Alzheimer's disease (AD) is the most prevalent form of dementia.

Although primarily a disease of the elderly, affecting up to 10% of the population over the age of 65, AD also affects significant numbers of younger patients with a genetic predisposition. It is a neurodegenerative disorder, clinically characterized by progressive loss of memory and cognitive function, and pathologically characterized by the deposition of extracellular proteinaceous plaques in the cortical and associative brain regions of sufferers. These plaques mainly comprise fibrillar aggregates of (3-amyloid peptide (Ap). The role of secretases, including the putative y- secretase, in the processing of amyloid precursor protein (APP) to form Ap is well documented in the literature and is reviewed, for example, in WO 01/70677.

There are relatively few reports in the literature of compounds with inhibitory activity towards y-secretase, as measured in cell-based assays.

These are reviewed in WO 01/70677. Many of the relevant compounds are peptides or peptide derivatives.

WO 00/50391 discloses a broad class of sulphonamides as modulators of the production of p-amyloid, but neither discloses nor suggests the compounds of the present invention.

The present invention provides a novel class of cyclohexyl sulphones which are useful in the treatment or prevention of AD by inhibiting the processing of APP by the putative y-secretase, thus arresting the production of Ap. The compounds of the invention generally combine a high affinity for the target enzyme with favourable pharmacokinetic properties.

According to the invention, there is provided a compound of formula I:

wherein n is 1 or 2 ; RI represents CF3 or C1-6alkyl, C2-6alkenyl, C3-9cycloalkyl or C3-6cycloalkylCl-6alkyl, any of which may bear up to 2 substituents selected from halogen, CN, CF3, OR3, COR3, CO2R3, OCOR4, SOzR4, N (R5) 2, and CON (R5) 2, or R1 represents aryl, arylC1-6alkyl, C-heterocyclyl or C-heterocycloylC1-6alkyl; R2 represents H or Cl-4alkyl ; R3 represents H, C1-4alkyl, phenyl or heteroaryl ; R4 represents Cl-4alkyl, phenyl or heteroaryl ; R5 represents H or Cl-4alkyl, or two R5 groups together with a nitrogen atom to which they are mutually attached complete an azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine or thiomorpholine-1, 1- dioxide ring ; Arl and Ar2 independently represent phenyl or heteroaryl, either of which bears 0-3 substituents independently selected from halogen, CN, N02, CF3, CHF2, OH, OCF3, CHO, CH=NOH, C1-4alkoxy, C1-4alkoxycarbonyl, C2-6acyl, C2-6alkenyl and Cl-4alkyl which optionally bears a substituent selected from halogen, CN, NO2, CF3, OH and C1-4alkoxy; "aryl"at every occurrence thereof refers to phenyl or heteroaryl which optionally bear up to 3 substituents selected from halogen, CN, NO2, CF3, OCFs, OR3, COR3, CO2R3, OCOR4, N (R5) 2, CON (R5) 2 and

optionally-substituted Cl-6alkyl, Cl-6alkoxy, C2-6alkenyl or C2-6alkenyloxy wherein the substituent is selected from halogen, CN, CF3, phenyl, OR3, C02R3, OCOR4, N (R5) and CON (R5) 2 ; and "C-heterocyclyl"and"N-heterocyclyl"at every occurrence thereof refer respectively to a heterocyclic ring system bonded through carbon or nitrogen, said ring system being non-aromatic and comprising up to 10 atoms, at least one of which is O, N or S, and optionally bearing up to 3 substituents selected from oxo, halogen, CN, NOz, CF3, OCF3, OR3, COR3, C02R3, OCOR4, OSO2R4, N (R5) 2, CON (R5) 2 and optionally-substituted phenyl, Cl-6alkyl, C1-6alkoxy, C2-6alkenyl or C2-6alkenyloxy wherein the substituent is selected from halogen, CN, CF3, OR3, CO2R3, OCOR4, N (R5) 2 and CON (R5) 2 ; or a pharmaceutically acceptable salt thereof.

Where a variable occurs more than once in formula I, the individual occurrences are independent of each other, unless otherwise indicated.

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 include methyl, ethyl, n-propyl, isopropyl and t-butyl. Derived expressions such as "C2-6alkenyl", "hydroxyC1-6alkyl", "heteroarylC1-6alkyl", "C2-6alkynyl" and "C1-6alkoxy" are to be construed in an analogous manner.

The expression"C3-gcycloalkyl"as used herein refers to nonaromatic monocyclic or fused bicyclic hydrocarbon ring systems comprising from 3 to 9 ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl and bicyclo [2.2. 1]heptyl. Monocyclic systems of 3 to 6 members are preferred.

The expression"C3-6 cycloalkylCl-6alkyl"as used herein includes cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

The expression"C2-6acyl"as used herein refers to Ci-salkylcarbonyl groups in which the alkyl portion may be straight chain, branched or cyclic, and may be halogenated. Examples include acetyl, propionyl and trifluoroacetyl.

The expression"heterocyclyl"as defined herein includes both monocyclic and fused bicyclic systems of up to 10 ring atoms selected from C, N, O and S. Mono-or bicyclic systems of up to 7 ring atoms are preferred, and monocyclic systems of 4,5 or 6 ring atoms are most preferred. Examples of heterocyclic ring systems include azetidinyl, pyrrolidinyl, 3-pyrrolinyl, terahydrofuryl, 1, 3-dioxolanyl, tetrahydrothiophenyl, tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, imidazolidinyl, oxazolidinyl, thiazolidinyl, 2,5-diazabicyclo [2.2. l] heptyl, 2-aza-5-oxabicyclo [2.2. l] heptyl and 1,4- dioxa-8-azaspiro [4.5] decanyl. Unless otherwise indicated, heterocyclyl groups may be bonded through a ring carbon atom or a ring nitrogen atom where present."C-heterocyclyl"indicates bonding through carbon, while "N-heterocyclyl"indicates bonding through nitrogen.

