)benzylidene)propane-<NUM>-sulfinamide (<NUM>) in THF (<NUM>) was added to a suspension of activated Zn (<NUM>), CuCl (<NUM>) and ethyl <NUM>-bromoacetate (<NUM>) in THF (<NUM>) at <NUM>. The reaction mixture was stirred at <NUM> for <NUM> hours, and filtered. The filtercake was washed with DCM (<NUM>), the combined organic filtrates were concentrated. The residue was purified by chromatography (SiO<NUM>, Petroleum ether/Ethyl acetate = <NUM>/<NUM> to <NUM>/<NUM>) to afford ethyl (S)-<NUM>-(((R)-tert-butylsulfinyl)amino)-<NUM>-(<NUM>-(trifluoromethoxy) phenyl)propanoate (<NUM>, crude).

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

To a solution of ethyl (S)-<NUM>-(((R)-tert-butylsulfinyl)amino)-<NUM>-(<NUM>-(trifluoromethoxy) phenyl)propanoate (<NUM>) in THF (<NUM>) was added LiAlH<NUM> (<NUM>) at <NUM>. The resulting mixture was stirred at <NUM> for <NUM> hour, and then quenched by sequential addition of H<NUM>O (<NUM>), <NUM>% NaOH (<NUM>) solution and H<NUM>O (<NUM>) at <NUM>. The mixture was filtered. The residue was concentrated to afford the crude (R)-N-((<NUM>)-<NUM>-hydroxy-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)propyl)-<NUM>-methylpropane-<NUM>-sulfinamide(<NUM>).

The crude (R)-N-((S)-<NUM>-hydroxy-<NUM>-(<NUM>-(trifluoromethoxy) phenyl)propyl)-<NUM>-methylpropane-<NUM>-sulfinamide (<NUM>)from the previous reaction step, was dissolved in MeOH (<NUM>) and added HCl/MeOH (<NUM>, <NUM>). The reaction mixture was stirred at <NUM> for <NUM> hours, and was concentrated to afford (S)-<NUM>-amino-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)propan-<NUM>-ol hydrochloride (<NUM>, crude).

Crude ethyl (S)-<NUM>-(((R)-tert-butylsulfinyl)amino)-<NUM>-(<NUM>-(trifluoromethoxy) phenyl)propanoate from the previous reaction step (<NUM>) was dissolved in THF (<NUM>) and added Boc<NUM>O (<NUM>) and NaHCO3 (<NUM>). The reaction mixture was stirred at <NUM> for <NUM> hours. The mixture was concentrated, and the residue was diluted with water (<NUM>), extracted by DCM (<NUM>×<NUM>), and the combined organic extracts were dried over Na<NUM>SO<NUM>, filtered and concentrated. The residue was purified by chromatography (SiO<NUM>, Petroleum ether/Ethyl acetate = <NUM>/<NUM> to <NUM>/<NUM>) to afford tert-butyl (<NUM>)-(<NUM>-hydroxy-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)propyl)carbamate (<NUM>).

To a solution of tert-butyl (S)-(<NUM>-hydroxy-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)propyl)carbamate (<NUM>) in DCM (<NUM>) was added Et<NUM>N (<NUM>) and methanesulfonyl chloride (<NUM>) at <NUM>. The reaction mixture was stirred at <NUM> for <NUM> hours, and then washed with ice water (<NUM>), dried over anhydrous Na<NUM>SO<NUM>, filtered and concentrated to afford ((S)-<NUM>-((tert-butoxycarbonyl)amino)-<NUM>-(<NUM>-(trifluoromethoxy) phenyl)propyl methanesulfonate (<NUM>).

