NOVEL1, 3 DISUBSTITUTED AZETIDINE DERIVATIVES FOR USE AS 5HT2A RECEPTOR LIGANDS The present invention relates to a class of azetidine derivatives which act on serotonin receptors (also known as 5-hydroxytryptamine or 5-HT receptors). More particularly, the invention concerns 1- (arylalkyl)-substituted azetidine derivatives comprising additional substitution at the 3-position. These compounds are potent and selective antagonists of the human 5-HT2A receptor and are therefore useful as pharmaceutical agents, especially in the treatment and/or prevention of adverse conditions of the central nervous system, including sleep disorders such as insomnia and psychotic disorders such as schizophrenia and psychiatric disorders such as anxiety.

Compounds of the invention may display more effective binding to the human 5-HT2A receptor than to other human receptors such as D2, 5HT2C and IKr receptors.

They can therefore be expected to manifest fewer side-effects than compounds which do not discriminate in their binding affinity between such receptors. In addition these compounds have lower effects on the IKr receptors and there is a separation of the desired effect from side effects such as cardiac effects.

By virtue of their potent human 5-HT2A receptor antagonist activity, the compounds of the present invention are effective in the treatment of neurological conditions including sleep disorders such as insomnia, psychotic disorders such as schizophrenia, and also depression, anxiety, panic disorder, obsessive-compulsive disorder, pain, eating disorders such as anorexia nervosa, and dependency or acute toxicity associated with narcotic agents such as LSD or MDMA; and moreover are beneficial in controlling the extrapyramidal symptoms associated with the administration of neuroleptic agents. They may further be effective in the lowering of intraocular pressure, and may also be effective in treating menopausal symptoms, in particular hot flushes (see Waldinger et al, Maturitas, 2000,36, 165-8).

Various classes of compounds containing inter alia a sulphonyl moiety are described in WO 01/64632, WO 00/43362, WO 96/35666, EP-A-0261688, EP- 0304888, and US Patents 4,218, 455 and 4,128, 552, DE-A-3901735 and Fletcher et al, R Med. Chez., 2002,45, 492-503. None of these publications, however, discloses or suggests the particular class of compounds provided by the present invention.

The compounds according to the present invention are potent and selective 5- HT2A receptor antagonists typically having a human 5-HT2A receptor binding affinity (Ki) of 100 nM or less, frequently of 50 nM or less and in preferred cases of 10 nM or less. The compounds of the invention may possess at least a 10-fold selective affinity, suitably at least a 20-fold selective affinity and preferably at least a 50-fold selective affinity, for the human 5-HT2A receptor relative to the human dopamine Da receptor.

The compounds of this invention may possess at least a 10-fold selective affinity, suitably at least a 20-fold selective affinity and preferably at least a 50-fold selective affinity of the human 5-HT2A receptor relative to the IKr. The compounds of this invention may possess at least a 10-fold selective affinity, suitably at least a 20-fold selective affinity and preferably at least a 50-fold selective affinity for the human 5- HT2A receptor relative to the human 5-HT2c receptor. Preferred compounds show selectivities of at least 100 fold relative to the human 5-HT2c receptor.

The present invention provides a compound of formula I: I wherein n is 0,1, 2 or 3; W is CH2, CO, CHF or CH (OH); Y is CH2, CHF or CF2 ; ZisH, ForOH ; Arl is phenyl optionally bearing up to 3 substituents selected from halogen, CN, NO2, Rl, oR2, COR2, CO2R2, COR', SR2, S (O) tRl where t is 1 or 2, N (R2) 2, CON (R2) 2, NR2CORl and SO2N (R2) 2; Ar2 is phenyl or heteroaryl, said heteroaryl having 5 or 6 ring atoms of which one, two or three are selected from N, O and S but not more than one of which is O or S, said heteroaryl optionally being benzo-fused, and said phenyl or heteroaryl optionally bearing up to 3 substituents selected from halogen, CN, N02, Rl and OR2 ; Rl is a hydrocarbon group comprising up to 6 carbon atoms optionally bearing up to 5 fluorine substituents; and

R2 is Rl or H; or two R2 groups attached to the same nitrogen atom may complete a morpholine or thiomorpholine ring, or a 5-or 6-membered heterocycle wherein the remaining ring atoms are selected from C and N to a maximum of 4 ring nitrogens in total; or a pharmaceutically acceptable salt or hydrate thereof.

Where a variable occurs more than once in formula I or in a substituent thereof, the individual occurrences of that variable are independent of each other, unless otherwise specified.

As used herein, the expression"hydrocarbon group"refers to groups consisting solely of carbon and hydrogen atoms. Such groups may comprise linear, branched or cyclic structures, singly or in any combination consistent with the indicated maximum number of carbon atoms, and may be saturated or unsaturated, including aromatic when the indicated maximum number of carbon atoms so permits.

As used herein, the expression''Cl-xalkyl''where x is an integer greater than 1 refers to straight-chained and branched alkyl groups wherein the number of constituent carbon atoms is in the range 1 to x. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl. Derived expressions such as"C2-6alkenyl","hydroxyCl- 6alkyl","heteroarylCl-6alkyl","C2-6alkynyl"and"Cl-6alkoxy"ar e to be construed in an analogous manner. Most suitably, the number of carbon atoms in such groups is not more than 6.

The term"halogen"as used herein includes fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred.

For use in medicine, the compounds of formula I may be in the form of pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of formula I or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, benzenesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.

Alternatively, where the compound of the invention carries an acidic moiety, the

compound of formula I may exist as a zwitterion, or a pharmaceutically acceptable salt may be formed by neutralisation of said acidic moiety with a suitable base. Examples of pharmaceutically acceptable salts thus formed include alkali metal salts such as sodium or potassium salts; ammonium salts; alkaline earth metal salts such as calcium or magnesium salts; and salts formed with suitable organic bases, such as amine salts (including pyridinium salts) and quaternary ammonium salts. The compounds of formula I are typically in the form of the free base, the hydrochloride salt, the benzenesulfonate salt or the methanesulfonate salt.

When the compounds according to the invention have one or more asymmetric centres, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.

In the compounds of formula I, n is 0,1, 2 or 3 and W is CH2, CO, CHF or CH (OH). In a preferred embodiment W is CH2 or CO. When n is 0 W is preferably CH2. Specific examples of linkers represented by-[CH2] n-W-include CH2, CH2CH2, CH2CO, and CH2CH2CH2CO.

Y is CH2, CHF or CF2. In a particular embodiment Y is CH2.

Z is H, F or OH. Preferably, Z is H or F.

Arl is phenyl which optionally bears up to 3 substituents as defined previously.

