OA16888A - (4-phenylimidazol-2-YL) ethylamine derivatives useful as sodium channel modulators - Google Patents

Abstract

The invention relates to imidazole derivatives, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes. More particularly the invention relates to a new imidazole Nav1.8 modulators of formula (I) <img file="OA16888A_A0001.tif"/> or a pharmaceutically acceptable salt thereof, wherein R1 , R2 , R3 , R4 and R5 are as defined in the description. Nav1.8 modulators are potentially useful in the treatment of a wide range of disorders, particularly pain.

Description

The Invention relates to imidazole dérivatives. More particularly, this invention relates to dérivatives of (4-phenylimidazol-2-yl}ethylamlne, to their use In medlcine, to compositions containing them, to processes for their préparation and to Intermediates used in such processes.

Background

The imidazole dérivatives of the présent invention are sodium channel modulators. In particular they are modulators of the Nay1.8 sodium channel. Preferred Imidazole dérivatives of the Invention show an affinity for the Nay1.8 channel which Is greater than their affinity for other sodium channels such as the Nav1.5 sodium channel and the tetrodotoxln-sensitive sodium channels (TTX-S). The Imidazole dérivatives of the Invention hâve a number of therapeutic applications and potential therapeutic applications. In particular they are useful In the treatment of pain.

Voltage-gated sodium channels are found In ail excitable cells Including myocytes of muscle and neurons of the central and perlpheral nervous system. In neuronal cells, sodium channels are primarily responsible for generating the rapld upstroke of the action potential. In this manner sodium channels are essential to the initiation and propagation of electrical signais In the nervous system. Proper and appropriate function of sodium channels Is therefore necessary for normal function of the neuron. Consequently, aberrant sodium channel function is thought to underlie a variety of medical disorders (see Hubner C.A., Jentsch T.J., Hum. Mol. Genet., 11(20): 2435-45 (2002) for a general review of inherited Ion channel disorders) Including epilepsy (Yogeeswarl et al., Curr. Drug Targets, 5(7): 589-602 (2004)), arrhythmia (Noble D.₍ Proc. Natl. Acad. Sci. USA, 99(9): 5755-6 (2002)) myotonla (Cannon, S.C., Kidney Int. 57(3): 772-9 (2000)), and pain (Wood, J.N. étal., J. Neuroblol., 61(1): 55-71 (2004)).

There are currently at least nine known members of the family of voltage-gated sodium channel (VGSC) alpha subunlts. Names for this family include SCNx, SCNAx, and

Na_vx.x. The VGSC family has been phylogenetlcally divided into two subfamilies Nav1.x (ali but SCN6A) and Nay2.x (SCN6A). The Navl.x subfamily can be functlonally subdivlded Into two groups, those which are sensitive to blocking by tetrodotoxin (TTXsensitive or TTX-S) and those which are résistant to blocking by tetrodotoxin (TTX5 résistant or TTX-R).

The Na_v1.8 channel Is a voltage-gated sodium channel which Is expressed In noclceptors, the sensory neurones responsible for transduclng painful stimuli. The rat channel and the human channel were cloned In 1996 and 1998 respectively (Nature 10 1996; 379; 257-262; Pain 1998(Nov); 78(2):107-114). The Na_v1.8 channel was previously known as SNS (sensory neurone spécifie) and PN3 (peripheral nerve type 3).

The Nav1.8 channel Is atypical in that It shows résistance to the blocking effects of the puffer fish toxin tetrodotoxin and It is beiieved to underlie the slow-voltage-gated and tetrodotoxin-résistant (TTX-R) sodium currents recorded from dorsal root ganglion 15 neurones. The closest molecular relative to the Nay1.8 channel Is the Nay1.5 channel, which Is the cardiac sodium channel, with which It shares approximately 60% homology.

The Nav1.8 channel Is expressed most hlghly In the ’small cells* of the dorsal root ganglia (DRG). These are thought to be the C- and A-delta cells which are the putative poiymodal noclceptors, or pain sensors. Under normal conditions, the Nay1.8. channel 20 is not expressed anywhere other than subpopulations of DRG neurones. The Nav1.8 channels are thought to contribute to the process of DRG sensitisation and also to hyperexcitabiiity due to nerve injury. Inhlbitory modulation of the Nav1.8 channels is almed at reduclng the excitability of noclceptors, by preventing them from contributing to the excltatory process.

Studies hâve shown that Nay! .8 knock-out leads to a blunted pain phenotype, mostly to Inflammatory challenges (A.N. Akoplan étal., Nat. Neuroscl. 1999; 2; 541-548) and that Nav1>8 knockdown reduces pain behaviours, in this case neuropathie pain (J. Lal étal., Pain, 2002(Jan); 95(1-2): 143-152). Coward étal, and Ylangou étal., hâve shown that 30 Na_v1.8 appears to be expressed in pain conditions (Pain. 2000(March); 85(1-2): 41-50 and FEBS Lett. 2000(Feb 11); 467(2-3): 249-252).

The Nav1-8 channel has also been shown to be expressed In structures relating to the back and tooth puip and there Is évidence for a rôle In causaigla, Inflammatory bowel 35 conditions and multiple scierosls (Bucknill et al., Spine. 2002(Jan 15); 27(2):135-140:

Shembalker étal., EurJPaln. 2001; 5(3): 319-323: Lalrd et al., J Neurosci. 2002(0ct 1);

22(19): 8352-8356: Black et al., Neuroreport. 1999(Apr 6); 10(5): 913-918 and Proc. Natl. Acad. Sel. USA 2000:97: 11598-11602).

Examples of modulators of the Nav1-8 sodium channel are disclosed !n W02008/135826 and W02008/135830. There Is, however, an ongoing need to provide new Nav1.8 sodium channel Inhibitors that are good drug candidates. These drug candidates should hâve one or more of the following properties: be well absorbed from the gastrolntestlnal tract; be metabollcally stable; hâve a good metabollc profile, in particular with respect to the toxlclty or aüergenicity of any métabolites formed; or possess favourable pharmacokinetic properties whllst stlll retaining their activity profile as Nav1.8 channel Inhibitors. They should be non-toxlc and demonstrate few sideeffects. Idéal drug candidates should exist in a physical form that Is stable, nonhygroscoplc and easlly formulated.

Summarv of the Invention

According to a first aspect of the Invention there Is provided a compound of formula (i)

(I) or a tautomer thereof, or a pharmaceutically acceptable sait of said compound or tautomer, wherein: *

R¹ and R^z, together with the carbon to which they are attached, form a 4- to 7membered ring, wherein:

one member of said ring is O: and the remalning members of said ring are CFrR⁷, which may be the same or different at each occurrence;

R³ Is selected from the group consisting of H, (Ci-C₃)alkyi, cyclopropyl, cyclopropyl-CHz-, -CH₂OH, -CH₂OCH₃₁ (C_rC₃)fiuoroalkyl, -OH, -OCH₃, F, -NH₂₁ NHCH₃, -N(CH₃)₂ and -NHC(O)CH₃; ·

R⁴ Is selected from the group consisting of -CF₃, -OCF₃, -OCHF₂, Cl and -SFs;

R⁵ Is selected from the group consisting of H and -CH₃;

R⁶ and R⁷ are Independently selected from the group consisting of H, -CH₃₁ -OH, -OCH₃, F, -NH₂, NHCH₃ and -N(CH₃)₂.

Described below are a number of embodiments (E) of this first aspect of the Invention, where for convenlence E1 Is Identical thereto.

E1 A compound of formula (I) as defined above, a tautomer thereof, or a pharmaceutically acceptable sait of said compound or said tautomer.

E2 A compound according to E1 wherein R¹ and R², together with the carbon to which they are attached, form a 4- to 7-membered ring of formula

wherein m Is 1,2 or 3 and n is 1 or 2. Such a compound is represented by formula (la).

E3 A compound according to E2 wherein m is 1 and n is 1. Such a compound is represented by formula (lb).

(lb)

E4 A compound according to any of E1 to E3 wherein R³ is selected from the group consisting of H, methyl, ethyl, n-propyl and Isopropyl.

E5 A compound according to any of E1 to E4 wherein R⁵ Is H.

In a further aspect of the invention there is provided a compound according to formula (I) as described above for use as a médicament.

in a further aspect of the invention there is provided a compound according to formula (I) as described above for use in the treatment of pain.

In a further aspect of the invention there is provided a compound according to formula (I) as described above for use In the manufacture of a médicament for the treatment of 20 pain.

• In a further aspect of the invention there is provided a pharmaceutical composition comprising a compound according to formula (I) as described above and one or more pharmaceutically acceptable carriers. .

In one embodiment, the pharmaceutical composition is adapted for topical administration.

In another embodiment, the pharmaceutical composition Is adapted for intra-ocular administration.

·

In a further aspect of the Invention there is provided a method for the treatment of a condition for which a Nav1.8 modulator is indicated comprising the administration to a subject of a therapeutically effective amount of a compound according to formula (I) as described above.

In a further aspect of the invention there is provided a method for the treatment of pain In a subject in need of such treatment comprising the administration to said subject of a therapeutically effective amount of a compound according to formula (I) as described above.

Detailed description of the Invention

Alkyl groups, containing the requisite number of carbon atoms, can be unbranched or 25 branched. (Ct-CaJAIkyl includes methyl, ethyl, 1-propyl and 2-propyl.

Fluoroalkyl includes monofluoroalkyl, polyfluoroalkyl and perfluoroalkyl. Examples of (CrCsJfluoroalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2trifluoroethyl, heptafluoro-n-propyi and 1,1,1,3,3,3-hexafluoro-2-propyl.

The compounds of formula (I) can exlst in tautomeric forms. Specifically, the 2,4disubstituted imidazole can exist as the (1 H)-tautomer or the (3H)-tautomer. It will be understood that a 2,4-disubstituted-(3/-/)-lrriidazole may also be described as a 2,5disubstituted-(1 H)-imidazole.

IH-tautomer 3H-tautomer

The compounds of formula (I) may exist In substantially pure (1H)-tautomeric form, substantially pure (3H)-tautomeric form, or as a mixture of tautomeric forms. Ail such 5 tautomers and mixtures of tautomers are included within the scope of the présent

Invention. References herein to spécifie compounds should be understood to refer to the compound and/or Its tautomer.

Certain compounds of formula (I) Include one or more stereogenic centers and so may 10 exist as optical Isomers, such as enantiomers and disastereomers. Ail such Isomers and mixtures thereof are included within the scope of the présent invention. .

Hereinafter, ail references to compounds of the invention include compounds of formula (I) or pharmaceutically acceptable salts, solvatés, or multi-component complexes 15 thereof, or pharmaceutically acceptable solvatés or multi-component complexes of pharmaceutically acceptable salts of compounds of formula (I), as discussed In more detail below.

Preferred compounds of the Invention are compounds of formula (I) or pharmaceutically 20 acceptable salts thereof.

Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, blcarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, 25 fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromlde/bromide, hydrolodide/iodide, Isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stéarate, succinate, 30 tannate, t art rate, tosylate, trifluoroacetate and xinofoate salts.

Hemlsalts of acids and bases may also be formed, for example, hemlsulphate salts.

The skilled person will appreclate that the aforementloned salts Include ones wherein the counterion Is optically active, for example d-lactate or l-lyslne, or racemic, for example dl-tartrate or dl-arglnlne.

For a review on suitable salts, see “Handbook of Pharmaceutical Salts: Properties, Sélection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of three methods:

(i) by reacting the compound of formula (I) with the desired acid or base;

(ii) by removlng an acid- or base-lablle protecting group from a suitable precursor of the compound of formula (I) using the desired acid or base; or (iii) by converting one sait of the compound of formula (I) to another by reaction with an appropriate acid or base or by means of a suitable Ion exchange column.

Ail three reactions are typically carried out in solution. The resulting sait may preclpitate out and be collected by filtration or may be recovered by évaporation of the solvent. The degree of Ionisation In the resulting sait may vary from completely lonlsed to almost non-lonlsed.

The compounds of formula (I) or pharmaceutically acceptable salts thereof may exist in both unsolvated and solvated forms. The term ‘solvaté’ is used herein to describe a molecular complex comprising a compound of formula (I) or a pharmaceutically acceptable sait thereof and one or more pharmaceutically acceptable solvent molécules, for example, éthanol. The term 'hydrate' Is employed when said solvent Is water. Pharmaceutically acceptable solvatés In accordance with the Invention Include those wherein the solvent of crystallizatlon may be isotoplcally substituted, e.g. D2O, d₀acetone and dg-DMSO.

A currently accepted classification System for organic hydrates Is one that defines isolated site, channel, or metal-ion coordinated hydrates · see Polvmorphlsm In

Pharmaceutical Solids by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995),

Incorporated herein by reference. Isolated site hydrates are ones in which the water _Λ θ

V molécules are Isolated from direct contact with each other by intervenlng organic molécules, ln channel hydrates, the water molécules lie in iattice channels where they are next to other water molécules. In metal-ion coordinated hydrates, the water molécules are bonded to the métal Ion. .

When the solvent or water is tightly bound, the complex will hâve a well-defined stoichiometry Independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvatés and hygroscopic compounds, the water/solvent content will be dépendent on humidity and drying conditions. In such cases, non-stoichiometry 10 will be the norm.

The compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. The term 'amorphous’ refers to a state in which the material lacks long range order at the molecular level and, depending upon 15 température, may exhibit the physical properties of a solid or a liquid. Typically such materials do not glve distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid. Upon heating, a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass transition’). The term 'crystalline’ refers to a solid phase ln 20 which the material has a regular ordered internai structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point*).

Also Included within the scope of the invention are multi-component complexes (other than salts and solvatés) of compounds of formula (I) or pharmaceutically acceptable salts thereof wherein the drug and at least one other component are présent in stoichiometric or non-stoichiometric amounts. Complexes of this type inciude clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as 30 crystalline complexes of neutral molecular constituants which are bound together through non-covalent Interactions, but could also be a complex of a neutral molécule with a sait. Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together - see Chem Commun, 17, 1889-1896, by O. Almarsson and M. J. Zaworotko (2004), incorporated herein by reference. For a general review of multi-component complexes, see J Pharm Sci, 64 (8), 1269-1288, by Haleblian (August 1975), Incorporated herein by reference.

The compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is lntermediate between the true crystalline state and the true liquid state (either melt or solution). Mesomorphlsm arising as the resuit of a change in température is described as 'thermotropic* and that resulting from the addition of a second component,-such as water or another solvent, is described as ‘lyotropic*. Compounds that hâve the potentiel 10 to form lyotropic mesophases are described as 'amphiphilic' and conslst of molécules which possess an ionic (such as -COO Na⁺, -COO K*, or -SO3'Na⁺) or non-ionic (such as -NN⁺(CH3)₃) polar head group. For more Information, see Crvstals and the Polarizino Microscope by N. H. Hartshome and A. Stuart, 4*¹ Edition (Edward Arnold, 1970), incorporated herein by reference.

·

The compounds of the invention may be administered as prodrugs. Thus certain dérivatives of compounds of formula (I) which may hâve little or no pharmacological activity themselves can, when administered into or onto the body, be converted Into compounds of formula (I) having the desired activity, for example, by hydrolytic 20 cleavage. Such dérivatives are referred to as ‘prodrugs’. Further information on the use of prodrugs may be found in ‘Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Sériés (T Higuchl and W Stella) and ’Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E B Roche, Amerlcan Pharmaceutical Association).

Prodrugs can, for example, be produced by replacing appropriate functionalities présent ln a compound of formula (I) with certain moieties known to those skiiled in the art as 'pro-moieties' as described, for example, in Design of Prodrugs by H Bundgaard (Elsevier, 1985).

Examples of prodrugs include phosphate prodrugs, such as dihydrogen or dialkyi (e.g. di-tert-butyl) phosphate prodrugs. Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found ln the aforementioned references.

Also included within the scope of the Invention are métabolites of compounds of formula (I), that is, compounds formed In vivo upon administration of the drug. Some examples of métabolites in accordance with the invention include, where the compound of formula (I) contains a phenyl (Ph) moiety, a phénol dérivative thereof (-Ph > -PhOH);

Compounds of the invention containing one or more asymmetric carbon atoms can exist as two or more stereoisomers. Included within the scope of the invention are all stereoisomers of the compounds of the Invention and mixtures of one or more thereof.

Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a sait or dérivative) using, for example, chiral high pressure liquid chromatography (HPLC).

Altematively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the 20 diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantlomerically-enriched form using chromatography, typically HPLC, on an 25 asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2%. to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.

Mixtures of stereoisomers may be separated by conventional techniques known to those skilled in the art; see, for example, Stereochemistry of Organic Compounds** by E. L. Eliel and S. H. Wilen (Wiley, New York, 1994.

. ¹² φ The scope of the invention includes ail crystal forms of the compounds of the invention, including racemates and racemic mixtures (conglomérâtes) thereof. Stereoisomeric conglomérâtes may also be separated by the conventional techniques described herein just above.

The scope of the invention includes ail pharmaceutically acceptable isotopically-labelled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which prédominâtes ln nature.

Examples of isotopes suitable for Inclusion in the compounds of the Invention include Isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ^MCI, fluorine, such as ¹⁸F, iodine, such as ¹²³l and ^Î25l, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵0,¹⁷O and ¹⁸O, phosphorus, such as “P, and sulphur, such 15 as³⁵S.

