WO2004089911A1 - Pyrazole derivatives as gamma-secretase inhibitors useful in the treatment of alzheimer’s disease - Google Patents

Abstract

The compounds of formula (I): inhibit gamma-secretase and hence are of utility in the treatment or prevention of Alzheimer's disease.

Description

PYRAZOLE DERIVATIVES AS GAMMA-SECRETASE INHIBITORS USEFUL IN THE TREATMENT OF ALZHEIMER'S DISEASE

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 sulphonamide, sulphamate and sulphamide derivatives, comprising a rø-disubstituted benzene or pyridine ring and a substituted pyrazole moiety, which inhibit the processing of APP by γ-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 in the cortical and associative brain regions of sufferers. These plaques mainly comprise fibrillar aggregates of β- amyloid peptide (Aβ). The role of secretases, including the putative γ-secretase, in the processing of amyloid precursor protein (APP) to form Aβ 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 γ-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 01/70677 and WO 02/36555 disclose, respectively, sulphonamido- and sulphamido-substituted bridged bicycloalkyl derivatives which are believed to be useful in the treatment of Alzheimer's disease, but do not disclose or suggest compounds in accordance with the present invention.

The present invention provides a novel class of sulphonamide, sulphamate and sulphamide derivatives comprising a m-disubstituted benzene or pyridine ring. The compounds inhibit the processing of APP by the putative γ-secretase, and thus are useful in the treatment or prevention of AD. According to the invention there is provided a compound of formula I:

wherein :

A represents CH or N;

X represents a bond, O or NR²;

Y represents a bond, (CHR⁸)_n, CR⁸=CR⁸, O-CHR⁸, CHR⁸-O or CHR⁸-NR⁸, where n is 1 or 2 and each R⁸ is independently H or Cι_ alkyl;

Z represents Ar or N(R⁹)₂, with the proviso that when Z represents N(R⁹) , Y represents a bond or (CHR⁸)_n;

R¹ represents a hydrocarbon group of 1-10 carbon atoms which is optionally substituted with up to 3 halogen atoms, or heteroaryl of 5 or 6 ring atoms optionally bearing up to 3 substituents independently selected from halogen, CF₃, CHF₂, CH F, N0₂, CN, OCF₃, Cι-₆alkyl and Cι_₆alkoxy; or when X represents NR², R¹ and R² together may complete a heterocyclic ring of up to 6 members which optionally bears up to 3. substituents independently selected from halogen, CF₃, CHF₂, CH₂F, N0₂, CN, OCF₃, Cι-₆alkyl and Cι_₆alkoxy;

R² represents H or

or together with R¹ completes a heterocyclic ring as defined above;

R³ represents H or

R⁴ represents Ci-ealkyl,

R⁵ represents H or Cι-₆alkyl;

R⁶ is bonded to one of the nitrogen atoms of the pyrazole ring and represents a hydrocarbon group of 1-5 carbon atoms which is optionally substituted with up to 3 halogen atoms;

R⁷ represents H or Cι_₆alkyl;

R⁹ represents H or a hydrocarbon group of 1-10 carbon atoms which is optionally substituted with up to 3 halogen atoms, provided that at least one R⁹ is not H; or the two R⁹ groups complete a heterocyclic ring of 5 or 6 members which is optionally substituted with CF₃ or up to 3 halogen atoms; and

Ar represents phenyl or 6-membered heteroaryl, either of which bears 0-3 substituents independently selected from halogen, CF₃, CHF₂, CH₂F, NO , CN, OCF₃, Cι-₆alkyl and Cτ_₆alkoxy; or a pharmaceutically acceptable salt thereof.

Where a variable occurs more than once in formula I or in a substituent thereof, the individual occurrences of that variable are independent of each other, unless otherwise specified. As used herein, the expression "hydrocarbon group" refers to groups consisting solely of carbon and hydrogen atoms. Such groups may comprise linear, branched or cyclic structures, singly or in any combination consistent with the indicated maximum number of carbon atoms, and may be saturated or unsaturated, including aromatic when the indicated maximum number of carbon atoms so permits. As used herein, the expression "Cι-_Xalkyl" where x is an integer greater than 1 refers to straight-chained and branched alkyl groups wherein the number of constituent carbon atoms is in the range 1 to x. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl. Derived expressions such as "C₂-₆alkenyl", "hydroxyCi- ₆alkyl", "heteroarylCι-₆alkyF'₅ "C₂-₆alkynyr and "Cι.₆alkoxy" are to be construed in an analogous manner. Most suitably, the number of carbon atoms in such groups is not more than 6.

The expression "C₃-₆cycloalkyl" as used herein refers to nonaromatic monocyclic hydrocarbon ring systems comprising from 3 to 6 ring atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclohexenyl. The expression "cycloalkylalkyl" as used herein includes groups such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

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

For use in medicine, the compounds of formula I may be in the form of pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of formula I or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, benzenesulphonic 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 maybe 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 arnine 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, A represents CH or N, and thus completes a benzene or pyridine ring. Preferably, A represents CH. In the compounds of formula I, X represents a bond, O or NR², but preferably represents a bond or NR².

Y represents a bond or a linking group selected from (CHR⁸)_n, CR⁸=CR⁸, O- CHR⁸, CHR⁸-0 or CHR⁸-NR⁸, where n is 1 or 2 and each R⁸ is independently H or Cι_ ₄alkyl. Suitable identities for R⁸ include H, methyl and ethyl, but preferably Y comprises at most one R⁸ group that is other than H. Suitable identities for Y include a bond, CH₂, CH₂CH₂, CH=CH, OCH₂, CH₂0, CH(Me)O, CH₂NH and CH₂N(Et). When Z is Ar, preferred identities for Y include CH₂, OCH₂, CH₂CH₂ and CH₂O, especially CH₂O. When Z is N(R⁹)₂, Y is preferably CH₂.