The expression"heteroaryl"as used herein means a monocyclic system of 5 or 6 ring atoms, or fused bicyclic system of up to 10 ring atoms, selected from C, N, O and S, wherein at least one of the constituent rings is aromatic and comprises at least one ring atom which is other than carbon. Monocyclic systems of 5 or 6 members are preferred. Examples of heteroaryl groups include pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furyl, thienyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, triazolyl and thiadiazolyl groups and benzo-fused analogues thereof. Further examples of heteroaryl groups include tetrazole, 1,2, 4-triazine and 1,3, 5-triazine. Pyridine rings may be in the N-oxide form.

Where a phenyl group or heteroaryl group bears more than one substituent, preferably not more than one of said substituents is other than halogen or alkyl. Where an alkyl group bears more than one

substituent, preferably not more than one of said substituents is other than halogen.

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 advantageously 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, sulfuric acid, benzenesulfonic acid, methanesulfonic 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, 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.

Where the compounds according to the invention have at least one asymmetric centre, 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 1 or 2, preferably 2.

Rl is preferably CF3, aryl or arylalkyl, or an alkyl, alkenyl, cycloalkyl or cycloalkylalkyl group, optionally substituted as described

previously. Preferred substituents include halogen (especially fluorine or chlorine), CF3, CN, OR3 (especially OH, OMe and OEt), COR3 (especially acetyl), C02R3 (especially COACH, CO2Me and C02Et), S02R4 (especially methanesulfonyl), N (R5) 2 (especially when the R5 groups complete a ring) and CON (R5) 2 (especially CONH2).

Examples of alkyl groups represented by R1 include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, 2,2, 2-trifluoroethyl, chloromethyl, 3-chloropropyl, 2-chloro-2-propyl, cyanomethyl, 2- hydroxyethyl, 2-methoxyethyl, 2-hydroxy-2-methylpropyl, carboxymethyl, methoxycarbonylmethyl, 1-carboxyethyl, 1-ethoxycarbonylethyl, carbamoylmethyl, 2- (pyrrolidin-1-yl) ethyl, 2- (morphohn-4-yl) ethyl and MeS02CH2-.

Examples of alkenyl groups represented by R'include vinyl and allyl.

Examples of cycloalkyl and cycloalkylalkyl groups represented by R include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl and cyclopentylmethyl.

When Rl represents aryl or arylalkyl, the aryl group may be phenyl or heteroaryl (especially 5-or 6-membered heteroaryl), optionally substituted as defined previously. Preferred substituents include halogen (especially chlorine, bromine or fluorine), CN, CF3, OCF3, alkyl (especially methyl), OH, alkoxy (especially methoxy) and alkoxycarbonyl (such as methoxycarbonyl). Preferred heteroaryl groups include pyridine, pyrimidine, furan, thiophene, thiazole, isothiazole, isoxazole, pyrazole, imidazole, triazole, thiadiazole and tetrazole, especially pyridine, furan, thiophene, thiazole, isothiazole, isoxazole, pyrazole, imidazole, triazole, and tetrazole.

Examples of aryl groups represented by R'include phenyl, 2-, 3- and 4-fluorophenyl, 2,4-difluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2- cyanophenyl, 2-methylphenyl, 2-trifluoromethylphenyl, 2-methoxyphenyl, 5-chloro-2-methoxyphenyl, 2-pyridyl, 4-pyridyl, 6-chloro-3-pyridyl, 2-furyl,

2-thienyl, 3-thienyl, 2-thiazolyl, 5-isothiazolyl, 2-imidazolyl, 2- methylfuran-3-yl, 5-chloro-2-thienyl, 4-chloro-2-thienyl, 3-chloro-2-thienyl, 3-bromo-2-thienyl, 4-bromo-2-thienyl, 5-methyl-2-thienyl, 2- <BR> <BR> <BR> (methoxycarbonyl)-3-thienyl, 4-methylthiazol-3-yl, 1-methylimidazol-2-yl, 1-methylimidazol-5-yl, 1-methylimidazol-4-yl, 3-chloro-1, 5- dimethylpyrazol-4-yl, 3, 5-dimethylisoxazol-4-yl, 1-methyl-1, 2,3, 4-tetrazol- 5-yl, 1, 2,4-triazol-3-yl, 1-methyl-1, 2,4-triazol-3-yl, 2-methyl-1, 2,4-triazol-3- yl and 4-methyl-1, 2, 4-triazol-3-yl.

Arylalkyl groups represented by RI are typically optionally substituted benzyl, phenethyl, heteroarylmethyl or heteroarylethyl groups. Examples include benzyl, 2-furylmethyl, 2-thienylmethyl and 1- (2-thienyl) ethyl. Preferred examples include benzyl.

R2 preferably represents H or methyl, most preferably H.

R3 preferably represents H, Cl-4alkyl, phenyl, pyridyl, or 5- membered heteroaryl. Most preferably, R3 represents H or C1-4alkyl.

R4 preferably represents C1-4alkyl, phenyl, pyridyl, or 5-membered heteroaryl. Most preferably, R3 represents C1-4alkyl.

Arl and Ar2 independently represent optionally substituted phenyl or heteroaryl. Arl is preferably selected from optionally substituted phenyl and optionally substituted 6-membered heteroaryl. Preferred 6- membered heteroaryl embodiments of Ar1 include optionally substituted pyridyl, in particular optionally substituted 3-pyridyl. Ar1 is preferably selected from 6- (trifluoromethyl)-3-pyridyl and phenyl which is optionally substituted in the 4-position with halogen, CN, vinyl, allyl, acetyl, methyl or mono-, di-or trifluoromethyl. In one preferred embodiment of the invention Arl represents 4-chlorophenyl. In another preferred embodiment Arl represents 4-trifluoromethylphenyl. In a further preferred embodiment, Arl represents 6- (trifluoromethyl)-3-pyridyl.