Typically, if more than one substituent is present, the substituents are halogen atoms, preferably fluorine atoms. When a single substituent is present, it is typically attached in the 4-position. Preferred substituents include halogen, CN, Rl, oR2, N (R2) 2 and CON (R2) 2, where Rl and R2 are as defined previously. Typically Rl is a non-aromatic hydrocarbon group optionally substituted with up to 5 (preferably up to 3) fluorine atoms. Preferably, the hydrocarbon group is a Cl 6alkyl, C2 6alkenyl or C3 6cycloalkyl group, most suitably a Cl 4alkyl group. Suitable identities for Rl include methyl, ethyl, n-propyl, isopropyl, t-butyl, CF3, CHF2, CH2F, allyl and cyclopropyl, of which methyl, ethyl and CF3 are preferred. R2 represents H or Rl, or two R2 groups attached to the same nitrogen can complete a ring as defined previously. Examples of such rings include morpholine, thiomorpholine, pyrrolidine, piperidine, piperazine, imidazole and triazole. Examples of substituents on Arl include halogen (especially

Cl or F), CN, methyl, CF3, methoxy, CF30, CONH2, morpholin-4-yl and 1,2, 3-triazol- 1-yl. Particularly preferred examples of groups represented by Arl include 2- fluorophenyl, 4-fluorophenyl and 2, 4-difluorophenyl.

Ar2 represents phenyl or 5-or 6-membered heteroaryl as defined previously, either of which may bear up to 3 substituents as defined previously. Suitable 5-and 6- membered heteroaryl groups include furan, pyrrole, thiophene, oxazol, isoxazole, thiazole, isothiazole, imidazole, pyridine, pyrimidine and their benzo-fused derivatives. Preferred heteroaryl groups are 5-membered and benzo-fused, such as benzothiophene, benzothiazole, benzisoxazole and benzisothiazole. Typically, if more than one substituent is present on Ar2, the substituents are halogen atoms, preferably fluorine atoms, and/or alkyl groups. Preferred substituents include halogen (especially F or Cl), CN, Cl 4alkyl (especially methyl) and CF3.. When Ar2 is a benzo-fused heteroaryl group, said optional substituent (s) may be located on the fused benzene ring. Specific examples of groups represented by Ar2 include 4-fluorophenyl, 2,4- difluorophenyl, 4-fluoro-2-methylphenyl, 2-chlorophenyl, 6-fluorobenzothiophene-3- yl, benzothiazol-2-yl, 6-fluorobenzisothiazol-3-yl and 6-fluorobenzisoxazol-3-yl.

In a particular embodiment, when Ar2 is a benzo-fused heteroaryl group W is CH2 and n is 0.

A first subset of the compounds of the invention is defined by formula II : II and the pharmaceutically acceptable salts and hydrates thereof; wherein: Wl is CH2 or CO; Z'is H or F ; Ar la is 2-fluorophenyl, 4-fluorophenyl or 2,4-difluorophenyl ; Ar2a is 4-fluorophenyl, 2, 4-difluorophenyl or 4-fluoro-2-methylphenyl; and n and Y are as defined previously.

In this subset, n is preferably 1.

A second subset of the compounds of the invention is defined by formula IH :

and the pharmaceutically acceptable salts and hydrates thereof; wherein Ar2b is 6-fluorobenzisothiazol-3-yl or 6-fluoroisoxazol-3-yl; and Y, Zl and Arla are as defined previously.

Specific examples of compounds in accordance with the invention include those exemplified hereinafter and pharmaceutically acceptable salts and hydrates thereof.

The compounds of the present invention have an activity as antagonists of the human 5-HT2A receptor and hence find use in the treatment or prevention of disorders mediated by 5-HT2A receptor activity.

The invention also provides pharmaceutical compositions comprising one or more compounds of this invention and a pharmaceutically acceptable carrier.

Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, transdermal patches, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. The principal active ingredient typically is mixed with a pharmaceutical carrier, e. g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate and dicalcium phosphate, or gums, dispersing agents, suspending agents or surfactants such as sorbitan monooleate and polyethylene glycol, and other pharmaceutical diluents, e. g. water, to form a homogeneous preformulation composition containing a compound of the present invention, or a pharmaceutically acceptable salt thereof.

When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such

as tablets, pills and capsules. This preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Typical unit dosage forms contain from 1 to 100 mg, for example 1,2, 5,10, 25,50 or 100 mg, of the active ingredient.

Tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, liquid-or gel-filled capsules, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil or coconut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, poly (ethylene glycol), poly (vinylpyrrolidone) or gelatin.

The present invention also provides a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof for use in a method of treatment of the human body. Preferably the treatment is for a condition mediated by 5-HT2A receptor activity.

The present invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt or hydrate thereof in the manufacture of a medicament for treating or preventing a condition mediated by 5-HT2A receptor activity in humans.

Also disclosed is a method of treatment of a human subject suffering from or prone to a condition mediated by 5-HT2A receptor activity which comprises

administering to that subject an effective amount of a compound according to formula I or a pharmaceutically acceptable salt or hydrate thereof.

In one aspect of the invention, the condition mediated by 5-HT2A receptor activity is sleep disorder, in particular insomnia. In a further aspect of the invention, the condition mediated by 5-HT2A receptor activity is selected from psychotic disorders (such as schizophrenia), depression, anxiety, panic disorder, obsessive- compulsive disorder, pain, eating disorders (such as anorexia nervosa), dependency or acute toxicity associated with narcotic agents such as LSD or MDMA, and hot flushes associated with the menopause.

In the treatment envisaged herein, for example of insomnia or schizophrenia, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day but preferably once per day, for example before going to bed.

If desired, the compounds according to this invention may be co-administered with another sleep inducing or anti-schizophrenic or anxiolytic medicament. Such co- administration may be desirable where a patient is already established on sleep inducing or anti-schizophrenic or anxiolytic treatment regime involving other conventional medicaments. In particular, for the treatment of sleep disorders, the compounds of the invention may be co-administered with a GABAA receptor agonist such as gaboxadol, or with a short term and/or rapid-onset hypnotic such as zolpidem, or a benzodiazepine, a barbiturate, a prokineticin modulator, an antihistamine, trazodone, or derivative oftrazodone as disclosed in WO 03/068148.

The compounds of formula I may be obtained by reaction of compounds of formula (la) with compounds of formula (2): wherein G is a leaving group such as mesylate, tosylate or halide (especially bromide) and n, W, Y, Z, Arl and Ar2 have the same meanings as before. The reaction takes place under typical alkylation conditions, e. g. in a solvent such as DMF, acetonitrile,

acetone, or 2-butanon at ambient or moderately elevated temperatures (e. g. about 70- 90°C), in the presence of a base such as potassium carbonate.