Certain isotopically-labelled compounds of the invention, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive Isotopes tritium, i.e. ³H, and carbon-14, I.e. ¹⁴C, are 20 particularly useful for this purpose ln view of their ease of incorporation and ready means of détection. Substitution with heavier Isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or redueed dosage requlrements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as 25 ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

Isotopically-labeied compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to 30 those described in the accompanying Examples and Préparations using an appropriate isotopicaily-iabeled reagent in place of the non-labeled reagent previously employed.

Also within the scope of the invention are intermediate compounds as hereinafter defined, ail salts, solvatés and complexes thereof and ail solvatés and complexes of

Λ ¹³

W salts thereof as defined hereînbefore for compounds of formula (I). The Invention includes ail polymorphs of the aforementioned species and crystal habits thereof.

When preparing a compound of formula (I) in accordance with the invention, a person skilled In the art may routinely select the form of Intermediate which provides the best combination of features for this purpose. Such features Include the melting point, solubility, processability and yield of the intermediate form and the resulting ease with which the product may be purified on isolation.

The compounds of the invention may be prepared by any method known in the art for the préparation of compounds of analogous structure. In particular, the compounds of the invention can be prepared by the procedures described by reference to the Schemes that follow, or by the spécifie methods described In the Examples, or by similar processes to either.

The skilled person will appreciate that the experimental conditions set forth In the schemes that follow are Illustrative of suitable conditions for effecting the transformations shown, and that it may be necessary or désirable to vary the précisé conditions employed for the préparation of compounds of formula (I). It will be further 20 appreciated that it may be necessary or désirable to carry out the transformations in a different order from that described In the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.

In addition, the skilled person will appreciate that It may be necessary or désirable at any stage in the synthesis of compounds of the invention to protect one or more sensitive groups, so as to prevent undesirable side reactions. In particular, it may be necessary or désirable to protect amino or carboxylic acid groups. The protecting groups used in the préparation of the compounds of the invention may be used in conventional manner. See, for example, those described in 'Greene’s Protective 30 Groups in Organic Synthesis' by Theodora W Greene and Peter G M Wuts, third édition, (John Wiley and Sons, 1999), In particular chapters 7 (“Protection for the Amino Group) and 5 (“Protection for the Carboxyl Group), incorporated herein by reference, which aiso describes methods for the removal of such groups.

.

• Ail of the Imidazole dérivatives of the formula (I) can be prepared by the procedures described In the general methods presented below or by routine modifications thereof. The présent invention also encompasses any one or more of these processes for preparing the imidazole dérivatives of formula (I), In addition to any novel intermediates 5 used therein.

In the following general methods, Ar represents ·

and R¹, R², R³, R⁴ and R⁵ are as previously defined for an imidazole dérivative of the 10 formula (I) unless otherwise stated. In order to improve the legibility the schemes show structures wherein R® and R⁷ are both H. Compounds wherein R® and/or R⁷ are other than H may be prepared using analogous methods.

According to a first process, compounds of formula (I) may be prepared from compounds of formula (IV), as illustrated by Scheme 1.

(IV) (D

Scheme 1

X is a suitable leavlng group, typically Br.

Y is a suitable amine protecting group, typically tert-butoxycarbonyl, benzyloxycarbonyl or alkylsulfinyl

Compounds of formula (II) are either commercially available or may be prepared according to the methods set out in Schemes 2 (for compounds wherein Y is tert· butoxycarbony! or benzyloxycarbonyl) or 3 (for compounds wherein Y is alkylsulf inyi).

Compounds of formula (V) are either commercially available or may be prepared according to the methods set out in Scheme 4.

Compounds of formula (III) may be prepared from compounds of formula (II) according to process step (i), by alkylation with a compound of formula (V) in the presence of base in a suitable solvent. Typical conditions comprise combining an acid of formula (II) and an α-haio-ketone of formula (V) with an excess of base in a suitable solvent at a • température between room température and 50°C. Preferred conditions comprise using 1.05 équivalents of α-bromo-ketone of formula (V) and 1.5 équivalents of caesium carbonate In acetonitrile at room température, or 1 équivalent of α-bromo-ketone of formula (V) and 1.5 équivalents of triethylamlne In acetone at 50°C, or 1 équivalent of a5 bromo-ketone of formula (V) and 1.5 équivalents of triethylamlne in ethyl acetate at room température.

Compounds of formula (IV) can be prepared from compounds of formula (III) by process step (ii), a cyclisation reaction, In the presence of a suitable ammonium sait, typically 10 ammonium acetate. Typical conditions comprise an excess of ammonium sait In a suitable organic solvent at a température between 100°C and 130°C. Preferred conditions comprise 10 équivalents of ammonium acetate in anhydrous toluene at 100°C-130°C.

Compounds of formula (I) can be prepared from compounds of formula (IV) by process step (iii), a deprotection reaction under hydrogenolysls or acidic conditions. Typical conditions are dépendent on the nature of the protecting group. Where the protecting group is a tert-butoxycarbonyl group, conditions are acid mediated. Preferred conditions are an excess of HCl In 1,4-dioxane at room température. Where the 20 protecting group Is a benzyloxycarbonyl group, conditions are either acid mediated, typically using HBr In acetic acid at room température or by hydrogenolysls over a suitable hydrogénation catalyst, typically Pd/C or Pd(OH)a/C.

.

• According to a second process, compounds of formula (VI) (I.e. compounds of formula (II) wherein Y is fert-butyioxycarbonyl or benzyioxycarbonyl, R³ is hydrogen and R¹ and

R² together with the carbon atom to which they are attached form a 4- to 7-membered ring of formula z°x (H₂C)„ JCH₂)_m Λ ^s ' where m Is 1, 2 or 3 and n Is 1 or 2) may be prepared by the process lllustrated by Scheme 2.

Vî?

(VII) vl

Scheme 2

R^a Is a suitable alkyl protecting group, typically methyi or ethyl.

Y is terf-butyloxycarbonyl or benzyioxycarbonyl.

m is 1,2 or 3, and n is 1 or 2.

Compounds of formula (VII) are commercially availabie or can be prepared using published methods.

Compounds of formula (VIII) can be prepared from compounds of formula (VII) by a Wittig-type reaction according to process step (iv), with a ketone of formula (VII) and 20 either a phosphonate ester In the presence of a strong base or a phosphorane In a suitable solvent. In the case of the phosphonate ester, typical conditions comprise the _ ¹⁸ φ phosphonate ester in the presence of a strong base In anhydrous THF at 0°C. Preferred conditions comprise triethyl phosphonoacetate with 1.1 équivalents of sodium hydride in anhydrous THF at 0°C. In the case of the phosphorane, preferred conditions comprise 1.01 équivalents of (carbethoxymethylene)triphenylphosphorane in 5 dichloromethane at 0°C.

Compounds of formula (IX) can be prepared from compounds of formula (VIII) by process step (v), a conjugate addition reaction with a Michael acceptor of formula (VIII) and ammonia. Preferred conditions comprise an excess of ammonia in an alcohoiic 10 solvent at a température between 100°C and 150°C In a sealed vessel.

Compounds of formula (X) can be prepared from compounds of formula (IX) by process step (vl), a protection reaction of an amino ester of formula (IX). Typical conditions are dépendent on the nature of the amine protecting group. Where the protecting group is a 15 benzyloxycarbonyl group, typical conditions comprise benzylchloroformate In the presence of a base in a suitable solvent. Preferred conditions comprise 1.2 équivalents of benzylchloroformate and 3 équivalents of Ν,Ν-diisopropylethyiamine In acetonitrile at room température, or 1.3 équivalents of benzylchloroformate and an aqueous solution of sodium carbonate in fert-butylmethyl ether at 5-20°C.

Compounds of formula (VI) can be prepared from compounds of formula (X) by process step (vii), a hydrolysis reaction of a protected amino ester of formula (X). Typical conditions comprise a base in a suitable solvent at a température between room température and 75°C. Preferred conditions comprise an aqueous solution of sodium 25 hydroxide in methanol at 75°C or an aqueous solution of sodium hydroxide in tert· butylmethylether at room température. .

According to a third process, compounds of formula (XI) (i.e. compounds of formula (II) wherein Y is alkylsulf inyl and R¹ and R² together with the carbon atom to which they are attached form a 4- to 7-membered ring of formula

where m is 1, 2 or 3 and n is 1 or 2) may be prepared by the process illustrated by Scheme 3.

viii (XII)

(VII) η₂Λ ix (XIV) (XIII)

Q

Q

HO R (XV) (XI)

Scheme 3

R^a is a suitable alkyl protecting group, typicaliy methyl or ethyl. '

Q is a suitable alkyl protecting group, typicaliy tert-butyl.

m Is 1,2 or 3, and n Is 1 or 2.

Compounds of formula (XIII) are commercially available.

Compounds of formula (XII) can be prepared from compounds of formula (VII) by an imine formation reaction according to process step (viii), with a ketone of formula (VII) and a sulfinamlde of formula (XIII) In the presence of base in a suitable solvent.

Preferred conditions comprise 1.0 équivalent of an alkyl sulfinamlde (XIII) and 1.0 équivalent of caesium carbonate In dichoromethane at room température.

Compounds of formula (XV) can be prepared from compounds of formula (XII) by process step (ix), addition of a lithium enolate of formula (XIV) to a sulfinlme of formula (XII). The lithium enolate Is formed In situ from the appropriate ester In the presence of a lithium base In a suitable solvent at -78°C. Preferred conditions comprise of 2.1 équivalents of the appropriate ester and 2 équivalents of lithium dilsopropylamlne in anhydrous THF at -78°C, followed by addition of the sulfinimlne of formula (XII).

Compounds of formula (XI) can be prepared from compounds of formula (XV) by process step (x), a hydrolysis reaction of the protected amino ester of formula (XIII). Typical conditions comprise a base In a suitable solvent at room température. Preferred conditions comprise an aqueous solution of sodium hydroxide in methanol.

According to a fourth process, compounds of formula (V) may be prepared using the methods illustrated In Scheme 4.

O ^CH3 (XVI) HN CH,

6h₃ (XVII)

(XVIII) (V)

Scheme 4

Compounds of formula (V) can be prepared from compounds of formula (XVIII) according to process step (xlii), a halogénation reaction. Preferred bromination (whereby X Is Br) réaction conditions comprise a bromlnatlng agent, such as trimethyiphenylammonlum tribromlde, In a suitable solvent at 0°C.

• If non-commercial, compounds of formula (XVIII) can be prepared from compounds of formula (XVII) according to process step (xii), displacement of a Welnreb amlde. Preferred conditions comprise methyl lithium In a suitable solvent at 0°C.

Compounds of formula (XVII) can be prepared from compounds of formula (XVI) according to process step (xl), an amlde bond formation. Preferred conditions comprise 0,N-dimethylhydroxylamlne hydrochloride and suitable base, such as triethylamîne In a suitable solvent at room température.

Referring to the general methods above, It will be readily understood to the skilled person that where protectlng groups are présent, these will be generally Interchangeable with other protectlng groups of a similar nature, e.g. where an amine Is described as being protected with a tert-butoxycarbonyl group, this may be readily interchanged with any suitable amine protectlng group. Suitable protectlng groups are described In 'Protective Groups In Organic Synthesis' by T. Greene and P. Wuts (3^rt édition, 1999, John Wiley and Sons).

The présent Invention also relates to novel lntermcdiate compounds as defined above, ail salts, solvatés and complexes thereof and ali solvatés and complexes of salts thereof 20 as defined hereinbefore for imidazole dérivatives of formula (I). The invention Includes ali polymorphs of the aforementloned specles and crystal habits thereof.

When preparing Imidazole dérivatives of formula (I) or amino acids of formula (VI) In accordance with the Invention, it Is open to a person skilled in the art to routinely select 25 the best order of steps with which to syntheslse the intermediates, and to choose the form of the lntermcdiate compounds which provides the best combination of features for this purpose. Such features include the meitlng point, soiubllity, processability and yield of the intermedlate form and the resulting case with which the product may be purified on Isolation.

Compounds of the Invention Intended for pharmaceutical use may be administered as crystalline or amorphous products or may exist in a continuum of solid states ranglng from fully amorphous to fully crystalline. They may be obtained, for example, as solid 35 plugs, powders, or films by methods such as précipitation, crystallization, freeze drying,

W spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

They may be administered alone or In combination with one or more other compounds of the invention or In combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation In association with one or more pharmaceutically acceptable excipients. The term 'excipient* is used herein to describe any Ingrédient other than the compound(s) of the Invention. The choice of excipient will to a large extent dépend on factors such as the particular mode of 10 administration, the effect of the excipient on soiubility and stabiiity, and the nature of the dosage form.

In another aspect the Invention provides a pharmaceutical composition comprising a compound of the invention together with one or more pharmaceutically acceptable 15 excipients.

Pharmaceutical compositions suitable for the delivery of compounds of the présent Invention and methods for their préparation will be readily apparent to those skilled In the art. Such compositions and methods for their préparation may be found, for 20 example, In Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishlng Company, 1995).

Suitable modes of administration include oral, parentéral, topical, inhaied/intranasal, rectal/intravaginal, and ocular/aural administration.

Formulations suitable for the aforementioned modes of administration may be formulated to be immédiate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.

The compounds of the invention may be administered orally. Oral administration may Involve swallowing, so that the compound enters the gastrolntestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth. Formulations suitable for oral administration Include solid formulations such as tablets, capsules containing particuiates, liquids, or powders, 35 lozenges (including liquld-fiiled), chews, multl- and nano-particulates, gels, solid • solution, liposome, films, ovules, sprays, liquid formulations and buccal/mucoadhesive patches..

Liquid formulations inciude suspensions, solutions, syrups and élixirs. Such formulations may be employed as fillers ln soft or hard capsules and typically comprise a carrier, for example, water, éthanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oïl, and one or more emulsifylng agents and/or suspendlng agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.

·

The compounds of the Invention may also be used ln fast-dissolvlng, fast-dislntegratlng dosage forms such as those described in Expert Opinion ln Therapeutic Patents, 11 (6), 981-986, by Llang and Chen (2001).

For tablet dosage forms, depending on dose, the drug may make up from 1 weight % to weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form. ln addition to the drug, tablets generally contain a dislntegrant. Examples of dlslntegrants Inciude sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovldone, 20 poiyvlnylpyrrolldone, methyl cellulose, mlcrocrystalllne cellulose, lower alkyl-substltuted hydroxypropyl cellulose, starch, pregelatlnlsed starch and sodium alglnate. Generally, the dislntegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.

Blnders are generally used to impart cohesive qualifies to a tablet formulation. Suitable blnders Inciude mlcrocrystalllne cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, poiyvlnylpyrrolldone, pregelatlnlsed starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-drled monohydrate, anhydrous and the like), mannitol, xylitol, 30 dextrose, sucrose, sorbltol, mlcrocrystalllne cellulose, starch and dlbasic calcium phosphate dihydrate.

Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glldants such as sllicon dioxlde and talc. When présent,

A ²⁴

W surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glldants may comprise from 0.2 weight % to 1 weight % of the tablet.

Tablets also generally contain lubrlcants such as magnésium stéarate, calcium stéarate, 5 zinc stéarate, sodium stearyl fumarate, and mixtures of magnésium stéarate with sodium lauryl sulphate. Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet. Other possible Ingrédients include antl-oxldants, colourants, flavouring agents, preservatives and taste-masklng agents.

Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % dlslntegrant, and from about 0.25 weight % to about 10 weight % lubricant. Tablet blends may be compressed directly or by roller to form 15 tablets. Tablet blends or portions of blends may altematively be wet-, dry-, or meltgranulated, melt congealed, or extruded before tablettlng. The final formulation may comprise one or more layers and may be coated or uncoated; It may even be encapsulated. The formulation of tablets Is discussed In Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. Lleberman and L. Lachman (Marcel Dekker, New York, 20 1980).

Suitable modified release formulations for the purposes of the invention are described In US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in Pharmaceutical 25 Technology On-line, 25(2), 1-14, by Verma et al (2001). The use of chewing gum to achieve controlled release Is described in WO 00/35298.

The compounds of the Invention may also be administered directly Into the blood stream, Into muscle, or Into an Internai organ. Suitable means for parentéral 30 administration Include intravenous, Intraarterial, intraperitoneal, Intrathecal,

Intraventrlcular, Intraurethral, Intrasternal, Intracranlai, Intramuscular, subcutaneous and trans-tympanlc. Suitable devlces for parentéral administration include needle (Including microneedle) injectors, needle-free Injectors and infusion techniques.

λ ²⁵ φ Parentéral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a stérile nonaqueous solution or as a dried form to be used In conjunctlon with a suitable vehicle 5 such as stérile, pyrogen-free water. '

The préparation of parentéral formulations under stérile conditions, for example, by lyophilisation, may readily be accomplished using standard pharmaceutical techniques well known to those skilled In the art.

The solublllty of compounds of formula (I) used In the préparation of parentéral solutions may be Increased by the use of appropriate formulation techniques, such as the Incorporation of solublllty-enhanclng agents. Formulations for parentéral administration may be formulated to be Immédiate and/or modified release. Modlfled release 15 formulations Include delayed-, sustalned-, pulsed-, controlled-, targeted and programmed release. Thus compounds of the Invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an Implanted depot providing modified release of the active compound. Examples of such formulations Include drugcoated stents and poly(dl-lactlc-coglycollc)acld (PGLA) mlcrospheres.

