CYCLOHEXYL SULPHONE DERIVATIVES AS GAMMA-SECRETASE INHIBITORS The present invention relates to a novel class of compounds, their salts, pharmaceutical compositions comprising them, processes for making them and their use in therapy of the human body. In particular, the invention relates to novel cyclohexyl sulphones which inhibit the processing of APP by y-secretase, and hence are useful in the treatment or prevention of Alzheimer's disease.

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 the cortical and associative brain regions of sufferers. These plaques mainly comprise fibrillar aggregates-of P-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 ofsulphonamides 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 Aß.

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

I wherein X represents SCN, SRl, S (O) Rl, (CRaRb)mSO2R1, SO2N(R2) 2, S02NHCOR1, SO2NHN (R2) 2, OSO2N (R2) 2, OS (O) N (R2) 2, OSO2NHCOR1, COR4, NHCOR1, NHCO2Rl, NHCON (R2) 2, NHSO2R1 or NHSO2N(R2)2; m is 0 or 1 Ra represents H or C1-4alkyl; Rb represents H, C1-4alkyl, CO2H, C1-4alkoxycarbonyl or C1- 4alkylsulphonyl ; or Rb may combine with Ri to form a 5-or 6-membered ring ; L represents a bond, =CH- or -(CHRa)n-; with the proviso that L does not represent a bond when X represents NHCOR1, NHCO2R1 or NHSO2Rl and with the proviso that if L represents =CH-, X represents SO2R1 or COR4; n is 1, 2 or 3; R1 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, OCOR3a, SO2R3a, N (R5) 2, and CON (R5) 2, or R1 represents aryl, arylCi-salkyl, C-heterocyclyl or C-heterocyclylC1-6alkyl; or R1 may combine with Rb to form a 5-or 6-membered ring ;

each R2 independently represents H, C1-6alkoxy, or C1-6alkyl, C2- 6alkenyl, C3-9cycloalkyl or C3-6cycloalkylC1-6alkyl, any of which may bear up to 2 substituents selected from halogen, CN, CF3, OR3, COR3, C02R3, OCOR3a, and CON (R5) 2 ; or aryl, arylC1-6alkyl, C-heterocyclyl or C-heterocyclylC1-6alkyl; or two R2 groups together with a nitrogen atom to which they are mutually attached complete an N-heterocyclyl group ; R3 represents H, C1-4alkyl, phenyl or heteroaryl ; R3a represents Cl-4alkyl, phenyl or heteroaryl ; R4 represents (CRaRb) SO2Rl, pyridine N-oxide, or phenyl or heteroaryl which bear a substituent selected from CO2H, methylenedioxy, difluoromethylenedioxy, COR3, C-heterocyclyl, C1-4alkylsulphonyl and substituted C1-6alkyl, Cl-salkoxy, C2-6alkenyl or C2-6alkenyloxy wherein the substituent is selected from halogen, CN, CF3, OR3, CO2R3, OCOR3a, N (R5) 2 and CON (R5) 2 ; 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,-Cl-4alkoxy, C1-4alkoxycarbonyl, C2-6acyl, C2-6alkenyl and Alkyl 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, OCF3, OR3, COR3, CO2R3, OCOR3a, 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, COzR3, OCOR3a, N (R5) 2 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, NO2, CF3, OCFs, OR3, COR3, C02R3, OCOR3a, OSO2R3a, N (R5) 2, CON (R5) z and optionally-substituted phenyl, C1-6alkyl, C1-6alkoxy, C2-6alkenyl or C2-6alkenyloxy wherein the substituent is selected from halogen, CN, CF3, OR3, C02R3, OCOR3a, 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"Ci-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","hydroxyCl-6alkyl", "heteroarylCl-salkyl","C2-6alkynyl"and"Cl-6alkoxy"are to be construed in an analogous manner.

The expression"C3-scycloalkyl"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 C1-5alkylcarbonyl 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. 1] heptyl, 2-aza-5-oxabicyclo [2.2. 1] 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, 0 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.

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, sulphuric acid, benzenesulphonic acid, methanesulphonic 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, X represents SCN, Sur1, S (O) R1, (CRaRb) mSO2Rlx SO2N (R2) 2, S02NHCOR1, S02NHN (R2) 2, OS02N (R2) 2, OS (O) N (R2) 2, OS02NHCOR1, COR4, NHCOR1, NHC02R1, NHCON (R2) 2, NHSO2R1 or NHSO2N (R2) 2. In a preferred embodiment, X is selected from SRl, (CRaRb) mSO2R1, S02N (R2) 2, OS02N (R2) 2, COR4, NHCORl, NHC02R1, NHCON (R2) 2, NHSO2R1 and NHSO2N (R2) 2.

When X represents (CRaRb) mSO2Rl, m is 0 or 1. In one embodiment, m is 0. In an alternative embodiment, m is 1.

When m is 1, Ra represents H or Cl-4alkyl such as methyl, ethyl or propyl. When m is 1, Rb represents H, C1-4alkyl (such as methyl, ethyl or propyl), COsH, C1-4alkoxycarbonyl (such as CO2Me or C02Et) or C1- 4alkylsulphonyl (such as methanesulphonyl) ; or Rb may combine with R1 to form a 5-or 6-membered ring, in particular a tetrahydrothiophene-1, 1- dioxide ring or a tetrahydrothiopyran-1, 1-dioxide ring.

When m is 1, preferred identities for the moiety-CRaRb-include : L represents a bond, =CH- or -(CHRa)n-; but when L represents a bond, X cannot represent NHCOR1, NHCO2Rl or NHS02Rl; and when L represents =CH-, X must represent SO2R1 or COR4.

When L represents a bond or- (CHRa) n-, the moiety-L-X is preferably in the cis stereoconfiguration relative to the 1SO2 moiety.

When L represents- (CHRa)n-, n is 1,2 or 3 (preferably 1 or 2), and each Ra is independently H or C1-4alkyl such as methyl or ethyl (especially methyl), but L preferably comprises not more than one Ra group that is other than H.

Particularly preferred examples of L include a bond,-CH2-and -CH2CH2-.

Rl is preferably CF3, aryl or arylalkyl, or an alkyl, 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 CO2H, COzMe and CO2Et) and CON (R5) (especially CONHz).

Examples of alkyl groups represented by Ri include methyl, ethyl, n-propyl, isopropyl, t-butyl, isobutyl, 2,2,2-trifluoroethyl, cyanomethyl, 2- hydroxyethyl, 2-methoxyethyl, 2-hydroxy-2-methylpropyl, carboxymethyl,

ethoxycarbonylmethyl, 1-carboxyethyl, 1-ethoxycarbonylethyl, carbamoylmethyl and MeCOCH2-.

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

When Rl represents aryl or arylalkyl, the aryl group may be phenyl or heteroaryl, optionally substituted as defined previously. Preferred substituents include halogen (especially chlorine or fluorine), CF3, OCF3, alkyl (especially methyl), OH and alkoxy (especially methoxy). Preferred heteroaryl groups include pyridine, pyrimidine, furan, thiophene, thiazole, imidazole, triazole, thiadiazole and tetrazole.

Examples of aryl groups represented by Rl include phenyl, 2- fluorophenyl, 4-fluorophenyl, 2, 4-diiGuorophenyl, 2-chlorophenyl, 2-, 3-and 4-hydroxyphenyl, 2-trifluoromethoxyphenyl, 2-methoxyphenyl, 2-pyridyl (and the corresponding N-oxide), 4-pyridyl, 2-pyrimidinyl, 2-furyl, 2- thienyl, 2-thiazolyl, 2-imidazolyl, 2-methylfuran-3-yl, 4-methylthiazol-3-yl,, 5-methyl-1, 3, 4-thiadiazol-2-yl, 1-methylimidazol-2-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.

When X represents SO2NHCORl or OSO2NHCORl, Ri is very aptly CF3, C1-6alkyl or C3-6cycloalkyl, for example methyl.

When X represents S (O) Rl, Rl very aptly represents aryl, for example 2-pyridyl or 1-methyl-1, 2, a, 4-tetrazol-5-yl.

When X represents NHCO2Rl, Rl very aptly represents Ci-alkyl (for example methyl) or arylalkyl (for example benzyl).

When X represents NHCORl, RI very aptly represents Cl-6alkyl (for example methyl) or substituted Cl. Galkyl (for example 2,2, 2-trifluoroethyl or 1-hydroxy-2, 2, 2-trifluoroethyl).

For any N (R2)2 fragment, preferably either at least one of the R2 groups represents H or Cl-6alkyl such as methyl, or the two R2 groups complete an N-heterocyclyl group. When one R2 group represents Cl- 6alkoxy (such as methoxy), the other preferably represents Cl-6alkyl (such as methyl).

When N (R2) 2 does not represent N-heterocyclyl, preferably one R2 is H or methyl and the other is H, methoxy, aryl (such as phenyl) or optionally substituted alkyl or cycloalkyl. Preferred substituents include CF3, OR3 (such as OH and OMe), C02R3 (such as t-butoxycarbonyl) and OCOR3a (such as acetoxy). Within this embodiment, preferred identities for N (R2) 2 include NH2, NHMejf NHEt, NHiPr, NHtBu, NMe2, N (Me) OMe, NHPh, NH-cyclobutyl, NHCH2CF3, NHCH2C02tBu, NHCH2CH2OCOMe and NHCH2CH20H.