((S)-<NUM>-((tert-butoxycarbonyl)amino)-<NUM>-(<NUM>-(trifluoromethoxy) phenyl)propyl methanesulfonate obtained in the previous step was dissolved in DMSO (<NUM>) and added KCN (<NUM>) at <NUM>. The reaction mixture was stirred at <NUM> for <NUM> hours, and then diluted with <NUM>% Na<NUM>CO<NUM> solution (<NUM>) and extracted with EtOAc (<NUM>×<NUM>). The combined organic extracts were washed with water (<NUM>) and brine (<NUM>), then dried over Na<NUM>SO<NUM>, filtered and concentrated. The residue was purified by chromatography (SiO<NUM>, Petroleum ether/Ethyl acetate = <NUM>/<NUM> to <NUM>/<NUM>) to afford tert-butyl (S)-(<NUM>-cyano-<NUM>-(<NUM>-(trifluoromethoxy)phenyl) propyl)carbamate (<NUM>).

To a solution of tert-butyl (S)-(<NUM>-cyano-<NUM>-(<NUM>-(trifluoromethoxy)phenyl) propyl)carbamate (<NUM>,) in MeOH (<NUM>) was added HCl/MeOH (<NUM>, <NUM>). The mixture was stirred at <NUM> for <NUM> hours and concentrated to afford (S)-<NUM>-amino-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)butanenitrile hydrochloride (<NUM>).

Prepared as described for IIi using <NUM>-(trifluoromethoxy)benzaldehyde as starting material.

This intermediate was prepared as described for IIk, Step <NUM>-<NUM>.

To a solution of ethyl (R)-<NUM>-((tert-butoxycarbonyl)amino)-<NUM>-(<NUM>-(trifluoromethoxy)phenyl) acetate(<NUM>) in EtOH (<NUM>) was added NaBH4 (<NUM>) at <NUM>. The mixture was removed from the cold bath and stirred for <NUM> hours. The reaction was quenched with water (<NUM>) and concentrated. The residue was purified by column chromatography (SiO<NUM>, Petroleum ether/Ethyl acetate = <NUM>/<NUM> to <NUM>/<NUM>) to afford the product (<NUM>).

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

To a solution of tert-butyl (R)-(<NUM>-hydroxy-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethyl)carbamate (<NUM>) and MeI (<NUM>) in THF (<NUM>) was added NaH (<NUM>, <NUM>% in mineral oil) at <NUM>. The mixture was stirred at <NUM> for <NUM> hour and stirred at <NUM> for <NUM> hours. Water (<NUM>) was added to quench the reaction. THF was removed and EtOAc (<NUM>) was added into the residue. The solution was washed by water (<NUM>×<NUM>) and concentrated. The residue was purified by column chromatography (SiO<NUM>, Petroleum ether/Ethyl acetate = <NUM>/<NUM> to <NUM>/<NUM>) to afford tert-butyl (R)-(<NUM>-methoxy-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethyl)carbamate (<NUM>).

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

To a solution of tert-butyl (R)-(<NUM>-methoxy-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethyl)carbamate (<NUM>) in MeOH (<NUM>) was added HCl/MeOH (<NUM>, <NUM>) at <NUM>. The mixture was stirred at <NUM> for <NUM> hours. The mixture was concentrated to afford the desired product (<NUM>, crude).

Prepared according to literature as described in<NPL>.

To a solution of <NUM>,<NUM>-difluorocyclobutanone (<NUM>), Zn (<NUM>) and I<NUM> (<NUM>) in THF (<NUM>) under N<NUM>, ethyl <NUM>-bromoacetate (<NUM>) 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>) in MeOH (<NUM>) and H<NUM>O (<NUM>), NaOH (<NUM>) 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.

A solution of <NUM>-(<NUM>-fluorocyclopropyl)ethanone (<NUM>), Zn (<NUM>) and I<NUM> (<NUM>) in THF (<NUM>) was stirred at <NUM> until the solution changed to colorless and ethyl <NUM>-bromoacetate (<NUM>) was added dropwise. The resulting mixture was stirred at <NUM> for <NUM> hour and <NUM> for <NUM> hours. The reaction was washed with <NUM>% aq. H<NUM>SO<NUM> (<NUM>) and extracted with EtOAc (<NUM>×<NUM>). The organic extracts were washed with brine (<NUM>), dried over Na<NUM>SO<NUM> and concentrated to afford ethyl <NUM>-(<NUM>-fluorocyclopropyl)-<NUM>-hydroxy-butanoate (<NUM>, crude).