Ar2 preferably represents optionally substituted phenyl, in particular phenyl bearing 2 or 3 substituents selected from halogen, CN, CF3 and optionally-substituted alkyl. Ar2 is typically selected from phenyl

groups bearing halogen substituents (preferably fluorine) in the 2-and 5- positions or in the 2-, 3-and 6-positions, or from phenyl groups bearing a fluorine substituent in the 2-position and halogen, CN, methyl or hydroxymethyl in the 5-position. In a preferred embodiment of the invention, Ar2 represents 2, 5-difluorophenyl.

In a particular embodiment, Arl is 6-trifluoromethyl-3-pyridyl, 4- chlorophenyl or 4-trifluoromethylphenyl and Ar2 is 2, 5-difluorophenyl.

A preferred subclass of the compounds of the invention are the compounds of formula II : II wherein X represents N or CH ; R6 represents H, F, Cl, Br, CN, CF3, CH=CH2 or CH3 ; R7 represents F, Cl, Br, CN, CH3 or CH20H ; and Rl has the same definition and preferred identities as before; and pharmaceutically acceptable salts thereof.

When X represents N, R6 is preferably CF3.

In a preferred embodiment, Rl is selected from: (a) CF3 ; (b) Alkyl which optionally bears up to 2 substituents selected from halogen, CN, CF3, OR3, C02R3, SO2R4, N (R5) 2, and CON (R5) 2 ; and (c) phenyl, pyridyl or 5-membered heteroaryl which optionally bear up to 3 substituents selected from halogen, CN, CF3, OR3, COR3, C02R3, OCOR4, N (R5) 2, CON (R5) z and optionally-substituted Cl-6alkyl, Cl-6alkoxy, C2-6alkenyl or C2-6alkenyloxy wherein the substituent is selected from halogen, CN, CF3, phenyl, OR3, COzR3, OCOR4, N (R5) 2 and CON (R5) 2 ;

where R3, R4 and R5 have the same definitions and preferred identities as before.

Rl very aptly represents CF3.

Examples of individual compounds in accordance with the invention are provided in the Examples section appended hereto.

The compounds of formula I have an activity as modulators of the processing of APP by y-secretase.

The invention also provides pharmaceutical compositions comprising one or more compounds of formula I or the pharmaceutically acceptable salts thereof 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. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e. g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums or surfactants such as sorbitan monooleate, polyethylene glycol, and other pharmaceutical diluents, e. g. water, to form a solid preformulation composition containing a homogeneous mixture of 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 solid 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 250 mg, for

example 1, 2,5, 10,25, 50,100, 200 or 250 mg, of the active ingredient.

The 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, 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 (vinylpyrrolidone) or gelatin.

The present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human body. Preferably the treatment is for a condition associated with the deposition of ß-amyloid. Preferably the condition is a neurological disease having associated P-amyloid deposition such as Alzheimer's disease.

The present invention further provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing Alzheimer's disease.

The present invention further provides a method of treatment of a subject suffering from or prone to a condition associated with the

deposition of (3-amyloid which comprises administering to that subject an effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof. Preferably the condition is a neurological disease having associated p-amyloid deposition such as Alzheimer's disease.

For treating or preventing Alzheimer's Disease, a suitable dosage level is about 0.01 to 250 mg/Kg per day, preferably about 0.10 to 100 mg/Kg per day, especially about 1.0 to 50 mg/Kg, and for example about 10 to 30 mg/Kg of body weight per day. Thus, a dose of about 500mg per person per day may be considered. The compounds may be administered on a regimen of 1 to 4 times per day. In some cases, however, dosage outside these limits may be used.

The compounds of formula I in which R2 is H may be prepared by reacting a sulfinyl chloride R1SOCl or a sulfonyl chloride R1SO2Cl or a sulfonic anhydride (RIS02) 20 with an amine of formula III : ; III where R1, Arl and Ar2 have the same meanings as before. The reaction is typically carried out at ambient or reduced temperature in the presence of a tertiary amine such as triethylamine in an aprotic solvent such as dichloromethane.

The compounds of formula I in which R2 is other than H may be prepared by alkylation of the corresponding compounds of formula I in which Rl is H, e. g. by heating with the appropriate alkyl iodide in THF in the presence of sodium hydride.

The amines of formula III may be obtained by reduction of the azides IV: where Arl and Ar2 have the same meanings as before. The azides IV are obtained via nucleophilic displacement of the mesylates V (a), formed from the trans alcohols V (b) by reaction with methanesulfonyl chloride:

V (a) R = SO2Me (b) R = H where Arl and Ar2 have the same meanings as before. The alcohols V (b) are obtained by reduction of the cyclohexanones VI : where Ar1 and Ar2 have the same meanings as before. The reduction may be carried out using sodium borohydride in ethanol, with isolation of the trans isomer by chromatography.

The synthesis of cyclohexanones VI and their conversion to amines III, is described in WO 02/081435.

It will be apparent to those skilled in the art that individual compounds of formula I prepared by the above routes may be converted into other compounds in accordance with formula I by means of well known synthetic techniques such as alkylation, esterification, amide coupling, hydrolysis, oxidation and reduction. Such techniques may likewise be carried out on precursors of the compounds of formula I. For example, substituents on the aromatic groups Ar1 or Ar2 may be added or

interconverted by means of standard synthetic processes carried out on the compounds of formula I or their precursors. For example, a chlorine or bromine atom on Arl or Ar2 may be replaced by vinyl by treatment with vinyltributyltin in the presence of tri-t-butylphosphine, cesium fluoride and tris (dibenzylideneacetone) dipalladium (0). Ozonolysis of the vinyl group provides the corresponding formyl derivative, which may be transformed in a variety of ways, including oxidation to the corresponding acid, reduction to the corresponding benzyl alcohol, and conversion to the corresponding nitrile by treatment with hydroxylamine then triphenylphosphine and carbon tetrachloride.