The compounds of the invention may also be administered topically to the skin or mucosa, that Is, dermally or transdermally. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, olntments, dusting powders, dresslngs, foams, films, skin patches, wafers, Implants, sponges, fibres, bandages and 25 microemulslons. Liposomes may also be used. Typical carriers include alcohol, water, minerai oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Pénétration enhancers may be Incorporated - see, for example, J Pharm Sel, 88 (10), 955-958, by Annin and Morgan (October 1999).

Other means of topical administration Include delivery by eiectroporatlon, iontophoresis, phonophoresls, sonophoresls and mlcroneedle or needle-free (e.g. Powderject™, Bloject™, etc.) Injection.

The compounds of the Invention can also be administered Intranasally or by Inhalation, 35 typically In the form of a dry powder (either alone, as a mixture, for example, In a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholîpids, such as phosphatidylchollne) from a dry powder Inhaler or as an aérosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamlcs to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3heptafluoropropane. For Intranasa! use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.

The pressurised container, pump, spray, atomlzer, or nebuliser contains a solution or suspension of the compound(s) of the Invention comprising, for example, éthanol, aqueous éthanol, or a suitable alternative agent for disperslng, solubilising, or extendlng release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, olelc acid, or an oligolactic acid.

Prior to use in a dry powder or suspension formulation, the drug product Is micronlsed to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminutlng method, such as spirai Jet milling, fluid bed Jet milling, supercritical fluid processing to form nanoparticles, high pressure homogénisation, or spray drying.

Capsules (made, for example, from gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use In an inhaler or insufflator may be formulated to contain a powder mix of the compound of the Invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, rnannitol, or magnésium stéarate. The lactose may be anhydrous or In the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mlst may contain from 1 pg to 20mg of the compound of the Invention per actuation and the actuation volume may vary from 1 pl to 100pl. A typical formulation may comprise a compound of formula (I), propylene glycol, stérile water, éthanol and sodium chlorlde. Alternative solvents which may be used Instead of propylene glycol include glycerol and polyethylene glycol.

a ²⁷ φ Suitable fiavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention Intended for

Inhaled/intranasal administration.

In the case of dry powder inhalers and aérosols, the dosage unit is determined by means of a valve which delivers a metered amount. Unlts in accordance with the invention are typically arranged to admlnfster a metered dose or “pufT containing from 1pg to 100mg of the compound of formula (I). The overall dally dose will typically be In the range 1 pg to 200mg which may be administered In a single dose or, more usuaily, 10 as divlded doses throughout the day.

The compounds of the Invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, microblcide, vaginal ring or enema. Cocoa butter Is a traditional suppository base, but various alternatives may be used as appropriate.

The compounds of the invention may also be administered dlrectly to the eye or ear, typically In the form of drops of a mlcronised suspension or solution In isotonie, pHadjusted, stérile saline. Other formulations suitable for ocuiar and aurai administration Include ointments, biodégradable (e.g. absorbable gel sponges, collagen) and non20 biodégradable (e.g. silicone) implants, wafers, lenses and particulate or veslcular Systems, such as nlosomes or liposomes. A polymer such as crossed-llnked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for éxample, hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum, may be Incorporated together 25 with a preservative, such as benzalkonium chloride. Such formulations may also be delivered by iontophoresis.

The compounds of the Invention may be combined with soluble macromoiecular entitles, such as cyciodextrin and suitable dérivatives thereof or polyethylene glycol30 containing polymers, in order to improve their solubllity, dissolution rate, taste-masking, bioavallabllity and/or stability for use In any of the aforementloned modes of administration. '

Drug-cyciodextrin complexes, for example, are found to be generally useful for most 35 dosage forms and administration routes. Both Inclusion and non-inclusion complexes za

V may be used. As an alternative to direct complexation with the drug, the cyclodextrin may be used as an auxiliary additive, I.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found In International Patent Applications Nos. WO 5 91/11172, WO 94/02518 and WO 98/55148.

For administration to human patients, the total daily dose of the compounds of the Invention Is typically In the range 1mg to 10g, such as 10mg to 1g, for example 25mg to 500mg depending, of course, on the mode of administration and efflcacy. For example, 10 oral administration may require a total daily dose of from 50mg to 100mg. The total daily dose may be administered in single or divlded doses and may, at the physlcian's discrétion, fall outslde of the typical range given herein. These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physlclan will readily be able to détermine doses for subjects whose weight fails outslde this range, 15 such as infants and the eiderly.

As noted above, the compounds of the Invention are useful because they exhiblt pharmacological activity in animais, I.e., Nav1.8 channel modulation. More particularly, the compounds of the invention are of use in the treatment of disorders for which a 20 Nav1.8 modulator Is indicated. Preferably the animal Is a mammal, more preferably a human.

In a further aspect of the Invention there Is provided a compound of the Invention for use as a médicament.

In a further aspect of the Invention there is provided a compound of the invention for the treatment of a disorder for which a Nav1.8 modulator is Indicated. ·

In a further aspect of the Invention there Is provided use of a compound of the Invention 30 for the préparation of a médicament for the treatment of a disorder for which a Nay1.8 modulator Is Indicated.

In a further aspect of the Invention there Is provided a method of treating a disorder In an animal (preferably a mammal, more preferably a human) for which a Nav1.8

V modulator is indicated, comprising adminlsterlng to said animal a therapeutically effective amount of a compound of the Invention.

Disorders for which a Nay1.8 modulator is Indicated Include pain, particularly 5 neuropathie, nociceptive and Inflammatory pain.

Physiological pain Is an Important protective mechanlsm designed to wam of danger from potentially Injurious stimuli from the extemal environment. The system opérâtes through a spécifie set of primary sensory neurones and is activated by noxious stimuli 10 via peripheral transducing mechanisms (see Millan, 1999, Prog. Neurobiol., 57, 1-164 for a revlew). These sensory fibres are known as nociceptors and are characteristically small diameter axons with slow conduction velocities. Nociceptors encode the Intensity, duration and quality of noxious stimulus and by virtue of their topographically organised projection to the spinal cord, the location of the stimulus. The nociceptors are found on 15 nociceptive nerve fibres of which there are two main types, A-delta fibres (myelinated) and C fibres (non-myelinated). The activity generated by nociceptor Input is transferred, after complex processing ln the dorsal hom, either directly, or via brain stem relay nuclel, to the ventrobasa! thalamus and then on to the cortex, where the sensation of pain Is generated.

Pain may generally be classified as acute or chronic. Acute pain begins suddenly and Is short-lived (usually twelve weeks or less). It is usually associated with a spécifie cause such as a spécifie Injury and is often Sharp and severe. It Is the kind of pain that can occur after spécifie Injuries resulting from surgery, dental work, a strain or a sprain. 25 Acute pain does not generally resuit in any persistent psychologlcal response. ln contrast, chronic pain Is long-term pain, typically persisting for more than three months and leading to significant psychological and emotional problems. Common examples of chronic pain are neuropathie pain (e.g. painfu! diabetic neuropathy, postherpetlc neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain and 30 chronic post-surgical pain.

When a substantlal Injury occurs to body tissue, via disease or trauma, the characteristics of nociceptor activation are altered and there is sensitisation ln the periphery, locally around the Injury and centrally where the nociceptors termlnate. 35 These effects lead to a hightened sensation of pain, ln acute pain these mechanisms

V can be useful, in promoting protective behaviours which may better enable repair processes to take place. The normal expectation would be that sensitlvlty retu ms to normal once the Injury has healed. However, In many chronic pain states, the hypersensltivity far outlasts the healing process and Is often due to nervous system 5 Injury. This injury often leads to abnormalities In sensory nerve fibres associated with maladaptation and aberrant activity (Woolf & Salter, 2000, Science, 288,1765-1768).

Clinlcal pain is présent when discomfort and abnormal sensitlvlty feature among the patients symptoms. Patients tend to be qulte heterogeneous and may présent with 10 various pain symptoms. Such symptoms include: 1) spontaneous pain which may be dull, buming, or stabblng; 2) exaggerated pain responses to noxlous stimull (hyperalgesia); and 3) pain produced by normally innocuous stimull (aliodynla - Meyer et al., 1994, Textbook of Pain, 13-44). Although patients sufferlng from various forms of acute and chronic pain may hâve similar symptoms, the underlylng mechanlsms may be 15 different and may, therefore, requlre different treatment strategies. Pain can also therefore be divided into a number of different subtypes according to differing pathophysiology, including nociceptive, inflammatory and neuropathie pain.

Nociceptive pain is Induced by tissue Injury or by intense stimull with the potential to 20 cause Injury. Pain afferents are activated by transduction of stimull by noclceptors at the site of Injury and activate neurons In the spinal cord at the level of their termlnation. This is then relayed up the spinal tracts to the braln where pain Is perceived (Meyer et al., 1994, Textbook of Pain, 13-44). The activation of noclceptors activâtes two.types of afferent nerve fibres. Myelinated A-delta fibres transmit rapidly and are responslble for 25 sharp and stabbing pain sensations, whilst unmyelinated C fibres transmit at a slower rate and convey a dull or achlng pain. Moderate to severe acute nociceptive pain is a prominent feature of pain from central nervous system trauma, stralns/spralns, bums, myocardial infarction and acute pancreatitis, post-operative pain (pain foliowing any type of surglcal procedure), posttraumatlc pain, rénal colic, cancer pain and back pain. 30 Cancer pain may be chronic pain such as tumour related pain (e.g. bone pain, headache, facial pain or viscéral pain) or pain associated with cancer therapy (e.g. postchemotherapy syndrome, chronic postsurgical pain syndrome or post radiation syndrome). Cancer pain may also occur in response to chemotherapy, Immunotherapy, hormonal therapy or radlotherapy. Back pain may be due to hemlated or ruptured 35 Intervertabrai dises or abnormalities of the lumber facet joints, sacrolliac joints,

Q parasplnal muscles or the posterlor longitudinal ligament. Back pain may résolve naturally but In some patients, where It lasts over 12 weeks, It becomes a chronic condition which can be particularly debllitatlng.

Neuropathie pain Is currently defined as pain Initiated or caused by a primary lésion or dysfunction In the nervous system. Nerve damage can be caused by trauma and disease and thus the term 'neuropathie pain' encompasses many disorders with diverse aetlologles. These Include, but are not limited to, peripheral neuropathy, dlabetlc neuropathy, post herpetic neuralgia, trigemlnal neuralgla, back pain, cancer neuropathy, 10 HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain and pain associated with chronic alcohollsm, hypothyroldlsm, uremla, multiple sclerosls, spinal cord Injury, Parklnson’s disease, epllepsy and vltamln deficlency. Neuropathie pain is pathological as It has no protective rôle. It Is often présent well after thé original cause has disslpated, commonly lasting for years, signiflcantly decreaslng a patients 15 quality of life (Woolf and Mannlon, 1999, Lancet, 353, 1959-1964). The symptoms of neuropathie pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6, S141 -S 147; Woolf and Mannlon, 1999, Lancet, 353, 1959-1964). They Include spontaneous pain, which can be continuous, and paroxysmai or abnormal evoked pain, such as 20 hyperalgesla (Increased sensitlvlty to a noxious stimulus) and allodynla (sensitivlty to a normally Innocuous stimulus).

The Inflammatory process is a complex sériés of blochemical and cellular events, activated in response to tissue injury or the presence of foreign substances, which 25 results in swelling and pain (Levlne and Taiwo, 1994, Textbook of Pain, 45-56). Arthrltlc pain is the most common inflammatory pain. Rheumatoid disease Is one of the commonest chronic Inflammatory conditions In developed countries and rheumatoid arthritis Is a common cause of disability. The exact aetlology of rheumatoid arthritis Is unknown, but current hypothèses suggest that both genetic and microblologlcal factors 30 may be Important (Grennan & Jayson, 1994, Textbook of Pain, 397-407). It has been estlmated that almost 16 million Americans hâve symptomatlc osteoarthrltls (OA) or degenerative joint disease, most of whom are over 60 years of âge, and this Is expected to increase to 40 miïiîon as the âge of the population increases, maklng this a public health problem of enormous magnitude (Houge & Mersfelder, 2002, Ann 35 Pharmacother., 36, 679-686; McCarthy et al.. 1994, Textbook of Pain, 387-395). Most • patients with osteoarthritis seek medical attention because of the associated pain. Arthritis has a significant Impact on psychosocial and physlcal function and Is known to be the leadîng cause of disability In later life. Ankylosing spondylitis Is aiso a rheumatic disease that causes arthritis of the spine and sacroiliac joints. It varies from Intermittent 5 épisodes of back pain that occur throughout life to a severe chronlc disease that attacks the spine, peripheral joints and other body organs.

Another type of infiammatory pain Is viscéral pain which Includes pain associated with Inflammatory bowel disease (IBD). Viscéral pain is pain associated with the viscera, 10 which encompass the organs of the abdominal cavity. These organs Include the sex organs, spleen and part of the digestive system. Pain associated with the viscera can be divided Into digestive viscéral pain and non-digestive viscéral pain. Commonîy encountered gastrointestinal (Gl) disorders that cause pain Include functional bowel disorder (FBD) and inflammatory bowel disease (IBD). These Gl disorders Include a 15 wlde range of disease states that are currently only moderately controlled, Including, In respect of FBD, gastro-esophageal reflux, dyspepsia, Irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and, in respect of IBD, Crohn’s disease, lleitis and ulcerative colitis, ali of which regularly produce viscéral pain. Other types of viscéral pain include the pain associated with dysmenorrhea, cystitls and 20 pancreatitis and pelvic pain.

It shouid be noted that some types of pain hâve multiple aetiologies and thus can be ciassified In more than one area, e.g. back pain and cancer pain hâve both nociceptive and neuropathie components.

'

Other types of pain include:

• pain resulting from musculo-skeietal disorders, including myalgia, fibromyalgia, spondylitis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, glycogenolysis, polymyositis and pyomyositis;

· heart and vascular pain, including pain caused by angina, myocardical infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma and skeletal muscle Ischemia;

• head pain, such as migraine (Including migraine with aura and migraine without aura), cluster headache, tension-type headache mixed headache and headache associated with vascular disorders;

erythermalgia; and • orofaclal pain, including dental pain, otic pain, buming mouth syndrome and temporomandibular myofascial pain.

A Nav1.8 modulator may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, partîcularly in the treatment of pain. Such combinations offer the possibility of significant advantages, Including patient compliance, ease of dosing and synergistic activity.

ln the combinations that follow the compound of the Invention may be administered simultaneously, sequentially or separately ln combination with the other therapeutic agent or agents.