When N (R2) 2 represents N-heterocyclyl, the heterocyclic ring is typically an optionally substituted azetidine, pyrrolidine, 3-pyrroline, piperidine, morpholine, thiomorpholine or 2-aza-5- oxabicyclo [2.2. 1]heptane ring. Azetidine and pyrrolidine are preferred, and azetidine is particularly preferred. Preferred substituents include oxo, halogen (especially fluorine), CF3, OR3 (especially OH), OCOR3a (especially acetoxy and trimethylacetoxy), OS02R3a (especially methanesulphonyloxy), CO2R3 (especially C02H and C02Me), N (R5) 2 (especially dimethylamino) and alkyl (especially methyl). Examples of preferred N-heterocyclyl groups include azetidin-1-yl, pyrrolidin-1-yl, 3- pyrrolin-1-yl, piperidin-1-yl, morpholin-4-yl, thiomorpholin-4-yl, 2-aza-5- oxabicyclo [2.2. 1]hept-2-yl, 3-oxo-azetidin-1-yl, 3-hydroxyazetidin-1-yl, 3- acetoxyazetidin-1-yl, 3- (dimethylamino) azetidin-1-yl, 3- methanesulphonyloxyazetidin-1-yl, 3, 3-difluoroazetidin-1-yl, 3-hydroxy-3- methylazetidin-1-yl, 2-carboxypyrrolidin-1-yl, 2-

methoxycarbonylpyrrolidin-1-yl, 3-fluoropyrrolidin-1-yl, 3,3- difluoropyrrolidin-1-yl, 2-(trifluoromethyl) pyrrolidin-1-yl, 3-oxo-pyrrolidin- 1-yl, 3-hydroxypyrrolidin-1-yl, 3-hydroxy-3-methylpyrrolidin-1-yl, 3- (trimethylacetoxy) pyrrolidin- 1-yl, 4- (trifluoromethyl) piperidin- 1-yl and 4, 4-difluoropiperidin-1-yl.

When X represents SO2NHN (R2) 2, OS (O) N (R2) 2 or NHCON (R2) 2, very aptly both R2 groups represent methyl, or one R2 represents H and the other represents C1-6alkyl, such as methyl or ethyl.

In the embodiments in which X represents COR4, R4 is selected from (CRaRb) SO2Rl, pyridine N-oxide, or phenyl or heteroaryl which is substituted as defined previously.

When R4 represents (CRaRb) SO2R1, Ra and Rb preferably independently represent H or C1-4alkyl, or Rb together with R'completes a 5-or 6-membered ring. Suitable rings include tetrahydrothiophene-1, 1, - dioxide and tetrahydrothiopyran-1, 1-dioxide. Tetrahydrothiophene-1-, 1, - dioxide is preferred. In this context, R1 is very aptly optionally-substituted C1-6alkyl, especially methyl, or else completes a ring with Rb. Examples of preferred groups represented by R4 in this embodiment include CH2SO2Me, CH (Me) SO2Me, C (Me) 2SO2Me and 1,1-dioxo- tetrahydrothiophen-2-yl.

When R4 represents pyridine N-oxide, the pyridine ring may be bonded through the 2-, 3-or 4-position, but the 2-position is preferred.

R4 may alternatively represent phenyl or heteroaryl, either of which must bear a substituent selected from C02H, methylenedioxy, difluoromethylenedioxy, COR3, C-heterocyclyl, Cl-4alkylsulphonyl and substituted Cl-salkyl, Cl-6alkoxy, C2-6alkenyl or C2-6alkenyloxy wherein the substituent is selected from halogen, CN, CF3, OR3, CO2R3, OCOR3a, N (R5) and CON (R5) 2. In this context, preferred heteroaryl groups are 5- membered, such as furan, pyrrole and thiophene, furan and pyrrole being particularly preferred and furan most preferred. Examples of preferred substituents include CO2H, difluoromethylenedioxy, formyl, 1,3-dioxolan-

2-yl, methanesulphonyl, hydroxymethyl, allyl, allyloxy,- (CH2) x-CO2R3, -O (CH2) y-CO2R3,-CH=CH-C02R3,- (CH2) x-N (R5) 2 and-O (CH2) y-N (R5) 2, where x is 1,2 or 3 and y is 2 or 3. In this context R3 is very aptly H, methyl or ethyl, and N (R5) 2 is very aptly morpholin-4-yl or 1,1-dioxo- thiomorpholin-4-yl.

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 Arl include optionally substituted pyridyl, in particular optionally substituted 3-pyridyl. Arl 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 A1 represents 6-(trifluoromethyl)-3-ps. ridyl.

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 4-chlorophenyl or 4- trifluoromethylphenyl or 6- (trifluoromethyl)-3-pyridyl and Ar2 is 2,5- difluorophenyl.

A subclass of the compounds of the invention comprises the compounds of formula II:

wherein n, X, Ar1 and Ar2 have the same definitions and preferred identities as before ; and pharmaceutically acceptable salts thereof.

Preferably n is 1 or 2.

In a subset of the compounds of formula II, X is selected from NHCOR1, NHC02R1 and NHS02R1 where Ri has the same definition and preferred identities as before.

A second sub-class of the compounds of the invention comprises the compounds of formula III: III wherein p is 0,1, 2 or 3 ; Y is SCN, Suri, S (O) RI, (CRaRb)mSO2R1, SO2N (R2) 2, SO2NHCOR1, SO2NHN (R2) 2, OS02N (R2) 2, OS (O) N (R2) 2, OS02NHCOR1, COR4, NHCON (R2) 2 or NHSO2N (R2) 2 ; and m, Ra, Rb, R1, R2, R4, Arl and Ar2 have the same definitions and preferred identities as before ; and pharmaceutically acceptable salts thereof.

Preferably p is 0,1 or 2.

In a subset of the compounds of formula III, Y is selected from SCN, SRl, S (O) Rl, (CRaRb) mSO2RI, SO2N (R2) 2, SO2NHCOR1 and SO2NHN (R2) 2 ; preferably from SCN, SR1, (CRaRb) mSO2Rl and S02N (R2) 2 ; and most preferably from (CRaRb) mSO2Rl and SO2N (R2) 2. Within this subset, p is preferably 1 or 2. In one preferred embodiment Y is (CRaRb) mSO2Rl. In

another preferred embodiment Y is SO2N (R2) 2, in which case p is very aptly 1 and N (R2) 2 is very aptly N-heterocyclyl.

In a second subset of the compounds of formula III, Y is selected from OSO2N (R2) 2, OS (O) N (R2) 2, OSO2NHCORl, NHCON (R2) 2, NHS02N (R2) 2 and COR4. Within this subset, p is preferably 0 or 1. In one preferred embodiment p is 0 and Y is OS02N (R2) 2. In another preferred embodiment, p is 1 and Y is NHCON (R2) 2. In a further preferred embodiment, p is 1 and Y is COR4. In a further preferred embodiment, p is 0 and Y is NHS02N (R2) 2. In a further preferred embodiment, p is 1 and Y is NHS02N (R2) 2.

A third sub-class of the compounds of the invention comprises the compounds of formula IV : IV wherein Z represents SOzRl or COR4 ; and Rl, R4, Arl and Ar2 have the same definitions and preferred identities as before ; and pharmaceutically acceptable salts thereof.

In a preferred embodiment, Z is SO2R1.

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 (3-amyloid. Preferably the condition is a neurological disease having associated (3-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 P-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.

Compounds of formula I in which L is- (CH2) p- and X represents SCN, SRl or (CRaRb) mSO2Rl may be prepared by reaction of, respectively, MSCN, MSRl or M (CRaRb) mSO2Rl with a compound of formula (1) : (1) where M is a metal cation (preferably an alkali metal cation, such as Li or Na), G is a leaving group, and R1, Ra, Rb, Arl, Ar2, m and p have the same meanings as before. Suitable identities for G include halide (especially bromide or iodide) and alkyl-or arylsulphonate. Iodide and mesylate are particularly suitable. The metallated derivatives MSR I and M (CRaRb) mSO2Rl may be generated by reaction of the corresponding hydrides with NaOH, LiOH, NaH, BuLi, LiN (iPr) 2 or similar, and are typically reacted in situ with the compounds (1).

Compounds of formula I in which X represents S (O) RI may be prepared from the corresponding compounds in which X represents SR by oxidation with one equivalent of m-chloroperoxybenzoic acid. The oxidation takes place at ambient temperature in a dichloromethane-water mixture. Oxidation of the same compounds with two equivalents of m- chloroperoxybenzoic acid, or with sodium periodate in the presence of Ru02 catalyst, provides an alternative route to compounds in which X represents (CRaRb) mSO2Rl and m is 0.

Compounds of formula I in which L is- (CH2) p- and X represents, S02N (R2) 2 or S02NHN (R2) 2 may be prepared by reaction of (R2) 2NH or (R2) 2NNH2 respectively with a sulphonyl chloride of formula (2):

where R2, Arl, Ar2 and p have the same meanings as before. The reaction is typically carried out in dichloromethane at ambient temperature, either using excess of the amine or using an additional base such as potassium carbonate, pyridine or triethylamine.

Compounds of formula I in which X represents SO2NHCORl may be prepared from the corresponding compounds in which X represents SO2NH2 by coupling with RlCO2H. Any of the standard peptide coupling procedures may be used, for example the use of dimethylaminopyridine and 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide.

Compounds of formula I in which L is- (CH2) p- and X represents OSO2N (R2) 2 may be prepared by reaction of a sulphamoyl chloride (R2) 2NSO2Cl with an alcohol of formula (3): (3) where R2, Arl, Ar2 and p have the same meanings as before. The reaction is typically carried out in dichloromethane at ambient temperature in the presence of a base such as pyridine or triethylamine. The sulphamoyl chlorides (R2) 2NSO2C1 are available by reaction of (R2) 2NH with sulphuryl chloride in acetonitrile at ambient temperature.

Compounds of formula I in which X represents OSO2NHCOR1 may be prepared from the corresponding compounds in which X represents OSO2NH2 by coupling with RlCO2H. Any of the standard peptide coupling procedures may be used, for example the use of dimethylaminopyridine and 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide.

Compounds of formula I in which L is -(CH2)p- and X represents OS (O) N (R2) may be prepared by treating an alcohol of formula (3) first with thionyl chloride, and then with (R2) zNH. The reaction with thionyl chloride is typically carried out at-78oC, and the resulting intermediate reacted in situ with the amine at the same temperature, then allowed to warm to ambient temperature.