To a solution of ethyl <NUM>-(<NUM>-fluorocyclopropyl)-<NUM>-hydroxy-butanoate (<NUM>) in EtOH (<NUM>) was added a solution of NaOH (<NUM>) in H<NUM>O (<NUM>). The reaction mixture was stirred at <NUM> for <NUM> hours and then extracted with EtOAC (<NUM>×<NUM>). The aqueous layer was acidified by <NUM>% HCl to pH=<NUM> and extracted with EtOAC (<NUM>×<NUM>). The combined organic extracts were washed with brine (<NUM>), dried over Na<NUM>SO<NUM> and concentrated to afford <NUM>-(<NUM>-fluorocyclopropyl)-<NUM>-hydroxy-butanoic acid (<NUM>, crude).

Zn (<NUM>) in THF (<NUM>) was added TMSCl (<NUM>), 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>) was added dropwise at such a rate that the solvent boiled gently. The resulting mixture was stirred at <NUM> for <NUM> hour and <NUM> for <NUM> hour, then a solution of <NUM>-cyclopropylethanone (<NUM>) 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 desired product (<NUM>, crude).

A mixture of crude methyl <NUM>-cyclopropyl-<NUM>-hydroxybutanoate (<NUM>) and LiOH·H<NUM>O (<NUM>) 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>).

To a mixture of Zn (<NUM>) and I<NUM> (<NUM>) in THF (<NUM>) was added <NUM>,<NUM>,<NUM>-trifluorobutan-<NUM>-one (<NUM>) and ethyl <NUM>-bromoacetate (<NUM>) 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>) 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).

The following were prepared by the same methodology as described for IIIe, using the relevant starting materials:.

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

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

To a solution of ethyl <NUM>-(<NUM>,<NUM>-dimethylcyclobutyl)-<NUM>-oxo-propanoate (IVd) (<NUM>) in MeOH (<NUM>) was added NaBH<NUM> (<NUM>). The mixture was stirred at <NUM> for <NUM>. and quenched by addition of H<NUM>O (<NUM>), concentrated and then diluted with EtOAc (<NUM>), dried over Na<NUM>SO<NUM>, filtered and evaporated. The residue was purified by chromatography (SiO<NUM>, Petroleum ether/Ethyl acetate=<NUM>/<NUM> to <NUM>/<NUM>) to afford ethyl <NUM>-(<NUM>,<NUM>-dimethylcyclobutyl)-<NUM>-hydroxy-propanoate (<NUM>).

<NUM>H NMR (DMSO-d6 <NUM>): δ <NUM> (d, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

To a solution of ethyl <NUM>-(<NUM>,<NUM>-dimethylcyclobutyl)-<NUM>-hydroxy-propanoate (<NUM>) in MeOH (<NUM>) was added a solution of NaOH (<NUM>) in H<NUM>O (<NUM>). The mixture was stirred at <NUM> for <NUM> hours. The reaction mixture was added <NUM>% HCl solution to adjust pH = <NUM>-<NUM>, then diluted with H<NUM>O (<NUM>) and extracted with EtOAc (<NUM>×<NUM>), the combined organic layers were dried over Na<NUM>SO<NUM>, filtered and concentrated to afford <NUM>-(<NUM>,<NUM>-dimethylcyclobutyl)-<NUM>-hydroxy-propanoic acid (<NUM>). <NUM>H NMR (DMSO-d6 <NUM>): δ <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

The following was prepared by the same methodology as described for IIIh, using the relevant starting materials:.

<NUM>H NMR (DMSO-d6 <NUM>): δ <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>).