Alternatively, compounds of formula I in which n is 1 or more may be formed by reacting amines (la) with aldehydes (3): Ar2-W- (CH2) m-CHO (3) where m is 0,1 or 2 and W and Ar2 have the same meanings as before. The reaction takes place in the presence of sodium cyanoborohydride in alcoholic solution (eg methanol) at ambient temperature.

The amines (la) may be preformed or formed iii situ from compounds (lb) where Prt is a protecting group. Preferred protecting groups include diphenylmethyl (which may be removed by hydrogenation over a Pd (OH) 2 catalyst) and t- butoxycarbonyl (BOC) (which may be removed by treatment with acid, eg trifluoroacetic acid or HC1 in aqueous dioxan).

Compounds (lb) in which Y is CH2 are obtainable by oxidation of thioethers (4): where Z and Arl have the same meanings as before. Suitable oxidants include Oxone, in methanol at 0°C to ambient temperature.

Thioethers (4) in which Z is H are obtainable by treatment of mesylates (5a) with thiophenols ArlSH (eg in refluxing acetonitrile in the presence of potassium carbonate), where Arl has the same meaning as before. Mesylates (5a) are obtained by treatment of hydroxymethyl derivatives (5b) with methanesulfonyl chloride in an inert solvent such as dichloromethane in the presence of base such as triethylamine.

Thioethers (4) in which Z is OH are obtainable by reaction of epoxide (6) with thiophenols ArlSH :

where Arl has the same meaning as before, and Prt is preferably diphenylmethyl. The reaction takes place in the presence of strong base such as sodium hydride in an aprotic solvent such as THF at about 0°C. The synthesis of epoxide (6) (Prt = diphenylmethyl) is described in W097/42189.

Thioethers (4) in which Z is F are obtainable by reaction of the thioethers (4) in which Z is OH with (diethylamino) sulfur trifluoride, for example in dichloromethane at-10°C to ambient temperature.

Compounds (lb) in which Y is CHF or CF2 are obtainable from the corresponding compounds in which Y is CH2 by fluorination with N- fluorobenzenesulfonimide, for example in THF at-78°C to ambient temperature.

Typically, a mixture of mono-and di-fluorinated products is obtained which may be separated by chromatography. In this process, the protecting group Prt is preferably BOC.

An alternative route to compounds (lb) in which Y is CH2 and Z is H involves reaction of mesylates (5a) with Arl-SO2~M+, where M is an alkali metal (preferably Na) and Arl has the same meaning as before. The reaction takes place in DMF at about 80°C in the presence of sodium iodide. The desired sulfone is produced along with a sulfinate ester by-product, from which it may be separated by conventional chromatographic techniques.

In cases where any of the substituents in any of the compounds require protection during any of the preceding reactions this may be effected in conventional manner. Alternatively there may be instances where a particular substituent may be introduced after the above reactions are performed. Thus for example where a nitrile is required as a substituent it may be introduced by replacing a bromine atom, for example reacting the appropriate bromo-compound of the formula (I) in an anhydrous solvent such as dimethylformamide with zinc cyanide in the presence of tetrakis (triphenylphosphine) palladium with heating, for example to 85-95°C.

Introduction of a nitrile or heterocycle can be also performed by replacement of fluorine by nucleophilic displacement, for example by heating with NaCN or a triazole in DMSO. Other modifications of substituents can be carried out by conventional art methods, for example as set out in WO 00/43362 or Fletcher et al, J : Med. Chem., 2002,45, 492-503.

Where they are not commercially available, the starting materials and reagents used in the above-described synthetic schemes may be prepared by conventional means.

It will be appreciated that where more than one isomer can be obtained from a reaction the resulting mixture of isomers can be separated by conventional means.

Where the above-described process for the preparation of the compounds according to the invention gives rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The novel compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative HPLC, or the formation of diastereomeric pairs by salt formation with an optically active acid, such as di-p-toluoyl-D-tartaric acid or di-p-toluoyl-L-tartaric acid, followed by fractional crystallization and regeneration of the free base. The novel compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, such techniques may be carried out on racemic synthetic precursors of the compounds of interest.

Compounds were tested at the 5-HT2A receptor as well as IKr and 5-HT2C receptor using the methodology described in Fletcher et al, J. Med. Chem., 2002,45, 492-503.

The following examples illustrate the invention.

Example 1 1-r2-(2,4-Difluorophenvl) ethyll-3r (4-fluorophenvl) sulfonvllmethvl} azetidine Step 1: rl- (Diphenvlmethvl) azetidin-3-vllmethvl methanesulfonate A solution of l-(diphenylmethyl)-3-(hydroxymethyl) azetidine (lg, 3. 9mmol) [prepared by reduction of 1- (diphenylmethyl) azetidine-3-carboxylic acid (CAS No.: 36476-87-6) using LiAlH4 in refluxing THF] and Et3N (0. 71mL, 5. 1mmol) in THF (30mL) was treated with methanesulfonyl chloride (0.36mL, 4. 7mmol) and stirred for

2 h at room temperature. The precipitate was removed by filtration and washed with THF. The liquors were evaporated and the residue partitioned between water and DCM. The DCM layer was separated and the aqueous re-extracted. The combined organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was triturated with isohexane, the solid then isolated by filtration and dried to give the title compound as an orange solid (l. lg, 84%). m/z (ES+) 332 (M+H) +.

Step 2: 1- (Diphenvlmethyl)-3- f f (4-fluorophenvl) thiolmethyl} azetidine A solution of the foregoing mesylate (0. 8g, 2. 4mmol) in MeCN (30mL) was degassed with nitrogen. 4-Fluorothiophenol (0. 51mL, 4. 8mmol) and powdered K2CO3 (1.3g, 9. 6mmol) were then added and the reaction heated at reflux for 1 h. The cooled mixture was transferred to a separating funnel and diluted with DCM (lOOmL) and water. The organic layer was separated and the aqueous re-extracted. The combined organics were dried (Na2S04), filtered and evaporated. The residue was purified by silica column chromatography eluting with 5% EtOAc/isohexane then 10% EtOAc/isohexane to give the title compound as a colourless oil (0.86g, 97%). mlz (ES+) 364 (M+H) +.

Step 3: 1- (Diphenvlinethyl)-3-f r (4-fluorophenvl) sulfonvllyl} azetidine A mixture of the foregoing sulfide (lg, 2. 75mmol) and oxone (3.4g, 5. 5mmol) in MeOH (50mL) was stirred for 8 days. DCM (250mL) and saturated NaHC03 solution were added and stirred for 10 min. The organic layer was separated and the aqueous re-extracted. The combined organics were washed with brine, dried (Na2S04), filtered and evaporated. The residue was purified on a silica column eluting DCM then 5% EtOAc/DCM. The title compound was collected as a colourless gum (0.7g, 64%). milz (ES+) 396 (M+H) +.