Suitable hydrocarbon groups represented by R¹ include alkyl, cycloalkyl, cycloalkylalkyl, alkenyl, phenyl and benzyl groups optionally bearing up to 3 halogen substituents, the preferred halogen substituent being fluorine or chlorine, especially fluorine. Said alkyl, cycloalkyl, cycloalkylalkyl and alkenyl groups typically comprise up to 6 carbon atoms. Examples of hydrocarbon and fluorinated hydrocarbon groups represented by R¹ include 4-fluorophenyl, benzyl, n-propyl, 2,2-dimethylpropyl, n- butyl, isopropyl, t-butyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, allyl, cyclobutyl and cyclopropylmethyl. Heteroaryl groups represented by R¹ are either 5-membered or 6-membered and are optionally substituted as defined previously. Preferred 5-membered heteroaryl groups include those containing a sulphur atom, such as thienyl, thiazolyl and isothiazolyl. Preferred 6-membered heteroaryl groups include pyridyl, in particular 3- pyridyl. Preferred substituents include halogen (especially chlorine or fluorine), CF₃ and alkyl (such as methyl). If two or more substituents are present, preferably not more than one of them is other than halogen or alkyl. Preferred heteroaryl groups are unsubstituted or monosubstituted with halogen.

When R¹ represents an optionally substituted phenyl, benzyl or heteroaryl group, X is preferably a bond.

9 1 _' 7 When X represents NR , R may combine with R to complete a heterocyclic ring of up to 6 members which is optionally substituted as defined previously. Said ring preferably comprises at most one heteroatom selected from O, N and S in addition to the nitrogen to which R¹ and R² are mutually attached. Suitable rings include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl. Preferred substituents include- CF₃, halogen (especially chlorine or fluorine) and alkyl such as methyl. If two or more substituents are present, preferably not more than one of them is other than halogen or alkyl.

R² may alternatively represent H or Ci^alkyl, such as methyl. Preferably, R² represents H. R³ represents H or Ci^alkyl, such as methyl, but preferably represents H.

R⁴ represents Cι-₆alkyl, preferably Ci^alkyl, and R⁵ represents H or Cι_₆alkyl, preferably H or Ci^alkyl. Suitable alkyl groups include methyl and ethyl. Preferably, R⁴ is methyl and R⁵ is H, or both of R and R⁵ are methyl. Most preferably, both of R⁴ and R⁵ represent methyl. R⁶ maybe attached to either of the nitrogen atoms in the pyrazole ring. In one embodiment, R⁶ is attached to the nitrogen atom that is adjacent to the carbon atom to which Y is attached, h an alternative (preferred) embodiment, R⁶ is attached to the nitrogen atom which is remote from the carbon atom to which Y is attached. R⁶ represents a hydrocarbon group of 1-5 carbon atoms which is optionally substituted with up to 3 halogen atoms, and thus may comprise cyclic or acyclic hydrocarbon residues or combinations thereof, saturated or unsaturated, up to a maximum of 5 carbon atoms in total. The hydrocarbon group represented by R⁶ is preferably unsubstituted or is substituted with up to 3 fluorine atoms Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, cyclopropyl, cyclopropylmethyl and allyl. Preferred examples include methyl, ethyl and isopropyl, especially methyl and ethyl. Most preferably, R⁶ represents ethyl.

R⁷ represents H or Cι.₆alkyl, preferably H or Cι_₄alkyl such as methyl or ethyl. Most preferably, R⁷ represents H.

R⁹ represents H or a hydrocarbon group as defined previously, or the two R⁹ groups complete a heterocyclic ring as defined previously. The two R⁹ groups cannot both be H. Preferred hydrocarbon groups are Cι-₆alkyl, optionally bearing up to 3 halogen substituents, fluorine being preferred. Suitable examples include 3,3,3- trifluoropropyl. Preferably, the two R⁹ groups complete a 5- or 6- (preferably 6-) membered ring, optionally substituted with up to 3 halogens or with CF₃. Said ring preferably comprises not more than one heteroatom, selected from N, O and S, in addition to the N atom to which the R⁹ groups are attached. Preferred rings include piperidine, morpholine and tetrahydropyridine. Suitable identities for the N(R⁹)₂ moiety include 3,3,3-trifluoropropylamino, 4,4-difluoropiperidin-l-yl, morpholin-4-yl, 4-(trifluoromethyl)piperidine- 1 -yl, and 4-trifluoromethyl- 1,2,3 ,6-tetrahydropyridin- 1 - yl, of which 4-trifluoromethyl-l,2,3,6-tetrahydropyridin-l-yl is particularly preferred. Ar represents phenyl or 6-membered heteroaryl, either of which bears 0-3 substituents independently selected from halogen, CF₃, CHF₂, CH₂F, NO₂, CN, OCF₃, Cι_₆alkyl and Cι.₆alkoxy. Examples of suitable 6-membered heteroaryl groups represented by Ar include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl, of which pyridyl is a preferred example. Preferably, the phenyl or heteroaryl ring bears 0 to 2 substituents. Preferred substituents include halogen (especially chlorine and fluorine), CN, Cι-₆alkyl (especially methyl), Cι.₆alkoxy (especially methoxy), OCF₃ and CF₃. If two or more substituents are present, preferably not more than one of them is other than halogen or alkyl. Examples of groups represented by Ar include phenyl, monohalophenyl, dihalophenyl, trihalophenyl, cyanophenyl, methylphenyl, methoxyphenyl, trifluoromethylphenyl, trifluoromethoxyphenyl, pyridyl, monohalopyridyl and trifluoromethylpyridyl, wherein "halo" refers to fluoro or chloro. Suitable specific values for Ar include phenyl, 2-fluorophenyl, 2-chlorophenyl, 3- fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 3,4,5- trifiuorophenyl, 2-cyanophenyl, 3 -cyanophenyl, 4-cyanophenyl, 4-methylphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 2-(trifluoromethyl)phenyl, 4- (trifluoromethyl)phenyl, 4-(trifluoromethoxy)phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrazin-2-yl, 5-methylpyridin-2-yl, 5-fluoropyridin-2-yl, 5-chloropyridin- 2-yl, 5-(trifluoromethyl)pyridin-2-yl and 6-(trifluoromethyl)pyridin-3-yl. Preferred examples include phenyl, 4-fluorophenyl, 2-fluorophenyl, 3 -fluorophenyl, 4- cyanophenyl, 3 -cyanophenyl, 2-cyanophenyl, 2-chlorophenyl and 3-methoxyphenyl. In a particularly preferred embodiment, Ar represents 4-fluorophenyl.