Compounds of formula I in which L is -(CH2)p- and X represents NHCORi, NHCO2R1, NHS02Rl or NHSO2N (R2) 2 may be prepared by reacting an amine of formula (4) with, respectively, R1COCl, R10COCl, R1SO2Cl and (R2) 2NS02Cl : (4) where Rl, Arl, Ar2 and p have the same meanings as before. The reaction is typically carried out in dichloromethane at ambient or reduced temperature, in the presence of a base such as pyridine or triethylamine.

Alternatively, the compounds in which X represents NHCORI may be prepared by coupling of amines (4) with RlCO2H. Any of the standard peptide coupling procedures may be used, for example the use of 1- hydroxybenzotriazole or dimethylaminopyridine and 1- (3- dimethylaminopropyl)-3-ethylcarbodiimide.

An alternative route to the compounds of formula I in which L is- (CH2) p- and X represents NHS02N (R2) 2 involves reacting an amine of formula (4) with catechol sulphate and reacting the resulting sulphamate with (R2) 2NH. The first step is typically carried out in THF at 0°C, and the second step at 80OC in dioxan.

Compounds of formula I in which L is- (CH2) p- and X represents NHCON (R2) 2 may be prepared by treating an carboxylic acid of formula (5) first with diphenylphosphoryl azide, and then with (R2) 2NH :

where R2, Arl, Ar2 and p have the same meanings as before. The first step is typically carried out in toluene at 110°C in the presence of triethylamine, and the second step at ambient temperature in the same solvent.

Compounds of formula I in which X represents COR4, and R4 represents substituted phenyl or heteroaryl, may be prepared by reaction of a compound of formula (6a) with R4-Ml :

(6) where MI represents Li or MgBr and Arl, Ar2 and L have the same meanings as before. The reaction is typically carried out in THF or diethyl ether at reduced temperature. When MI is MgBr, R4 preferably represents substituted phenyl.

Compounds of formula I in which X represents COR4, and R4 represents (CRaRb) SO2Rl, may be prepared by reaction of a compound of formula (6b) with R4-Li. The reaction is typically carried out in THF or diethyl ether at reduced temperature.

Compounds of formula I in which L represents =CH-and X represents SO2Rl may be prepared by reaction of a cyclohexanone (7):

with CH3-SO2Rl, followed by dehydration of the resulting tertiary alcohol ; where Rl, Arl and Ar2 have the same meanings as before. The first step is typically carried out in THF at-78°C in the presence of strong base such as lithium diisopropylamide. The dehydration may be effected by converting the alcohol to the corresponding mesylate and treating the latter with 1, 8-diazabicyclo [5.4. 0] undec-7-ene in THF at ambient temperature.

The compounds of formula (1) in which G is iodide may be obtained by reaction of the corresponding compounds of formula (5) with iodosobenzene diacetate and iodine under irradiation. The compounds of formula (1) in which G is alkyl-or arylsulphonate are available from the reaction of the corresponding compounds of formula (3) with the appropriate sulphonyl chloride.

The sulphonyl chlorides of formula (2) may be obtained by reaction of the compounds of formula (1) with potassium thioacetate, hydrolysis of the resulting thioester to give the corresponding thiol, then treatment of the thiol with potassium nitrate and sulphuryl chloride.

The alcohols of formula (3) in which p is 1,2 or 3 are available by reduction of the acids of formula (5), the value of p increasing by 1 in the process. The alcohols of formula (3) in which p is 0 are available from the reduction of the cyclohexanones of formula (7). Reduction with L- Selectride provides the cis isomer selectively. Reduction with sodium borohydride provides a mixture of cis and trans isomers which may be separated by chromatography.

The amines of formula (4) are available from the carboxylic acids (5) by sequential reaction with oxalyl chloride, sodium azide and benzyl alcohol, followed by hydrolysis of the resulting carbamate. Alternatively, they may be obtained from the mesylates of the alcohols (3) by displacement with azide ion, followed by reduction.

The carboxylic acids of formula (5) in which p is 0 are available from the alcohols (3) in which p is 0 by formation of the mesylate ester, followed

by nucleophilic displacement with cyanide ion and hydrolysis of the resulting nitrile. The corresponding acids in which p is 1 are formed by condensation of cyclohexanones (7) with ethyl (diethoxyphosphinyl) acetate, followed by reduction of the resulting alkenyl ester (i. e. (6b) where L is =CH-) and hydrolysis of the ester group. The corresponding acids in which p is 2 or 3 are obtainable by standard methods of homologation. For example, reduction of an acid (5) in which p is 1 provides an alcohol (3) in which p is 2, and mesylation, displacement with cyanide, and hydrolysis provides the corresponding acid in which p is 2. Repeating this process provides the acid (5) in which p is 3.

The N-methoxyamides (6a) are obtained-from the corresponding carboxylic acids by treatment first with oxalyl chloride and then with N, O- dimethylhydroxylamine.

Detailed procedures for the synthesis of compounds of formulae (1) (6), and cyclohexanones (7), are provided in WO 02/081435 and US 2003/01144-96 Al.

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, a compound of formula I in which X is SCN may be treated with trimethyl (trifluoromethyl) silane and tetrabutylammonium fluoride to provide the corresponding compound in which X is SCFs, which in turn may be oxidised to the corresponding compound wherein X is SO2CF3.

Similarly, a compound of formula I wherein X is (CRaRb) SO2Rl or CO (CRaRb) SO2Rl and one or both of Ra and Rb is H may be alkylated so as to provide the corresponding compound in which one or both of Ra and Rb is alkyl. Alternatively, if in the aforesaid compound Rb is CO2H,

decarboxylation via refluxing with sodium chloride in DMSO provides the corresponding compound in which Rb is H.

Also, substituents on the aromatic groups Ai I 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, in esters (6b) 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.

Compounds of formula I in which L comprises a pendant alkyl group are obtainable by alkylation of the corresponding compounds wherein L is - (CH2) n-, or by alkylation of a precursor such as an ester (6b) wherein L is - (CH2) n-.

Pyridine groups may be oxidised to the corresponding N-oxides by treatment with urea hydrogen peroxide and trifluoroacetic anhydride in dichloromethane at 0°C.

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 WO01/70677. A preferred assay to determine such activity is as follows : 1) SH-SY5Y cells stably overexpressing the ßAPP 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/100, uL 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 10aL compound/well, gently mix and leave for 18h at 37°C, 5% CO2.

5) Prepare reagents necessary to determine amyloid peptide levels, for example by Homogeneous Time Resolved Fluorescence (HTRF) assay.

6) Plate 160jjL aliquots of HTRF reagent mixture to each well of a black 96-well HTRF plate.

7) Transfer 40, uL 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 10plL/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 ED5o of less than 1, uM, typically less than 0. 5µM, 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-Chlorophenyl) sulfonyl]-4- (2, 5-difluorophenyl) cyclohexanone

Prepared as described in WO 02/081435 (Example 2).

Intermediate B : [4- (4-Chloro-benzenesulfonyl)-4- (2, 5-difluoro-phenyl)- cyclohexyl]-acetic acid ethyl ester

Prepared as described in WO 02/081435 (Example 48).

Intermediate C :[4-(4-Chlorphenylsulfonyl)-4-(2,5-difluoro-phenyl)- cyclohexyl]-acetic acid

Prepared as described in WO 02/081435 (Example 50).

Intermediate D: 2-[4-(4-Chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)- cyclohexyl]-ethanol

To Intermediate C (1 g, 2.3 mmol) in dry tetrahydrofuran (80 mL) at 0°C under nitrogen were added triethylamine (0.4 mL, 2.8 mmol) and iso- butylchloroformate (0. 36 mL, 2.8 mmol). The reaction was stirred for 1.5 h, filtered, the filtrate re-cooled to 0°C and sodium borohydride (435 mg, 11 mmol) in water (10 mL) added dropwise. After stirring at 0°C for 1 h the reaction was concentrated, diluted with ethyl acetate, washed with water and brine and then dried (MgS04), filtered and evaporated. The residue was purified by flash column chromatography on silica, eluting with iso- hexane/ethyl acetate (1 : 1), to give the alcohol as a white solid (960 mg Intermediate E : Iodo- [4- (4-Chloro-benzenesulfonyl)-4- (2, 5-difluoro- phenyl)-cyclohexyl]-methane A stirred solution of Intermediate C (6.85 g, 16.0 mmol. ), iodosobenzene diacetate (14.4 g, 44.7 mmol. ) and iodine (6.20 g, 24 mmol.) in dry benzene (200 mL) was heated to reflux under irradiation by a 250W tungsten lamp. After 45 minutes, further iodosobenzene diacetate (3.0 g, 9.3 mmol. ) and iodine (1.5 g, 5.8 mmol. ) were added and reflux under irradiation continued for a further lh. The reaction was cooled and diluted with ethyl acetate (200 mL) then washed with aqueous sodium thiosulfate (10%, 2 x 200 mL), water (200 mL), aqueous sodium hydroxide solution (1M, 200 mL) and brine (200 mL) then dried (MgSO4) and evaporated to leave a residue which was purified by flash column chromatography on silica, eluting with ether : dichloromethane : iso-hexane (1 : 1 : 8), to afford iodo- [4- (4-chloro-benzenesulfonyD-4- (2, 5-difluoro-phenyl)- cyclohexylJ-methane (6.00 g, 74%).

Intermediate F: 2-Iodo- [4- (4-Chloro-benzenesulfonvl)-4- (2, 5-difluoro- phenyl)-cyclohexyl]-ethane

A solution of Intermediate D (414 mg, 1 mmol), imidazole (272 mg, 4 mmol) and triphenylphosphine (524 mg, 2 mmol) in toluene (15 mL) was stirred at room temperature for 10 minutes, then iodine (279 mg, 1.1 mmol) was added. The reaction was stirred at ambient temperature for 2.5h then at 65°C for lh. Upon cooling, the mixture was decanted and evaporated to dryness. The residue was extracted into ether (3 x 50 mL) and the combined organics evaporated then filtered through a plug of silica, eluting with ether : iso-hexane (1 : 4) to give the desired iodide (252 mg).