Step 3a : 1- (Diphenvlmethyl)-3-ff (4-fluorophenvl) sulfonvllmethvlazetidine (Alternative route) [1- (Diphenylmethyl) azetidin-3-yl] methyl methanesulfonate [Step 1] (3.15g, 9. 50mmol), sodium 4-fluorobenzenesulfinate (2.65g, 14. 3mmol) and sodium iodide (2. 18g, 14. 5mmol) were combined in dimethylformamide (50mL). The mixture was

stirred at 80°C (oil bath temperature) under nitrogen for 1.5 h. The solution was allowed to cool to room temperature, poured into water (500mL) and extracted with ethyl acetate (2 x 200mL). The organic extracts were washed with brine (200mL), combined, dried (MgS04) and concentrated in vacuo. The residue was purified by flash chromatography, eluting with 5-20% ethyl acetate in dichloromethane, to afford an oil which crystallised on standing. Recrystallisation from ethyl acetate/isohexane gave the title compound, identical to the product obtained via steps 2 and 3.

Step 4: 3-f f f4-Fluorophenvl) sulfonvllmethvl azetidine hydrochloride The foregoing sulfone (0.7g, 1. 8mmol), EtOH (60mL), 5N HC1 (0. 5mL, 2. 5mmol), 20% Pd (OH) 2 on carbon (0.6g) and water (5mL) were combined and shaken for 2 h under 50 psi of hydrogen on a Parr machine. The catalyst was removed by filtration and the filtrate evaporated. The residue was triturated with ether and filtered to collect the title compound as a white solid (375mg, 80%). into (ES+) 230 (M+H) +.

Step 5: 1-r2- (2, 4-Difluorophenvllethvll-3- f ( (4fluorophenvl) sulfonvllmethvl azetidine The foregoing azetidine hydrochloride (115mg, 0.43mmol), K2CO3 (176mg, 1. 28mmol), 2,4-difluorophenethyl bromide (140mg, 0. 64mmol) and DMF (5mL) were combined and heated at 70°C for 12 h. The mixture was evaporated by forming an azeotrope with xylene and the resultant residue partitioned between DCM and water.

The DCM layer was separated and the aqueous re-extracted. The combined organics were washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified using silica column chromatography eluting 0.5% MeOH/DCM then 2% MeOH/DCM. Further purification was carried out using preparative HPLC with UV detection using 20-95% gradient MeCN using 0.1% TFA in the aqueous phase. The MeCN was evaporated from the product fractions, the aqueous made basic and extracted with EtOAc. The combined organics were washed with brine, dried (Na2S04), filtered and evaporated to give a colourless gum (66mg, 41%).'H NMR (400 MHz, CDC13) 8 2. 82 (3H, m), 3.35 (2H, d, J= 6.4 Hz), 3.40 (2H, m), 6.72-6. 80 (2H, m), 7.08-7. 12 (1H, m), 7.24 (2H, t, J= 8.7 Hz), 7.88-7. 91 (2H, dd, J= 8.7 and 5.1 Hz). mlz (ES+) 370 (M+H) +.

Example 2 1- (4-Fluorophenyl)-2- (3- f f (4-fluorophenvl) sulfonvl] methyl} azetidin-1-yl) ethanone A mixture of 3-{[(4-fluorophenyl)sulfonyl]methyl} azetidine hydrochloride (75mg, 0. 28mmol) in MeCN (5mL) was treated with Et3N (97µL, 0. 7mmol) and 2-bromo-4'- fluorophenylacetophenone (68mg, 0. 31mmol) and stirred for 30 min at room temperature. The reaction was evaporated and the residue dissolved in DCM and purified using silica chromatography. The column was eluted with 1% MeOH/DCM to give the title compound as a white solid (70mg, 68%). 1H NMR (500 MHz, CDC13) 15 2.94-2. 99 (1H, m), 3.10 (2H, t, J= 7.4 Hz), 3.42 (2H, d, J= 7.4 Hz), 3.62 (2H, t, J= 7.4 Hz), 3.87 (2H, s), 7.12 (2H, t, J= 8. 8 Hz), 7.25 (2H, t, J= 8.6 Hz), 7.90-7. 94 (4H, m). nilz (ES+) 366 (M+H) +.

Example 3 <BR> <BR> <BR> <BR> <BR> <BR> 1- (4-Fluorophenvl)-4- (3-f F (4-fluorophenvl) sulfonvllmethyl} azetidin-1-vl) butan-1-one hydrochloride A stirred mixture of 3-{[(4-fluorophenyl) sulfonyl] methyl} azetidine hydrochloride (150mg, 0. 56mmol), 2-butanone (5mL), potassium carbonate (0.25g, 1. 81mmol), sodium iodide (20mg, 0. 13mmol) and 4-chloro-l- (4-fluorophenyl) butan-l-one (115µL, 0. 68mmol) was heated at reflux for 5 h under an inert atmosphere. The cooled reaction mixture was partitioned between EtOAc and water. The EtOAc extracts were washed with water and saturated brine then dried (MgS04), filtered and concentrated in vacuo. The resultant material was purified by column chromatography on silica eluted with a gradient of 0-15% MeOH-EtOAc to give the free base. This was dissolved in EtOAc and treated with 1M HC1 in diethyl ether. The solvents was removed in vacuo to give 1-(4-fluorophenyl)-4-(3-{[(4- fluorophenyl) sulfonyl] methyl} azetidin-l-yl) butan-l-one hydrochloride as a white solid (16mg). 1H NMR (400 MHz, CD30D) 8 1.90-1. 99 (2H, m), 3.17 (2H, t, J = 6.6 Hz), 3.25-3. 35 (3H, m), 3. 68 (2H, d, J= 7.3 Hz), 4.0-4. 2 (2H, br s), 4.2-4. 4 (2H, br

s), 7.20-7. 27 (2H, m), 7.39-7. 46 (2H, m), 7.98-8. 04 (2H, m), 8.05-8. 10 (2H, m). iillz (ES+) 394 (M+H) +.

Example 4 2-(3-{[(2,4-Difluorophenyl)sulfonyl]methyl}azetidin-1-yl)-1- (4- fluorophenyl) ethanone hydrochloride Step 1: 3-{[(2,4-Difluorophenyl)sulfonyl]methyl}azetidine hydrochloride Prepared as described in Example 1, Steps 1-4 using 2, 4-difluorothiophenol in Step 2, and isolated as a colourless solid (264mg NMR (500 MHz, d6-DMSO) 8 3. 01- 3.11 (1H, m), 3.75-3. 85 (2H, m), 3. 88-3. 96 (3H, m), 7.39-7. 42 (1H, m), 7.69-7. 73 (1H, m), 7.89-7. 93 (1H, m), 8. 98-9. 15 (2H, br s). m/z (ES+) 248 (M+H) +.