Et<NUM>N (<NUM>) and MgCl<NUM> (<NUM>) were added to a suspension of (<NUM>-ethoxy-<NUM>-oxo-propanoyl)oxy potassium salt (<NUM>) in MeCN (<NUM>) and stirred at <NUM> for <NUM> hours. A pre-stirred mixture of carbonyl-diimidazole (CDI) (<NUM>) and <NUM>-(difluoromethyl) cyclopropane carboxylic acid (<NUM>) 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 (SiO<NUM>, eluent of <NUM>~<NUM>% Ethyl acetate/petroleum ether gradient) to yield the product (<NUM>).

The following was prepared by the same methodology as described for IVa, using the relevant starting materials:.

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

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

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

A solution of (R)-<NUM>-(difluoromethoxy)-<NUM>-(<NUM>-(difluoromethoxy)phenyl) ethan-<NUM>-amine hydrochloride (IIa)(<NUM>), methyl <NUM>,<NUM>-dimethyl-<NUM>-oxo-pentanoate (<NUM>), TEA (<NUM>) and DMAP (<NUM>) in toluene (<NUM>) was stirred at <NUM> for <NUM> hours. The mixture was diluted with EtOAc (<NUM>), washed with water (<NUM>) and brine (<NUM>), dried over Na<NUM>SO<NUM> and concentrated. The crude was purified by chromatography (SiO<NUM>, <NUM>% EA in Petroleum Ether) to give (R)-N-(<NUM>-(difluoromethoxy)-<NUM>-(<NUM>-(difluoromethoxy) phenyl)ethyl)-<NUM>,<NUM>-dimethyl-<NUM>-oxopentanamide
(<NUM>).

The following intermediate was prepared by similar methodology as Va, using the relevant intermediates.

Prepared from IIk and <NUM>,<NUM>-dimethyl-<NUM>-oxo-pentanoic acid.

To a solution of (R)-N-(<NUM>-(difluoromethoxy)-<NUM>-(<NUM>-(difluoromethoxy) phenyl)ethyl)-<NUM>,<NUM>-dimethyl-<NUM>-oxopentanamide (Va) (<NUM>) in MeOH (<NUM>) was added NaBH<NUM> (<NUM>) at <NUM>. The resulting mixture was stirred at <NUM> for <NUM> hour. The mixture was concentrated and the residue was redissolved in EtOAc (<NUM>) and washed with water (<NUM>) and brine (<NUM>), dried over Na<NUM>SO<NUM> and concentrated.

N-((R)-<NUM>-(difluoromethoxy)-<NUM>-(<NUM>-(difluoromethoxy) phenyl) ethyl)-<NUM>-hydroxy-<NUM>,<NUM>-dimethylpentanamide was separated by chromatography.

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

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

SFC: tR = <NUM> (SFC Method <NUM>), ee% = <NUM>%.

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

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

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

N-((R)-<NUM>-ethoxy-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethyl)-<NUM>-hydroxy-<NUM>,<NUM>-dimethylpentanamide was separated by chromatography.

<NUM>H NMR (DMSO-d6 <NUM>): δ <NUM> (d, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>), <NUM> (s, <NUM>).

<NUM>H NMR (DMSO-d6 <NUM>): δ <NUM> (d, <NUM>), <NUM> (t, J=<NUM>, <NUM>), <NUM> (t, <NUM>), <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, , <NUM>), <NUM> (s, <NUM>).

N-((R)-<NUM>-(difluoromethoxy)-<NUM>-(<NUM>-(difluoromethoxy)phenyl) ethyl)-<NUM>-hydroxy-<NUM>-(<NUM>-(trifluoromethyl)cyclopropyl)propanamide was separated by chiral SFC.

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

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

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

SFC: tR = <NUM> (SFC Method <NUM>), ee% = <NUM>,<NUM> %.

N-((R)-<NUM>-(difluoromethoxy)-<NUM>-(<NUM>-(trifluoromethoxy) phenyl)ethyl)-<NUM>-hydroxy-<NUM>-(<NUM>-(trifluoromethyl) cyclopropyl)propanamide was separated by chiral SFC.