Intermediate G : 4-(4-Chloro-benzenesulfonvl)-4-(2. 5-difluoro-phenvl)- cyclohexanol A solution of Intermediate A (10. 05 g, 26 mmol) in tetrahydrofuran (200 mL) cooled to-78°C was treated with L-Selectride (1.0 M solution in tetrahydrofuran, 31.4 mL, 31.4 mmol). After stirring at-78°C for 2 hours the reaction was quenched with aqueous hydrochloric acid (2M).

The solvent was evaporated and the product extracted into ethyl acetate and washed with water followed by brine, and evaporated to an oil which

was purified by flash chromatography eluting with ethyl acetate : hexane 1: 1 to afford the desired intermediate (6g).

Intermediate H: 2-[4-(4-Chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)- cvclohexyl]-N-methoxy-N-methyl-acetamide Prepared as described in WO 02/081435 (Example 219).

Intermediate I: [4-(4-Chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)- cvelohexvl]-methanethiol To a solution of Intermediate E (2.05 g, 4. 0 mmol. ) in N, N- dimethylformamide (80 mL) was added potassium thioacetate (2.3 g, 20 mmol. ) and the solution stirred for 2h. at ambient temperature then diluted with water (100 mL) and extracted into ether (2 x 100 mL). The combined organic layers were washed with water (3 x 100 mL) and brine (100 mL), dried (MgSO4) and evaporated to leave the crude thioacetic acid 4- (4-chloro-benzenesulfonyl)-4- (2, 5-difluoro-phenyl)-cyclohexylmethyl ester (1.81 g). This was dissolved in methanol (80 mL), 1M aqueous sodium hydroxide solution (20 mL) was added and the mixture vigorously stirred for lh. Water (50 mL) was added and the mixture extracted into ethyl acetate (2 x 100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried (MgSO4) and evaporated to leave a residue of the desired thiol (1. 65g, quant.).

Intermediate J : C- [4- (4-Chloro-benzenesulfonyl)-4- (2, 5-difluoro-phenyl)- cyclohexyl]-methylamine

To a stirred solution of Intermediate C (75 mg, 0.18 mmol. ) in tetrahydrofuran (10 mL) was added oxalyl chloride (0.02 mL, 0.23 mmol. ) and l\§N-dimethylformamide (1 drop) and the mixture stirred at ambient temperature for 90 minutes then evaporated. Toluene (10 mL) was added then evaporated and the residue taken up in benzene (2 mL) and cooled in an ice bath. A solution of tetrabutylammonium bromide (1 mg) and sodium azide (23 mg, 0.36 mmol. ) in water (1 mL) was added, the cooling bath removed and the mixture allowed to stir at ambient temperature for 2 hours. The layers were separated and the organic phase washed with brine (10 mL), dried (MgSO4) and filtered. Benzyl alcohol (0.1 mL) was added and the mixture heated to reflux for 18 hours then cooled and diluted with ethyl acetate (10 mL), washed with water (10 mL) and brine (10 mL), dried (MgSO4) and evaporated to leave a residue which was purified by flash column chromatography on silica, eluting with ethyl acetate : iso-hexane (1 : 3), to afford the desired benzyl carbamate (60mg).

MS (ES+) 534 ( [MH] +).

To the foregoing carbamate (40 mg, 0.08 mmol. ) was added hydrobromic acid (1 mL of a 45% w/v solution in acetic acid). The reaction was stirred for 90 minutes,-diethyl ether- (10 mL) and water (10 mL) added, the organic phase washed with aqueous hydrochloric acid (2N, 10 mL), the combined aqueous phases basified to pH 12 with 4N aqueous

sodium hydroxide solution then extracted into ethyl acetate (2 x 10 mL).

The combined organic layers were dried (MgSO4) and evaporated to give the primary amine intermediate (26 mg) which was used without further purification.

Intermediate K :4-(2,5-Difluoro-phneyl)-4-(4-trifluoromethyl- benzenesulfonyl)-cyclohexanone Prepared as described in WO 02/081435 (Example 41).

Intermediate L= [4- (2, 5-Difluoro-phenyl)-4- (4-trifluoromethyl- benzenesulfonyl)-cyclohexyl]-acetic acid Prepared as described in WO 02/081435 (Example 232).

Intermediate M: Iodo- [4- (2, 5-Difluoro-phenyl)-4- (4-trifluoromethyl- benzenesulfonyl)-cyclohexyl]-methane Prepared from Intermediate L by the method of Intermediate E Intermediate N : 2- [4- (2, 5-Difluoro-phenyl)-4- (4-trifluoromethyl- benzenesulfonyl)-cyclohexyl]-ethanol

Intermediate L (14.1 g, 0.031 mol) in tetrahydrofuran (250 mL) was treated with triethylamine (5.1 mL, 0.036 mol) and ibutylchloroformate (4.64 mL, 0.036 mol) at 0°C. After stirring for 1.5 hours, the precipitate was filtered off and the filtrate re-cooled to 0°C, before being treated with sodium borohydride (1. 9g, 0.05 mol) in water (10 mL) and stirred for 1 hour. The reaction was concentrated, diluted with ethyl acetate and washed with water and brine. The separated organic phase was dried over magnesium sulfate, filtered and evaporated to dryness. The alcohol was purified by silica gel chromatography eluting with ethyl acetate and hexane mixtures to give 11.5g.

Intermediate O : 4- (2, 5-Difluoro-phenyl)-4- (4-trifluoromethyl- benzenesulfonyl)-cyclohexanol Prepared from Intermediate K by the method of Intermediate G. Intermediate P : Methanesulfonic acid 2- [4- (2, 5-difluoro-lphen 4-4- trifluoromethyl-benzenesulfonyl)-cyclohexyl]-ethyl ester

Intermediate N (3.80 g, 8.48 mmol) and triethylamine (1.17 mL) in dichloromethane (150 mL) was treated dropwise with mesyl chloride, maintaining the internal temperature below-40°C. After complete addition the reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was washed with water (50 mL), 10% aqueous citric acid (50 mL) and saturated sodium bicarbonate solution (50 mL) then dried over magnesium sulfate. After evaporation to dryness, the product was triturated with diethyl ether to give 4.2g.

Intermediate Q : [4- (4-chloro-benzenesulfonyl)-4- (2, 5-difluoro-phen cyclohexyl]-methanesulfonyl chloride Intermediate I (1.65 g, 4.0 mmol. ) in acetonitrile (120 mL) was cooled to 0°C under nitrogen. Potassium nitrate (1.01 g, 10 mmol. ) then sulfuryl chloride (0.80 mL, 10 mmol. ) were added, the mixture stirred at 0°C for 2 hours, then diluted with a saturated aqueous solution of sodium hydrogencarbonate (100 mL). The mixture was extracted into ethyl acetate (2 x 100 mL) and the combined organics washed with saturated aqueous sodium hydrogencarbonate (100 mL) and brine (100 mL), dried

(MgS04) and evaporated to leave a residue which was purified by column chromatography on silica, eluting with diethyl ether: iso-hexane (1 : 2), to afford the title compound as a colourless solid (0.81g).

Intermediate R: 4- [ (4-Chlorophenyl) sulfonyl]-4- (2, 5- difluorophenvl) cyclohexylamine

Prepared as described in WO 02/081435 (Example 39).

Intermediate S: 4-(2,5-Difluorophenyl)-4-(4- trifluoromethylbenzenesulfonyl)-cyclohexylamine

Prepared as for Intermediate R, using Intermediate K, except that the borohydride reduction was carried out at-20°C.

MS (ES+) MH+ 420 Intermediate T: 4- (2, 5-Difluorophenyl)-4- (6-trifluoromethyl-pyridine-3- sulfonyl)-cvclohexvlamine

(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 (MgS04) and evaporated in vacuo. Purification by column chromatography on silica gave the (trifluoromethyl) pyridinethiol as a yellow oil (0.79 g, 44%).

(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).

(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 tert-butoxide (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.

(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.

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

Example 1: C- [4- (4-Chloro-benzenesulfonyl)-4- (2, 5-difluoro-phenyl)- cyclohexyl]-N-phenyl-methanesulfonamide

Prepared from Intermediate Q and excess aniline by refluxing in tetrahydrofuran under nitrogen. MS (ES+) 562 ([MNa] +).

Example 2 : [4- (2, 5-Difluoro-phenyl)-4- (4-trifluoromethyl- benzenesulfonyl)-cyclohexyl]-methanesulfonamide

Intermediate M (650 mg, 1.3 mmol) was converted to the corresponding thiol and then to the corresponding sulfonyl chloride by the methods of Intermediate I and Intermediate Q. (Yield 365 mg white solid). This was dissolved in dichloromethane (30 mL) and ammonia gas bubbled into the

solution until saturation. The reaction was stirred for a further 30 min before filtering through Celite. After concentration, the residue was purified by flash chromatography on silica, eluting with iso-hexane/ethyl acetate (1 : 1), to give the sulfonamide as a white solid (150 mg).

MS (ES+) 498 ([MH]+).