A Nav1 -8 modulator of formula (I), or a pharmaceutically acceptable sait thereof, as defined above, may be administered ln combination with one or more agents selected from: · • an alternative Na_v1.8 modulator (e.g. as disclosed ln WO 2008/135826, more partîcularly N-[6-Amlno-5-(2-chloro-5-methoxyphenyl)pyrldln-2-yl]-1 -methyl-1 Hpyrazole-5-carboxamide);

• an alternative sodium channel modulator, such as a Nav1-3 moduiator (e.g. as disclosed ln W02008/118758); or a Nav1-7 channel modulator e.g. as disclosed in WO 2009/012242);

• an inhibitor of nerve growth factor signaling, such as: an agent that binds to NGF and Inhibits NGF biological activity and/or downstream pathway(s) mediated by NGF signaling (e.g. tanezumab), a TrkA antagonist or a p75 antagoinsist;

• a compound which increases the levels of endocannabinoid, such as a compound with fatty acid amid hydrolase Inhibitory (FAAH) activity, ln particular those disclosed ln WO 2008/047229 (e.g. N-pyridazin-3-yl-4-(3-([5-(trifluoromethyl)pyridine-2yl]oxy}benzyiidene)plperldene-1-carboxamlde);

• an opioid analgésie, e.g. morphine, heroin, hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperldine, fentanyl, cocaïne, codeine, dihydrocodéine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprénorphine, butorphanol, nalbuphine or pentazocine;

• a nonsteroldal antiinflammatory drug (NSAID), e.g. aspirln, diclofenac, difiusinal, etodolac, fenbufen, fenoprofen, flufenlsal, flurblprofen, ibuprofen, Indomethacin, _ ³⁴

V ketoprofen, ketorolac, meclofenamic acid, mefenamlc acid, meloxïcam, nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazlne, oxaprozin, phenylbutazone, piroxlcam, sulfasalazine, sulindac, tolmetin orzomepirac;

• a barbiturate sédative, e.g. amobarbital, aprobarbital, butabarbltal, butabltal, mephobarbital, metharbltal, methohexltal, pentobarbital, phenobartital, secobarbital, talbutal, theamylal or thlopental;

• a benzodiazépine having a sédative action, e.g. chlordlazepoxide, clorazepate, diazepam, fiurazepam, lorazépam, oxazepam, temazepam or trlazolam; ' • an Hi antagonist having a sédative action, e.g. diphenhydramine, pyrilamine, 10 promethazine, chlorphenlramlne or chlorcycllzine;

• a sédative such as glutethimlde, meprobamate, methaqualone or dichloralphenazone;

• a skeletal muscle relaxant, e.g. baciofen, carisoprodol, chlorzoxazone, cyclobenzaprine, methocarbamo! or orphrenadine;

«an NMDA receptor antagonist, e.g. dextromethorphan ((+)-3-hydroxy-N-methylmorphinan) or its métabolite dextrorphan ((+)-3-hydroxy-N-methylmorphlnan), ketamlne, memantine, pyrroloquinollne quinine, cis-4-(phosphonomethyl)’2piperidinecarboxyilc acid, budiplne, EN-3231 (MorphiDex®, a combination formulation of morphine and dextromethorphan), toplramate, neramexane or perzlnfote! Including an NR2B antagonist, e.g. Ifenprodil, traxoprodil or (-)-(R)-6-{2[4’(3-fluorophθny!)-4-hydroxy·1·plpθridiny!]·1·hydroxyθthyl·3,4-dihydro-2(1H)quinolinone;

• an alpha-adrenergic, e.g. doxazosln, tamsulosin, clonidine, guanfacine, dexmetatomidlne, modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido·

1,2,3,4-tetrahydrolsoqulnol-2-yl)-5-(2-pyrldyl) qulnazollne;

• a tricyclic antldepressant, e.g. deslpramlne, Imipramine, amitriptyline or nortriptyline;

• an anticonvulsant, e.g. carbamazeplne, lamotrigine, toplratmate or valproate;

• a tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1 antagonist, e.g. (aR,9R)-7-[3,5-bis(trlf!uoromethy!)benzyl]-8,9,10,11 -tetrahydro-9-methyl-5-(4- methylphenyl)-7H-[1,4]dlazoclno[2_t1-g][1_t7]-naphthyridine-6-13-dione (TAK-637), 5· [[(2R,3S)-2-[(1R)-1-[3,5-bls(trifluoromethyl)pheny!]ethoxy-3-(4-f!uorophenyl)-4morpholinyl]-methyi]-1,2-dihydro-3H-1,2,4-triazo!-3-one (MK-869), aprepltant, lanepltant, dapitant or 3-[[2-methoxy-5-(trifiuoromethoxy)phenyl]-methylamino]-2phenylplperldine (2S.3S);

_Λ ³⁵

W · a muscarinic antagonist, e.g oxybutynln, tolterodine, propivorlno, tropslum chloride, darifenacin, solifenacln, temlverlne and Ipratroplum;

• a COX-2 sélective inhibitor, e.g. celecoxib, rofecoxib, parecoxib, vaidecoxib, deracoxib, etorlcoxlb, or lumlracoxlb;

· a coal-tar analgésie, In particular paracétamol;

• a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine, thioridazine, mesorldazine, trifluoperazlne, fluphenazine, clozaplne, olanzapine, rispéridone, ziprasidone, quetiapine, sertlndole, ariplprazola, soneplprazole, blonanserin, lloperldone, perosplrone, racloprlde, zoteplne, bifeprunox, asenapine, lurasldone, amisulpride, balaperidone, pallndore, epllvanserln, osanetant, rlmonabant, meciinertant, Miraxion® or sarizotan;

• a vanlllold receptor agonlst (e.g. resinferatoxln) or antagonist (e.g. capsazeplne);

• a beta-adrenerglc such as propranolol;

• a local anaesthetlc such as mexlletlne;

· a cortlcosterold such as dexamethasone;

• a 5-HT receptor agonlst or antagonist, particularly a 5-HTib/id agonlst such as eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatrlptan;

• a δ-ΗΤίΑ receptor antagonist such as R(+)-alpha-(2,3-dlmethoxy-phenyi)-1 -[2-(4fluorophenylethyi)]-4-plperldinemethanol (MDL-100907);

· a 5-HTa antagonist, such as ondansetron • a chollnerglc (nlcotlnic) analgésie, such as Ispronlcllne (TC-1734), (E)-N-methyl-4-(3pyridinyl)-3-buten-1 -amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chioropyridine (ABT-594) or nicotine;

• Tramadol®;

· a PDEV Inhibitor, such as 5-[2-ethoxy-5-(4-methyl-1-piperazlnyl-sulphonyi)phenyl]-1 methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrlmidin-7-one (slldenafil), (6R,12aR)-2₁3,6,7_f12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)pyrazinofë'J'ie.lj-pyridotS^-bJindole-M-dlone (IC-351 or tadalafil), 2-[2-ethoxy-5(4-ethyl-piperazin-1 -yl-1 -sulphonyl)-phenyl]-5-methyl-7-propyi-3H-lmidazo[5,1 30 f][1,2,4]triazln-4-one (vardenafil), 5-(5-acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(1 -ethyl3-azotldinyl)-2₁6-dihydro-7/-/-pyrazolo[4,3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3pyridinyl)-3-ethyi-2-(1-isopropyi-3-azetidinyi)-2,6-dihydro-7H-pyrazolo[4,3dJpyrimidin-7-one, 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyi)pyridin-3-yi]_:3-ethyl-

2-[2-methoxyethyl]-2_I6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, 4-[(3-chloro-416888 methoxybenzyl)amlno]-2-[(2S)-2-(hydroxymethyl)pyrrolÎclin-1-yl]-N-(pyrlmlclin-2ylmethyl)pyrimldine-5-carboxamide, 3-(1-methyl-7-oxo-3-propyl-6,7-dihydro-1 Hpyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1-methylpyrrolidln-2-yl)ethyl]-4· propoxybenzenesulfonamide; .

• an alpha-2-delta ligand such as gabapentln, pregabalin, 3-methylgabapentln, (1 a,3a,5a)(3-amlno-methyl-blcyclo[3.2.0]hept-3-yl)-acetlc acid, (3S.5R)-

3-amlnomethyl-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-octanolc acid, (2S,4S)-4-(3-chlorophenoxy)proline, (2S,4S)-4-(3-fluorobenzyl)-proline, [(1R,5R,6S)-6-(amlnomethyl)bicyclo[3.2.0]hept’6yljacetlc acid, 3-(1 -aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadlazol-5-one, C-[1 (1 H-tetrazol-5-ylmethyl)-cycloheptyi]-methylamlne, (3S,4S)-(1 -amlnomethyl-3,4dlmethyl-cyclopentyl)-acetic acid, (3S,5R)-3-amlnomethyl-5-methyl-octanolc acid, (3S,5R)-3-amino-5-methyl-nonanolc acid, (3S,5R)-3-amino-5-methyl-octanolc acid, (3R,4R,5R)-3-amlno-4,5-dimethyl-heptanolc acid and (3R,4R,5R)-3-amlno-4,5dimethyl-octanolc acid;

• metabotropic glutamate subtype 1 receptor (mGluRI) antagoniste « a serotonin reuptake inhibitor such as sertrailne, sertrallne métabolite demethylsertraline, fiuoxetine, norfluoxetine (fiuoxetine desmethyl métabolite), fiuvoxamine, paroxetine, citalopram, citalopram métabolite desmethylcitalopram, escltaiopram, d.l-fenfluramlne, femoxetlne, Ifoxetine, cyanodothlepln, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;

• a noradrenaline (norepinephrine) reuptake inhibitor, such as maprotlllne, lofepramlne, mirtazepine, oxaprotiline, fezolamine, tomoxetine, mianserln, buproprion, buproprion métabolite hydroxybuproprion, nomlfensine and viloxazlne (Vivaian®), especlally a sélective noradrenaline reuptake Inhibitor such as reboxetlne, in particular (S.S)-reboxetine;

• a dual serotonin-noradrenailne reuptake Inhibitor, such as venlafaxlne, venlafaxlne métabolite O-desmethylvenlafaxine, clomipramine, clomipramine métabolite desmethylciomlpramine, duloxetine, milnacipran and Imipramine;

• an Inducible nitric oxide synthase (INOS) inhibitor such as S-[2-[(1 -Iminoethyl)amino]ethyl]-L-homocystelne, S-[2-[(1-lmlnoethyl)-amino]ethyl]-4,4-dioxo-L-cystelne, S-[2-[(1-imlnoethyl)amino]ethyl]-2-methyl-L-cystelne, (2S,5Z)-2-amlno-2-methyl-7[(1-iminoethyl)amino]-5-heptenolc acid, 2-[[(1 R,3S)-3-amlno-4- hydroxy-1-(5thiazolyl)-butyl]thlo]-5-chloro-3-pyridinecarbonitrile; 2-[[(1 R,3S)-3-amino-4-hydroxy-1 (5-thiazolyi)butyl]thlo]-4-chlorobenzonitrlle, (2S,4R)-2-amlno-4-[[2-chloro-516888 (trifluoromethyl)phenyl]thlo]-5-thiazolebutanol,

2-[[(1R,3S)-3-amlno-4-hydroxy-1-(5-thlazolyl) butyl]thlo]-6-(trifluoromethyl)-3’ pyridinecarbonitrile, 2-[I(1R,3S)-3-amlno-4-hydroxy-1 -(5-thiazolyl)butyl]thlo]-5chlorobenzonitrile, N-[4-[2’(3-chlorobenzylamlno)ethyl]phenyl]thlophene-2carboxamldine, or guanldinoethyldisulflde;

• an acetylcholinesterase Inhibitor such as donepezil;

• a prostaglandin E2 subtype 4 (EP4) antagonlst such as /V-[({2-[4-(2-ethyl-4,6dlmethyl-1H-lmldazo[4,5-c]pyridin-1-yl)phenyl]ethyl}amlno)-carbonyl]-4methylbenzenesulfonamlde or 4-((1 S)-1-(([5-chloro-2-(3-fluorophenoxy)pyridin-3yl]carbonyl}amlno)ethyi]benzolc acid;

• a mlcrosomal prostaglandin E synthase type 1 (mPGES-1) Inhibitor;

• a leukotriene B4 antagonlst; such as 1-(3-blphenyl-4-ylmethyl-4-hydroxy-chroman-7- yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-Carboxyethyl)-3-[6-(4methoxyphenyl)-5E· hexenyljoxyphenoxyj-valerlc acid (ONO-4057) or DPC-11870, • a 5-llpoxygenase Inhibitor, such as zlleuton, 6-[(3-fluoro-5-[4-methoxy-3,4,5,6- tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1 -methyl-2-qulnolone (ZD-2138), or

2,3,5-trimethyl-6-(3-pyrldylmethyl),1,4-benzoquinone (CV-6504).

There Is also Included within the scope the présent Invention combinations of a compound of the Invention together with one or more additlonal therapeutic agents which slow down the rate of metabollsm of the compound of the Invention, thereby leading to Increased exposure In patients. Increasing the exposure In such a manner Is known as boostlng. This has the benefit of Increasing the efficacy of the compound of the Invention or reduclng the dose required to achieve the same efficacy as an unboosted dose. The metabollsm of the compounds of the Invention Includes oxidatlve processes carried out by P450 (CYP450) enzymes, particularly CYP 3A4 and conjugation by UDP glucuronosyl transferase and sulphatlng enzymes. Thus, among the agents that may be used to Increase the exposure of a patient to a compound of the présent Invention are those that can act as Inhibitors of at least one Isoform of the cytochrome P450 (CYP450) enzymes. The Isoforms of CYP450 that may be bénéficiais Inhibited Include, but are not limited to, CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4. Suitable agents that may be used to inhibit CYP 3A4 Include ritonavlr, saqulnavir, kétoconazole, N-(3,4-difluorobenzyl)-N-methyl-2-{[(4methoxypyridin-3-yl)amino]sulfonyl)benzamlde and N-( 1 -(2-(5-(4-fluorobenzyl)-3(pyridin-4-yl)-1H-pyrazol-1-yl)acetyl)plperidin-4-yi)methanesulfonamide.

• ³⁸

It Is within the scope of the Invention that two or more pharmaceutical compositions, at least one of which contains a compound of the Invention, may convenlently be combined In the form of a kit suitable for coadmlnistratlon of the compositions. Thus the 5 kit of the Invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of the Invention, and means for separately retaining said compositions, such as a container, dlvlded bottle, or dlvlded fol! packet. An example of such a kit Is the familiar blister pack used for the packaging of tablets, capsules and the like. The kit of the Invention Is particularly suitable for admlnisterlng 10 different dosage forms, for example, oral and parentéral, for administering the separate compositions at different dosage Intervals, or for tltratlng the separate compositions against one another. To assist compliance, the kit typically comprises directions for administration and may be provided with a so-called memory ald.

In another aspect the Invention provides a pharmaceutical product (such as In the form of a kit) comprising a compound of the invention together with one or more additional therapeutically active agents as a combined préparation for simultaneous, separate or sequential use In the treatment of a disorder for which a Nav1.8 modulator Is Indlcated.

It Is to be appreciated that ail references herein to treatment Include curative, palliative and prophylactic treatment.

In the non-limiting Exampies and Préparations that are set out later In the description, and in the aforementioned Schemes, the following the abbreviations, définitions and 25 analytical procedures may be referred to:

AcOH Is acetic acid,

Cs₂CO₃ Is caesium carbonate;

Cu(acac)₂ Is copper (II) acetylacetonate;

Cul Is copper (I) iodide;

Cu(OAc)₂Is copper (II) acetate;

DAD Is diode array detector; '

DCM is dichloromethane; methylene chloride; '

DIPEA Is N-ethyldiisopropylamine, N.N-diisopropylethylamlne;

DMAP Is 4-dimethylamlnopyrldine;

DMF is N,N-dlmethylformamlde;

DMSO Is dimethyl sulphoxide;

EDCI Is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimlde hydrochloride;

EDTA Is ethylenedlamlnetetraacetlc acid;

ELSD Is evaporative light scatterlng détection;

Et₂O Is dlethyl ether;

EtOAc Is ethyl acetate;

EtOH Is éthanol;

HCl Is hydrochloric acid;

IPA Is Isopropanol;

lr2(OMe)zCOD2 is bls(1,5-cyclooctadlene)dl-p-methoxydilrldlum (i);

K2CO3 Is potassium carbonate;

KHSO4 Is potassium hydrogen sulphate;

KOAc Is potassium acetate;

KOH Is potassium hydroxide;

K3PO4 Is potassium phosphate tribaslc;

LCMS Is liquid chromatography mass spectrometry (R_t = rétention time) .

LIOH Is lithium hydroxide;

MeOH Is methanol;

MgSO₄ls magnésium sulphate;

NaH Is sodium hydrlde;

NaHCO₃ Is sodium hydrogencarbonate;

Na2CO₃ is sodium carbonate;

NaHSO₃ Is sodium bisuiphlte; .

NaHSO₄ Is sodium hydrogensulphate;

NaOH Is sodium hydroxide;

Na₂SO₄ Is sodium sulphate;

NH4CI Is ammonium chloride;

NMP Is M-Methyl-2-pyrrolidone;

Pd/C Is palladium on carbon;

Pd(PPh₃)4 is palladium tetrakis(triphenylphosphine); .

Pd(dppf)2Ci2 is [l.l’-bistdiphenylphosphinoîferrocenejdichloropalladiumill), complex with dichloromethane;

THF Is tetrahydrofuran;

TH P Is tetrahydropyran;

φ TLC Is thln layer chromatography; and

WSCDI Is 1-(3-dimethylamlnopropyl)-3-ethylcarbodilmlde hydrochloride.

The invention is lllustrated by the following représentative Examples.

¹H Nuclear magnetlc résonance (NMR) spectra were In ail cases consistent with the proposed structures. Characteristic chemical shlfts (6) are given ln parts-per-mlilion downfield from tetramethyisllane using conventions! abbreviations for désignation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The mass spectra (MS) were recorded using either electrospray ionisation (ESI) or atmospheric pressure chemical ionisation (APCI). The following abbreviations hâve been used for common solvents: CDCIg, deuterochloroform; DMSO-cfe, deuterodimethylsulphoxlde; CD₃OD, deuteromethanol; THF, tetrahydrofuran. LCMS Indicates liquid chromatography mass spectrometry (Rt = rétention time). Where ratios of solvents are given, the ratios are 15 by volume.

Certain compounds of the Examples and Préparations were purified using Automated Préparative High Performance Liquid Chromatography (HPLC). Reversed-phase HPLC conditions were on FractlonLynx Systems. Samples were submitted dissolved ln 1 mL of 20 DMSO. Depending on the nature of the compounds and the results of a pre-anaiysis, the purification was performed under either acidlc conditions (’A-HPLC¹) or baslc conditions (’B-HPLC) at ambient température. Acidlc runs were carried out on a Sunfire Prep C18 OBD column (19 x 100 mm, 5 pm), basic runs were carried out on an Xterra Prep MS C18 (19 x 100 mm, 5 pm), both from Waters. A flow rate of 18 mL/mln 25 was used with mobile phase A: water + 0.1% modifier (v/v) and B: acetonitrtie + 0.1% modifier (v/v). For acidic runs the modifier was formlc acid, for basic run the modifier was diethyiamlne. A Waters 2525 blnary LC pump supplled a mobile phase with a composition of 5% B for 1 min then ran from 5% to 98% B over 6 min followed by a 2 min hold at 98% B. .