Step 2: 2-(3-{[(2,4-Difluorophenyl)sulfonyl]methyl}azetidin-1-yl)-1- (4- fluorophenyl) ethanone hydrochloride 3- [ (2, 4-Difluorophenyl) sulfonyl] azetidine hydrochloride (60mg, 0. 21mmol) and 2-bromo-1- (4-fluorophenyl) ethanone (52mg, 0. 23mmol) were stirred together at room temperature with K2CO3 (90mg, 0. 65mmol) in DMF (3 mL) under an inert atmosphere. Water was added to the mixture after 5.5 h and the mixture was then extracted with EtOAc. The organic extracts were washed with water and saturated brine then dried (MgS04), filtered and concentrated in vacuo. The resultant material was purified using preparative thin layer chromatography on silica eluted with 50% EtOAc-isohexane to give the free base. This was then dissolved in EtOAc and treated with 1M HC1 in diethyl ether. The solids was filtered off and dried in vacuo to give 2- (3-1 [ (2, 4-difluorophenyl) sulfonyl] methyl} azetidin-1-yl)-1- (4-fluorophenyl) ethanone hydrochloride as a colourless solid (12 mg).'H NMR (500 MHz, d6-DMSO) 8 3.09- 3.19 (2H, m), 3.95 (2H, d, J= 7.1 Hz), 4. 01-4. 16 (2H, br s), 4.17-4. 29 (2H, m), 5.06 (2H, s), 7.40-7. 47 (3H, m), 7.70-7. 75 (1H, m), 7.91-7. 94 (1H, m), 7.99-8. 02 (2H, m), 10.72 (1H, br s). m/z (ES+) 384 (M+H) +.

Example 5 2- (3-Fluoro-3-{[(4-fluorophenyl)sulfonyl]methyl}azetidin-1-yl) -1-(4- fluorophenyl)ethanone hydrochloride Step 1: 1- (Diphenvlmethvl)-3-f{ (4-fluorophenvl) thiolmeth azetidin-3-ol Sodium hydride (0.128g of a 60% dispersion in mineral oil, 3.2mmol) was added to a solution of 4-fluorobenzenethiol (0.29mL, 2.7mmol) in THF (lOmL). The resulting mixture was stirred at room temperature for 10 min and then cooled to 0°C. A solution of 5-(diphenylmethyl)-1-oxa-5-azaspiro [2.3] hexane [prepared by the method of J. L. Castro Pineiro et al. WO 97/42189] (0. 68g, 2. 71mmol) in THF (8mL) was added and the resulting mixture stirred at-1°C for 40 min then at room temperature overnight. The reaction mixture was poured into water (200mL) and extracted with EtOAc (lOOmL then 50mL). The organic extracts were washed with saturated brine (lOOmL), combined, dried (MgSO4) and concentrated. The residue was purified by flash silica chromatography, eluting with 25% EtOAc/isohexane, to give the title product as an oil (0. 82g, 80%). 1H NMR (400 MHz, CDC13) 8 2.67 (1H, s), 2.94-2. 96 (2H, m), 3.18-3. 20 (2H, m), 3.43 (2H, s), 4.34 (1H, s), 6.96-7. 02 (2H, m), 7.15-7. 19 (2H, m), 7.23-7. 26 (4H, m), 7.34-7. 36 (4H, m), 7.41-7. 46 (2H, m). (376 MHz, CDC13) bu-115. 2. nilz (ES+) 380 (M+H) +.

Step 2: 1- (Diphenvlmethvl)-3-fluoro-3-f f (4-fluorophenvl) sulfonyllmethyl} azetidine (Diethylamino) sulfur trifluoride (75mL, 0. 57mmol) was added dropwise to a solution of 1- (diphenylmethyl)-3- { [ (4-fluorophenyl) thio] methyl} azetidin-3-ol (17 lmg, 0. 451mmol) in DCM (5mL) at-10°C. The resulting solution was stirred at-10°C under nitrogen for 20 min, the cooling bath removed and the mixture stirred for a further 30 min. The reaction was quenched by the addition of saturated aqueous sodium hydrogen carbonate (5mL), the organic layer and the aqueous phase extracted with DCM (2 x 5mL). The combined organic extracts were dried (MgS04) and evaporated. The residue was purified by flash silica chromatography, eluting with 3: 1 DCM/isohexane then DCM to give an oil (136mg). A portion of this material (129mg) was dissolved in methanol (5mL), the solution cooled to 0°C and treated with

oxone (464mg, 0.75mmol). The resulting mixture was stirred at 0°C for 1 h then at room temperature overnight. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and extracted with DCM (40mL then 2 x 20mL). The combined organic extracts were dried (MgS04) and evaporated. The residue was purified by preparative thin layer chromatography, eluting with 3: 1 DCM/isohexane to afford the title compound as an oil (67mg, 38%). 1H NMR (500 MHz, CDC13) 8 3.23 (2H, dd, J= 22.5 andlO. 3 Hz), 3.54-3. 59 (2H, m), 3.76 (2H, d, J= 21 Hz), 4.37 (1H, s), 7.17-7. 22 (4H, m), 7.25-7. 28 (4H, m), 7.36-7. 38 (4H, m), 7.90 (2H, dd, J= 8. 8 and 5.1 Hz). (376 MHz, CDC13) au-103. 6, -146.5. m/z (ES+) 414 (M+H) +.

Step 3 : 2- (3-Fluoro-3-ff (4-fluorophenyl) sulfonvllmethvl} azetidin-1-vl)-1- (4- fluorophenvl) ethanone hydrochloride 1M HC1 in diethyl ether (0. 18mL, 0. 18mmol) and palladium hydroxide on carbon (26. 1mg ; 20wt. %) were added to a solution of 1-(diphenylmethyl)-3-fluoro-3-{[(4- fluorophenyl) sulfonyl] methyl} azetidine (57mg, 0. 138mmol) in MeOH (lOmL). The resulting mixture was hydrogenated on Parr apparatus, 50psi max. , for 2.5 h. The mixture was filtered and concentrated in vacuo. The residual solid was washed twice with diethyl ether. The resulting solid was dissolved in DMF (2mL) and treated with potassium carbonate (64mg, 0. 46mmol) then 2-bromo-4'-fluoroacetophenone (34mg, 0. 156mmol). The reaction mixture was stirred at room temperature for 1.5 h, diluted with water (20mL) and extracted with EtOAc (2 x lOmL). The combined organic extracts were washed with saturated brine (lOmL), dried (MgS04) and concentrated.