Examples 3-33 The sulfonamides in examples 3-33 were prepared from Intermediate Q by treatment with the appropriate amine in dichloromethane. The reaction was diluted with ethyl acetate, washed with 2N HCl and brine, dried (MgSO4) and evaporated to leave a residue which was purified by column chromatography on silica. In cases where a salt of the required amine is used, abase, for example pyridine or potassium carbonate, may be added.- Example-NR2 MS (ES+) 3 amino 486 ([MNa] +) 4 cyclobutylamino 540 ([MNa] +) 5 piperidin-1-yl 532 ([MH] +) 6 2-trifluoromethylpyrrolidin-1-yl 603 ([MNH4] +) 7 3,3-difluoropyrrolidin-1-yl 554 ([MH]+) 8 (R)-3-fluoropyrrolidin-1-yl 536 ([MH]+) 9 (S)-3-fluropyrrolidin-1-yl 536 ([MH]+) 10 5-aza-2-oxabicyclo [2.2. llhept-5-yl 546 ( [MHI+) 11 4,4-difluropiperidin-1-yl 585 ([MNH4] +) 12 N-methoxy-N-methylamino 530 ( [MNa] +) 13 morpholin-4-yl 534 ( [MH] +) Example-NR2 MS (ES+) 14 pyrrolidin-1-yl 518 ( [MH] +) 15 azetidin-1-yl 504 ([MH]+) 16 t-butylamino 537 ( [MNH4] +) 17 2, 2, 2-trifluoroethylamino 568 ([MNa]+) 18 (R)-2- (methoxycarbonyl) pyrrolidin-1-yl 576 ([MH]+) 19 (S)-2- (methoxycarbonyl) pyrrolidin-1-yl 576 ([MH]+) 20 t-butoxycarbonylmethylamino 600 ([MNa]+) 21 hydrazinyl 479 ( [MH] +) 22 dimethylamino 492 ([MH] +) 23 isopropylamino 528 ([MNa]+) 24 3, 3-difluoroazetidin-1-yl 540 ([MH] +) 25(a) (R)-2-carboxypyrrolidin-1-yl 562 ([MH]+) 26 (S)-2-carboxypyrrolidm-l-yl562 ( [MH] +) 27(b) glycinyl 522 ([MH]+) 28(c) acetylamino 528 ([MNa]+) 29 3-acetoxyazetidin-1-yl 562 ([MH] +) 30(a) 3-hydroxyazetidin-1-yl 520 ([MH]+) 31 (d) 3-oxo-azetidin-1-yl 535 ( [MNH4] +) 32(e) 3-hydroxy-3-methyl-azetidin-1-yl 534 ([MH]+) 33(f) 3-methanesulfonyloxy-azetidin-1-yl 598 ([MH]+)

(a)-hydrolysis of Ex. 18, 19 or 29 using L@OH in aqueous THF.

(b) -treatment of Ex. 20 with trifluoroacetic acid in dichloromethane.

(c) -coupling of Ex. 27 with acetic acid using dimethylaminopyridine and 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in dichloromethane.

(d) -oxidation of Ex. 30 using Dess-Martin periodinane in dichloromethane at ambient temperature.

(e) -treatment of Ex. 31 with MeMgBr in THF at ambient temperature.

(0-treatment of Ex. 30 with methanesulfonyl chloride and triethylamine in dichloromethane at 0OC. Example 34: 2- [4- (4-Chloro-benzenesulfon, envl)- cyclohexylmethylsulfanvl]-pyridine

To a stirred solution of Intermediate E (150 mg, 0.29 mmol) in ethanol (10 mL) under nitrogen was added potassium hydroxide (18 mg, 0.32 mmol) and 2-mercaptopyridine (36 mg, 0.32 mmol). The mixture was stirred and heated to reflux for 16 hours. After cooling, the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (MgSO4) and evaporated to leave a residue (154 mg) which was purified by preparative thin layer chromatography eluting with ethyl acetate : iso-hexane 1 : 6 to afford the desired product (118 mg). MS (ES+) 494 ( [MH] +), 318 ( [M-ArS02-] +).

Example 35: 2- [4-(4-Chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)- cyclohexylmethanesulfonyl]-pyridine To a stirred solution of the product from Example 34 (40 mg, 0.081 mmol) in dichloromethane (10 mL) under nitrogen was added 3- chloroperoxybenzoic acid (62 mg, 50-55% w/w in water, 0.18 mmol). The mixture was stirred at ambient temperature for 18h. The reaction was diluted with dichloromethane, washed with sodium sulfite solution and brine, dried (MgSO4) and evaporated to afford the desired product (56 mg).

MS (ES+) 526 ([MH]+), 350 ([M-ArSO2-]+), 548 ( [MNah). Example 36 2- [4- (4-Chloro-benzenesulfonyl)-4- (2, 5-difluoro-phenyl)- cvclohexylmethanesulfinyl]-pyridine

Prepared by oxidation of Example 34 by the method of Example 35 using one equivalent of 3-chloroperoxybenzoic acid.

MS (ES+) 510 ([MH] +) 334 ([M-ArSO2-] +) 532 ([MNa]+).

Example 37 : 2- [4- (4-Chloro-benzenesulfonyl)-4- (2, 5-difluoro-phenyl)- cyclohexylmethanesulfonyl]-pyridine-N-oxide Prepared from Example 35 by treatment with urea hydrogen peroxide (2 equivalents) and trifluoroacetic anhydride (2 equivalents) in dichloromethane at 0°C. MS (ES+) 542 ([MH]+), 366 ([M-ArSO2-]+).

Example 38: 1-(4-Chlorophenylsulfonyl)-1-(2,5-difluoro-phenyl)-4-[(2- propyl) sulfonlmethvl]-cyclohexane Intermediate E (150 mg, 0.29 mmol) was reacted with 2-propanethiol (30 µL, 0.32 mmol) by the method of Example 34. The resulting sulfide, in ethyl acetate (1 mL), was added to a stirring solution of sodium periodate (139 mg, 0.65 mmol) in a 1: 2 solution of ethyl acetate : water (3 mL) and a catalytic amount of ruthenium (IV) oxide. The reaction mixture was

stirred at ambient temperature over 30 min. , diluted with water, extracted with ethyl acetate, washed with brine, dried (MgSO4) and evaporated to give a residue (135 mg) which was purified by preparative thin layer chromatography eluting with ethyl acetate : iso-hexane 1 : 3 to afford the desired product (39 mg). MS (ES+) 513 ([MNa]+), 508 ([MNH4] +).

Examples 39-75, 78-90 In the following examples, Intermediate E or Intermediate M was reacted with the appropriate thiol as in Example 34 and (where necessary) oxidised as in Example 35 (Method A) or as in Example 38 (Method B), or as in Example 36 (Method C). Ex. No. n Method W R MS (ES+)/ (ES-) 39 2 A Cl CH2CF3 548 ([MNH4] +), 553 ([MNa] +) 40 2 A Cl n-propyl 508 ([MNH4] +) 41 2 A Cl isobutyl 522 ([MNH4] +), 527 ([MNa]+) 42 2 Cl 4-pyridyl 350 ([M-ArSO2~] +) 526 ([MH]+), 548 ( [MNa] +) 43 2 A Cl 2-pyrimidinyl 351 ([M-ArSO2-]+) 527 ([MH]+) 44 2 A Cl 4-Me-2-370 ([M-ArSO2~] +) thiazolyl 546 ([MH]+), 568 ([MNa] +) Ex. No. n Method W R MS (ES+)/ (ES-) 45 2 A Cl 5-Me- [1, 3, 4]- 371 ( [M-ArS02] +) thiadiazol-2-yl 547 ([MH] +), 569 ([MNa] +) 46 2 Cl 2-Me-3-furyl 546 ([MNH4] +), 551 ([MNa] +) 47 2 A Cl-CH2COCH3 527 ([MNa] +) 48 2 A Cl 2-furylmethyl 546 ([MNH4] +) 551 ([MNa] +) 49 2 A Cl 1-(2-thienyl)-576 ([MNH4] +) ethyl 581 ([MNa] +) 50 2 A Cl benzyl 556 ( [MNH4] +) 561 ([MNa] +) 51 2 A Cl cyclopentyl 517 ( [MH] +) 534 ([MNH4] +) 539 ([MNa] +) 52 2 A Cl 2-thiazolyl 356 ([M-ArSO2~] +) 554 ([MNa] +) 53 2 A Cl cyclohexyl 531 ([MH] +) 548 ( [MNH4] +) 553 ([MNa] +) 54 2 A Cl 2-thienyl 548 ( [MNH4] +) 553 ([MNa] +) 55 2 A Cl 1-Me-lH-353 ([M-ArSO2-] +) imidazol-2-yl 529 ([MH] +) 56 2 A Cl/-N 354 ([M-ArSO2-] +) N 530 ( [MHI+) I Me 552 ([MNa] +) 57 2 B Cl t-butyl 522 ([MNH4] +) 527 ([MNa] +) 58 2 B Cl 2-OH-ethyl 493 ( [MH] +) Ex. No. n Method W R MS (ES+)/ (ES-) 515 ([MNa] +) 59 2 B Cl 1H-imidazol-339 ( [M-ArS02 +) 2-yl 515 ([MH] +) 60 2 B Cl 1-Me-lH-335 ([M-ArSO2] +) tetrazole-5-yl 531 ( [MH] +), 553 ( [MNa] +) 61 2 B Cl 1H- [1, 2, 4]-340 ([M-ArSO2~] +) triazol-3-yl 516 ([MH] +), 538 ([MNa] +) 62 1 c Cl I-Me-lH-339 (IM-ArSO2-1+) tetrazole-5-yl 515 ([MH] +), 537 ([MNa] +). 63 2 A (a) Cl CH2C (Me) 2OH 538 ([MNH4] +), 543 ( [MNa] +) 64 2 A (b) Cl CH2CHaOMe 507 ([MH] +), 524 ( [MNH4] +), 529 ([MNa] +). 65 2 A (c) C1 cyclopropyl 511 ([MNa] +) 66 2 A (d) Cl NN 354 ([M-ArSO2~] +) N-N 530 ( [MH] +), 552 ([MNa] +) 67 2 A « Cl Me, 354 ( [M-ArS02] +) N-N 530 (WHI+), 552 ( [MNal+). 68 2 A (c) C1 cyclobutyl 327 ([M-ArSO2~] +) 525 ([MNa] +). 69 0. Cl CH2CO2Et 503 ([MH] +) 70 2 B Cl CHzCO2Et nd 71- (e) Cl CH2CO2H nd Ex. No. n Method W R MS (ES+)/ (ES-) 72 0 Cl CH (Me) C02Et nd 73 2 B Cl CH (Me) C02Et nd 74 2 B(e) Cl CH (Me) CO2H nd 75 a B(e) Cl CH2CO2H nd 78 0 - CF3 2-pyridyl 509 ([MH-F] +) 79 0 - CF3 2-pyrimidinyl 529 ([MH]+), 510 ( [MH-F] +) 80 2 A CF3 2-pyridyl 560 ([MH]+) 81'2'ACFs 2-pyrimidinyl561 ( [MH] +) 82 2 A Cl ethyl 477 ([MH]+) 83 2 B Cl 2-CF3O-Ph 626 ([MNH4]+) 84 2 B Cl 2-MeO-Ph 555 ([MH]+) 85 2 B Cl 2-F-Ph 565 ([MNa]+) 86 2 B Cl 4-F-Ph 565 ([MNa]+) 87 2 B Cl 2, 4-di-F-Ph 583 ( [MNa] +) 88 2 B Cl 2-OH-Ph 539 ( [M-H]-) 89 2 B Cl 3-OH-Ph 539 ( [M-H]-) 90 2 B Cl 4-OH-Ph 539 ( [M-H]-)

nd = not determined (a) -2-mercaptoethyl acetate as thiol ; treatment with MeMgBr in THF prior to oxidation.