Where they are not themselves commercially available, the starting materials and reagents employed in the above-described synthetic schemes may be obtained by the application of standard techniques of organic synthesis to commercially available materials.

It will be appreciated that many of the above-described synthetic schemes may give rise to mixtures of stereoisomers. Such mixtures may be separated by conventional means such as fractional crystallisation and preparative chromatography.

Certain compounds according to the invention may exist as optical isomers due to the presence of one or more chiral centres or because of the overall asymmetry of the molecule. Such 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 and/or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallisation 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.

During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973 ; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3rd ed. , 1999. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

An assay which can be used to determine the level of activity of compounds of the present invention is described in W001/70677. A preferred assay to determine such activity is as follows: 1) SH-SY5Y cells stably overexpressing the PAPP C-terminal fragment SPA4CT, are cultured at 50-70% confluency. lOmM sodium butyrate is added 4 hours prior to plating.

2) Cells are plated in 96-well plates at 35,000 cells/well/lOOuL in Dulbecco's minimal essential medium (DMEM) (phenol red-free) + 10% foetal bovine serum (FBS), 50mM HEPES buffer (pH7. 3), 1% glutamine.

3) Make dilutions of the compound plate. Dilute stock solution 18.2x to 5.5% DMSO and llx final compound concentration. Mix compounds vigorously and store at 4°C until use.

4) Add lOgL compound/well, gently mix and leave for 18h at 37°C, 5% C02- 5) Prepare reagents necessary to determine amyloid peptide levels, for example by Homogeneous Time Resolved Fluorescence (HTRF) assay.

6) Plate 1601lu aliquots of HTRF reagent mixture to each well of a black 96-well HTRF plate.

7) Transfer 401lu conditioned supernatant from cell plate to HTRF plate. Mix and store at 4°C for 18 hours.

8) To determine if compounds are cytotoxic following compound administration, cell viability is assessed by the use of redox dye reduction.

A typical example is a combination of redox dye MTS (Promega) and the

electron coupling reagent PES. This mixture is made up according to the manufacturer's instructions and left at room temperature.

9) Add lOuL/well MTS/PES solution to the cells ; mix and leave at 37°C.

10) Read plate when the absorbance values are approximately 0.4-0. 8.

(Mix briefly before reading to disperse the reduced formazan product).

11) Quantitate amyloid beta 40 peptide using an HTRF plate reader.

Alternative assays are described in Biochemistry, 2000,39 (30), 8698-8704.

See also, J Neuroscience Methods, 2000,102, 61-68.

The Examples of the present invention all had an EDso of less than 0. 51lM, in most cases less than 100nM, and in preferred cases less than lOnM, in at least one of the above assays.

The following examples illustrate the present invention.

EXAMPLES Intermediate A 4- (4-chlorobenzenesulfonyl)-4- (2, 5-difluorophenyl) cyclohexylamine (1) 4- [ (4-Chlorophenyl) sulfonyl]-4- (2, 5-difluorophenyl) cyclohexanone was prepared as described in WO 02/081435 (Example 2).

This cyclohexanone (0.1 g, 0.26 mmol) in methanol (2 ml) was treated with NaBH4 (0.098 g, 0.26 mmol), stirred for 1 hour, quenched with HC1 (1N, 10 ml), diluted with ethyl acetate (20 ml), then the organic phase was separated, dried (MgSO4) and evaporated to dryness. The trans 4- [ (4- chlorophenyl) sulfonyl]-4- (2, 5-difluorophenyl) cyclohexanol was purified on silica eluting with hexane-ethyl acetate mixtures. 0.052 g. IH NMR CDC13 7.39-7. 33 (4H, m), 7.11-7. 02 (2H, m), 6.88-6. 82 (1H, m), 3.80-3. 73 (1H, m),

2.80-2. 60 (2H, m), 2.22-2. 16 (2H, m), 2.08-2. 04 (2H, m), 1.53 (1H, br) and 1.27-1. 13 (2H, m).

(2) To this alcohol (2.7 g, 6.9 mmol) and triethylamine (1.45 ml, 10.3 mmol) in dichloromethane (50 ml) was added methanesulfonyl chloride (0.645 ml, 8.9 mmol) at-30°C. After 30 minutes the mixture was washed with water (20 ml), 10% aqueous citric acid (20 ml) and saturated aqueous sodium hydrogen carbonate (50 ml), dried (MgS04) and evaporated to dryness. The solid was triturated with ether to give the mesylate (2.6 g).

(3) The mesylate (1.5 g, 3.2 mmol) in dimethylformamide (5 ml) was treated with sodium azide (315 mg, 4.8 mmol) and heated to 90°C for 6 hrs. The mixture was treated with water (80 ml), and extracted with diethyl ether (3 x 50 ml), dried (MgSO4) and evaporated to dryness. The solid was triturated with ether to give the cis azide (1.4 g) (4) The azide (1 g, 2.55 mmol) in tetrahydrofuran (10 ml) and water (1 ml), was treated with triphenylphosphine (740 mg, 2.8 mmol) at room temperature for 15 mins, water (5 ml) was added and the mixture was heated at reflux for 4 hrs. After cooling to room temperature and passage through SCX Varian Bond Elut cartridge, the basic fraction was evaporated to give the primary amine. MS MH+ 386 (388).