In one subset of the compounds of formula I, X is a bond and R¹ represents Cι-₆alkyl which is optionally substituted with up to 3 fluorine atoms, or phenyl, benzyl or 5- or 6-membered heteroaryl, any of which is optionally substituted with chlorine or fluorine. Within this embodiment, suitable identities for R¹ include n-propyl, n-butyl, 2,2,2-trifluoroethyl, benzyl, 4-fluorophenyl, 2-thienyl, 5-chloro-2-thienyl, 5- isothiazolyl and 6-chloro-pyridin-3-yl. Within this embodiment, preferred identities for R^l include n-propyl, 2,2,2-trifluoroethyl, 4-fluorophenyl, benzyl, 2-thienyl and 5- chloro-2-thienyl, in particular 2,2,2-trifluoroethyl and 5-chloro-2-thienyl.

In a second subset of the compounds of formula I, X is O and R¹ represents alkyl, alkenyl, cycloalkyl or cycloalkylalkyl of up to 6 carbon atoms which is optionally substituted with up to 3 fluorine atoms.

In a third subset of the compounds of formula I, X is NH or NMe and R¹ represents alkyl, alkenyl, cycloalkyl or cycloalkylalkyl of up to 6 carbon atoms which is optionally substituted with up to 3 fluorine atoms. Within this embodiment, suitable identities for R¹ include ethyl, n-propyl, isopropyl, n-butyl, 2,2- dimethylpropyl, t-butyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, cyclobutyl, cyclopentyl and cyclopropylmethyl. In a fourth subset of the compounds of formula I, X represents NR² and R¹ and R² complete a heterocyclic ring as described previously.

In a fifth subset of the compounds of Formula I, Z represents Ar. Specific compounds in accordance with the invention are disclosed in the Examples appended hereto.

The compounds of the present invention have an activity as inhibitors of γ- secretase.

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

When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. Tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, liquid- or gel-filled capsules, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil or coconut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyethylene glycol), 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 β- amyloid. Preferably the condition is a neurological disease having associated β- 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.

Also disclosed is a method of treatment of a subject suffering from or prone to Alzheimer's disease which comprises administering to that subject an effective amount of a compound according to the present invention or a pharmaceutically acceptable salt thereof. For treating or preventing Alzheimer's disease, a suitable dosage level is about

0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, more preferably about 0.1 to 50 mg/kg of body weight per day, and for the most preferred compounds, about 0.1 to 10 mg/kg of body weight per day. The compounds maybe administered on a regimen of 1 to 4 times per day. In some cases, however, a dosage outside these limits may be used.

The compounds of formula I may be prepared by reaction of an amine (1) with R^X-SOzCl:

(1)

where A, X, Y, R¹, R³, R⁴, R⁵, R⁶, R⁷ and Z have the same meanings as before. The reaction typically takes place at ambient temperature in an aprotic solvent such as dichloromethane in the presence of a base such as triethylamine.

Amines (1) in which R³ is H and R⁵ is H may be prepared by reaction of nitrites (2) with R⁴Mg-Hal and LiAlE :

(2)

where Hal represents halogen (especially bromine or iodine) and A, Y, R⁴, R⁶, R⁷ and Z have the same meanings as before. The reaction may be carried out in THF at ambient temperature.

Amines (1) in which R³ is H and R⁴ and R⁵ represent identical alkyl groups may be prepared by treatment of nitrites (2) with excess R⁴Li in the presence of CeCl . The reaction takes place between -78°C and ambient temperature in THF.

Amines (1) in which R is alkyl may be prepared by N-alkylation of the corresponding primary amines using standard techniques.

Nitrites (2) maybe prepared by reaction of keto-enols (3) with R⁶NHNH₂ :

(3)

where A, Y, R⁶, R⁷ and Z have the same meanings as before. The reaction may be carried out in refluxing ethanol and typically provides a mixture of both the positional isomers, which is separable by chromatography.

Keto-enols (3) in which R⁷ is H may be obtained by reaction of ketones (4) with Z-Y-CO R:

(4) where R is H or

such as methyl, and A, Y and Z have the same meanings as before. The reaction takes place in the presence of lithium diisopropylamide in THF between -78°C and ambient temperature. When a carboxylic acid Z-Y-CO₂H is used as the reagent, it is preferably pre-reacted with l,l'-carbonyldiimidazole.

Keto-enols (3) in which R⁷ is alkyl may be obtained by alkylation of the corresponding keto-enols in which R⁷ is H, e.g. by refluxing with the appropriate alkyl iodide in acetone in the presence of alkali metal carbonate.

An alternative route to nitrites (2) in which R⁷ is H involves reaction of triflates (5) with 3-cyanobenzeneboronic acid or 6-cyanopyridine-2-boronic acid as appropriate:

where Tf represents trifluoromethanesulphonyl (triflyl) and R⁶, Y and Z have the same meanings as before. Very aptly, Y is a bond and Z is Ar. The reaction may be carried out in refluxing toluene in the presence of a base such as sodium carbonate and a palladium catalyst such as (Ph₃P) Pd(0). Triflates (5) are available by treatment of pyrazolones (6) with triflic anhydride in pyridine, e.g. at -10°C to ambient temperature. Pyrazolones (6) in which Y is a bond and Z is Ar are obtainable by reaction of R⁶NHNH₂ with Ar-C≡C-CO₂Me, where R⁶ and Ar have the same meanings as before. The reaction may be carried out in refluxing methanol, and typically provides a mixture of the two positional isomers which may be separated by conventional means.