(b)-2-mercaptoethanol as thiol ; O-methylation (MeI, NaH, DMF) prior to oxidation.

(c)-thiol prepared by reaction of cycloalkylMgBr with sulfur then LiAIH4 in THF.

(d)-via alkylation of Ex. 61 (MeI, K2CO3, DMF) then chromatographic separation of 1 : 1 mixture of positional isomers on silica ; Ex. 66 the more polar isomer.

(e) -via hydrolysis of corresponding ester (LiOH in aqueous MeOH).

Example 76 : 1-(4-Trifluoromethylphenylsulfonyl)-1-(2,5-difluoro- phenyl)-4-methanesulfonylmethyl-cyclohexane To Intermediate M (240 mg, 0.42 mmol) in ethanol (8 mL) was added sodium methanesulfinate (136 mg, 1.33 mmol). The reaction was refluxed for 18 h and after cooling was diluted with water, and extracted with ethyl acetate (x3). The organic extracts were washed with water and brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica eluting with ethyl acetate to give the title compound (80 mg). MS (ES+) 519 ([MNa] +).

Example 77: 2- [4- (4-Chloro-benzenesulfonyl)-4- (2, 5-difluoro-phenyl)- cyclohexylmethanesulfonyl]-acetamide

Prepared from Example 75 by treatment with pentafluorophenol and dicyclohexylcarbodiimide in ethyl acetate atO°C, then treatment with ammonia (2M in methanol) at 50°C in a sealed tube for 16 h.

MS (ES+) 506 ([MH]+). Example 91 : [4-(4-Chloro-benzenesulfonyl)-4- (2, 5-difluoro-phenyl)- cyclohexyl]-methylisothiocyanate

To a stirred solution of Intermediate E (118 mg, 0.23 mmol) in N,N- dimethylformamide (10 mL) was added potassium isothiocyanate (112 mg, 1.05 mmol) and the mixture warmed to 80°C for 18 hours. Upon cooling, ethyl acetate (20 mL) was added and the solution washed with water (3 x 20 mL) and brine (20 mL), dried (MgSO4) and evaporated to leave a residue which was purified by flash column chromatography on silica, eluting with diethyl ether : iso-hexane 1: 3, to afford the desired product (89 mg, 0.18 mmol. ). MS (ES+) 459 ( [MNH).

Example 92: {[4-(4-chloro-benzenesulfonsl)-4-(2, 5-diflwuoro-phenvl)- cyclohexyl]-methyl}-trifluoromethyl sulfone The product from Example 91 (80 mg, 0.18 mmol) in tetrahydrofuran (5 mL) at 0°C was treated with trimethyl (trifluoromethylsilane (0.055 mL, 0.36 mmol) tetrabutylammonium fluoride (0.04 mL of a 1M solution in tetrahydrofuran, 0.04 mmol) and the mixture stirred for 5 minutes at 0°C then 3 hours at room temperature. Diethyl ether (20 mL) was added and the solution washed with water (2 x 20 mL) and brine (20 mL), dried (MgSO4) and evaporated to leave a residue which was purified by flash column chromatography on silica eluting with diethyl ether : iso-hexane 1 : 3, to afford {[4-(4-chloro-benzenesulfonyl)-4-(2, 5-difluoro-phenyl)-cyclohexyl]- methyl} -trifluoromethyl sulfide (49 mg,).

Of this, 47 mg (0.1 mmol) was oxidised to the sulfone by the method described in Example 38. Final purification was by flash column chromatography on silica eluting with diethyl ether : iso-hexane 1 : 2, to afford the desired product (38 mg). MS (ES+) 534 ([MNH4] +).

Example 93 : 2- [4- (4-Chloro-benzenesulfonyl)-4- (2, 5-difluoro-phenyl)- cyclohexylmethanesulfonyl]-furan To a solution of furan (0.043 mL, 0.67 mmol) in tetrahyrofuraii (5 mL) at -40°C under nitrogen was added n-butyl lithium (0.41 mL of a 1.6M solution in hexanes, 0.66 mmol) and the reaction allowed to attain room temperature over 1 hour. Upon receding to 0°C, sulfur (6 mg, 0.19 mmol) was added and the reaction stirred for 30 minutes at 0°C before a solution of Intermediate E (100 mg, 0.20 mmol) in ethanol (5 mL) was added. The mixture was then warmed to 60°C for 75 minutes, cooled, quenched by the addition of a saturated aqueous solution of ammonium chloride (20 mL), then extracted into ethyl acetate (2 x 30 mL). The combined organics were washed with water (2 x 10 mL) and brine (20 mL), dried (MgSO4) and evaporated to leave a residue of the crude furan thioether (102 mg).

This was oxidised to the sulfone by the method described in Example 38.

Final purification was by flash column chromatography on silica, eluting with diethyl ether : iso-hexane 1 : 1, to afford the desired product (26 mg).

MS (ES+) 532 ( [MNH4] +). Example 94: 1-(4-Chlorophenslsulfonsl)-1-(2, 5-difluoro-phenyl)-4- methanesulfonvlmethylene-csclohexane

To a stirred solution of diisopropylamine (0.72 mL, 5.2 mmol) in tetrahydrofuran (40 mL) at-78°C was added dropwise a solution of n- butyl lithium (1.6M in hexanes, 3.2 mL, 5.1 mmol). The mixture was allowed to warm briefly to room temperature then recooled to-78°C and dimethyl sulfone (470 mg, 5.1 mmol) in tetrahydrofuran (10 mL) added dropwise. After stirring for 20 minutes at-78°C, Intermediate A (640 mg, 1.67 mmol) in tetrahydrofuran (lO mL) was added and stirring continued for a further 1 hour. The reaction was quenched by the addition of saturated aqueous ammonium chloride (50 mL), allowed to warm to room temperature then extracted into ethyl acetate (2 x 50 mL). The combined organics were washed with 2N aqueous hydrochloric acid (2 x 50 mL) and brine (50 mL), dried (MgSO4) and evaporated to leave a residue which was purified by flash column chromatography on silica, eluting with. ethyl acetate : iso-hexane 1 : 1, to afford 4-(4-chloro-benzenesulfonyl)-4t (2, 5- difluoro-phenyl)-1-methanesulfonylmethyl-cyclohexanol (630 mg).

MS (ES+) 496 ( [MNH4] +).

The alcohol from the foregoing step (420 mg, 0.88 mmol) in dichloromethane (20 mL) was cooled to 0°C under nitrogen and triethylamine (0.25 mL, 1.7 mmol) and methane sulfonyl chloride (0.1 mL, 1.3 mmol) were added. The reaction was stirred for 1 hour at 0°C then further triethylamine (0.5 mL, 3.4 mmol) and methane sulfonyl chloride (0.21 mL, 2.7 mmol) added. After a further 30 minutes, the solution was washed with 2N aqueous hydrochloric acid (2 x 10 mL) and brine (10 mL), dried (MgS04), evaporated and the residue taken up in tetrahydrofuran (20 mL). 1, 8-diazabicyclo [5.4. 0] undec-7-ene (0.26 mL, 1.7 mmol) was

added and the mixture stirred for 5 minutes. Ethyl acetate (30 mL) was added, the solution washed with IN aqueous sodium hydroxide (20 mL), and the aqueous layer extracted with further ethyl acetate (10 mL). The combined organic layers were washed with 2N aqueous hydrochloric acid (20 mL) and brine (20 mL), dried (MgSO4) and evaporated to leave a residue which was purified by flash column chromatography on silica eluting with ethyl acetate : iso-hexane 1 : 1, to afford the desired product (196 mg).

MS (ES+) 478 ( [MNH4] +).

Example 95= 1- (4-Chlorophenylsulfonyl)-1- (2, 5-difluoro-phenyl)-4- methanesulfonylmethyl-cyclohexane The product of Example 94 (150 mg, 0.32 mmol) in tetrahydrofuran (20 mL) at-40°C was treated dropwise with L-Selectride (1M solution in tetrahydrofuran, 0.5 mL, 0.5 mmol). The reaction was stirred at-40°C for 90 minutes, then quenched by the addition of ethanol (4 drops) then water (10 mL). The mixture was extracted into ethyl acetate (2 x 50 mL) and the combined organics washed with brine (50 mL), dried (MgSO4) and evaporated to leave a residue which was purified by flash column chromatography on silica eluting with diethyl ether : dichloromethane : iso- hexane 1: 2 : 1, to afford the desired product (107 mg).

MS (ES+) 480 ( [MNH4] +). Example 96: 1-(4-Chlorophenylsulfonyl)-1-(2, 5-difluoro-phenyl)-4- phenvlsulfbnylmethyl-cyclohexane

Prepared as in Example 76 using Intermediate E, sodium phenylsulfinate and DMF as solvent. MS (ES+) 542 ([MNH4] +).

Example 97 : 1- (4-Chlorophenylsulfonyl)-l- (2, 5-difluoro-phenyl)-4- [ (cyanomethyl) sulfonylmethyl]-cyclohexane To a stirred solution of Intermediate I (120 mg, 0.29 mmol) in acetonitrile (5 mL) was added potassium carbonate (41 mg, 0.30 mmol) and a solution of chloroacetonitrile (0.04 mL, 0.64 mmol) in acetonitrile (10 mL) and the reaction warmed to 50°C for 2 hours. Upon cooling, the mixture was filtered and the filtrate evaporated. The residue was taken up in ethyl acetate (3 mL) and oxidised to the sulphone by the method described in Example 83. Finalpurification was by flash column chromatography on silica eluting with diethyl ether: iso-hexane 1: 1, to afford the desired product (51 mg).