Intermediate B 4- (2, 5-difluorophenyl)-4- (4-<BR> trifluoromethylbenzenesulfonyl) cyclohexylamine Prepared as for Intermediate A, using the appropriate cyclohexanone (WO 02/081435, Example 41) in step (1), except that the borohydride reduction was carried out at-200C.

MS (ES+) MH+ 420 Intermediate C 4- (2, 5-difluorophenyl)-4- (6-trifluoromethyl-pyridine-3-sulfonyl)-<BR> cyclohexylamine (1) A solution of 3-amino-6- (trifluoromethyl) pyridine (1.62 g, 0.01 mol) in concentrated hydrochloric acid (1.7 mL), was treated with ice (2 g) and cooled to 0°C. Sodium nitrite (0.71 g, 0.01 mol) in water (2 mL) was added slowly, the reaction mixture stirred for 5 minutes at 0°C then treated slowly with a solution of potassium ethyl xanthate (1.92 g, 0.012 mol) in ethanol-water. The reaction mixture was heated at 50-55°C for 30 minutes, cooled and diluted with diethyl ether and water. The organic layer was washed with brine, dried (MgSO4) and evaporated in vacuo. The resulting xanthate was dissolved in ethanol (30 mL) and treated with potassium hydroxide (3 g) and refluxed (90°C) for 2 h. After cooling and filtering, the filtrate was acidified with citric acid and diluted with diethyl ether. The organic layer was washed with brine, dried (MgSO4) and evaporated in vacuo. Purification by column chromatography on silica gave the (trifluoromethyl) pyridinethiol as a yellow oil (0.79 g, 44%).

1H NMR (360 MHz, CDCl3) 8 8.57 (1H, d, J = 2.0 Hz), 7.74 (1H, dd, J = 8.1, 2. 0 Hz), 7.54 (1H, d, J = 8. 1 Hz), 3.62 (1H, s).

(2) This thiol (0.5 g, 2.8 mmol) was reacted first with 2,5-difluorobenzyl bromide and subsequently with 3-chloroperoxybenzoic acid by the procedure described for Intermediate 1 in WO 02/081435 to gave the pyridyl benzyl sulfone as a white powder (0.82 g, 87% over 2 steps).

1H NMR (400 MHz, CDC13) 5 8.93 (1H, d, J = 2.1 Hz), 8.18 (1H, dd, J =8.1, 2.1 Hz), 7.80 (1H, d, J = 8.1 Hz), 7.21-7. 17 (1H, m), 7.10-7. 04 (1H, m), 6.93- 6.88 (1H, m), 4.46 (2H, s).

(3) This sulfone (50 mg, 0.15 mmol) in tetrahydrofuran (5 mL) at 0°C was treated with potassium tert-butoxide (17 mg, 0.15 mmol), then with 2,2-bis (2-iodoethyl)-1, 3-dioxolane (H. Niwa et al, J. Am. Chem. Soc. , 1990, 112,9001) (86 mg, 0.23 mmol), stirred for 1 h at room temperature and then for 1 h at 70°C. The cooled reaction mixture was treated with more potassium terkbutoxide (1.2 equivalents) and 2,2-bis (2-iodoethyl)-1, 3- dioxolane (0.3 equivalents). After heating at 70°C for lh, then cooling to room temperature, the reaction mixture was diluted with diethyl ether and water, the layers separated and the organic layer washed with water and brine, dried (MgSO4) and evaporated in vacuo. Purification by column chromatography on silica gave the desired cyclohexanone cyclic ketal (38 mg, 56%) as a white solid.

1H NMR (360 MHz, CDC13) 5 8.68 (1H, d, J = 2.0 Hz), 7.92 (1H, dd, J = 2. 0, 8.1 Hz), 7.73 (1H, d, J = 8.1 Hz), 7.19-7. 07 (2H, m), 6.90-6. 82 (1H, m), 3.99-3. 88 (4H, m), 2.7 (2H, vbrm), 2.5 (2H, vbrappt), 1.85 (2H, brappd), 1.54-1. 26 (2H, m).

(4) This ketal (30 mg, 0.065 mmol) was heated at 50°C overnight with p-toluenesulfonic acid (15 mg) in 80% acetic acid-water. The reaction mixture was partitioned between diethyl ether and water and the organic layer washed with saturated aqueous sodium hydrogencarbonate solution and brine, dried (MgSO4) and evaporated in vacuo. Purification by column chromatography on silica gave the cyclohexanone (25 mg, 92%) as a white solid.

1H NMR (400 MHz, CDC13) 8 8.67 (1H, d, J = 2.0 Hz), 7.97 (1H, dd, J = 8.1, 2.0 Hz), 7.77 (1H, d, J = 8.1 Hz), 7.28-7. 16 (2H, m), 6.99-6. 90 (1H, m), 3.01- 2.97 (2H, m), 2.68-2. 57 (4H, m), 2.26-2. 17 (2H, m).

(5) The cyclohexanone was converted to the title amine by the procedure of Intermediate A, except that the borohydride reduction was carried out at-78°C. M/Z 421 (MH+).

Sulfonyl Chlorides The sulfonyl chlorides used in these examples were typically commercially available, or available by literature routes. Representative syntheses include the following: 2-methyl-1-propanesulfonyl chloride To 2-methyl-1-propanethiol (200 mg, 2.22 mmol) at 0°C in acetonitrile under nitrogen was added KNOWS (561 mg, 5.5 mmol) then sulfuryl chloride (0.45 ml, 5.5 mmol). The reaction mixture was stirred at 0°C for 3h, diluted with NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgS04) and evaporated to give the sulfonyl chloride (293 mg, 95%) 2-chlorosulfonyl-1-methylimidazole Bleach (12% w/w aq, 110 ml) was cautiously added dropwise to a solution of 2-mercapto-1-methylimidazole (2.0 g) in conc. H2SO4 (50 ml) cooled to 0°C. After stirring 30 minutes at 0°C the mixture was diluted with H20 (30 ml) and dichloromethane (30 ml). The aqueous layer was re-extracted with dichloromethane and the combined organic layers dried (MgS04) and evaporated to give the product as an oil (730 mg).