The residue was purified by preparative thin layer chromatography, eluting with 1: 1 EtOAc/isohexane, to afford an oil (20mg, 38%). This material was dissolved in EtOAc and treated with 1M HC1 in diethyl ether (0. 067mL). The mixture was diluted with diethyl ether and triturated to give a crystalline solid which was collected under suction to afford the title compound (21mg).'H NMR (500 MHz, d6-DMSO) 8 4.44 (2H, d, J= 22 Hz), 4.51-4. 57 (2H, m), 4.65-4. 71 (2H, m), 5.20 (1H, s), 7.45-7. 49 (2H, m), 7.52-7. 56 (2H, m), 8.00-8. 03 (4H, m). nilz (ES+) 384 (M+H) +.

Example 6 <BR> <BR> <BR> <BR> <BR> <BR> 1-f 2- (2, 4-Difluorophenvl) ethvll-3-f fluoror (4-fluorophenvl) sulfonvllmethyl} azetidine hydrochloride Stepl : tert-ButYl3-f (4-fluorophenvl) sulfonyllmethyl} azetidine-1-carboxylate Triethylamine (0. 12mL, 0. 86mmol) was added to a suspension of 3-{[(4- fluorophenyl) sulfonyl] methyl} azetidine hydrochloride [Example 1, Step 4] (205mg, 0.77mmol) in DCM (5mL), the resulting mixture was stirred at room temperature for 5 min then a solution of di-tert-butyl dicarbonate (176mg, 0. 81mmol) in DCM (2. 5mL) was added. The reaction mixture was stirred for 2.5 h then washed with 5% aqueous citric acid (lOmL) and saturated aqueous sodium hydrogen carbonate (lOmL). The aqueous washes were extracted with DCM (2 x 5mL), the combined organics dried (MgS04) and concentrated to an oil. Diethyl ether and isohexane were added and the mixture evaporated to give the title compound as a white solid (241mg, 95%). 1H NMR (500 MHz, CDC13) 8 1.41 (9H, s), 2.92-3. 01 (1H, m), 3.37 (2H, d, J= 7.6 Hz), 3.64 (2H, br s), 4.40 (2H, t, J= 8.6 Hz), 7.24-7. 28 (2H, m), 7.89-7. 92 (2H, m).

Step 2 : tert-Butyl3-ffluoror (4-fluorophenvl) sulfonyllmethyl} azetidine-l-carboxylate <BR> <BR> <BR> <BR> and tert-butvl 3-fdifluoror (4-fluorophenyl) sulfonlmethyl} azetidine-1-carboxvlate n-Butyllithium (0.53mL of a 1.6M solution in hexanes, 0. 85mmol) was added to a solution of tert-butyl 3- {[(4-fluorophenyl) sulfonyl] methyl} azetidine-l-carboxylate (227mg, 0. 69mmol) in THF (5mL) cooled to-78°C. The reaction mixture was stirred at-78°C for 30 min and treated with N-fluorobenzenesulfonimide (269mg, 0. 85mmol) in THF (3mL). The reaction mixture was stirred at-78°C for 5 min, the cooling bath was removed allowing the reaction mixture to warm to room temperature over 10 min and then stirred for a further hour. The reaction mixture was poured into water (40mL) and extracted with EtOAc (2 x 20mL). The extracts were washed with saturated brine (20mL), combined, dried (MgS04) and evaporated. The residue was dissolved in THF (5mL), cooled to-78°C and treated with n-butyllithium, (0. 56mL of a 1.6M solution in hexanes, 0. 90mmol). The resulting mixture was stirred at-78°C for 20 min and then treated with N-fluorobenzenesulfonimide (275mg, 0. 87mmol) in

THF (3mL). The reaction mixture was stirred at-78°C for 5 min, the cooling bath was removed allowing the reaction mixture to warm to room temperature over 10 min and then stirred for a further 2 h. The reaction mixture was poured into water (40mL) and extracted with EtOAc (2 x 20mL). The extracts were washed with saturated brine (20mL), combined, dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting with 2.5% to 10% EtOAc/DCM to give tert-butyl 3- {difluoro [(4-fluorophenyl) sulfonyl] methyl} azetidine-1-carboxylate (64mg, 25%). 1H NMR (500 MHz, CDC13) 8 1.43 (9H, s), 3.22 (2H, br s), 3.54-3. 65 (1H, m), 4.13-4. 15 (2H, m), 7.31-7. 34 (2H, m), 7.99-8. 02 (2H, m); as the first eluting product and then tert-butyl 3-{fluoro[(4-fluorophenyl)sulfonyl]methyl}azetidine-1-carbox ylate (88mg, 37%). 1H NMR (500 MHz, CDCl3) 8 1.44 (9H, s), 3.24-3. 36 (1H, m), 3.96 (1H, br s), 3.99-4. 02 (2H, m), 4. 15 (1H, dt, J= 9 and 1. 5 Hz), 5.29 (1H, dd, J= 48 and 6 Hz), 7. 28-7. 32 (2H, m), 7.95-7. 97 (2H, m).

Step 3: 1-r2- (2z4-Difluorophenyl) ethyll-3- {fluoro (4- fluorophenvl) sulfonyllmethYl azetidine hydrochloride 4M HCl in dioxane (4mL) was added to tert-butyl 3- {fluoro [ (4- fluorophenyl) sulfonyl] methyl} azetidine-l-carboxylate (84mg, 0. 24mmol) and the resulting solution stirred at room temperature for 1.3 h. The solution was evaporated, diethyl ether added and the mixture re-evaporated to give a foam (73mg). This material was dissolved in MeOH (3mL) and a solution of (2,4- difluorophenyl) acetaldehyde (45mg, 0. 29mmol) in toluene (0.9mL) added, followed by sodium cyanoborohydride (20mg, 0. 32mmol). The resulting mixture was stirred at room temperature for 2 h, after which time a further portion of sodium cyanoborohydride (lOmg, 0. 16mmol) was added. The reaction mixture was stirred for 1.3 h, diluted with 0. 5M aqueous sodium hydroxide solution (20mL) and extracted with EtOAc (2 x 10mL). The extracts were washed with saturated brine (lOmL), combined, dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting with 1: 1 EtOAc/isohexane then EtOAc to afford an oil. This material was dissolved in EtOAc, the resulting solution heated and treated with 1M HCl in diethyl ether (0. 16mL). The mixture was evaporated and the residual solid recrystallised from EtOAc to give the title product (32mg, 31%). 1H NMR (400 MHz,

CD30D) 8 2.95 (2H, t, J= 7.7 Hz), 3.48-3. 51 (2H, m), 3.73-3. 86 (1H, m), 4.24-4. 43 (4H, m), 5. 80 (1H, dd, J= 47.5 and 3.6 Hz), 6.96-7. 03 (2H, m), 7.36-7. 41 (1H, m), 7.47 (2H, t, J= 8. 7 Hz), 8. 02-8. 06 (2H, m). m/z (ES+) 388 (M+H) +.