An alternative route to nitrites (2) in which Y represents CHR⁸-O involves reaction of Ar-OH with alcohols (7) :

(7) (8) where A, R⁶, R⁷, R⁸ and Ar have the same meanings as before. The reaction may be carried out in THF at ambient temperature in the presence of triphenylphosphine and a dialkylazodicarboxylate. Alcohols (7) are available by treatment of the corresponding aldehydes (8) with sodium borohydride (when R⁸ is H) or with the appropriate Grignard reagent (when R⁸ is alkyl). The aldehydes (8) are obtainable by acid hydrolysis of acetals (9):

R⁶

(9) where A, R⁶, R⁷, R⁸ and Ar have the same meanings as before. The acetals (9) are obtained by condensation of methylglyoxal dimethylacetal with 3-cyanobenzoyl chloride or 6-cyanopyrid-2-oyl chloride as appropriate, followed by optional alkylation of the resulting keto-enol and treatment thereof with R⁶NHNH₂ in the manner described above for the conversion of (3) to (2). The condensation of methylglyoxal dimethylacetal with 3-cyanobenzoyl chloride or 6-cyanopyrid-2-oyl chloride maybe carried out in THF at -78°C in the presence of lithium diisopropylamide.

An alternative route to nitrites (2) in which Y represents CH₂-NR⁸ involves reaction of aldehydes (8) with ArNHR and sodium cyanoborohydride, where R and Ar have the same meanings as before. Alternatively, the alcohol group in (7) may be converted to a leaving group such as chloride, mesylate or tosylate, then reacted with ArNHR⁸. Similarly, displacement of said leaving group by reaction with (R⁹)₂NH provides nitrites (2) in which Y is CH₂ and Z is N(R⁹)₂.

It will be apparent to those skilled in the art that the reaction steps summarised above need not always be carried out in the sequence described above. For example, the nitrite group in compounds (9) may be subjected to reductive alkylation as described for the conversion of (2) to (1), and the resulting amine reacted with R^X- SO₂Cl, prior to the elaboration of the acetal group into the Y-Z moiety.

It will also be appreciated that a given compound in accordance with formula I may be converted into another compound also in accordance with formula I by means of standard synthetic techniques such as alkylation, oxidation, reduction, esterification, amide coupling, hydrolysis, electrophilic substitution and nucleophilic substitution. Alternatively, such conversions may be carried out on synthetic precursors of the compounds of formula I. It will also be appreciated that where more than one isomer can be obtained from a reaction then the resulting mixture of isomers can be separated by conventional means.

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

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

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, 3^rd Ed., John Wiley & Sons, 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 WOO 1/70677. A preferred assay to detennine such activity is as follows:

1) SH-SY5Y cells stably overexpressing the βAPP 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/lOOμL in Dulbeccos 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 1 lx final compound concentration. Mix compounds vigorously and store at 4°C until use.

4) Add lOμL compound/well, gently mix and leave for 18h at 37°C, 5% CO₂. 5) Prepare reagents necessary to detennine amyloid peptide levels, for example by Homogeneous Time Resolved Fluorescence (HTRF) assay.

6) Plate 160μL aliquots of HTRF reagent mixture to each well of a black 96-well HTRF plate. 7) Transfer 40μL 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 lOμL/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 compounds of the present invention generally show high potency as measured by the above assays. Thus the following Examples all had an ED₅₀ of less than lμM, typically less than 250nM, and frequently less than lOnM in at least one of the above assays.

The following examples illustrate the present invention.

EXAMPLES Example 1

2,2,2-Trifluoro-N-ri-(^'3-{3-r4-fluorophenoxymethyll-l-methyl-lH-pyrazol-5- yl>phenyl -l-methylethyllethanesulfonamide

Step 1: 3-(5-Dimemoxymethyl-l-methyl-lH-pyrazol-3-yl -benzonitrile and 3-(3- Dimethoxymethyl-l-methyl-lH-pyrazol-5-yl)-benzonitrile

A solution of BuLi (66 mmol) in hexanes (1.6 M, 41.2 mL) was added dropwise over 10 min to a stirred solution of ^jPr₂ΝH (9.2 mL, 66 mmol) in THF (50 mL) at 0°C under N₂. After 40 min, the reaction was cooled to — 78°C and a solution of methylglyoxal dimethyl acetal (7.81 mL, 66 mmol) in THF (40 mL) was added dropwise over lOmin and the mixture was stirred for a further hour. A solution of 3- cyanobenzoyl chloride (4.96 g, 30 mmol) in THF (30 mL) was added over 1 min and the reaction stirred at -78°C for 30 min before warming to RT and stirring for a further hour. The reaction was quenched by the addition of 1M citric acid solution (100 mL) and then extracted with Et O (2 x 150 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO₄) and concentrated under reduced pressure to yield the crude 1,3-dicarbonyl compound. MeOH (50mL) and methylhydrazine (3.2 mL, 60 mmol) were added to this crude residue and the mixture heated at reflux for 90 min. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica eluting with 50% EtOAc/wo-hexanes to yield first 3-(5-dimethoxymethyl-l-methyl-lH- pyrazol-3-yl)-benzonitrile(3.3 g, 42 %) and then the eluent was changed to 100 % EtOAc to yield 3-(3-dimethoxymethyl-l-methyl-lH-pyrazol-5-yl)-benzonitrile (2.5 g, 32 %). 3-(5-Dimethoxymethyl-l-methyl-lH-ρyrazol-3-yl)-benzonitrile: 1H NMR (CDC1₃, 500 MHz) δ 8.07 (IH, s), 7.99 (IH, d, J= 7.9 Hz), 7.54 (IH, d, J= 7.9Hz), 7.47 (IH, t, J= 7.9 Hz), 6.66 (IH, s), 5.50 (IH, s), 3.93 (3H, s), 3.36 (6H, s). 3-(3-Dimethoxymethyl-l-methyl-lH-pyrazol-5-yl)-benzonitrile: 1H NMR (CDC1₃, 500 MHz) δ 7.75-7.65 (3H, m), 7.60 (IH, t, J= 7.7 Hz), 6.42 (IH, s), 5.49 (IH, s), 3.89 (3H, s), 3.44 (6H, s).