Détection was achieved using a Waters 2487 dual wavelength absorbance detector set at 225 nm followed ln sériés by a Polymer Labs PL-ELS 2100 detector and a Waters ZQ 2000 4 way MUX mass spectrometer ln parallel. The PL 2100 ELSD was set at 30°C with 1.6 Umin suppiy of Nitrogen. The Waters ZQ MS was tuned with the following parameters:

ES+ Cône voltage: 30 v Capillary: 3.20 kv

ES- Cône voltage:-30 v Capillary:-3.00 kv

Desolvatlon gas: 600 L/hr

Source Temp: 120°C.

Scan range 150-900 Da

The fraction collection was trlggered by both MS and ELSD.

Quality control (QC) analysis was performed using a LCMS method. Acidic runs were carried out on a Sunfire C18 (4.6 x 50 mm, 5 pm), basic runs were carried out on a Xterra C18 (4.6 x 50 mm, 5 pm), both from Waters. A flow rate of 1.5 mL/min was used with mobile phase A: water + 0.1% modifier (v/v) and B: acetonitrile + 0.1% modifier (v/v). For acidic runs the modifier was formic acid, for basic run the modifier was ammonia. A Waters 1525 binary LC pump ran a gradient elution from 5% to 95% B over 3 min followed by a 1 min hold at 95% B. Détection was achieved using a Waters MUX UV 2488 detector set at 225 nm followed In sériés by a Polymer Labs PL-ELS 2100 detector and a Waters ZQ 2000 4 way MUX mass spectrometer in parallel. The PL

2100 ELSD was set at 30°C with 1.6 L/min supply of Nitrogen. The Waters ZQ MS was tuned with the following parameters:

ES+ Cône voltage: 25 v Capillary: 3.30 kv

ES- Cône voltage:-30 v Capillary:-2.50 kv

Desolvatlon gas: 800 L/hr

Source Temp: 150°C.

Scan range 160-900 Da

Unless carried out by Auto-HPLC (under conditions of A-HPLC or B-HPLC as just described, LCMS conditions were run according to one of the conditions given below (where ratios of solvents are given, the ratios are by volume):

minute LC-MS gradient and instrument conditions

Acid run: A: 0.1 % formic acid in water B: 0.1 % formic acid in acetonitrile Column: C18 phase Phenomenex Gemini 50 x 4.6 mm with 5 micron particle size. Gradient: 95-5% A over 3 min, 1 min hold, 1ml/min. UV:210 nm-450 nm DAD. Température: 50°C

2 minute LC-MS gradient and instrument conditions

Acid run: A: 0.1 % formic acid In water B: 0.1 % formic acid in acetonitrile Column: Cw phase Fortis Pace 20 x 2.1 mm with 3 micron particle size. Gradient: 70-2% A over 1.8 min, 0.2 minhold, 1.8 ml/mln. UV: 210 nm-450 nmDAD. Température:75°C

C18 30 minute method LC-MS gradient and Instrument conditions

A: 0.1% formlc acid In H₂O B: 0.1% formlc acid In MeCN Column: Phenomenex Ci₈ phase Gemini 150 x 4.6 mm with 5 micron particle slze Gradient: 98-2% A over 18 mîn, 2 min hoid, 1ml/min. UV: 210 nm-450nm DAD. Température: 50°C.

Phenvl Hexvl 30 minute method LC-MS gradient and instrument conditions '

A: 10 mM ammonium acetate in H₂O B: 10 mM ammonium acetate in méthanol Column: Phenomenex Phenyl Hexyl 150 x 4.6 mm with 5 micron particie size Gradient: 98-2% A over 18min, 2 min hold, 1 ml/min. UV: 210 nm - 450 nm DAD. Température: 50°C

Unless otherwise noted, HPLC analysis conditions were run according to the conditions given below:

Ultra acid method HPLC gradient and instrument conditions ’

HPLC analysis was performed using the ultra acid method. Zorbax SB-Ci₈ (3.0 x 50 mm, 1.8 pm), supplied by Crawford sclentific at a column température of 50°C. A flow rate of 1.2 mL/min was used with mobile phase A: water + 0.05% TFA (v/v) and B: acetonitrile. An Agllent 1100 LC pump ran a gradient elution from 5% to 100% B over 3.5 min followed by a 1 min hold at 100% B.

Example 1

3-(f4-i4.fTrlf1uoromethoxvÎDhenvll-1H-imidazol-2-vDmethvlHetrahvdro-2H-Dvran-3amine

METHOD A

To benzyl [3-({4-[4-(trlfluoromethoxy)phenyl]-1 H-lmidazol-2-yl}methyl)tetrahydro-2Hpyran-3-yl]carbamate (Préparation 1,0.120 g, 0.253 mmol) in acetic acid (1 mL) was added a solution of HBr In acetic acid (48%, 2 mL) and the reaction left to stir at room température for 1.5 hours before concentrating In vacuo. The residue was azeotroped with cyclohexane to yield an orange solid. The solid was purified by Isolute™ SÇX Ion exchange coiumn eluting with méthanol followed by 7M ammonia In méthanol to afford a yellow oil. The oil was further purified by préparative HPLC conditions (B-HPLC) to afford the title compound.

LCMS (acidic QC method) Rt « 2.16 min MS m/z 342 [MH]⁺

Example 2

34Γ4-ί4-ϋ1ιΙθΓθ-3·πΊθ1ίινΙρΙΐθηνΙ)-1Η-ίπΊΐά3ΖθΙ·2·νΙ1πΊθ1ίινΠοχθί3η-3-3ΠΊίηθ

METHOD B

Benzyl (3-{[4-(4-chlorO'3-methylphenyl)-1H-lmldazol-2-yl]methyl)oxetan-3-yl)carbamate (Préparation 3,0.150 g, 0.364 mmol) was dissolved In methanol (5 mL) and hydrogenated at 50°C through a 20% Pd(OH)2 on carbon CATCART™ (30 mm) supplied by Thaïes Nanotechnology Inc® using the Thaïes Nanotechnology Inc® HC2 hydrogenater at a flow rate of 1 mL/min and a pressure of 1 Bar. The reaction was concentrated In vacuo. The residue was purified by préparative HPLC conditions (AHPLC) to afford the title compound.

LCMS (acidic QC method) Rt = 1.99 min MS m/z 278 [MH]⁺

The following examples 3 to 6 were prepared by methods analogous to Methods A and B as described for Examples 1 and 2 above. Unless otherwise noted, préparation details are as described for the method referred to.

Example 3 3-(i4-r4-(Trifiuoromethoxv)phenvlb1H-imidazol-2-vDmethvl)tetrahvdrofuran-3-amine

Prepared by Method A using benzyl [3-({4-[4-(trifluoromethoxy)phenyl]-1 H-lmidazol'2yl)methyl)tetrahydrofuran-3-yl]carbamate (Préparation 2,0.132 g, 0286 mmol) but without the need for Initial purification via Isolute™ SCX Ion exchange column to afford the title compound.

LCMS (acldic QC method) Rt = 2.23 min

MS m/z 323 [MH]⁺

Example 4

3-(f4-f4-(Trlfluoromethvl)phenvll-1/-/-lmldazol-2-vllmethvl)oxetan-3-amine

Prepared by Method B using benzyl [3-({4-[4-(trifluoromethyl)phenyl]-1 H-lmldazol-2-yl} methyl)oxetan-3-yl]carbamate (Préparation 5,0.135 g, 0.310 mmol) to afford the title compound. '

LCMS (acldic QC method) Rt = 2.15 min MS m/z 298 [MH]⁺

Example 5

J *

3-(Î4-f4-iDifluoromethoxvÎphenvn-1H-lmldazol-2-vnmethvlÎoxetan-3-amine

Prepared by Method B using benzyl [3-({4-[4-(difluoromethoxy)phenyl]-1 H-imldazol-2yl}methyl)oxetan-3-yl]carbamate (Préparation 6,0.133 g, 0.310 mmol). Purified by préparative HPLC conditions (B-HPLC) to afford the title compound. ,

LCMS (acldic OC method) Rt = 2.30 min

MS m/z 296 [MH]⁺

Example 6

3-(f4-r4-fPentafluoro-X^fl-sulfanvl)Dhenvl1-1 H-lmldazol-2-vnmethvl)oxetan-3-amlne

Prepared by Method B using benzyl [3-({4-[4-(pentafluoro-X^e-sulfanyl)phenyl]-1 H5 lmldazol-2-yl}methyl)oxetan-3-yl]carbamate (Préparation 7,0.100 g, 0.204 mmol). Purifîed by préparative HPLCconditions (B-HPLC) to afford the title compound.·

LCMS (acidic QC method) Rt = 2.31 min

MS m/z 356 [MH]+

Example 7

4-((4-f4-(Trifluoromethoxv)phenvl1-1H-lmldazol-2-vnmethvÎ)tetrahvdro-2H-pvran-4- amine

To tert-butyl [4-({4-[4-(trifluoromethoxy)phenyl]-1 H-imldazol-2-yl}methyl)tetrahydro-2H15 pyran-4-yl]carbamate (Préparation 4,0.166 g, 0.376 mmol) was added 4M hydrogen chloride In 1,4-dioxane (3 mL) and the reaction left to stlr at room température for 18 hours before concentrating In vacuo. The residue was purifîed by préparative HPLC conditions (A-HPLC) to afford the title compound.

LCMS (acidic QC method) Rt = 1.98 min

MS m/z 342 [MH]⁺

3-({4-[4-(Trifluoromethoxv]phenvn-1H-lmîdazol-2-vlÎmethvhoxetan-3-amlne

Example 8

Benzyl [3-({4-[4-(trifluoromethoxy)phenyl]-1Wmldazol-2-yl}methyl)oxetan-3-yllcarbamate (Préparation 11,311g, 695 mmol) was dissolved in methanoi (3.2 L). 5% Palladium on carbon E105 R/W (EVONiK) (22 g, 7wt%) was added and the reaction hydrogenated at 40°C, 100 psi for 18 hours. Hydrogen uptake was monitored and showed the reaction to be complété after 4 hours. The mixture was cooled to room température and filtered over Arbocel®. The filter cake was washed with methanoi (2 x 1 L) and the filtrats concentrated In vacuo to afford a solid. The solid was dissolved in ethyl acetate (1 L) and filtered through a carbon tablet to remove traces of palladium. The solution was warmed to 50°C and heptane (1 L) added. The solution was cooled siowly whereupon at 40°C crystallisation was observed. The mixture was stirred at room température for 72 hours. The solid was collected by filtration and washed with ethyl acetate : heptane (1:1,250 mL). The solid was dried In vacuo al 40°C for 18 hours to afford the title compound as a crystalline solid.

HPLC (ultra acid method) Rt = 1.996 min.

Example 9

3-( 1 -ί4-Γ4·(Τ rifluoromethoxylphenvIM /-Aimidazol-2-vllethvnoxetan-3-amine

To a solution of 2-methyi-M-[3-(1-{4-[4-(trifiuoromethoxy)phenyl]-1M-lmldazol-2-yl)ethyl)oxetan-3-yl]propane-2-suifinamide (Préparation 9,0.320 g, 0.74 mmol) In methanoi (4 mL) at 0°C was added 4M hydrogen chloride In 1,4-dioxane (4 mL) and the reaction left to stir for 2 hours. Solid sodium hydrogen carbonate was added to the reaction, followed by a saturated aqueous solution of sodium hydrogen carbonate. The mixture was extracted with dlchloromethane. The organic layer was dried over MgSÜ4 and concentrated In vacuo. The residue was purified by silica gel column chromatography to afford the title compound (0.243 g, 91% yield).

LCMS (2 mîn) Rt = 0.96 min MS m/z 328 [MH]+

Examples 10 & 11

3-K1 S)-1 -i4-f4-(Trifluoromethoxv)Dhenvll-l H-lmldazol-2-vllethvnoxetan-3-amlne and

3-iï 1 fî)-1 -f4-r4-fTrifluoromethoxv)phenvn-1 /7-lmidazol-2-vl)ethvlloxetan-3-amine

Racemlc 3-(1 -{4-[4-(trifiuoromethoxy)phenyl]-1 H-lmldazol-2-yl}ethyl)oxetan-3-amlne (Example 9,0.243 g, 0.743 mmol) was dissolved In éthanol (1 mL). Enantlomers were separated by chiral préparative HPLC under basic conditions at ambient température on 15 a Chlralpak AD-H column (250*, 20 mm l.d) supplied by Dalcel Chemical Industries. A flow rate of 18 mL/mln was used with mobile phase A: heptane and B: IPA + 0.1% dlethylamlne (v/v). Two Agitent 1200 prep pumps supplied a mobile phase with a composition of 20% B. Run time was 10 minutes per 0.1 mL Injection volume. Détection was achleved using an Agitent 1200 multiple wavelength UV absorbance 20 detector set at 220 nm.

Enantiomer 1 : Rt ~ 5.89 min. >99.5% ee (58 mg, 24%)

Enantiomer 2: Rt = 8.42 min. >99.5% ee (89 mg, 37%)

Enantiomer 1:¹HNMR (CDCI₃): δ 1.35 (d, 3H), 3.21 (s, 2H), 3.64 (q, 1 H), 4.39 (d, 1 H),

4.43 (d, 1 H), 4.52 (d, 1H), 4.66 (d, 1 H), 7.13-7.22 (m, 3H), 7.75 (br s, 2H).

Enantiomer 2:¹ HNMR (CDCl₃): δ 1.35 (d, 3H), 3.21 (s, 2H), 3.64 (q, 1H),4.39(d, 1H),

4.43 (d, 1H), 4.52 (d, 1H), 4.66 (d, 1H), 7.13-7.22 (m, 3H), 7.75 (br s, 2H).

3-(1-(4-f4-(Trifluoromethvl)Dhenvn-1 H-lmÎdazol-2-vÎlethvnoxetan-3-amlne

Example 12

Benzyl [3-( 1 -{4-[4-(trifluorom ethyl)phe ny I]-1 H-imidazol-2-yl}ethyl)oxetan-3-yl]carbamate (Préparation 8,0.95 g, 2.13 mmol) was dissolved ln methanol (20 mL) and hydrogenated at room température and 100 psi. The reaction mixture was then filtered over Arbocel® and the resulting filtrate concentrated ln vacuo. The residue was purified by slllca gel column chromatography to afford the title compound as a solid (0.42 g, 63%). ‘

LCMS (2 min) Rt = 0.75 min. MS m/z 312 [MH⁴], 310 [MH]

Examples 13& 14

34(1 S)-1 -f4-r4-ÎTrifluoromethvnphenvl1-1 H-lmldazol-2-vlÎethvlloxetan-3-amine and

34(1 RM 4444-(TrifluoromethvQphenvl1-1 H-lmidazol-2-vllethvl]oxetan-3-amlne

Racemic 3-(1 -{4-[4-(trifluoromethyl)phenyl]-1 H-imidazcl-2-yl)ethyl)oxetan-3-amine (Example 12,0.410 g, 1.32 mmol) was dissolved in éthanol (8.2 mL). Enantiomers were separated by chiral préparative HPLC under basic conditions at ambient température on a Chiralpak AD-H column (250*, 21.2 mm l.d) supplied by Daicel Chemical Industries. A flow rate of 18 mL/mln was used with a mobile phase of: 70% heptane + 30% IPA + 0.3% diethyiamine (v/v) supplied by an Agiient 1200 prep pump. An injection volume of 1 mL was used per run.

Détection was achieved using an Agiient 1200 multiple wavelength UV absorbance detector set at 220 nm and 254 nm.

Enantiomer 1 : Rt = 4.85 min. >99.5% e© (144 mg, 35%)

Enantiomer 2: Rt = 5.89 min. >97.6% ee (142 mg, 35%)

Enantiomer 1:¹HNMR (de-DMSO): δ 1.25 (m, 3H), 3.35 (m, 1H), 4.23 (m, 1 H), 4.30 (m,

1H), 4.43 (m, 2H), 7.63 (m, 3H), 7.90 (m, 2H).

Enantiomer 2:¹HNMR (de-DMSO): δ 1.25 (m, 3H), 3.35 (m, 1 H), 4.23 (m, 1H), 4.30 (m,

H), 4.43 (m, 2H), 7.63 (m, 3H), 7.90 (m, 2H).

Example 15

3-i1-(4-f4-(Trifluoromethoxv)phenvn-1 H-imidazol-2-vl)propvDoxetan-3-amine

To a solution of 2-methyl-M-[3-(1-{4-[4-(trifluoromethoxy)phenyl]-1 H-imidazol-2-yl}propyl)oxetan-3-yl]propane-2-sulfinamlde (Préparation 10,0.450 g, 1.01 mmol) in methanol (5 mL) at 0°C was added 4M hydrogen chloride In 1,4-dioxane (1 mL) and the reaction left to stir for 4 hours. Solid sodium hydrogen carbonate was added to the reaction, followed by a saturated aqueous solution of sodium hydrogen carbonate. The mixture was extracted with dichloromethane. The organic layerwas dried over MgSÛ4 and concentrated in vacuo. The residue was purified by silica gel column · chromatography to afford the title compound (0.154 g, 45% yield).

’HNMR (CDCI₃): δ 1.0 (t, 3H), 1.65 (m, 2H), 3.4 (m, 1H), 4.25 (d, 1H), 4.45 (m, 2H), 4.75 (d, 1H), 7.2-7.3 (m, 4H), 7.75 (d, 2H).