Example 7 3-{Difluoro[(4-fluorophenyl)sulfonyl]methyl}-1-[2-(2,4- difluorophenyl) ethyllazetidine hydrochloride Prepared in an analogous manner to Example 6, Step 3 using ter-butyl 3- {difluoro [ (4- fluorophenyl) sulfonyl] methyl} azetidine-l-carboxylate (Example 6, Step 2).

IH NMR (400 MHz, CD30D) 8 2.97 (2H, t, J= 7.8 Hz), 3.52-3. 55 (2H, m), 4.06-4. 16 (1H, m), 4.50 (4H, br s), 6.96-7. 03 (2H, m), 7.37-7. 42 (1H, m), 7.53 (2H, t, J= 8. 7 Hz), 8.10-8. 12 (2H, m). m/z (ES+) 406 (M+H) +.

Example 8 6-Fluoro-3-f (3-ff (4-fluorophenvllsulfonyllmethylazetidin-1-yl methyll-1, 2- benzisothiazole hydrochloride Step 1: 3-Bromomethyl-6-fluoro-1, 2-benzisothiazole A mixture of 6-fluoro-3-methyl-1, 2-benzisothiazole [prepared by the method of D. M.

Fink and J. T. Strupczewski, Tetrahedron Lett. , 1993, 34, 6525] (761mg, 4. 55mmol), N-bromosuccinimide (0.89g, 5. 0mmol) and benzoyl peroxide (102mg (70% (w/w)), 0.29mmol) in CC14 (25mL) was heated at reflux under nitrogen for 6 h. The mixture was allowed to cool and filtered under suction. The filtrate was concentrated and the residue purified by flash silica chromatography, eluting with 1: 2 then 1: 1 DCM/isohexane to give the title compound as a white solid (569mg, 51%). 1H NMR (500 MHz, CDC13) 8 4.82 (3H, s), 7.25 (1H, dt, J= 8.8 and 2.2 Hz), 7.60 (1H, dd, J= 8.1 and 2.2 Hz), 8. 07-8. 10 (1H, m). (471 MHz, CDC13) #F -111. 9.

Step 2 : 6-Fluoro-3-r (3-{ [4-fluorophenvl) sulfonvllmethvl} azetidin-1- ? methvll-1, 2- benzisothiazole hydrochloride 3-Bromomethyl-6-fluoro-1, 2-benzisothiazole (73mg, 0.3mmol) was added to a mixture of 3-{[(4-fluorophenyl)sulfonyl]methyl}azetidine hydrochloride (57mg, 0. 21mmol) and potassium carbonate (9lmg, 0. 66mmol) in DMF (2mL) and the resulting mixture stirred at room temperature for 18 h. The mixture was diluted with 0. 5M sodium hydroxide solution (20mL) and extracted with EtOAc (2 x 10mL). The organic extracts were washed with saturated brine (lOmL), combined, dried (MgS04) and concentrated. The residue was purified by preparative thin layer chromatography, eluting with 2.5% MeOH/DCM, to afford an oil which crystallised on standing (35mg, 41%). The solid was dissolved in EtOAc, the resulting solution heated and treated with 1M HC1 in diethyl ether (0. 1 lmL). The mixture was allowed to cool to give a crystalline solid which was collected under suction to afford the title compound (21mg). lH NMR (400 MHz, CD30D) 8 3.33-3. 41 (1H, m), 3.72 (2H, d, J= 7.6 Hz), 4.23-4. 28 (2H, m), 4.44-4. 49 (2H, m), 4.96 (2H, s), 7.35-7. 46 (3H, m), 7. 87-7. 90 (1H, <BR> <BR> <BR> m), 7. 99-8. 04 (2H, m), 8. 10-8.13 (1H, m). (471 MHz, CD30D) 8F-105. 2, -112. 7. into (ES+) 395 (M+H) +.

Example 9 6-Fluoro-3-[(3-{[(4-fluorophenyl)sulfonyl]methyl}azetidin-1- yl)methyl]-1,2- benzisoxazole hydrochloride Prepared in an analogous manner to Example 8, using 6-fluoro-3-methyl-1, 2- benzisoxazole [prepared by the method of G. T. Theodoridis, L. L. Maravetz and S. D.

Crawford, WO 97/12886].

'H NMR (500 MHz, CD30D) 5 3.32-3. 40 (1H, m), 3.73 (2H, d, J= 7. 6 Hz), 4.29-4. 33 (2H, m), 4.45-4. 49 (2H, m), 4.98 (2H, s), 7.29 (1H, dt, J= 9.0 and 2.0 Hz), 7.41-7. 45 (2H, m), 7.54 (1H, dd, J= 8. 6 and 2.0 Hz), 7.90 (1H, dd, J= 8.8 and 4.9 Hz), 8.00- 8.03 (2H, m). (471 MHz, CD30D) 8F-105. 1, -109.3. 7n/z (ES+) 379 (M+H) +.

Example 10 1-(4-Fluoro-2-methylphenyl)-2-(3-{[(4-fluorophenyl)sulfonyl] methyl}azetidin-1- yl) ethanone Stepl : 1-(4-Fluoro-2-methylPhenyl) ethanone To a solution of 2-bromo-5-fluorotoluene (5g, 26. 5mmol) in DMF (65ml) and water (15ml) was added butyl vinyl ether (6.6g, 65. 9mmol), palladium acetate (0. 18g, 0. 8mmol), 1, 3-bis (diphenylphosphino) propane (0.72g, 1. 75mmol) and potassium carbonate (4.4g, 31. 8mmol). The reaction was heated at 80°C for 48h under nitrogen.

The cooled reaction mixture was diluted with EtOAc (#250ml) and concentrated HCl added and shaken. Further EtOAc and water were added to obtain an easier separation of the 2 layers. The organic layer was washed with brine, dried (MgS04), and concentrated. The residue was purified on a plug of silica eluting with 3% EtOAc/isohexane to give the title compound as an oil (1.95g, 49%). 1H NMR (400 MHz, d6-DMSO) a 2.45 (3H, s), 2.54 (3H, s), 7.13-7. 17 (2H, m), 7.89-7. 93 (1H, m).