5-chlorosulfonyl-1-methyltetrazole Cl2 (g) was bubbled through a solution of 5-mercapto-1-methyltetrazole (1.518 g) in 2N HCl (25 ml) at 0°C. After 15 minutes the solid precipitate (880mg) was filtered off and washed with H20.

Example 1 methanesulfonic acid, N- [4- (4-chlorobenzenesulfonyl)-4- (2, 5- difluorophenyl)-cyclohexyl]-amide

Methanesulfonyl chloride (24 pL, 0.31 mmol) was added to a solution of Intermediate A (100 mg, 0.28 mmol) and triethylamine (77 pL, 0.56 mmol) in dichloromethane (1.5 ml) at 0OC. After stirring at ambient temperature for 12 hours, the reaction was partitioned between water (50 ml) and dichloromethane (50 ml), the phases separated and the aqueous layer washed twice more with dichloromethane. The combined organic layers were washed with 1N HC1. the acidic layer extracted twice with dichloromethane and the combined organics dried over K2COs and concentrated. Flash column chromatography eluting with 60/40 hexane/ ethyl acetate afforded the title compound (88.5 mg).

MS (ES-) [M-H] 462,464.

The following examples were prepared by the same procedure, using the appropriate sulfonyl or sulfinyl chloride : Example n R MS (ES- (MH-) unless otherwise stated) Example n R MS (ES- (MH-) unless otherwise stated) 2 2 CH2CF3 530,532 3 2 nPr 490, 492 4 2 benzyl 538,540 5 2 phenyl 524, 526 6 2 2-thienyl 530, 532 7 2 ethyl 476, 478 8 2 5-chloro-2-thienyl 566, 568 (M+H) + 9 2 n-butyl 504, 506 10 2 2-fluorophenyl 542, 544 11 2 3-fluorophenyl 542, 544 12 2 4-fluorophenyl 542, 544 13 2 2-pyridyl 525, 527 14 2 5-methyl-2-thienyl 546, 548 (MH) + 15 2 5-isothiazolyl 531, 533 16 2 4-chloro-2-thienyl 564, 566,568 17 2 2-(trifluoromethyl) phenyl 616/618 [M+Na] +. 18 2 CH2CH (CH3) 2 506, 508 [MH] + 2 CH2SO2Me 542, 544 [MH] + 20 2 2-methylphenyl 540, 542 [MH] + 21 2 4-Me-1, 2, 4-triazol-3-yl 529, 531 22 2 2-thiazolyl 531, 533 23 2 chloromethyl 494, 496,498 24 2 2-furyl 514, 516 25 2 2-chlorophenyl 558, 560 26 2 2-cyanophenyl 549,551 27 2 3, 5-di-Me-isoxazol-4-yl 543, 545 28 2 3-thienyl 530, 532 Example n R MS (ES- (MH-) unless otherwise stated) 29 2 3-chloropropyl 524,526 30 2 1-Me-tetrazol-5-yl 532, 543 [MH] + 31 2 1, 2, 4-triazol-3-yl 517, 519 [MH] + 32 2 3-chloro-2-thienyl 564, 566 33 2 1-Me-imidazol-5-yl 530, 532 [MH] + 34 2 1-Me-imidazol-4-yl 530, 532 [MH] + 35 2 1-Me-imidazol-2-yl 528, 530 36 2 2-bromophenyl 430 [MH-4-Cl-PhSO2] + 37 2 3-Cl-1, 5-di-Me-pyrazol-3-yl 38 2 CH2CO2Me 520, 522 39 1* Me 272 [M-ArSO2~] + 448 [MH] +, 470 [M+Na] + 40 2 3-bromo-2-thienyl 610, 612 41 2 4-bromo-2-thienyl 610, 612 42** 2 2-methoxy-5-chlorophenyl 588, 590 43** 2 2-methoxyphenyl 554, 556

*-MeSOCl-Corey et al J. Am. Chem. Soc., 90,5548-52 (968).

**-obtained as a 1: 1 mixture, separated by chromatography, using the sulfonyl chlorides obtained from treating 2-methoxybenzenethiol with sulfuryl chloride.

Example 44 [4- (4-Chlorobenzenesulfonyl)-4- (2, 5- difluorophenyl)cyclohexyl]aminosulfonyl-acetamide

Prepared from the ester of Example 38 by treatment with NH3 (25% aqueous solution) in ethanol. m/z (ES-) = 505/507.

Example 45 2-hydroxyethanesulfonic acid, N- [4- (4-chlorobenzenesulfonyl)-4- (2, 5- difluorophenyl)-cyclohexyl]-amide

Prepared from the ester of Example 38 by reduction with LiAlH4 in tetrahydrofuran. m/z (ES-) = 492/494.