LCMS (2 min) Rt = 1.57 min MS m/z 342 [MH]⁺, 340 [MH}‘

Examples 16 & 17 ’

3-«1 SÏ-1 -f4-f4-(Trlfluoromethoxv)phenvl1-1 H-imidazol-2-vllpropvl)oxetan-3-amine and • 3-f(1 /7)-1 -f4-[4-n'rifluoromethoxv)Dhenvl1-1 H-lmldazol-2-vl)DroDv0oxetan-3-amlne

Racemic 3-(1 -{4-[4-(trifluoromethoxy)phenyl]-1 H-lmîdazol-2-yl}propyl)oxetan-3-amine (Example 15,0.145 g, 1.01 mmol) was dissolved in a mixture of 70% heptane and 30%

IPA (3mL). Enantiomère were separated by chiral préparative HPLC under basic conditions at ambient température on a Chiraipak AD-H column (250*, 20 mm l.d) supplied by Dalcel Chemical Industries. A flow rate of 1 mL/mln was used with a mobile phase of: 90% heptane + 10% IPA + 0.1% diethylamine (v/v) delivered by a Waters 515 HPLC prep pump over a 20 minute run time. Détection was achieved using an Agilent

119 UV absorbance detector (UV), followed In sériés by a Polymer Labs PL-ELS 2100 detector (ELSD) and a Waters ZQ micromass mass spectrometer (MS).

Enantiomer 1 : Rt = 7.95 min. MS m/z 342 [MH]⁺

Enantiomer 2: Rt = 10.39 min. MS m/z 342 [MH]⁺

QC analysis was performed under basic conditions at ambient température on a Chiraipak AD-H column (250*, 10 mm l.d) supplied by Dalcel Chemical Industries. A flow rate of 1 mL/min was used with a mobile phase of: 80% heptane + 20% IPA + 0.2% diethylamine (v/v) over a 10 minute run time. Détection was achieved using an Agilent 20 100 detector (DAD), followed In sériés by a Polymer Labs PL-ELS 2100 detector (ELSD) and a Waters ZQ micromass mass spectrometer (MS).

Enantiomer 1 : Rt = 4.58 min. MS m/z 342 [MH]⁺ >99/5% ee

Enantiomer 2: Rt = 5.26 min. MS m/z 342 [MH]⁺ >99/5% ee t

I

Préparation 1

Benzvl r3-if4-r4-(trifluoromethoxvÎDhenvn-1H-lmidazol-2-vlÎmethvOtetrahvdro-2H-Dvran3-vncarbamate

METHOD C

Ammonium acetate (1.58 g, 20.5 mmol) was suspended in anhydrous toluene (10 mL) and heated to 100°C untii fully solLtoillsed. A solution of 2-oxo-2-[4-(trifluoromethoxy)phenyljethyl (3-{[(benzyloxy)carbony1]amino}tetrahydro-2H-pyran-3-yl)acetate (Préparation 20,1.11 g, 2.046 mmol) in anhydrous toluene (10 mL) was added to the 5 reaction. The température was Increased to 120°C and the reaction refluxed for 2.5 hours. Once cooled, the reaction was partitioned between dichloromethane (3x5 mL) and water (5 mL). The organic layer was separated by phase séparation cartridge and concentrated in vacuo to give an oll. The oil was purified by silica gel column · chromatography (0-50% ethyl acetate in heptane gradient elution) to afford the title 10 compound as a yellow oil (0.48 g, 49% yield).

’HNMR (CDCI₃): Ô 1.45 (m, 2H), 1.7 (m, 1H), 2.2 (m, 1H), 2.85 (d, 1H), 3.35 (m, 3H), 3.75 (m, 1H), 3.85 (m, 1H), 4.95 (d, 2H), 5.05 (d, 1H), 6.85 (br s, 1H), 7.1 (d, 2H), 7.3 (m, 5H), 7.6 (br m, 2H).

LCMS (2 min) Rt= 1.30 min MS m/z 476 [MH]⁺, 474 [MH]' '

Préparation 2

Benzvl [3-(f4-r4-itrifluoromethoxvÎDhenvl1-1H-lmÎdazol-2-vl)methvntetrahvdrofuran-3vllcarbamate

METHOD D

2-Oxo-2-[4-(trifluoromethoxy)phenyl]ethyl (3-{[(benzyloxy)carbonyl]aminoJtetrahydrofuran-3-yl)acetate (Préparation 13,0.634 g, 1.317 mmol), ammonium acetate (1.9 g, 25 mmol) and molecular sieves (3Â) were suspended in anhydrous toluene (5 mL) and heated to 110°C for 18 hours. Once cooled the reaction was partitioned 25 between dichloromethane (3x5 mL) and water (5 mL) The organic layer was separated by phase séparation cartridge and concentrated in vacuo to give an oil. The reaction had not gone to completion by 2 min LCMS analysis, therefore the oil, ammonium acetate (1.5 g, 19 mmol) and molecuiar sieves (3Â) were placed in a microwave vial with anhydrous toluene (5mL) and heated at 150°C for 1 hour In a 30 Biotage I nitiator™ microwave. Once cooled the reaction was partitioned between dichloromethane (3 x 5 mL) and water (5 mL) The organic iayer was separated by phase séparation cartridge and concentrated in vacuo to give an oil. The oil was purified by silica gel column chromatography (0-100% ethyl acetate In heptane gradient elution) to afford the title compound as a yellow oil (0.132 g, 22% yield).

LCMS (2 min) Rt = 1.30 min MS m/z 462 [MH]⁺, 460 [MH]*

The following Préparations 3 to 8 were prepared by methods analogous to Methods C and D as described for Préparations 1 and 2 above. Unless otherwise noted, préparation details are as described for the method referred to. *

Préparation 3

Benzyl (3-([4-(4-chloro-3-methvlphenvl)-1H-imidazol-2-vHmethvl)oxetan-3-vl)carbamate Prepared by Method C using 2-(4-chloro-3-methylphenyl)-2-oxoethyl (3-{[(benzyloxy)- carbonyl]amlno}oxetan-3-yl)acetate (Préparation 12,0.488 g, 1.13 mmol). The mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound (0.297 g, 64% yield).

LCMS (2 min) Rt = 1.25 min MS m/z 412 [MH}+

Preparation 4 terf-Butvl r4-((4-r4-(trif luoromeÎhoxv)phenvl1-1 Wmidazol-2-vl)methvl)tetrahvdro-2 Hpyran-4-vllcarbamate

Prepared by Method D using 2-oxo-2-[4-(trifluoromethoxy)phenyl]ethyl (4-[(tertbutoxycarbonyl)aminoJtetrahydro-2H-pyran-4-yl)acetate (Préparation 19,0.485 g, 1.051 mmol). The residue was purified by silica gel column chromatography (0-100% ethyl acetate + 3% triethylamine (v/v) In heptane gradient elution) to afford the title compound as a yellow oil (0.166 g, 36% yield).

LCMS (2 min) Rt = 1.25 min MS m/z 442 [MH]⁺, 440 [MH]*

Préparation 5

Benzyl r3-(f4-r4-(trifluoromeÎhvlÎphenvll-1H-lmidazol-2-vlÎmethvl)oxetan-3-vllcarbamaÎe

Prepared by Method C using 2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl (3-{[(benzyloxy)carbonyl]amino}oxetan-3-yl)acetate (Préparation 14,0.510 g, 1.13 mmol). The mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound (0.273 g, 56% yield).

• LCMS (2 min) Rt = 1.32 min MS m/z 432 [MH]⁺

Préparation 6 ’

Benzvl r3-((4-r4-fdifluoromethoxv)phenvl1-1H-lmidazol-2-vlÎmethvlÎoxetan-35 vOcarbamate

Prepared by Method C using 2-[4-(difluoromethoxy)phenyl]-2-oxoethyl (3-{[(benzyloxy)carbonyl]amlno)oxetan-3-yl)acetate (Préparation 15,0.508 g, 1.13 mmol). The mixture was partitioned between ethyi acetate and water. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound (0.269 g, 56% yield).

LCMS (2 min) Rt = 1.13 min MS m/z 430 [MH]⁺

Préparation 7

Benzvl i3-((4-r4-(DentafluoroA⁶-sulfanvl)phenvl1-1/ï-lmÎdazol-2-vl)methvl)oxetan-3vHcarbamate

Prepared by Method C using 2-oxo-2-[4-(pentafluoroA^e-sulfanyl)phenyl]ethyl (3{[(benzyloxy)carbonyl]amino}oxetan-3-yl)acetate (Préparation 18,0.9 g, 1.77 mmol). The reaction was refluxed for 18 hours. The mixture was partitioned between ethyl 20 acetate and water. The organic layer was dried over MgSO4 and concentrated In vacuo. The residue was purified by silica gel column chromatography to afford the title compound (0.227 g, 26% yield).

¹HNMR (CDCh): δ 3.50 (s, 2H), 4.70 (d, 2H), 4.85 (d, 2H), 5.10 (s, 2H), 5.80 (br s, 1 H), 25 7.3-7.45 (m, 8H), 7.65-7.8 (m, 3H).

LCMS (2 min) Rt = 1.44 min MS m/z 490 [MH]⁺, 512 [MNa]⁺, 488 [MH]'

Préparation 8

Benzvl f3-(1 -OW-itrifluoromethvOphenvII-l H-lmidazol-2-vl)ethvlÎoxetan-3-vllcarbamate Prepared by Method C using 2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl 2-(3-{[(benzyloxy)carbonyl]amino)oxetan-3-yl)propanoate (Préparation 22,2.15 g, 4.62 mmol). The reaction was refluxed for 12 hours. The mixture was partitioned between ethyi acetate and water. The organic layer was dried over MgSÜ4 and concentrated in vacuo. The .

residue was purified by silica gel column chromatography to afford the title compound (0.983 g, 48% yield).

LCMS (2 min) Rt = 0.97 min. MS m/z 446 [MH]⁺, 444 [MH]^-

Préparation 9 2-Μ6^ινΙ-Λ/·[3-(ΐ-(4-Γ4-ίίΐΊΑυοΓθΓηθΐΐΊθχν)ρ)ΐ6ηνΠ-1Η·ίπΜ3ζοΙ-2-νΠθΐ)ινΙ)οχ6ί3η-3vllpropane-2-sulf i namide 2-Oxo-2-[4-(trifluoromethoxy)phenyl]ethyl 2-{3-[(tert-butylsulfinyl)amino]oxetan-3-yl}· propanoate (Préparation 16,1.4 g, 3.10 mmol) and ammonium acetate (2.44 g, 31.0 mmol) were refluxed in toluene (40 mL) at 13O°C for 18 hours. Once cooled, water was added and the mixture extracted with ethyl acetate. The organic layer was dried over MgSO4 then concentrated /n vacuo. The residue was purified by silica gel coiumn chromatography to afford the title compound (0.323 g, 24% yield).

LCMS (2 min) Rt = 1.40 min MS m/z 432 [MH]⁺, 430 [MH]'

Préparation 10 2-Methvl-N-i3-i1-f4-f4-(trifluoromethoxv)phenvll-1 H-imidazol-2-vl)Dropvl)oxetan-3vllpropane-2-sulfinamlde 2-Oxo-2-[4-(trifluoromethoxy)phenyl]ethyl2-{3-[(tert’butylsulfinyl)amlno]oxetan-3-yl}· butanoate (Préparation 17,3.4 g, 7.3 mmol) and ammonium acetate (5.74 g, 73.0 mmol) were refluxed in toluene (40 mL) at 130°C for 18 hours. Once cooled, water was added and the mixture extracted with ethyl acetate. The organic layer was dried over MgSO₄ then concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound (2.527 g, 78% yield).

LCMS (2 min) Rt = 1.52 min MS m/z 446 [MH]⁺, 444 [MH]* .

LCMS (6 min acidic) Rt = 2.30 min MS m/z 446 [MH]⁺, 444 [MH]*

Préparation 11

Benzvl r3-(i4-r4-(trifluoromethoxv)phenvl1-1H-imidazoi-2-vl}methvl)oxetan-3vllcarbamate

Ammonium acetate (1.22 Kg, 15 mol) was stirred In toluene (12 L) and heated to 100°C for 30 minutes until the solid had melted. A solution of 2-oxo-2-[4-(trifluoromethoxy)16888 • 55 phenyljethyl (3-{[(benzyloxy)carbonyl]amlno}oxetan-3-yl)acetate (Préparation 21,700 g, 1.5 mol) in toluene (2 L) was added rapldly and the température Increased to 130°C and heated at vigorous reflux for 4 hours. The reaction was cooled to room température, water (4 L) added and the mixture stirred for 10 minutes before leaving to stand for 2 hours. The organic layer was separated and concentrated ln vacuo to afford a thick orange oil. Dichloromethane (5 L) was added and the solution gently agitated by tuming slowly on the rotary for 72 hours. A white precipitate was then observed. The solution volume was reduced in vacuo to 1 L and the mixture filtered through Arbocel®. The gelatinous solid was washed with dichloromethane (2 L) and the filtrate concentrated ln vacuo to afford a dark orange mobile oil. The oil was purified by silica gel column chromatography eluting with tert-butyl methyl ether to afford the title compound as a light orange oil (311 g, 46% yield).

HPLC (ultra acid method) Rt = 2.532 min.

Préparation 12

2-(4-Chloro-3-methvlphenvlÎ-2-oxoeÎhvl (3-ir(benzvloxvkarbonvnamlnoÎoxetan-3vDacetate

METHOD E .

(3-{[(Benzyioxy)carbonyl]amino}oxetan-3-yl)acetic acid (Préparation 25,0.3 g, 1.13 mmol), 2-bromo-1-(4-chloro-3-methyiphenyl)ethanone (0.294 g, 1.19 mmol) and césium carbonate (0.553 g, 1.70 mmol) were stirred ln acetonitrile (10 mL) at room température for 2 hours. The reaction was concentrated in vacuo and partitioned between ethyl acetate and water. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound which was used without purification ln the next step.

LCMS (2 min) Rt = 1.70 min MS m/z 432 [MH]⁺, 454 [MNaf, 430 [MH]'

Préparation 13

2-Oxo-2-r4-itrifluoromethoxv)phenvl1ethvl i3-ir(benzvloxv)carbonvl1amlnol· tetrahydrofuran-3-vbaceÎate

METHOD F (3-{{(Benzyloxy)carbonyl]amino}tetrahydrofuran-3-yl)acetic acid (Préparation 24,0.311 g, 1.11 mmoi) and triethylamine (0.233 mL, 1.67 mmoi) were stirred in acetone (4 mL).

A solution of 2-bromo-1 -[4-(trifluoromethoxy)phenyi]ethanone (0.315 g, 1.11 mmol) in acetone (4 mL) was added and the reaction heated to 50°C for 1 hour. Rapid formation of a white precipitate was observed. The reaction was partitioned between dichloromethane and water. The organic layer was separated by phase séparation cartridge and concentrated In vacuo to afford the title compound as an oil which was used without purification in the next step (0.634 g, 118% yield).

LCMS (2 min) Rt = 1.73 min MS m/z 482 [MH]⁺, 504 [MNa]*, 480 [MH]'

The following Préparations 14 to 20 were prepared by methods analogous to Methods E and F as described for Préparations 12 and 13 above. Uniess otherwise noted, préparation details are as described for the method referred to.

Préparation 14

2-Oxo-2-r4-(trifluoromethvlÎphenvHethvl (3-fr(benzvloxv)carbonvllamino)oxetan-3vOacetate

Prepared by Method E using (3-{[(benzyloxy)carbonyl]amino}oxetan-3-yl)acetlc acid (Préparation 25,0.3 g, 1.13 mmol) and 2-bromo-1-[4-(trifluoromethyl)phenyl]ethanone (0.317 g, 1.19 mmol) to afford the title compound.

LCMS (2 min) Rt « 1.68 min MS m/z 452 [ΜΗΓ, 474 [MNa]⁺, 450 [MH]’

Préparation 15

2-r4-(Difluoromethoxv)phenvl1-2-oxoethvl (3-n(benzvloxv)carbonvl1aminoloxetan-3vDacetate

Prepared by Method E using (3-{[(benzyloxy)carbonyllamlno}oxetan-3-yl)acetic acid (Préparation 25,0.3 g, 1.13 mmol) and 2-bromo-1-[4-(difluoromethoxy)phenyllethanone (0.315 g, 1.19 mmol) to afford the title compound.

LCMS (2 min) Rt = 1.63 min MS m/z 472 [MNaf, 448 [MH]'

Préparation 16

2-Oxo-2-f4-(trifluoromethoxv)phenvnethvl243-f(tert-buÎvlsulfinvl)amlno1oxetan-3vllpropanoate

Prepared by Method E using 2-{3-[(tert-butylsulfinyl)amino]oxetan-3-yl}propanoic acid (Préparation 26,1.18 g, 4.733 mmol) and 2-bromo-1-[4-(trifluoromethoxy)phenyl]16888 ethanone (1.47 g, 5.21 mmol). The residue was purified by sflica gel column chromatography to afford the title compound (1.413 g, 66% yield).