Step 2: 2-Bromo-1-(4-fluoro-2-methylphenyl)ethanone A solution of the foregoing acetophenone (1.95g, 12. 8mmol) in THF (35ml) was treated with phenyltrimethylammonium tribromide (4.82g, 12. 8mmol) portionwise.

Upon complete addition the suspension was stirred for a further 20min then water (150ml) was added. The mixture was extracted twice with EtOAc. The combined organics were dried (MgS04) and concentrated. The residue was purified on a silica plug column using 2% EtOAc/isohexane to give the title compound as a yellow oil (1.96g, 66%). 1H NMR (400 MHz, d6-DMSO) my 2.43 (3H, s), 4.85 (2H, s), 7.16-7. 24 (2H, m), 7.95-7. 99 (1H, dd, J= 6.0 & 8. 6 Hz).

Step 3: 1-(4-Fluoro-2-methylphenyl)-2-(3-{[(4- fluorophenYl ! sulfonyllmethyl} azetidin-1-yl) ethanone A mixture of 3- [ (4-fluorophenyl) sulfonyl] methyl} azetidine hydrochloride (75mg, 0. 28mmol) in MeCN (5mL) was treated with Et3N (97) L, 0. 7mmol) and 2-brom-1- (4-fluoro-2-methylphenyl) ethanone (72mg, 0. 31mmol) and stirred for 30 min at room

temperature. The reaction was evaporated and the residue dissolved in DCM and purified using lOg silica bond-elute cartridge on the personal flash master. The column was eluted with 0.5% MeOH/DCM then 1% MeOH/DCM to give the title compound as a cream solid (60mg, 56%). 1H NMR (500 MHz, CDC13) 2. 49 (3H, s), 2.93-2. 98 (1H, m), 3.08 (2H, t, J= 7.4 Hz), 3.41 (2H, d, J= 7.4 Hz), 3.62 (2H, t, J= 7.4 Hz), 3.77 (2H, s), 6.89-6. 95 (2H, m), 7.23-7. 27 (2H, t, J= 8.8 Hz), 7.61 (1H, dd, J = 5. 8 & 8.5 Hz), 7.90-7. 92 (2H, dd, J= 5.2 & 8.8 Hz). into (ES+) 380 (M+H) +.

Example 11 1-(4-Fluorophenyl)-2-(3-{[(2-fluorophenyl)sulfonyl]methyl}az etidin-1-yl) ethanone hydrochloride Step 1: 1-(Diphenylmethyl)-3-{[(2-fluorophenyl)sulfonyl]methyl}azeti dine 1- (Diphenylmethyl) azetidin-3-yl] metliyl methanesulfonate [Example 1, step 1] (3.15g, 9. 50mmol), sodium 2-fluorobenzenesulfinate (2.65g, 14. 3mmol) and sodium iodide (2. 18g, 14. 5mmol) were reacted in dimethylformamide (50mL) by the procedure of Example I Step 3a to afford the title compound (1.37g, 36%) ; lH NMR (500MHz, CDC13) # 2.80-2. 88 (3H, m), 3.33 (2H, t, J = 7.0 Hz), 3.57 (2H, d, J = 6.9 Hz), 4.28 (1H, s), 7.16 (2H, t, J = 7.3 Hz), 7.20-7. 26 (5H, m), 7.29-7. 35 (5H, m), 7.61- 7.65 (1H, m), 7.86-7. 90 (1H, m) ; 19F NMR (471MHz, CDCl3) 8-108. 9; m/z (ES+) 396 ([M+H]+, 100%).

Step 2: 3-{[(2-Fluorophenyl)sulfonyl]methyl}azetidine hydrochloride 1- (Diphenylmethyl)-3- {[ (2-fluorophenyl) sulfonyl] methyl} azetidine (1.33g, 3. 37mmol) was dissolved in ethanol (80mL). The solution was diluted with 2M hydrochloric acid (1. 8mL) and water (20mL). 20% Palladium hydroxide on carbon (0.63g) was added and the mixture shaken on a Parr apparatus under 50psi of hydrogen for 3.5 h. The catalyst was removed by filtration and the filtrate concentrated to a small volume. The solid present was redissolved by adding ethanol and the solution filtered. The filtrate was concentrated to a small volume once again to give a crystalline solid which was collected under suction, washed with cold ethanol and dried in vacuo to afford the title

compound as colourless crystals (0. 81g, 91%) ; IH NMR (500MHz, CD3OD) # 3.34- 3.42 (1H, m), 3.80 (2H, d, J = 7.6 Hz), 4.07 (2H, t, J = 10 Hz), 4.14 (2H, t, J = 10 Hz), 7.41-7. 49 (2H, m), 7.80-7. 84 (1H, m), 7.90-7. 92 (1H, m) ; 19F NMR (471MHz, CD30D) 8-110. 6; m/z (ES+) 230 ([M+H]+, 100%).

Step 3: 1-(4-Fluorophenyl)-2-(3-{[(2-fluorophenyl)sulfonyl]methyl}az etidin-1- yl) ethanone hydrochloride Triethylamine (13511L, 0. 97mmol) was added to a suspension of 3-{[(2- fluorophenyl) sulfonyl] methyl} azetidine hydrochloride (lOlmg, 0. 38mmol) in acetonitrile (5mL) and the mixture stirred for 3 minutes. 2-Bromo-4'- fluorophenylacetophenone (88mg, 0. 41mmol) was added and the resulting mixture stirred at room temperature for 30 minutes. The reaction mixture was concentrated i71 vacuo at ambient temperature, treated with water (20mL) and saturated sodium hydrogen carbonate (1mL) and extracted with ethyl acetate (2 x 25mL). The extracts were washed with brine (20mL), combined, dried (MgSO4) and evaporated. The residue was purified by preparative thin layer chromatography, eluting with 2: 1 ethyl acetate/dichloromethane, to afford an oil (100mg). This oil was dissolved in ethyl acetate and treated with 1M hydrogen chloride in diethyl ether (330pL) to give a gum.

Trituration with warming afforded a solid which was collected under suction, washed with ethyl acetate and dried in vacuo to give the title compound as a white solid (92mg, 60%) ; IH NMR (500MHz, DMSO-d6) 6 3.11-3. 17 (1H, m), 3.98 (2H, m), 4.12 (2H, m), 4.24 (2H, t, J = 9. 6 Hz), 5.11 (2H, s), 7.45 (2H, t, J = 8.7 Hz), 7.53 (1H, t, J = 7.6 Hz), 7.59 (1H, t, J = 9. 4 Hz), 7.85-7. 91 (2H, m), 8.01 (2H, dd, J = 5.5, 8.4 Hz), 11.04 (1H, s) ; 19F NMR (471MHz, DMSO-d6) 8-103. 4, -109.3 ; m/z (ES+) 366 ([M+H]+, 100%).