Step 2 : 1-T3-C3 -Dimethoxymethyl- 1 -methyl- lH-p yrazol-5- vD-phenvH - 1 - methylethylamine

Anhydrous CeCl₃ (8.28 g, 33.6 mmol) was pulverised and dried at 140°C, 1 mm Hg for 1 hour. After cooling to RT and introducing a N atmosphere, THF (200 mL) was added and the suspension was stirred for 15 min. The white slurry was cooled to — 78°C and a solution of MeLi (33.6 mmol) in Et₂O (1.6 M, 21.0 mL) added dropwise over 5 min. After a further hour, a solution of 3-(3-dimethoxymethyl-l-methyl-lH- pyrazol-5-yl)-benzonitrile (1.0 g, 3.89 mmol) in TΗF (10 mL) was added and the reaction stirred overnight gradually warming to RT. The reaction was quenched by the cautious addition of NΗ_tCl solution (100 mL) and then the organics were extracted with EtOAc (3 x 100 mL). The combined organics were washed with brine (100 mL), dried (MgSO₄) and concentrated under reduced pressure. The mixture was then purified by column chromatography on deactivated alumina eluting with 2 % MeOH/CH₂Cl₂ to yield the amine (267 mg, 24 %). 1H NMR (CDCI₃, 500 MHz) δ 7.57-7.50 (2H, m), 7.41 (IH, t, J= 7.8 Hz), 7.26 (IH, d, J= 7.8 Hz), 6.38 (IH, s), 5.50 (IH, s), 3.88 (3H, s), 3.44 (6H, s), 1.52 (6H, s).

Step 3: 2,2,2-Trifluoroethanesulfonic acid {l-r3-(3-dimethoxymethyl-l -methyl- 1H- Pyrazol-5-ylVphenvH-l-methylethyl|-amide

2,2,2-Trifluoroethylsulfonyl chloride (253 mg, 1.4 mmol) was added dropwise to a stirred solution of the amine from Step 2 (267 mg, 0.92 mmol) and Et₃N (193 DL, 1.4 mmol) in CH₂C1₂ (25 mL) at RT under N₂. The mixture was stirred at RT for 30 min and then diluted with CH C1₂ (25 mL), washed with NaHCO₃ solution (20 mL) and concentrated under reduced pressure to yield the crude sulfonamide (213 mg, 53 %). 1H NMR (CDC1₃, 360 MHz) δ 7.60-7.53 (2H, m), 7.49 (IH, t, J= 7.6 Hz), 7.37 (IH, d, J= 7.6 Hz), 6.38 (IH, s), 5.50 (IH, s), 5.02 (IH, s), 3.88 (3H, s), 3.47 (2H, q, J= 8.8 Hz), 3.44 (6H, s), 1.81 (6H, s). MS (ES⁺) Cι₈H₂₄F₃N₃O₄S requires: 435, found: 404 (M-OCH₃ ⁺, 100%).

Step 4: 2,2,2-Trifluoroethanesulfonic acid -r3-(3-formyl-l-methyl-lH-pyrazol-5- vD-phenyπ - 1 -methylethyl} -amide

The sulfonamide from Step 3 (209 mg, 0.48 mmol), TFA (0.5 mL), Η₂0 (2.0 mL) and THF (5.0 mL) were stined together at RT for 2 hours and then concentrated under reduced pressure to remove the organic solvents. The residue was neutralised with NaHC0₃ solution (20 mL), extracted with EtOAc (2 x 30mL), dried (MgS0₄) and concentrated under reduced pressure to yield the crude aldehyde (170 mg, 91%). 1H NMR (CDC1₃, 400 MHz) δ 9.88 (IH, s), 7.55-7.47 (2H, s), 7.44 (IH, t, J- 7.5 Hz), 7.29 (IH, d, J= 7.5 Hz), 6.77 (IH, s), 5.44 (IH, s), 3.90 (3H, s), 3.46 (2H, q, J= 8.9 Hz), 1.74 (6H, s). MS (ES⁺) Cι₆Hι₈F₃N₃O₃S requires: 389, found: 390 (M+H⁺, 100%).

Step 5: 2,2.2-Trifluoroethanesulfonic acid {l-r3-(3-hvdroxymethyl-l-methyl-lH- p yrazol-5 -vD-phenyll - 1 -methylethyl -amide

NaBH (8.2 mg, 0.22 mmol) was added to a stirred solution of the aldehyde from Step 4 (85 mg, 0.22 mmol) in EtOH (5 mL) at RT and the mixture was stined for a further 30 min. NEUCl solution (5 ml) was added and the EtOH removed under reduced pressure. The aqueous residue was extracted with EtOAc (2 x 30 mL), and the organics dried and concentrated under reduced pressure to yield the crude alcohol (75 mg, 88 %). 1H NMR (CDC1₃, 360 MHz) δ 7.55-7.48 (2H, s), 7.42 (IH, t, J= 7.5 Hz), 7.29 (IH, d, J= 7.5 Hz), 6.25 (IH, s), 5.00 (IH, s), 4.64 (2H, s), 3.78 (3H, s), 3.41 (2H, q, J= 8.9 Hz), 1.75 (6H, s). MS (ES⁴) Cι₆H₂₀F₃N₃O₃S requires: 391, found: 392 (M+H⁺, 100%).

Step 6: 2.2.2-Trifluoro-N-ri-(3-{3-r4-fluorophenoxymethyll-l-methyl-lH-ρyrazol-5- yl>phenyl -l-methylethyllethanesulfonamide

Diisopropyl azodicarboxylate (57 mg, 0.27 mmol) was added dropwise to a stined solution of the alcohol from Step 5 (75 mg, 0.19 mmol), PPh₃ (75 mg, 0.27 mmol) and

4-fluorophenol (26 mg, 0.23 mmol) in TΗF (10 mL) under Ν and the resulting mixture was stined at RT for 2 hours. Further DIAD (19 mg, 0.09 mmol), PPh₃ (25 mg, 0.09 mmol) and 4-fluorophenol (11 mg, 0.09 mmol) were added and stirring was continued for a further 30 min. The reaction mixture was then concentrated under reduced pressure white loading on to MgSO₄ and then purified by column chromatography on silica eluting with 100% Et₂0 to yield the desired ether (19 mg, 20 %). 1H NMR (CDC1₃, 360 MHz) δ 7.58-7.53 (2H, s), 7.49 (IH, t, J- 7.5 Hz), 7.37 (IH, d, J= 7.5 Hz), 6.97 (4H, app. d, J= 6.1 Hz), 6.41 (IH, s), 5.05 (2H, s), 4.99 (IH, s), 3.88 (3H, s), 3.48 (2H, q, J= 8.9 Hz), 1.81 (6H, s). MS (ES⁴) C₂₂H₂₃F₄N₃O₃S requires: 485, found: 486 (M+ST, 100%).