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

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

(R)-<NUM>-(<NUM>,<NUM>-difluorocyclobutyl)-N-(<NUM>-(trifluoromethoxy)-<NUM>-(<NUM>-(difluoromethoxy)phenyl)ethyl)-<NUM>-oxopropanamide was separated by chiral SFC.

<NUM>H NMR (CDCl<NUM> <NUM>): δ <NUM> (t, <NUM>), <NUM> (d, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>), <NUM> (m, <NUM>), <NUM> (t, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>), <NUM>-<NUM> (m, <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]+.

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

(R)-<NUM>-(<NUM>,<NUM>-difluorocyclobutyl)-N-(<NUM>-(difluoromethoxy)-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethyl)-<NUM>-oxopropanamide was separated by chiral SFC.

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

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

<NUM>-(<NUM>,<NUM>-difluorocyclobutyl)-N-((S)-<NUM>-(<NUM>-(difluoromethoxy) phenyl)butyl)-<NUM>-hydroxypropanamide was separated by chiral SFC.

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

SFC: tR = <NUM> (SFC method <NUM>), ee% = <NUM>%.

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

SFC: tR = <NUM> (SFC Method <NUM>), ee% = <NUM>%.

N-((R)-<NUM>-(difluoromethoxy)-<NUM>-(<NUM>-(difluoromethoxy) phenyl)ethyl)-<NUM>-(<NUM>-ethylcyclopropyl)-<NUM>-hydroxypropanamide was separated by chiral SFC.

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

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

SFC: t = <NUM> (SFC Method <NUM>), ee% = <NUM> %.

To a solution of (R)-<NUM>-(difluoromethoxy)-<NUM>-(<NUM>-(difluoromethoxy)phenyl)ethan-<NUM>-amine hydrochloride (IIa) (<NUM>) and <NUM>-(<NUM>-fluorocyclopropyl)-<NUM>-hydroxy-butanoic acid (IIIc) (<NUM>) in DCM (<NUM>) was added N-hydroxybenzotriazole (HOBt) (<NUM>), <NUM>-Ethyl-<NUM>-(<NUM>-dimethylaminopropyl)carbodiimide (EDCI) (<NUM>) and Et<NUM>N (<NUM>). The mixture was stirred at <NUM> for <NUM> hours and then diluted with water (<NUM>), and extracted with EtOAc (<NUM>×<NUM>). The combined organic extracts were dried over Na<NUM>SO<NUM>, filtered and concentrated. The residue was purified by basic preparative HPLC to afford N-((R)-<NUM>-(difluoromethoxy)-<NUM>-(<NUM>-(difluoromethoxy)phenyl)ethyl)-<NUM>-(<NUM>-fluorocyclopropyl)-<NUM>-hydroxybutanamide (<NUM>).

N-((R)-<NUM>-(difluoromethoxy)-<NUM>-(<NUM>-(difluoromethoxy) phenyl)ethyl)-<NUM>-(<NUM>-fluorocyclopropyl)-<NUM>-hydroxybutanamide was separated by chiral SFC.

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

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

The following examples were prepared by similar methodology as described for Example 9a and Example 9b, using the relevant intermediates:.

N-((R)-<NUM>-(difluoromethoxy)-<NUM>-(<NUM>-(trifluoromethoxy) phenyl)ethyl)-<NUM>-(<NUM>-fluorocyclopropyl)-<NUM>-hydroxybutanamide was separated using chiral SFC.

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

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

<NUM>-cyclopropyl-N-((R)-<NUM>-(difluoromethoxy)-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethyl)-<NUM>-hydroxybutanamide was separated by chiral SFC.

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

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

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

N-((R)-<NUM>-(difluoromethoxy)-<NUM>-(<NUM>-(difluoromethoxy)phenyl) ethyl)-<NUM>,<NUM>,<NUM>-trifluoro-<NUM>-hydroxy-<NUM>-methylpentanamide was separated by chiral SFC.

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

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

N-((R)-<NUM>-(difluoromethoxy)-<NUM>-(<NUM>-(difluoromethoxy)phenyl) ethyl)-<NUM>-hydroxy-<NUM>,<NUM>-dimethylhexanamide was separated by chiral SFC.