Example 46 cyanomethanesulfonic acid, N- [4- (4-chlorobenzenesulfonyl)-4- (2, 5- difluorophenyl)-cyclohexyl]-amide

Prepared from the amide of Example 44 by treatment with thionyl chloride and a catalytic amount of dimethylformamide in toluene.

m/z (ES-) = 487/489 Example 47 trifluoromethanesulfonic acid, N- [4- (4-chlorobenzenesulfonyl)-4- (2, 5- difluorophenyl)-cyclohexyl]-amide Intermediate A (110 mg, 0.29 mmol) in dichloromethane (3 ml) cooled to 0°C was treated with triethylamine (99 µL, 0.43 mmol) followed by triflic anhydride (ll7p, L, 0.71 mmol). The reaction was stirred at 0°C for 2.5 hours, slowly warming to ambient temperature, then diluted with ethyl acetate, washed with 2N sodium hydroxide, dried (MgSO4) and evaporated to an orange oil which was purified by chromatography 15% ethyl acetate/ hexane to yield a white solid (16 mg). 1H NMR (360MHz, CDCl3) 6 7. 39- 7.30 (4H, m), 7.09-7. 04 (2H, m) 6.88-6. 81 (1H, m), 5.86-5. 84 (1H, m), 3.82- 3.80 (1H, m), 2.64-2. 42 (4H, m), 2.07-2. 02 (2H, m), 1.66-1. 59 (2H, m). m/z = 540,542 [M + Na] + Example 48 methanesulfonic acid, N- [4- (4-chlorobenzenesulfonyl)-4- (2, 5- difluorophenyl)-cyclohexyl]-N-methyl-amide

Prepared from the product of Example 1 by treatment with NaH and Mel in tetrahydrofuran. m/z = 500, 502 [MNa] + Examples 49-61, 68 The following examples were prepared similarly to Example 1, substituting Intermediate B for Intermediate A and using the appropriate sulfonyl chloride : Example R MS (MH+) unless otherwise stated 49 Me 499 50 2-furyl [MNa+] 572 51 ethyl [MH-] 513 52 CH2SO2Me [MNa+] 598 53 1-Me-imidazol-4-yl 564 54 5-isothiazolyl 567 55 2-pyridyl [MNa+] 583, 561 56 5-chloro-2-thienyl 600, 602 57 n-propyl 526 58 2-thienyl 566. 59 6-chloro-3-pyridyl 596, 598 60 3-thienyl 566 61* vinyl 510, [MH-SO2Ar+] 300 68 2-MeCO2-3-thienyl

*-prepared using 2-chloroethanesulfonyl chloride Example 62 trifluoromethanesulfonic acid, N- [4- (2, 5-difluorophenyl)-4- (4- trifluoromethyl-benzenesulfonyl)-cyclohexyll-amide

Intermediate B (170 mg, 0.41 mmol) in dry dichloromethane (5 ml) under nitrogen was treated at 0OC with triethylamine (80 pilz 0.62 mmol) and triflic anhydride (133 ; j. l, 0.82 mmol). The reaction was allowed to warm to room temperature, stirred for 3 h. diluted with dichloromethane, washed with water, brine, dried (MgSO4) filtered and evaporated. The residue was purified by flash chromatography eluting with iso-hexane/ethyl acetate (1 : 1) to give a white solid (60 mg).

1H NMR 8 (ppm) (DMSO): 1.46-1. 53 (2H, m), 1.81 (1H, s), 1.84 (1H, s), 2.41 (2H, t, J = 13. 1 Hz), 2. 56-2. 59 (1H, m), 2.59 (1H, d, J = 2.7 Hz), 3.64 (1H, s), 7.10-7. 23 (2H, m), 7.30-7. 36 (1H, m), 7.60 (2H, d, J = 8.2 Hz), 7.94 (2H, d, J = 7.6 Hz), 9.77 (1H, d, J = 7.6 Hz).

Example 63 2- (morpholin-4-yl) ethanesulfonic acid, N- [4- (2, 5-difluorophenyl)-4- (4- trifluoromethyl-benzenesulfonyl)-cyclohexyl]-amide Prepared from Example 61 by reaction with excess morpholine in dry dimethylformamide. MS [MH+] 597

Example 64 6- (morpholin-4-yl) pyridine-3-sulfonic acid, N- [4- (2, 5-difluorophenyl)-4- (4- trifluoromethyl-benzenesulfonyl)-cyclohexyl]-amide

Prepared from example 59 by refluxing in ethanol with morpholine.

Example 65 1, 1-dimethylethanesulfinic acid, N-[4-(2,5-difluorophenyl)-4-(4- trifluoromethyl-benzenesulfonyl)-cyclohexyl]-amide

Intermediate B (0.73 g, 1. 75 mmol) and 1,1-dimethylethyl sulfinamide (0.21g, 1.75 mmol) in tetrahydrofuran (20 ml) were treated with titanium (IV) ethoxide (0.36 ml, 1.75 mmol) and heated to 80OC for 18 hours. The reaction was quenched with water (0.35 ml) and stirred for 10 minutes before filtering through Celte. The sulfinimine was cooled to-300C and treated with L-Selectride TM (1.75 ml, 1.0 mmol solution), and stirred for 2 hours whilst warming to-50C. The reaction was then quenched with methanol (2 ml), and partitioned between ethyl acetate (50 ml) and brine (50 ml), dried (MgSO4) and evaporated to dryness. The product was

purified by silica gel chromatography eluting with ethyl acetate/hexane mixtures. Yield 120 mg. MS MH = 524.

Example 66 1, 1-dimethylethanesulfonic acid, N- [4- (2, 5-difluorophenyl)-4- (4- trifluoromethyl-benzenesulfonyl)-cyclohexyl]-amide

Prepared from the product from Example 65 by oxidation with m- chloroperoxybenzoic acid in dichloromethane. MS MH = 540.

Example 67 2-(pyrrolidin-1-yl) ethanesulfonic acid, N- [4- (2, 5-difluorophenyl)-4- (4- trifluoromethyl-benzenesulfonyl)-cyclohexyl]-amide

Prepared as in Example 63, substituting pyrrolidine for morpholine.

MS [MH+] 581 Examples 69-73 The following sulfonamides were prepared by the procedure of Example 1 using Intermediate C and the appropriate sulfonyl chloride. Example R MS (MH+) 69 methyl 499 70 2-thienyl 567 71 5-isothiazolyl 568 72 n-propyl 527 73* 2-chloro-2-propyl 561, 563

*Isopropylsulfonyl chloride was used.