MS (ES-) 486 ( [M-H]-). Example 98 : 1- (2, 5-Difluoro-phenvl)-1- (4-trifluoromethylphenylsulfonyl)- 4-propylsulfonvlethyl-cyclohexane

A stirred solution of Intermediate P (0.115 g, 0.22 mmol), 1-propanethiol (0.021 mL, 0.22 mmol) and powdered potassium hydroxide (0.015 mg, 0.26 mmol) in ethanol (5 mL) was heated at reflux for 45 minutes, then evaporated. The residue was dissolved in diethyl ether (25 mL), washed with brine (20 mL), dried over magnesium sulfate and evaporated to dryness.

The resulting crude thioether in dichloromethane (10 mL) was oxidised as described in Example 35. MS (ES+) 539 ( [Mlil+).

Examples 99 to 102 were prepared from Intermediate P by the method of Example 98 using the appropriate thiol.

Example R MS (ES+) 99 Isopropyl 539 ( [MH] +) 100 2-pyridyl 574 ( [MH] +) 101 2-pyrimidyl 575 ( [MH] +) 102 2-chlorophenyl 629 ([MNa]+) Example 103: 1- (4-Chlorophenylsulfonyl)-1- (2, 5-difluoro-phenyl)-4- [2- (methylsulfonyl) ethyl]-cyclohexane

Prepared from Intermediate F and sodium methylsulfinate by the method of Example 96. MS (ES+) 499 ([MNa] +).

Example 104 : 2- [4- (4-Chloro-benzenesulfonyl)-4- (2, 5-difluoro-phenyl)- csclohexyl]-ethanesulfonic acid amide Intermediate D (5.09 g, 12.3 mmol) was converted to the mesylate following the procedure of Intermediate P.

The foregoing mesylate (1.18 g, 2.4 mmol) was converted to the thiol following the procedure of Intermediate I.

This product was converted to the sulfonyl chloride by the procedure of Intermediate Q, which was dissolved in dichloromethane (10 ml) and ammonia gas bubbled through for 5 minutes. The resulting cloudy solution was stirred at ambient temperature for 15 minutes then evaporated and taken up in ethyl acetate (20 mL), washed with water (20 ml) and brine (20 mL), dried (MgSO4) and evaporated to leave a residue which was triturated with diethyl ether to afford the desired product (51 mg) MS (ES+) 500 ([MNa] +). Example 105 : 2- [4- (4-Chloro-benzenesulfonvl)-4- (2, 5-difluoro-phenyl) cyclohexyl]-ethanesulfonic acid acetyl-amide

Prepared from Example 104 by coupling with acetic acid in the presence of 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and dimethylaminopyridine in dichloromethane. MS (ES+) 542 ([MNa]+).

Example 106: 2- [4- (4-Chloro-benzenesulfonyl)-4- (2, 5-difluoro-phenyl)- cyclohexyl]-ethanesulfonic acid tert-butylamide Prepared by coupling [4- (4-chloro-benzenesulfonyl)-4- (2, 5-difluoro-phenyl)- cyclohexyl]-ethanesulfonyl chloride (see Example 104) with tert- butylamine in dichloromethane (5mL). MS (ES+) 556 ([MNa]+).

Example 107: 4- [4- (4-Chloro-benzenesulfonvl)-4- (2, 5-difluoro-phenyl)- cyclohexyl]-2-methanesulfonyl-butyric acid ethyl ester Ethyl methanesulfonylacetate (0. 285 mL, 2.15 mmol) was added dropwise to a solution of sodium hydride (60% dispersion in mineral oil, 94 mg, 2.37 mmol) in NN-dimethylformamide (7.0 mL) at 0°C. The reaction was stirred at 0°C for one hour, before the addition of Intermediate F (1.13 g, 2.15 mmol) in N, Ndimethylformamide (2 mL). The reaction was stirred

at 0°C for a further 2 hours, then for a furtherl2 hours, warming gradually. The reaction was partitioned between diethyl ether (150 mL) and 1M aqueous hydrochloric acid (150 mL), the phases separated and the aqueous layer washed with diethyl ether. The combined organic layers were washed with IN aqueous sodium hydrogencarbonate and brine, dried over MgS04 and concentrated. The residue was chromatographed using a Biotage Tm 40S column, eluting with 70/30 iso-hexane/acetone to give the title compound (769 mg). MS (ES-) 561 ([M-H]-).

Example 108 : 3- [4- (4-Chloro-benzenesulfonyl)-4- (2, 5-difluoro-phenvl)- cyclohexyl]-2-methanesulfonyl-propionic acid ethyl ester

Prepared by the procedure of Example 107 using Intermediate E.

MS (ES-) 547 ([M-H]-).

Example 109: 4- [4-(4-Chloro-benzenesulfonvl)-4-(2, 5-difluoro-phenvl)- cyclohexyl]-2-ethyl-2-methanesulfonyl-butyric acid ethyl ester

Prepared from Example 107 by alkylation with ethyl trifluoromethanesulfonate using NaH in dimethylformamide.

MS (ES-) 589 ([M-H]-). Example 110 : 4- [4- (4-Chloro-benzenesulfonvl)-4- (2, 5-difluoro-phenyl)- cyclohexyl]-2-ethyl-2-methanesulfonyl-butyric acid

The product of Example 109 was hydrolyzed by heating to 500C with LiOH in aqueous THF, followed by extractive work-up.

MS (ES-) 561 ([M-H]-).

Example 111: 1-(4-Chlorophenylsulfonyl)-1-(2,5-difluoro-phenyl)-4-[(3- sulfonylmethyl)pentyl]-cyclohexane

Prepared from Example 110 by refluxing with excess sodium chloride in 58% aqueous dimethylsulfoxide for 26 hours. MS (ES+) 519 ([MH]+).

Example 112: (2, 2, 2-Trifluoro-ethvl)-sulfamic acid 4-(2, 5-difluoro- phenyl)-4- (4-trifluoromethyl-benzenesulfonvl)- cyclohexyl ester Prepared from Intermediate O by treatment with trifluoroethyl sulfamoyl chloride and triethylamine in dry dichloromethane under nitrogen.

Example 113 : acetic acid 2- [4- (4-chloro-benzenesulfonyl)-4- (2, 5-difluoro- phenyl)-cyclohexyloxysulfonvlamino]-ethyl ester Prepared by treatment of Intermediate G by treatment with 2- acetoxyethylsulfamoyl chloride and triethylamine in N, N- dimethylacetamide at 60°C. MS (ES+) 574 ([MNa]+).

The sulfamoyl chloride was obtained from reaction of 2-aminoethyl acetate hydrochloride with sulfuryl chloride in acetonitrile.

Example 114 : (2-Hydroxy-ethyl)-sulfamic acid 4- (4-chloro- benzenesulfonyl)-4- (2, 5-difluoro-phenyl)-cyclohexyl ester Prepared from Example 113 by hydrolysis with LiOH in aqueous tetrahydrofuran. MS (ES+) 510 ( [MH] +).

Example 115 : Sulfinamic acid 4-(4-chloro-benzenesulfonyl)-4-(2, 5- difluoro-phenyl)-cyclohexyl ester Prepared from Intermediate G by treatment with thionyl chloride and pyridine in dichloromethane at-78°C and subsequently with ammonia gas, also at-78°C. was bubbled through keeping the temperature at- 78°C. After 20 minutes, the reaction vessel was sealed and left to stir for 19 hours slowly warming to room temperature. MS (ES-) 448 ([M-H]-).

Examples 116-120:

Prepared from Intermediate G or Intermediate O by the procedure of Example 113, carried out at ambient temperature. Example W NR2 MS (ES+)/ (ES-) 116 Cl NH2 488 ([MNa]+). 117 CF3 NH2 522 ([MNa]+) 118 Cl NHEt 516 ([MNa]+) 119 Cl NHCH2CF3 546 ([MH]-). 120 Cl NHtBu 520 ([MH]-)

Example 121 : Dimethvl-sulfamic acid 4- (4-chloro-benzenesulfonyl)-4- (2, 5-difluoro-phenyl)-cyclohexyl ester

Prepared from Example 116 by alkylation with excess MeI in tetrahydrofuran cooled to-78°C using lithium bis (trimethylsilyl) amide (1M solution in tetrahydrofuran) as base. MS (ES+) 516 ( [MNal+).

Example 122: Acetyl-sulfamic acid 4- (4-chloro-benzenesulfonyl)-4- (2, 5 difluoro-phenyl)-cyclohexyl ester

Prepared from Example 116 by treatment with acetic anhydride in pyridine at room temperature. MS (ES+) 530 ([MNa]+).

Example 123: Sulfamic acid 4- (2, 5-difluoro-phenyl)-4- (6-trifluoromethyl- p ridine-3-sulfonyl)-cyclohexyl ester

4-(2, 5-Difluoro-phenyl)-4-(6-trifluoromethyl-pyridine-3-sulfonyl) - cyclohexanone (Intermediate T, steps 1-4) was reduced to the cis- cyclohexanol using L-Selectride (1M in tetrahydrofuran) as described for Inermediate G This alcohol was treated with sulfamoyl chloride as in Examples 116-120 to give the desired product as a white solid. MS (ES+) 501 ([MH]+).

Examples 124-127. 129, 147-150 : The following were prepared from Intermediate H by reaction with ArMgBr in THF at 0°C.