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

SFC: tR = <NUM> (SFC Method <NUM>), ee% = <NUM> %.

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

N-((R)-<NUM>-(difluoromethoxy)-<NUM>-(<NUM>-(difluoromethoxy)phenyl)ethyl)-<NUM>-hydroxy-<NUM>,<NUM>-dimethylpentanamide was separated using chiral SFC.

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

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

N-((R)-<NUM>-(difluoromethoxy)-<NUM>-(<NUM>-(difluoromethoxy) phenyl)ethyl)-<NUM>-(<NUM>,<NUM>-dimethylcyclobutyl)-<NUM>-hydroxypropanamide was separated by chiral SFC.

<NUM>H NMR (DMSO-d6 <NUM>): δ <NUM> (d, <NUM>), <NUM> (t, <NUM>), <NUM> (d, <NUM>), <NUM> (t, <NUM>), <NUM> (s, <NUM>), <NUM> (d, <NUM>), <NUM> (t, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (s, <NUM>).

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

SFC: tR = <NUM> (SFC Method <NUM>), ee% = <NUM>.

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

<NUM>-cyclopentyl-N-((R)-<NUM>-(difluoromethoxy)-<NUM>-(<NUM>-(difluoromethoxy)phenyl)ethyl)-<NUM>-hydroxypropanamide was separated by chiral SFC.

<NUM>H NMR (DMSO-d6 <NUM>) δ <NUM> (d, <NUM>), <NUM> (t, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (t, <NUM>), <NUM> (d, <NUM>), <NUM> (t, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>).

<NUM>H NMR (DMSO-d6 <NUM>): δ <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (d, <NUM>), <NUM> (t, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (t, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM>-<NUM> (m, <NUM>).

<NUM>-(<NUM>-fluorocyclopropyl)-<NUM>-hydroxy-N-((R)-<NUM>-methoxy-<NUM>-(<NUM>-(trifluoromethoxy)phenyl)ethyl)butanamide was separated using chiral SFC.

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

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

To a solution of (R)-<NUM>-cyclopropoxy-<NUM>-(<NUM>-(difluoromethoxy)phenyl)ethan-<NUM>-amine hydrochloride (IIc) (<NUM>), (<NUM>)-<NUM>-hydroxy-<NUM>,<NUM>-dimethyl-pentanoic acid (IIIa) (<NUM>) and HATU (<NUM>) in DCM (<NUM>) was added DIEA (<NUM>). The mixture was stirred at <NUM> for <NUM> hours and concentrated. The crude was purified to give (S)-N-((R)-<NUM>-cyclopropoxy-<NUM>-(<NUM>-(difluoromethoxy) phenyl)ethyl)-<NUM>-hydroxy-<NUM>,<NUM>-dimethylpentanamide.

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

The following examples were prepared by similar methodology as described for example <NUM>, using the relevant intermediates:.

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

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

HPLC: tR = <NUM> (HPLC Method <NUM>), ee% = <NUM>%.

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

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

HPLC: tR = <NUM> (HPLC Method <NUM>), ee% = <NUM>%.

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

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

<NUM>H NMR (<NUM>, DMSO-d6): δ <NUM> (d, <NUM>), <NUM> (t, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (d, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (dd, <NUM>), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>).

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

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

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

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

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

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

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

SFC: tR = <NUM> (SFC Method <NUM>), ee% = <NUM> %.

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

SFC: tR = <NUM> (HPLC Method <NUM>), ee% = <NUM>%.

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

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

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

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

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

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

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

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> substituents selected from the group consisting of C<NUM>-C<NUM> alkyl, F, CHF<NUM> and 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>; and
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>-C<NUM> alkyl is substituted with C≡N, <NUM> F or C<NUM>-C<NUM> cycloalkyl;
R4 is selected from the group consisting of OCF<NUM>, or OCHF<NUM>
or a pharmaceutically acceptable salt of any of these compounds.