Example 2 N-Cvclobutyl-N-ri-(3-n-ethyl-3-r(4-fluorophenoxy methyll-lH-pyrazol-5- yll phenyl)- 1 -methylethyll sulfamide

Step 1: 3-(3-Dimethoxymethyl-l-ethyl-lH-pyrazol-5-yl)-benzonitrile

Prepared as described in Example 1 Step 1, substituting ethylhydrazine oxalate for methylhydrazine. The product was purified by column chromatography on silica eluting with 50-100 % EtOAc/tso-hexanes to separate it from the 1-ethyl-lH-pyrazol- 3-yl isomer.

1H NMR (CDC1₃, 500 MHz) δ 7.78-7.55 (4H, m), 6.38 (IH, s), 5.49 (IH, s), 4.15 (2H, q, J= 7.3 Hz), 3.44 (6H, s), 1.40 (3H, t, J= 7.3 Hz).

Step 2: 3-(l-Ethyl-3-formyl-lH-pyrazol-5-yl)-benzonitrile

A mixture of 3-(3-dimethoxymethyl-l-ethyl-lH-pyrazol-5-yl)-benzonitrile (5.0 g, 18.4 mmol), TFA (5.0 mL), Η₂0 (20 mL) and THF (50 mL) was stined at RT for 1 hour and then concentrated under reduced pressure to remove the organic solvents. The residue was neutralised with IN NaOH solution (100 mL), extracted with EtOAc (2 x 150mL), dried (MgSO₄) and concentrated under reduced pressure white dry loading onto MgSO₄. The mixture was then purified by column chromatography on silica eluting with 35-60% EtOAc/wø-hexanes to yield the desired aldehyde (2.91 g, 70 %). 1H NMR (CDCI3, 500 MHz) δ 10.00 (IH, s), 7.80-7.72 (IH, m), 7.70 (IH, s), 7.67- 7.60 (2H, m), 6.84 (IH, s), 4.23 (2H, q, J= 7.3 Hz), 1.49 (3H, t, J= 7.3 Hz). MS (ES⁺) C₁₃HnN₃O requires: 225, found: 226 (M+H⁺, 100%).

Step 3: 3-(l-Ethyl-3-hvdroxymethyl-lH-pyrazol-5-yl)-benzonitrile

NaBHi (252 mg, 6.6 mmol) was added portionwise to a stined solution of 3-(l-ethyl- 3-formyl-lH-pyrazol-5-yl)-benzonitrile (1.5 g, 6.6 mmol) in EtOΗ (25 mL) at 0°C. The mixture was warmed to RT and stined for a further 30 min., NΗ₄CI solution (10 ml) was added, the EtOH removed under reduced pressure, H₂O (30 mL) added, and the aqueous mixture extracted with EtOAc (2 x 70 mL). The combined organic extracts were washed with brine (25 mL), dried (MgS0₄) and concentrated under reduced pressure to yield the crude alcohol (1.49 g, quant.). 1H NMR (CDCI₃, 360 MHz) δ 7.78-7.54 (4H, m), 6.31 (IH, s), 4.72 (2H, s), 4.11 (2H, q, J= 7.3 Hz), 1.42 (3H, t, J= 7.3 Hz). MS (ES⁺) Cι₃H₁₃N₃O requires: 227, found: 228 (M+H⁺, 70%).

Step 4: 3-ri-Ethyl-3-(4-fluorophenoxymethyl -lH-pyrazol-5-yll-benzonitrile

Prepared by the procedure of Example 1 Step 6, using 1.0 g, (4.4 mmol) of the alcohol obtained in Step 3 above. The product was purified twice by column chromatography on silica, eluting once with 30-45% EtOAc/tso-hexane and again using 25 %

Et₂0/toluene to yield the desired ether (702 mg, 50 %). 1H NMR (CDC1₃, 360 MHz) δ 7.76-7.57 (4H, m), 7.03-6.90 (4H, m), 6.40 (IH, s), 5.06 (2H, s), 4.13 (2H, q, J= 7.2 Hz), 1.43 (3H, t, J= 7.2Hz). MS (ES⁺) Cι₉H₁₆FN₃O requires: 321, found: 322 (M+H⁺, 65%).

Step 5 : 1 - {3-f 1 -Ethyl-3-(4-fluorophenoxymethyl)- lH-pyrazol-5-vH-phenyl| - 1 - methylethyl amine

Prepared by the procedure of Example 1 Step 2 using the product of Step 4 (702 mg, 2.19 mmol), CeCl₃ (5.37 g, 21.9 mmol) and MeLi (1.6 M in Et₂0, 13.7 mL, 21.9 mmol) to yield, after purification by column chromatography on deactivated alumina using 1-4 % MeOH/CH₂Cl₂, the amine (296 mg, 38 %). 1H NMR (CDC1₃, 500 MHz) δ 7.63-7.56 (3H, m), 7.48 (IH, t, J= 7.5 Hz), 6.98 (4H, app. d, J= 6.3 Hz), 6.37 (IH, s), 5.06 (2H, s), 4.14 (2H, q, J= 7.3 Hz), 1.52 (6H, s), 1.43 (3H, q, J= 7.3 Hz). MS (ES⁺) C₂ιH₂₄FN₃O requires: 353, found: 337 (M-OCH₃+H⁺, 100%).