Example Ar MS (ES+) 124 n 393 ([M-ArSO2~] +), ° 591 ([MNa] +). F F 125 3-allyloxyphenyl 567 ([MNa] +). 1262- (Me02C-CH20)-Ph'401 ( [M-ArSOz-), 599 ([MNa] +) 127 (b) 2-(HO2C-CH20)-Ph 563 ([MH] +) 387 ( [M-ArS02] +). 129 (a), (b) 2-(HO2C-(CH2) 30)-Ph nd 147 3- (1, 3-dioxolan-2-yl) phenyl 583 ([MNa] +) 1483-CHO-Ph539 ( [MNa] +) 149 « 3-COH-Ph 555 ( [MNa] +) 150 (C) 2-CHO-Ph 517 ([MH] +) 151 (d) 2-CO2H-Ph 555 ([MNa] +) a)-starting from the Z-allyloxy derivative. Cleavage to the phenol occurred in situ, and this was alkylated with the relevant chloroester.

(b) -hydrolysis of corresponding ester as final step.

(c) -cleavage of the corresponding 1, 3-dioxolan as final step (pyridinium p- toluenesulfonate in aqueous acetone).

(d) -oxidation of corresponding aldehyde as final step (using Dess-Martin periodinane).

Example 128 : 2- [4- (4-Chloro-benzenesulfonyl)-4- (2, 5-difluoro-phenyl)- cyclohexyl]-1-{3-[2-(1,1-dioxo-thiomorpholin-4-yl)-ethoxy]-p henyl}- ethanone The product from Example 125 was treated with ozone in 1: 5 methanol : dichloromethane under nitrogen at-78°C to form the corresponding aldehyde. This aldehyde and 1, 1-dioxothiomorpholine in methanol/dichloromethane was treated with triethylamine, methanolic HCl and sodium cyanoborohydride to afford the desired product.

MS (ES+) 666 ([MH] +), 490 ([M-ArSO2] +) Example 130 l- [4- (4-Chloro-benzenesulfonyl)-4- (2, 5-difluoro'phenvl)- cyclohexyl]-3-methanesulfonyl-propan-2-one Dimethyl sulfone was reacted with 1 equivalent of lithium diisopropylamide in tetrahydrofuran at-78°C, and the resulting carbanion was reacted in situ with Intermediate B at-78°C for 30 minutes then at ambient temperature for 1 hour to yield the desired product.

MS (ES+) 505 ([MH] +). Example 131: 1-[4-(4-Chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)- cyclohexvl]-3-methanesulfonyl-3-methyl-butan-2-one

Prepared from Example 131 by alkylation with excess MeI in 1, 2- dimethoxyethane at room temperature using sodium hydride as base. ( MS (ES+) 555 ([MNa]+).

Example 132: 1- [4- (4-Chloro-benzenesulfonyl)-4- (2, 5-difluoro-phenyl)- cyclohexyl]-3-methanesulfonyl-butan-2-one The product from Example 130 was methylated as described in Example 131, using one equivalent each of MeI and NaH. MS (ES+) 541 ([MNa]+).

Example 133 2- [4-(4-Chloro-benzenesulfonvl)-4-(2 5-difluoro-phenvl)- cvelohexvl]-1- (1, 1-dioxo-tetrahydrothiophen-2-yl)-ethanone Prepared by the procedure of Example 130 using tetramethyl sulfone.

MS (ES+) 553 ([MNa]+).

Examples 134-146 The following were prepared by reaction of Intermediate H with ArLi in diethyl ether or THF at-78°C : Example Ar MS (ES+) 134 (a) 2-pyridyl-N-oxide 330 ([M-ArSO2~] +), 506 ([MH] +), 528 ( [MNa] +) 135 5-HOCH2-furan-2-yl 531 ([MNa] +) 136) 5-HCO-furan-2-yl507 ( [MH] +) 137 (c) 5-HOOC-furan-2-yl523 ( [MH] +) 138 (d) 0 CO2 Et 577 ( [MHI+). \C 139 3-HOCH2-furan-2-yl 509 ([MH] +). 140 (b) 3-HCO-furan-2-yl 529 ([MNa] +) 1413-HOOC-furan-2-yl523 ( [MH] +) 142577 ( [MH] +) O\>C02Et 143 (e) l 579 ([MH] +) OC02Et \=/ 144 « 551 ( [MH] +) O C02H 145 (e), (f) 0 C02H 551 ( [MHI+) \/ 146578 (tMH] +). o9Nò

(a) -oxidation as final step (urea hydrogen peroxide, trifluoroacetic anhydride in dichloromethane).

(b) -via oxidation of the corresponding hydroxymethyl compound (Dess- Martin periodinane in dichloromethane).

(c) -via oxidation of the corresponding aldehyde (sulfamic acid and sodium chlorite in dichloromethane/water).

(d) -via condensation of the corresponding aldehyde with (EtO) 2POCH2CO2Et.

(e) -via hydrogenation of the corresponding olefin (over Rh/C catalyst).

(f)-via hydrolysis of the corresponding ester (LiOH in aqueous THF).

(g)-via reaction of the corresponding aldehyde with morpholine and sodium cyanoborohydride in MeOH/HCl.

Example 152-155, 157, 161, 162 The following were prepared from Intermediate J by reaction with the appropriate acid chloride or anhydride and triethylamine in dichloromethane under nitrogen at ambient or reduced temperature (method A) or by coupling with the appropriate carboxylic acid in the presence of 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, hydroxybenzotriazole and triethylamine in DMF at ambient temperature (method B), or by refluxing in dioxan with sulfamide (method C). Example Method MS (ES+) 152 acetyl 442 ([MH] +) 153-SO2Me 154-CO2Me 458 ([MH] +) 282 ( [M-ArS02-] +) 155-SO2CF3 157-SO2NH2 161 -COCH2CF3 B 510 ([MH]+) 162-COCH (OH) CF3 526 ([MH] +) Example 156, 158-160

The following were prepared from Intermediate J by reaction with catechol sulphate in dry tetrahydrofuran under nitrogen at 0°C, and treatment of the resulting 2-hydroxyphenyl sulfamate with the appropriate amine R2NH at 80OC in dioxan. Example NR2 MS (ES+) 156 pyrrolidine 533 (([MH]+). 158 NHEt 507 ([MH]+), 529 ([MNa]+). 159 (L)-proline Me ester 591 ( [MH]+) 160(a) (L)-proline 577 ([MH]+) ta) by hydrolysis of Example 159 Examples 163-165

The following were prepared from Intermediate C by reaction with triethylamine and diphenylphosphoryl azide in toluene at 110°C for 3 hours, followed by treatment with the appropriate amine R2NH for a further 18 hours at ambient temperature.

MS (ES+) Example NR2 MS (ES+) 163 NHMe 457 ([MH] +) 164 NH2 443 ( [MH] +) 165 NMe2 471 ( [MH] +) Example 167: [4- (4-Chloro-benzenesulfonyl)-4- (2, 5-difluoro-phenyl)- cyclohexyl]-sulfamic amide Intermediate R (100 mg, 0.26 mmol in dioxane (4 ml) was treated with sulfamide (125 mg, 1.30 mmol) and heated to reflux for 1 hour, then cooled to room temperature, diluted with ethyl acetate, washed with H20, dried (MgSO4) and evaporated. Trituration of the residue in ether afforded the desired product (50 mg, 42% yield). m/z = 465, 467 [MH] + Examples 168-184: The following were prepared from Intermediate R by treatment with the appropriate sulfamoyl chloride and triethylamine in a mixture of dichloromethane and dimethylacetamide (3: 1) (Method A) ; or by treatment with the appropriate sulfamoyl chloride and Honig's base in acetonitrile at 80°C (Method B) The relevant sulfamoyl chlorides were prepared by published methods (DE 3429048 FR 2739858; J.Org.Chem., 41,4029-9, 1976 J. Heterocyclic Chem., 2000,773) or adaptations thereof. Example Method NR2 MS M/Z (ES-) 168 A NMe2 491, 493 169 A NHEt 491, 493 170 A NHCH2CF3 545, 547 171 A NHtBu 519, 521 172 A pyrrolidin-1-yl 517, 519 173 A azetidin-1-yl 503, 505 174 A 3, 3-difluoroazetidin-1-yl 539, 541 175 A 4-trifluoromethylpiperidin-1-yl 599, 601 176 B morpholin-1-yl 533, 535 177 B 0 619, 621 A/ , No-o I _Nor N'OH 179 (b) 3-oxo-pyrrolidin-1-yl 533, 535 180 (c) 3-OH-3-Me-pyrrolidin-1-yl 571, 573 181 B, (a) 3-hydroxy-azetidin-1-yl 521, 523 182 (b) 3-oxo-azetidin-1-yl- 183 (c) 3-OH-3-Me-azetidin-1-yl 535 184 (d) 3-Me2N-azetidin-1-yl 548

(a) -treatment of corresponding pivalate with DIBAL-H in toluene at ambient temp.

(b) -oxidation of corresponding alcohol with Dess-Martin periodinane I dichloromethane at ambient temperature.

(c) -reaction of corresponding ketone with MeMgBr in THF at 0°C.

(d) -reaction of Ex. 182 with Me2NH and sodium cyanoborohydride in MeOH at ambient temperature.

Example 185: Pyrrolidine-1-sulfonic acid [4- (2, 5-difluoro-phenyl)-4- (4- trifluoromethyl-benzenesulfonyl)-cyclohexyl]-amide Sulfuryl chloride (236 il, 2.9 mmol) in toluene (2 ml) was cooled to-3QOC and pyrrolidine (242 p. l, 29 mmol) added dropwise over 10 min. The reaction was stirred for 1.5 h at-300C, diluted with toluene, washed with water, aqueous HC1 (2 M) and brine, dried (MgSO4), filtered and evaporated to give an oil. This was dissolved in dichloromethane (1 ml) and added to a solution of Intermediate S (120 mg, 0.29 mmol) in dichloromethane (2 ml) at 00C and the reaction allowed to warm to room temperature and stirred for 18 h. The mixture was 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 (62 mg).

MS [MH+] 553 Example 186: Pyrrolidine-1-sulfonic acid [4- (2, 5-difluoro-phenyl)-4- (6- trifluoromethyl-pyridyl-3-sulfonyl)-cyclohexyl]-amide

Prepared by the procedure described for Example 185, using Intermediate T. m/z = 554 (MH+)