LCMS (2 min) Rt = 1.65 min MS m/z 452 [MH]⁺, 474 [MNa]⁺, 450 [MH]’

Préparation 17

2-Oxo-2-r4-(trifluoromethoxv)Dhenvnethvl 2-f3-f(tert-butvlsulfinvl)aminoloxetan-3vllbutanoate

Prepared by Method E using 2-{3-[(tert-butylsulfinyl)amino]oxetan-3-yl)butanoic acid (Préparation 27,2.658 g, 10.1 mmol) and 2-bromo-1-[4-(trifluoromethoxy)phenyl]ethanone (3.14 g, 11.1 mmol). The reaction was stirred at room température for 3 hours. The residue was purified by silica gel column chromatography to afford the title compound (3.435 g, 73% yield).

LCMS (2 min) Rt = 1.68 min MS m/z 466 [MH]⁺, 464 [MH]’

Préparation 18

2- Oxo-2-f4-foentafluoro-X^e-sulfanvl)phenvl]ethvl (3-U(benzyloxv)carbonvl]amino)oxetan-

3- vlÎacetate

Prepared by Method E using (3-{[(benzyloxy)carbonyl]amfno}oxetan-3-yl)acetic acid (Préparation 25,0.647 g, 2.44 mmol) and 2-bromo-1-[4-(pentafluoro-X^e-sulfanyl)phenyl]ethanone (Préparation 40,0.793 g, 2.44 mmol) to afford the title compound.

LCMS (2 min) Rt = 1.74 min MS m/z 510 [MH]⁺, 532 [MNa]⁺

Préparation 19

2-Oxo-2-f4-(trifluoromethoxv)phenvnethvl f4-î(tert-butoxvcarbonvhamino1tetrahvdro-2H· ovran-4-vl) acetate

Prepared by Method F using (4-[(tert-butoxycarbonyl)amino]tetrahydro-2H-pyran-4yl]acetic acid (0.259 g, 1.00 mmol) and 2-bromo-1-[4-(trifluoromethoxy)phenyl]ethânone (0.283 g, 1.00 mmol). The reaction was stirred at 50°C for 50 minutes. The residue was isolated as a crude oil that crystallised to afford the title compound as a soild (0.485 g, 105% yield).

LCMS (2 min) Rt = 1.73 min MS m/z 484 [MNa]⁺, 460 [MH]^-

Préparation 20

2-Oxo-2-f4-(trifluoromethoxv)phenvllethvl (3-iï(benzvloxv)carbonvnamlno)tetrahvdro2H-pyran-3-vDacetate

Prepared by Method F using i3-{[(benzyloxy)carbony!]amlno)tetrahydro-2H-pyran-3-y!)acetic acid (Préparation 23, 0.6 g, 2.05 mmol) and 2-bromo-1-[4-(trifluoromethoxy)phenyljethanone (0.579 g, 0.205 mmol). The reaction was stirred at 50°C for 1.5 hours.

LCMS (2 min) Rt = 1.75 min MS m/z 496, [MH]⁺, 518 [MNa]⁺, 494 [MH]'

Préparation 21

2-Oxo-2-r4-(trifluoromethoxv)phenvllethvl (3-ff(benzvloxv)carbonvllaminoÎoxetan-3vDacetate (3-[[(Benzyloxy)carbonyl]amino)oxetan-3-yl)aceticacid (Préparation 25, 1.011 Kg, 3.812 mol) was stirred in ethyl acetate (8 L). 2-Bromo-1-[4-(trif!uoromethoxy)pheny!]ethanone (1.08 Kg, 3.81 mol) was added, followed by triethylamine (585 mL, 4.19 mol). The reaction was initially fully solubilised, but a precipitate was then observed. The reaction was washed with water (2x4 L), then concentrated in vacuo to afford the title compound as a mobile orange oil (1.903 Kg, 107%, contains residual ethyl acetate).

HPLC (ultra acid method) Rt = 3.290 min.

Préparation 22

2-Oxo-2-r4-(trifluoromethvl)phenvnethvl 2-(3-ÎF(benzvloxv)carbonvl1amino)oxetan-3vltoropanoate

2-(3-{[(Benzyloxy)carbony!]amlno}oxetan-3-yl)propanoic acid (Préparation 28,1.5 g, 5.37 mmol) and triethylamine (1.12 mL, 8.06 mmol) were stirred In ethyl acetate (50 mL). 2-Bromo-1-[4-(trifluoromethyl)phenyl]ethanone (1.51 g, 5.64 mmol) was added and the reaction was stirred at room température ovemight. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was separated, dried over anhydrous magnésium sulphate, filtered and concentrated in vacuo. The residue was purifîed by silica gel column chromatography to afford the title compound as an oil (2.19 g, 88%).

¹HNMR (CDCI₃): δ 1.43 (m, 3H), 3.40 (m, 1 H), 4.70 (m, 2H), 4.Θ0 (m, 1H), 4.90 (m, 1 H),

5.10 (m, 2H), 5.35 (m, 2H), 6.05 (br s, 1H), 7.35 (m, 5H), 7.80 (m, 2H), 8.00 (m, 2H).

Préparation 23 Î3-if(Benzvloxv)carbonvnaminoltetrahvdro-2H-Pvran-3-vnacetÎc acid

METHOD G

Ethyl (3-amlnotetrahydro-2H-pyran-3-yl)acetate (Préparation 32,1.33 g, 7.109 mmol), benzyl chloroformate (1.53 g, 8.53 mmol) and Λ/,/V-dilsopropylethylamtne (3.72 mL, 21.3 mmol) were stirred in anhydrous acetonitrile (30 mL) for 18 hours at room température. The reaction was concentrated in vacuo then partitioned between ethyl acetate.and water. The organic layer was dried over MgSÛ4 and concentrated in vacuo. The residue was purified by silica gel column chromatography elutlng with heptane : ethyl acetate : methanol (100:0:0 - 0:90:10). The oil isolated was then dissolved In methanol (10 mL) and a 1M aqueous solution of sodium hydroxlde (10 mL) and heated to 75°C for 18 hours. The methanol was removed in vacuo and the mixture partitioned between dichloromethane (10 mL) and water. The aqueous layer was acidified with 2M aqueous hydrogen chloride and extracted with dichloromethane (4x10 mL). The organic layer was dried over MgSÛ4 to afford the title compound as a oil (0.6 g, 29% yield over 2 steps).

¹HNMR (CDCh): δ 1.5-1.6 (m, 1 H), 1.6-1.7 (m, 1 H), 1.7-1.8 (m, 1 H), 2.3 (m, 1 H), 2.7 (br m, 1H), 3.0 (br m, 1H), 3.5-3.6 (m, 2H), 3.8 (m, 1 H). 3.9 (d, 1H), 5.1 (s, 2H), 7.35-7.40 (m, 5H).

LCMS (2 min) Rt = 1.34 min MS m/z 292 [MH]', 316 [MNa]⁺ ·

The following Préparation 24 was prepared by a method analogous to Method G as described for Préparation 23 above. Unless otherwise noted, préparation details are as described for the method referred to.

Préparation 24 (3-fffBenzvloxvÎcarbonvl1aminoltetrahvdrofuran-3-vlÎacetic acid ·

Prepared by Method G using ethyl (3-amlnotetrahydrofuran-3-yl)acetate (Préparation

31,1.43 g, 8.25 mmol) to afford the title compound as an oil (0.311 g, 14% yield over 2 steps).

_A 60

LCMS (2 min) Rt = 1.26 min MS m/z 278 [MH]*, 302 [MNaf

Préparation 25 (34r(Benzvloxv)carbonvnaminoîoxetan-3-vl)acetic acid tert-Butyl methyl ether (2.5 L) and an aqueous solution of sodium carbonate (750 g In

2.2 L water, 7.07 mol) were stirred. Ethyl (3-aminooxetan-3-yl)acetate (Préparation 30, 875 g, 5.5 mol) was added to the reaction followed by further terf-butyl methyl ether (2.5 L). The reaction was cooled to 5°C and benzyl chloroformate (1.21 Kg, 7.09 mol) added in a controlled manner such as to maintain the température below 20°C. A precipitate was observed so further water (5 L) and terf-butyl methyl ether (1.5 L) were added to solubilise the reaction mixture. The biphasic mixture was separated. The organic layer was basified with 2M aqueous solution of sodium hydroxide (3.5 L) and stirred vigorously for 18 hours. The aqueous layer was separated and the remaining organic layer washed with water (1.5 L). The aqueous layers were combined and cooled to

15°C. Isopropyl acetate ( 5 L) was added followed by controlled addition of a 6M aqueous solution of hydrogen chloride (1.2 L), maintaining the température below 17°C. The reaction was stirred for 30 minutes. Solid crystallised out in the reactor so was dissolved In a mixture of ethyl acetate and methanol (—20 L). The solution was stirred at room température for 18 hours. The reaction was concentrated in vacuo to afford solid material. Ethyl acetate (5 L) was added and concentrated in vacuo. Further ethyl acetate (5 L) was added and the slurry heated to reflux to give an orange solution. The solution was cooled to 50°C and heptane (2.5 L) added. A thick slurry was observed that was stirred at room température for 18 hours. The solid was fiitered and dried on a sinter for 3 hours before drying in vacuo at 40°C for 18 hours to afford the title compound as a white crystalline solid (1.07 Kg, 73% yield).

¹HNMR (CDCIg): δ 3.1 (m, 2H), 4.6 (m, 2H), 4.7 (m, 2H), 5.1 (m, 2H), 7.2-7.4 (m, 5H).

Préparation 26 .

2-f3-f( tert-Butvlsulfinvl)amino]oxetan-3-vl)propanoic acid

Methyl 2-{3-[(tert-butylsulfinyl)amino]oxetan-3-yl]propanoate (Préparation 33,1.25 g, 4.746 mmol) was stirred In methanol (15 mL) and a 1M aqueous solution of sodium hydroxide (15 mL) for 3 hours at room température. The reaction was concentrated in vacuo and partitioned between diethyl ether and water. The pH of the aqueous layer was adjusted to pH3 with potassium hydrogen sulphate and extracted with '

dichloromethane. The organic layer was dried over MgSO₄ and concentrated in vacuo to afford the title compound that was used without purification in the next step.

Préparation 27

243-R ferf-Butvlsulfinvl)amino1oxeÎan-3-vlÎbuÎanoic acid

Methyl 2-{3-[(ferf-butylsulfinyl)amlno]oxetan-3-yl}butanoate (Préparation 35,2.89 g, 10.42 mmol) was stirred In methanoi (30 mL) and a 1M aqueous solution of sodium hydroxide (30 mL) for 18 hours at room température. The reaction was concentrated in vacuo and partitioned between diethyl ether and water. The pH of the aqueous iayer was adjusted to pH3 with potassium hydrogen suiphate and extracted with dichloromethane. The organic layer was dried over MgSO₄ and concentrated in vacuo to afford the title compound that was used without purification In the next step.

Préparation 28 2-(3-ff(Benzv1oxv)carbonvl1aminoÎoxeÎan-3-vQpropanoic acid Ethyl 2-(3-{[(benzyloxy)carbonyl]amino)oxetan-3-yl)propanoate (Préparation 29,43 g, 140 mmol) was stirred in methanoi (200 mL) and a 1M aqueous solution of sodium hydroxide (200 mL) for 18 hours at room température. The reaction was concentrated in vacuo and partitioned between diethyl ether and water. The pH of the aqueous layer was adjusted to pH3 with potassium hydrogen suiphate and extracted with dichloromethane. The organic layer was dried over MgSO₄ and concentrated in vacuo to afford the title compound that was used without purification In the next step.

Préparation 29

Ethyl 2-(3-ff(benzv1oxvÎcarbonvnamino)oxetan-3-v0propanoate

To a solution of ethyl 2-{3-[(tert-butylsulfinyl)amlno]oxetan-3-yl}propanoate (Préparation 34,40 g, 140 mmol) in methanoi (400 mL) at 0°C was added a 4M solution of hydrogen chloride In 1,4-dioxane (72 mL). After 2 hours, a 4M aqueous solution of sodium hydroxide (400 mL) was added drop-wise until pH 7 was achieved whilst maintaining the température at 0°C. The methanoi was removed in vacuo. The resulting solution was stirred with tetrahydrofuran (150 mL) and a 1M aqueous solution of sodium hydrogen carbonate (180 mL) at 0°C. Benzyi chloroformate (33.7 g, 187 mmol) was added and the reaction mixture stirred at room température for 18 hours. The organics were removed in vacuo and the resulting solution extracted with dichloromethane. The organic layer was dried over MgSO^, filtered and concentrated In vacuo. The resulting residue was purified by silica gel column chromatography to afford the title compound.

Préparation 30

Ethvl (3-amlnooxetan-3-vhacetate '

Ethyl oxetan-3-ylideneacetate (Préparation 38,781 g, 5.49 mol) was dissolved in 2M ammonia in éthanol (8.24 L) and heated to 100°C In a bomb for 5 hours. The reaction was concentrated in vacuo to afford the title compound as a mobile oil (750 g, 100% yield).

¹HNMR (CDCI₃): δ 1.25 (t, 3H), 2.0 (br S, 2H), 2.85 (s, 2H), 4.2 (q, 2H), 4.5 (d, 2H), 4.55 (d, 2H). *

Préparation 31

Ethvl (3-amÎnotetrahvdrofuran-3-vDacetate

Ethyl (2Z)-dihydrofuran-3(2H)-ylideneacetate (Préparation 36,1.29 g, 8.25 mmol) was stirred in 1,4-dioxane (7 mL) in a microwave vial. A solution of 7M ammonia in methanol (5 mL) was added and the reaction heated for 4 hours at 150°C in a Blotage Initiator™ microwave. The réaction was concentrated in vacuo, but later deemed not to hâve reached completion. A solution of 7M ammonia In methanol (7 mL) was added and the reaction heated agaln for 3 hours at 150°C in the microwave. A further portion of 7M ammonia in methanol (3 mL) was added and the reaction heated for a further 2 hours. The réaction was concentrated in vacuo to afford the title compound along with the methyl ester where trans-esterification had occurred. The material was used without further purification in the next step.

Préparation 32

Ethvl (3-aminotetrahvdro-2H-pyran-3-vl)acetate

Ethyl (22)-dihydro-2H-pyran-3(4H)-ylideneacetate (Préparation 37,1.21 g, 7.11 mmol) was stirred in 1,4-dioxane (7 mL) in a microwave vial. A solution of 7M ammonia In methanol (5 mL) was added and the reaction heated for 3 hours at 150°C in a Bîotage Initiator™ microwave. A further solution of 7M ammonia in methanol (2 mL) was added and the reaction heated agaln for 2 hours at 150°C ln the microwave. The reaction was concentrated In vacuo and the residue dissolved In a further portion of 7M ammonia In methanol (10 mL) and heated for a further 5 hours at 150°C In the microwave. The réaction was concentrated In vacuo to afford the title compound along with the methyl ester where trans-esterification had occurred. The material was used without further purification In the next step.

Préparation 33

Methyl 2-(3-l(tert-butvlsulfinvDamino1oxetan-3-vlÎpropanoate

Methyl propionate (2.71 g, 30.8 mmol) was dissolved In anhydrous THF (90 mL) and cooled to -78°C under nitrogen. LDA (2M solution In THF, 15 mL, 30 mmol) was added drop-wise. After 1 hour at -78°C, a solution of 2-methyl-W-oxetan-3-ylidenepropane-2sulfinamlde (Préparation 39,1.35 g, 7.703 mmol) in anhydrous THF (10 mL) was added. The reaction was gradually warmed to room température and stirred for 18 hours. The reaction was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was dried over MgSÛ4 and concentrated In vacuo. The residue was purified by silica gel column chromatography to afford the title compound as an oil (1.276 g, 63% yield).

¹HNMR (CDCh): δ 1.25 (s, 9H), 1.3-1.4 (m, 3H), 3.25 (m, 1H), 3.7 (m, 3H), 4.2 (br s, 0.4H), 4.45 (br s, 0.6H), 4.55 (m, 1.1 H), 4.6 (m, 0.9H), 4.75 (d, 0.6H), 4.85-5.0 (m, 1.4H).

Préparation 34

Ethyl 2-f3-iïtert-butvlsulfinvl)amino1oxetan-3-vBpropanoate

Λ/,Μ-diisopropylamlne (78 g, 770 mmol) was dissolved In anhydrous THF (200 mL) and cooled to -78°C under nitrogen. Butyl lithium (2.5M solution In hexane, 297 mL, 743 mmol) was added drop-wise. The reaction was removed from the cooling bath for 30 minutes, then re-cooled to -78°C. A solution of ethyl propionate (72.8 g, 713 mmol) In anhydrous THF (200 mL) was added drop-wise and the reaction allowed to stir at room température for 1 hour. The reaction was cooled to -78°C once agaln and a solution of 2-methyl-N-oxetan-3-ylidenepropane-2-sulfinamide (Préparation 39,50 g, 285 mmol) In anhydrous THF (200 mL) was added drop-wise. The reaction was stirred at between 40°C and -60°C for 4 hours before being quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was dried over MgSÜ4 and concentrated in vacuo. Purification by silica gel column chromatography (ethyl acetate elutîon) was not successful. The title compound was obtained as a yellow oil (40 g, 51% yield) and used without further purification.