Step 6: N-Cvclobutyl-N-r 1 -⁽3- { 1 -ethyl-3-r(4-fluorophenoxy methyl1- lH-pyrazol-5- yUphenylVl-methylethyllsulfamide

Prepared by the procedure of Example 1 Step 3 using the amine from Step 5 (100 mg, 0.28 mmol), Et₃N (114 mg, 1.1 mmol) and cyclobutylsulfamoyl chloride (192 mg, 1.1 mmol) to yield, after purification by column chromatography on silica using 70% Et₂O/t5O-hexanes and then by normal phase preparative HPLC, the sulfamide (17.5 mg, 12 %). ^lH NMR (CDC1₃, 360 MHz) δ 7.60-7.52 (2H, m), 7.44 (IH, t, J= 7.6 Hz), 7.30 (IH, d, J=7.6 Hz), 6.97 (4H, app. d, J= 6.3Hz), 6.37 (IH, s), 5.06 (2H, s), 4.55 (IH, s), 4.12 (2H, q, J= 7.3 Hz), 3.78 (IH, app. sextet, J= 8.3 Hz), 2.45-2.35 (2H₅ m), 1.93-1.82 (2H, m), 1.75 (6H, s), 1.72-1.60 (2H, m), 1.44 (3H, J- 7.3 Hz). MS (ES⁺) C₂₅H₃iFN₄0₃S requires: 486, found: 487 (M+H , 100%).

Example 3 2.2.2-Trifluoro-N-ri-(^'3-{3-r(4-fluorophenylamino methyll-l-methyl-lH-pyrazol-5- yll phenyl)- 1 -methylethyll ethanesulfonamide

ΝaBE (39 mg, 1,0 mmol) was added portionwise to a stined mixture of the aldehyde from Example 1 Step 4 (100 mg, 0.26 mmol), 4-fluoroaniline (29 mg, 0.26 mmol), ΝaOAc (63 mg, 0.78 mmol), Νa₂SO₄ (40 mg, 0.28 mmol), AcOΗ (0.22 mL) and EtOΗ (1.0 mL) at 0°C. The cooling bath was removed and the reaction allowed to warm to RT and stined overnight. The solvent was then removed under reduced pressure and the mixture was taken up in CH₂C1₂ (50 mL) and washed with NaHCO₃ solution (20 mL). The organic layer was concentrated under reduced pressure whilst dry loading on to MgSO₄ and then purified by column chromatography on silica eluting with 80% EtOAc/wo-hexane to yield the desired amine (89 mg, 72 %). ^lH NMR (CDC1₃, 360 MHz) δ 7.60-7.53 (2H, m), 7.47 (IH, t, J= 1.6 Hz), 7.35 (IH, d, J = 7.6 Hz), 6.90 (2H, app. t, J= 8.7 Hz), 6.67-6.60 (2H, m), 6.26 (IH, s), 5.14 (IH, s), 4.30 (2H, s), 4.13-4.03 (IH, broad s), 3.86 (3H, s), 3.52-3.40 (2H, m), 1.80 (6H, s). MS (ES^"") C₂₂H₂₄F₄N₄O₂S requires: 484, found: 485 (M+H⁺, 100%).

Example 4

2.2.2-Trifluoro-N-ri-(^,3-(3-r(^,ethvU4-fluorophenvnamino methyll-l-methyl-lH- pyrazol-5-vUphenyl)-l-methylethyllethanesulfonamide

ΝaB(CΝ)Η₃ (16 mg, 0.25 mmol) was added to a stined solution of 2,2,2-trifluoro-N- [l-(3-{3-[(4-fluorophenylamino)methyl]-l-methyl-lH-pyrazol-5-yl}phenyl)-l- methylethyl]ethanesulfonamide (Example 3) (61 mg, 0.13 mmol) and acetaldehyde (11 mg, 0.25 mmol) in MeCΝ (5 mL), and AcOΗ (1 drop) and the mixture was stirred at RT for 16 hours. The mixture was concentrated under reduced pressure and then partitioned between ΝaΗCO₃ solution (20 mL) and EtOAc (70 mL). The organics were washed with brine (20 mL) and concentrated under reduced pressure whilst dry loading onto MgSO . This residue was then purified by column chromatography on silica eluting with 100% Et₂O and then by normal phase preparative HPLC to yield the desired product (7.6 mg, 12 %). 1H NMR (CDC1₃, 500 MHz) δ 7.55-7.48 (2H, m), 7.45 (IH, t, J= 1.6 Hz), 7.32 (IH, d, J= 7.6 Hz), 6.91 (2H,^'t, J= 9 Hz), 6.78-6.71 (2H, m), 6.13 (IH, s), 4.91 (IH, s), 4.44 (2H, s), 3.85 (3H, s), 3.50-3.39 (4H, m), 1.80 (6H, s), 1.18 (3H, t, J= 7.1 Hz). MS (ES⁺) C₂₄H₂₈F₄N₄O₂S requires: 512, found: 513 (M+H⁺, 100%).

Example 5 2,2,2-Trifluoroethanesulfonic acid ri-f3-{3-ri-f4-fluorophenoxy -ethyl1-l-ethyl-lH- pyrazol-5-vU-phenyl)-l-methylethyl1-amide

Step 1: 2,2,2-Trifluoroethanesulfonic acid {l-r3-(l-ethyl-3-fonnyl-lH-pyrazol-5-ylV phenyll - 1 -methylethv -amide

- prepared by the procedure of Example 1 Steps 1-4, substituting ethylhydrazine for methylhydrazine in Step 1.

Step 2: 2,2,2-Trifluoroethanesulfonic acid (l-{3-ri-ethyl-3-(l-hvdroxyethyl) -1H- pyrazol-5-yll-phenyl}-l-methylethyl)-amide

A solution of MeMgl (1.47 mmol) in Et₂0 (3.0 M, 0.49 mL) was added dropwise over 2 min to a stined mixture of the aldehyde from Step 1 and TΗF (10 mL) at 0°C under N₂. The reaction mixture was stirred for 15 min and then quenched by the addition of NΗ₄CI solution (15 mL). The organics were extracted into EtOAc (40 mL), concentrated under reduced pressure, and purified by column chromatography on silica, eluting with 80% EtOAc/wo-hexane to yield the alcohol (121 mg, 58 %). 1H NMR (CDCI₃, 400 MHz) δ 7.60-7.45 (3H, m), 7.35 (IH, d, J= 7.6 Hz), 6.23 (IH, s), 5.08 (IH, s), 4.98 (IH, q,J= 6.5 Hz), 4.15-4.07 (2H, m), 3.53-3.42 (2H, m), 1.82 (6H, s), 1.57 (3H, d, J= 6.5 Hz), 1.39 (3H, t, J= 7.2 Hz). MS (ES⁺) C,₈H₂₄F₃N₃O₃S requires: 419, found: 420 (M+H*, 100%). Step 3: 2,2,2-Trifluoroethanesulfonic acid l-(3-{3-ri-(4-fluorophenoxy)-ethyll-l- ethyl-lH-pyrazol-5-yl|-phenyl)-l-methylethyll-amide