Example 74 trifluoromethanesulfonic acid, N- [4- (2, 5-difluorophenyl)-4- (6- trifluoromethyl-pyridine-3-sulfonyl)-cyclohexyl]-amide

Intermediate C (100 mg) in dichloromethane (5 ml) and treated with triethylamine (1 equivalent) and cooled to-78 °C.

Trifluoromethanesulfonic anhydride (2 equivalents) was added, the reaction mixture warmed to-40 °C and stirred at this temperature for 3 h.

The mixture was quenched with aqueous citric acid, diluted with ethyl

acetate and warmed to room temperature. The organic phase was separated, washed with brine, dried (MgSO, filtered and evaporated in vacuo. Purification by column chromatography (eluting with 5/1 hexane/ethyl acetate) gave the title compound (120 mg, 91%) as a white powder. 1H NMR (CDC13, 400 MHz) 8.60 (1H, d, J = 1.9), 7.91 (1H, dd, J = 8.2, 1.9), 7.74 (1H, d, J = 8.2), 7.26-7. 10 (2H, m), 6.88-6. 81 (1H, m), 5.70 (1H, brd, J = 5), 3.83 (1H, brs), 2.64-2. 48 (4H, m), 2.11-2. 07 (2H, m), 1.70- 1.65 (2H, m).

Example 75 trifluoromethanesulfonic acid, N- [4- (5-bromo-2-fluorophenyl)-4- (6- trifluoromethyl-pyridine-3-sulfonyl)-cyclohexyl]-amide Prepared by the procedures of Intermediate C (using 2-fluoro-5- bromobenzyl bromide in Step 2) and Example 1 (using trifluoromethanesulfonyl chloride). M/Z = 613,615 (MH+).

Example 76 trifluoromethanesulfonic acid, N- [4- (5-cyano-2-fluorophenyl)-4- (6- trifluoromethyl-pyridine-3-sulfonyl)-cyclohexyll-amide

Prepared from Example 75 (45 mg) by heating with copper cyanide (4 equivalents), pyridine (1 drop) in dimethylformamide at 180°C overnight.

M/Z = 559 (MH+).

Example 77 trifluoromethanesulfonic acid, N- [4- (2-fluoro-5-methyl-phenyl)-4- (6- trifluoromethyl-pyridine-3-sulfonyl)-cyclohexyl]-amide

Prepared from Example 75 by treatment with cesium fluoride (2. 2' equivalents), tri-tert-butylphosphine (12 mol%), tetramethyltin (2 equivalents), and Pd2 (dba) 3 (3 mol%) at 100°C in dioxan for 3 h M/Z = 549 (MH+).

Example 78 trifluoromethanesulfonic acid, N- [4-(2-fluoro-5- (hydroxymethyl)-phenyl)-4- (6-trifluoromethyl-pyridine-3-sulfonyl)-cyclohexyl]-amide

Prepared from Example 75 by (i) treatment with CsF (2.2 equivalents), tri- tert-butylphosphine (12 mol%), tributylvinyltin (2 equivalents), and Pd2 (dba) 3 (3 mol%) in dioxan at 100°C for 2 h. ; (ii) treatment of the resulting styrene with ozone at-78°C in dichloromethane/methanol ; and (iii) reduction of the resulting aldehyde at-78°C with sodium borohydride (2 equivalents) in ethanol. M/Z = 547 (M-OH+H+).

Example 79 trifluoromethanesulfonic acid, N- [4- (2, 5-difluorophenyl)-4- (4- vinylbenzenesulfonyl)-cyclohexyl]-amide

Prepared from Example 47 by treatment with tri-kbutylphosphine, cesium fluoride, Pd2 (dba) 3 and tributyl (vinyl) tin in dioxan at 100°C for 2 hours.

Example 80 trifluoromethanesulfonic acid, N-[4-(2,5-difluorophenyl)-4-(4- formylbenzenesulfonyl)-cyclohexyl]-amide

Prepared from Example 79 by treatment with ozone in dichloromethane/ methanol at -78°C.

Example 81 4-{1-(2,5-difluorophenyl)-4-[(trifluoromethanesulfonyl)amino ]- cyclohexanesulfonvl}-benzaldehyde oxime

Prepared from Example 80 by treatment with hydroxylamine hydrochloride and sodium acetate in refluxing ethanol.

Example 82 trifluoromethanesulfonic acid, N- [4- (2, 5-difluorophenyl)-4- (4- (fluoromethyl) benzenesulfonyl)-cyclohexyl]-amide

Prepared from Example 80 by (i) reduction with sodium borohydride in dry tetrahydrofuran at 0 OC and (ii) treatment of the resulting benzyl alcohol with diethylaminosulfur trifluoride in dry dichloromethane at-78 oC.

Example 83 trifluoromethanesulfonic acid, N- [4- (2, 5-difluorophenyl)-4- (4- (difluoromethyl) benzenesulfonyl)-cyclohexyl]-amide

Prepared from Example 80 by treatment with diethylaminosulfur trifluoride in dry dichloromethane at room temperature.

Example 84 trifluoromethanesulfonic acid, N- [4- (4-cyanobenzenesulfonyl)-4- (2, 5- difluorophenyl)-cyclohexyl]-amide

Prepared from Example 81 by treatment with triphenyl phosphine and carbon tetrachloride in acetonitrile.

Example 85 trifluoromethanesulfonic acid, N- [4- (benzenesulfonyl)-4-(2,5- difluorophenyl)-cyclohexyl]-amide

Prepared from Example 47 by hydrogenation over 10% palladium on carbon.