Préparation 35

Methyl 2-f3-iïtert-butvlsulfinvl)amino]oxetan-3-vDbutanoate

Methyl butyrate (5.67 g, 55.5 mmol) was dissolved in anhydrous THF (100 mL) and cooled to -78°C under nitrogen. LDA (2M solution in THF 27.1 mL, 54.2 mmol) was added drop-wise. After 1 hour at -78°C, a solution of 2-methyl-N-oxetan-3-ylidenepropane-2-sulfinamide (Préparation 39,2.43 g, 13.88 mmol) in anhydrous THF (10 mL) was added. The reaction was gradually warmed to room température and stirred for 18 hours. The reaction was quenched with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was dried over MgSO₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography to afford the title compound as an oil (2.89 g, 75% yield).

’HNMR (CDCb): δ 1.00 (m, 3H), 1.25 (s, 9H), 1.6-2.0 (m, 2H), 3.0 (m, 1H), 3.7 (m, 3Η),

4.3 (br s, 0.5H), 4.50 (m, 1 H), 4.55 (br s, 0.5H), 4.6 (m, 0.5H), 4.65 (m, 1H), 4.9 (m, 0.5H), 4.95 (m, 1H).

Préparation 36

Ethvl Î2Z)-dihvdrofuran-3(2H)-vlideneacetate

METHOD H

Sodium hydride (60% dispersion In oil, 0.65 g, 16.3 mmol) was cooled to 0°C under nitrogen before adding anhydrous THF (20 mL). Trlethyl phosphonoacetate (3 mL, 15.1 mmol) was added slowly over 40 minutes to control gas évolution. A solution of 3-oxotetrahydrofuran (1 g, 11.62 mmol) In anhydrous THF (2 mL) was added and the reaction gradually warmed to room température and stirred for 18 hours. The reaction was concentrated in vacuo and the residue partitioned between ethyl acetate (3 x 50 mL) and water (30 mL). The organic layer was dried over MgSO₄ and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-50% ethyl acetate in heptane gradient elutlon) to afford the title compound as an oil (1.29 g, 71% yield).

’HNMR (CDCI₃): δ 1.3 (m, 3H), 2.7 (m, 1H), 3.05 (m. 0.7H), 3.2 (m, 0.3H), 3.9 (t, 1 H),

3.95 (t, 0.7H), 4.15 (m, 2H), 4.4 (m, 0.7H), 4.6-4.7 (m, 0.6H), 4.75 (m, 1 H), 5.7-5.85 (m,

1H).

LCMS ( 2 min) Rt = 1.23 min

MS m/z 157 [ΜΗΓ

The following Préparation 37 was prepared by methods analogous to Method H as described for Préparation 36 above. Unless otherwise noted, préparation details are as described for the method referred to.

Préparation 37

Ethyl (2Z)-dihvdro-2H-pyran-3f4H)-vlldeneacetate

Prepared by Method H using dihydropyran-3-one (1 g, 9.99 mmol) to afford the title compound as an oil (1.214 g, 71 % yield).

’HNMR (CDCIa): δ 1.25 (m, 3H), 1.8 (m, 2H), 2.2 (m, 1 H), 3.0 (m, 1H), 3.75 (m, 2H), 4.0 (s, 1H), 4.1 (m, 2H), 4.7 (s, 1H), 5.65 (m, 1H).

LCMS (2 min) Rt = 1.33 min MS m/z 171 [MH]⁺

Dihydropyran-3-one can be prepared using the literature procedure Tet., 2004, 60,46, 10411.

Préparation 38

Ethyl oxetan-3-vlldeneacetate ‘

To a solution of (carbethoxymethylene)triphenylphosphorane (1.95 Kg, 5.61 mol) in dichloromethane (4 L) at 0°C was added over 1 hour, a solution of 3-oxetanone (400 g, 5.55 mol) in dichloromethane (2 L) maintaining the température below 10°C. The reaction was warmed gradually to room température and stirred for 1.5 hours. The reaction was warmed to 30°C and dichloromethane (-4 L) removed in vacuo. Heptane (5 L) was added and the mixture distilled under vacuum for a further 1 hour. Further heptane (2.5 L) was added, the température Increased to 50°C and the reaction continued to be distilled under vacuum for a further 2 hours. The mixture was cooled to 0°C and aged for 1 hour at atmospheric pressure. The solid was collected by filtration and washed with heptane (2 x 2.5 L). The pale yellow filtrate was concentrated in vacuo to afford the title compound as a pale yellow mobile liquid (757 g, 96% yield).

¹HNMR (CDCI3): δ 1.25 (t, 3H), 4.2 (q, 2H), 5.3 (m, 2H), 5.5 (m, 2H), 5.65 (m, 1 H).

Préparation 39

2- Methvl-/V-oxetan-3-vlideneoropane-2-sulfinamide .

3- Oxetanone (3 g, 41.63 mmol), tert-butyl sulfinamide (5.55 g, 45.8 mmol) and titanium (IV) ethoxide (13.5 mL, 62.4 mmol) were stirred in THF (200 mL) at 40°C for 72 hours. The mixture was cooled to room température and poured into a rapldly stirred aqueous solution of saturated sodium chloride (200 mL). The resulting suspension was filtered through Celite® and the filter cake washed with ethyl acetate. The organic layer was separated and washed with brine, then dried over MgSO4 and concentrated ln vacuo. The residue was purified by silica gel column chromatography to afford the title . compound as an oil (1.37 g, 19% yield).

¹HNMR (CDCI₃): 6 1.3 (s, 9H), 5.4-5.5 (m, 2H), 5.65 (m, 1H), 5.8 (m, 1H).

Préparation 40 2-Bromo-1-r4-Îpentafluoro-X^g-sulfanvQphenvl1ethanone To a solution of 1-[4-(pentafluoro-X^e-sulfanyl)phenyl]ethanone (Préparation 41,0.6 g,

2.44 mmol) ln THF (20 mL) at 0°C was added trimethylphenylammonium trlbromide (0.962 g, 2.56 mmol). After stirring for 2 hours at 0°C the reaction was quenched with a saturated aqueous solution of sodium hydrogen carbonate. The reaction was extracted with ethyl acetate and dried over MgSO4 before concentrating In vacuo to afford the title compound that was used without further purification.

Préparation 41 ‘

1-r4-(Pentafluoro-X⁶-sulfanvl)phenvl1ethanone

To a solution of N-methoxy-N-methyl-4-(pentafluoro-X^e-sulfanyl)benzamide (Préparation 42,3.0 g, 10.3 mmol) in THF (100 mL) at 0°C was added drop-wise methyl lithium (1.5M solution, 10.3 mL, 15.5 mmol). The reaction was stirred at 0°C for 2 hours, then quenched with a saturated aqueous solution of ammonium acetate. The reaction was extracted with ethyl acetate and dried over MgSÛ4 before concentrating In vacuo to afford the title compound that was used without further purification.

¹HNMR (CDCI3): δ 2.65 (s, 3H), 7.9 (d, 2H), 8.05 (d, 2H).

Préparation 42

N-Methoxv-N-methvl-4-(pentafluoro-X-sulfanvllbenzamide 4-(Pentafluoro-X^e-sulfanyl)benzoyl chloride (1.00 g, 3.751 mmol), O,N-dimethylhydroxylamine hydrochloride (0.402 g, 4.13 mmol), and triethylamine (0.835 g, 8.25 mmol) were stirred in dichloromethane for 2 hours at room température. The reaction was concentrated In vacuo and diethyl ether added. The solid was collected by filtration and purified by silica gel column chromatography to afford the title compound as a solid (0.557 g, 51% yield).

LCMS (2 min) Rt = 1.56 min MS m/z 292 [MH]^{+ 1}HNMR (CDCi₃): δ 3.4 (s, 3H), 3.55 (s, 3H), 7.8 (m, 4H).

Assay Method .

The ability of the Imidazole dérivatives of the formula (I) to Inhibit the Nav1.8 channel may be measured using the assay described below.

HEK cells stably transfected with hNav1.8, purchased from Millipore (Millipore Corp., Billerica, MA 01821), were maintalned according to manufacturées instructions. For electrophyslological studies, cells were removed from the culture flask by brief · trypslnlzation and re-plated at low density onto glass cover slips. Cells were typically used for electrophyslological experiments within 24 to 72 h after plating.

Electrophyslological Recording

Cover slips containing HEK cells expressing hNav1.8 were placed in a bath on the stage of an Inverted microscope and perfused (approximately 1 mL/min) with extracellular solution of the following composition: 138 mM NaCI, 2 mM CaCI2,5.4 mM KCI, 1mM MgCh, 10 mM glucose, and 10 mM HEPES, pH 7.4, with NaOH. Pipettes were filled with an intracellular solution of the following composition: 135 mM CsF, 5 mM CsCI, 2 mM MgCI₂,10 mM EGTA, 10 mM HEPES, pH 7.3 with NaOH, and had a résistance of 1 to 2 megaohms. The osmolarity of the extracellular and intracellular solutions was 300 mOsm/kg and 295 mOsm/kg, respectively. Ail recordings were made at room température (22-24°C) using AXOPATCH 200B amplifiers and PCLAMP software (Axon Instruments, Buriingame, CA). ' hNav1.8 currents ln HEK cells were measured using the whole-cell configuration of the patch-clamp technique (Hamili et al., 1981). Uncompensated sériés résistance was typically 2 to 5 mega ohms and >85% sériés résistance compensation was routinely achieved. As a resuit, voltage errors were negligible and no correction was applied. Current records were acquîred at 20 to 50 KHz and filtered at 5 to 10 KHz.

HEK cells stably transfected with hNav1.8 were vlewed under Hoffman contrast optics and placed In front of an array of flow pipes emittlng either control or compoundcontalning extracellular solutions. Ali compounds were dissolved ln dimethyl sulfoxlde to make 10 mM stock solutions, which were then diluted into extraceilular solution to attaln the final concentrations desired. The final concentration of dimethyl sulfoxlde (<0.3% dimethyl sulfoxide) was found to hâve no significant effect on hNav1.8 sodium currents.

The voltage-dependence of Inactivation was determined by applying a sériés of depoiarizlng prepulses (8 sec long ln 10 mV Incréments) from a négative holding potential. The voltage was then Immediateiy stepped to 0 mV to assess the magnitude of the sodium current. Currents eiicited at 0 mV were piotted as a function of prepulse potential to allow estimation of the voltage at which 50% of the channels were Inactivated (mldpoint of inactivation or V1/2). Compounds were tested for their ability to inhibit hNav1.8 sodium channels by activating the channel with a 20 msec voltage step to 0 mV following an 8 second conditionlng prepulse to the empirically determined V1/2. Compound effect (% inhibition) was determined by différence in current amplitude before and after application of test compounds. For ease of comparison, “estimated IC50 values were calculated from single point electrophysiology data by the following équation, (tested concentration, uM) X (100-% inhibltion/% Inhibition). Inhibition values <20% and >80% were excluded from the calculation.

ln some cases eiectrophysioiogical assays were conducted with PatchXpress 7000 hardware and associated software (Molecular Devices Corp). Ali assay buffers and solutions were Identical to those used in conventional whole-cell voltage clamp experiments described above. hNav1.8 celis were grown as above to 50% - 80% confluency and harvested by trypsinization. Trypslnlzed cells were washed and resuspended in extracellular buffer at a concentration of 1x10^e cells/mL. The onboard • 69 liquid handling facility of the PatchXpress was used for dispensing cells and application of test compounds. Détermination of the voltage midpoint of Inactivation was as described for conventional whole-cell recordings. Cells were then voltage-clamped to the empirically determined V^and current was activated by a 20 msec voltage step to 0 5 mV.

·

Estimated IC50 values for the compounds of formula I exemplified above are as follows.

Example No.	Nav1.8 EIC50 (μΜ)		Example No.	Nav1.8 EICso (μΜ)
1	0.19		10	0.0033
2	0.36		11	0.009
3	0.26		12	0.0097
4	0.36		13	0.0078 .
5	0.48		14	0.051
6	0.92		15	0.011
7	0.40		16	0.032
8	0.057		17	0.075
9	0.026

Where replicate experïments were conducted resulting In multiple sets of data for a test compound, the data presented represent the average value from ail replicate experiments.

Claims (14)

1. A compound according to formula (I) (I) or a tautomer thereof, or a pharmaceutically acceptable sait of said compound or tautomer, wherein:

R¹ and R², together with the carbon to which they are attached, form a 4- to 7membered ring, wherein:

one member of said ring is O; and the remaining members of said ring are CR^eR⁷, which may be the same or different at each occurrence;

R³ is selected from the group consisting of H, (Ct-C₃)aikyl, cyclopropyl, cyclopropyl-CH2-, -CHzOH, -CH2OCH3, (Ci-C₃)fluoroalkyl, -OH, -OCH₃, F, -NH2, NHCH₃, -N(CH₃)₂ and -NHC(O)CH₃;

R⁴ Is selected from the group consisting of -CF₃, -OCF₃, -OCHF₂, Cl and -SF₅;

R⁵ Is selected from the group consisting of H and -CH₃; and

R® and R⁷ are independently selected from the group consisting of H, CH₃-, -OH,

-OCH3, F, -NH₂, NHCH₃ and -N(CH₃)₂.

The compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable sait of said compound or tautomer, according to claim 1. wherein:

2.

R¹ and R², together with the carbon to which they are attached, form a 4- to 7membered ring of formula wherein mis 1,2or3andnis 1 or2.

3. The compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable sait of said compound or tautomer, according to claim 2, wherein m Is 1 and n is 1.

4. The compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable sait of said compound or tautomer, according to any preceding claim, wherein:

R³ is selected from the group consisting of H, methyl, ethyl, n-propyl and · isopropyl.

5. The compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable sait of said compound or tautomer, according to any preceding claim, wherein:

R⁵isH.

6. The compound of formula (I) according to any preceding claim selected from:

3-({4-[4-(Trifluoromethoxy)phenyl]-1 H-lmidazol-2-yl}methyl)tetrahydro-2H-pyran3-amlne,

3-{[4-(4-Chioro-3-methyiphenyl)-1 H-imldazol-2-yl]methyl}oxetan-3-amine, <1

3-({4-[4-(Trifluoromethoxy)phenyl]-1H-lmldazo1-2-yl}methy1)tetrahydrofuran-3amlne,

3-({4-[4-(Trifluoromethyl)phenyl]-1H-lmidazol-2-yl}methyl)oxetan-3-amlne,

3-({4-[4-(Difluoromethoxy)pheny1]-1 H-lmldazol-2-yl}methyl)oxetan-3-amine,

3- ({4-[4-(Pentafluoro-X⁶-sulfanyl)phenyl]-1H-lmldazol-2-yl}methyl)oxetan-3amine,

4- ({4-[4-(Trif1uoromethoxy)phenyl]-1H-lmldazol-2-yl}methyl)tetrahydro-2H-pyran4-amine,

3-({4-[4-(Trifluoromethoxy)phenyl]-1H-lmidazol-2-yl}methyl)oxetan-3-amlne,

3-(1-{4-[4-(Trifluoromethoxy)phenyl]-1H-lmldazol-2-yl}ethyl)oxetan-3-amlne,

3-[(1 S)-1 -{4-[4-(Trifluoromethoxy)phenyi]-1 H-lmidazol-2-yl}ethyl]oxetan-3-amine,

3-[(1 R)-1 -{4-[4-(Trifluoromethoxy)phenyl]-1 H-lmldazo1-2-yl}ethyl]oxetan-3-amlne,

3-(1-{4-[4-(Trifluoromethyl)phenyl]-1 H-lmldazol-2-yl}ethyl)oxetan-3-amlne,

3-[( 1 S)-1 -{4-[4-(Trif1uoromethyl)phenyl]-1 H-lmidazol-2-yl)ethyl]oxetan-3-amine,

3-[(1 fi)-1 -{4-[4-(Trifluoromethyl)phenyl]-1 H-lmldazol-2-yl}ethyl]oxetan-3-amlne,

3-(1-{4-[4-(Trifluoromethoxy)phenyl]-1H-lmidazol-2-yl)propyl)oxetan-3-amlne,

3-(1 -{4-[4-(Trifluoromethoxy)phenyl]-1 /+imidazoi-2-yi}propyl)oxetan-3-amine, and

3-(1-{4-[4-(Trif1uoromethoxy)phenyl]-1H-imidazol-2-yi}propyl)oxetan-3-amine, or a tautomer thereof, or a pharmaceutically acceptable sait of said compound or tautomer.

7. The compound of formula (1) or a tautomer thereof, or a pharmaceutically acceptable sait of said compound or tautomer, according to any one of claims 1 to 6, for use as a médicament.

8. The compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable sait of said compound or tautomer, according to any one of claims 1 to 6, for use In the treatment of pain.

9. A pharmaceutical composition comprising a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable sait of said compound or tautomer, as defined in any one of claims 1 to 6.

10. The pharmaceutical composition of claim 9 wherein the composition Is adapted for topical administration.

11. The pharmaceutical composition of claim 9 wherein the composition Is adapted for ocular administration.

12. The pharmaceutical composition of claim 9 which further comprises one or more additional therapeutic agents.

13. The use of a compound of formula (I) or a tautomer thereof, or a pharmaceutically acceptable sait of said compound or tautomer, as defined in any one of claims 1 to 6, for the manufacture of a médicament for use In the treatment of pain.

14. The use of a compound of formula (1) or a tautomer thereof, or a pharmaceutically acceptable sait of said compound or tautomer, as defined in any one of claims 1 to 6 in the manufacture of a médicament for treating a disorder for which a Nav1.8 Inhibitor Is indicated.