- prepared following the procedure of Example 1 step 6 using the alcohol from Step 2 (121 mg, 0.29 mmol), 4-fluorophenol (49 mg, 0.44 mmol), PPh₃ (113 mg, 0.44 mmol), and DIAD (85 mg, 0.44 mmol). The crude mixture was purified by column chromatography on silica eluting with 70% Et₂O/w -hexane and then by normal phase preparative HPLC to yield the ether (2.0 mg, 1 %). 1H NMR (CDC1₃, 500 MHz) δ 7.60-7.45 (3H, m), 7.36-7.30 (IH, m), 7.00-6.90 (4H, m), 6.28 (IH, s), 5.40 (IH, q, J = 6.6 Hz), 4.90 (IH, s), 3.53-3.42 (4H, m), 1.82 (6H, s), 1.69 (3H, d, J- 6.5 Hz), 1.40 (3H, t, J= 7.2 Hz). MS (ES⁺) C₂₄H₂₇F₄N₃O₃S requires: 513, found: 514 (M+H^", 100%).

Example 6

N-ri-(3-{l-Ethyl-3-r2-(4-fluorophenyl)ethyll-lH-pyrazol-5-yl|ρhenyl -l- methvtethyll-N-(2,2,2-trifluoroethyl sulfamide

Step 1: 3-r5-(4-Fluorophenyl)-3-oxo-pentanoyll-benzonitrile

A solution of BuLi (119 mmol) in hexanes (1.6 M, 74.3 mL) was added dropwise over 15 min to a stined solution of ^!Pr₂ΝΗ (16.6 mL, 119 mmol) in THF (150 mL) at 0°C under N₂. After 20 min, the reaction was cooled to -78°C and a solution of 3- cyanoacetophenone (17.2 mL, 119 mmol) in THF (50 mL) was added dropwise over 5 min and then the mixture was stined for a further hour.

Meanwhile, CDI (9.64 g, 59.4 mmol) was added to a stined solution of 3-(4- fluorophenyl)propionic acid (10.0 g, 59.4 mmol) in THF (100 mL) at RT under N₂.

This was then stined at RT for 45 min and added by cannula into the above solution at

— 78°C under N₂. The resulting solution was stirred at -78°C for 45 min, before warming to RT and stining for a further hour. The mixture was diluted with EtOAc (200 mL) and washed with 1M citric acid solution (2 x 100 mL), NaHCO₃ solution (2 x 100 mL) and brine (50mL), dried (MgSO₄) and concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with 25% EtOAc/iso-hexane to yield the dicarbonyl compound (4.75 g, 27 %). 1H NMR (CDC1₃, 360 MHz) δ 8.12 (IH, s), 8.05 (IH, d, J= 8.0 Hz), 7.78 (IH, d, J= 8.0 Hz), 7.57 (IH, t, J= 8.0 Hz), 7.20-7.10 (2H, m), 7.04-6.92 (2H, m), 6.10 (IH, s), 3.00 (2H, t, J= 8.6 Hz), 2.76 (2H, t, J= 8.6 Hz).

Step 2: 3-π-Ethyl-3-r2-(4-fluorophenyl)-ethyll-lH-pyrazol-5-yl>-benzoniτrile

A mixture of 3-[5-(4-fluorophenyl)-3-oxo-pentanoyl]-benzonitrile (1.0 g, 3.39 mmol), ethyl hydrazine oxalate (763 mg, 5.08 mmol) and Et₃N (709 DL, 5.08 mmol) in EtOΗ (50mL) was heated at reflux for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and Η₂O (50 mL). The organics were separated, washed with brine (50 mL), concentrated under reduced pressure, and the residue purified by column chromatography on silica eluting with 40% EtOAc/t.rø-hexanes to yield first 3-{l-ethyl-5-[2-(4-fluorophenyl)-ethyl]-lH- pyrazol-3-yl}-benzonitrile(280 mg, 26 %) (by-product) and then 3-{l-ethyl-3-[2-(4- fluorophenyl)-ethyl]-lH-pyrazol-5-yl}-benzonitrile (380 mg, 35 %).

3-{l-Ethyl-5-[2-(4-fluorophenyl)-ethyl]-lH-pyrazol-3-yl}-benzonitrile (byproduct): 1H NMR (CDC1₃, 500 MHz) δ 8.06 (IH, s), 7.98 (IH, d, J= 7.9 Hz), 7.58-7.42 (2H, m), 7.16-7.08 (2H, m), 7.04-6.93 (2H, m), 6.34 (IH, s), 4.03 (2H, q, J= 7.3 Hz), 2.98 (2H, t, J= 7.4 Hz), 2.91 (2H, t, J= 7.4 Hz), 1.41 (3H, t, J= 7.3 Hz). MS (ES⁺) C₂₀Hι₈FN₃ requires: 319, found: 320 (M+H⁺, 100%).

3- {l-Ethyl-3-[2-(4-fluorophenyl)-ethyl]-lH-pyrazol-5-yl}-benzonitrile: 1H NMR (CDCI3, 500 MHz) δ 7.75-7.66 (2H, m), 7.63-7.55 (2H, m), 7.18 (2H, dd, J= 8.5, 5.6 Hz), 6.96 (2H, t, J= 8.5 Hz), 6.06 (IH, s), 4.09 (2H, q, J= 7.3 Hz), 2.98-2.88 (4H, m), 1.39 (3H, t, J= 7.3 Hz). MS (ES⁺) C₂₀H,_gFN₃ requires: 319, found: 320 (M+ϊf, 100%).

Step 3 : 1 -(3- { 1 -Ethyl-3-r2-(4-fluorophenyl)-ethyll- lH-pyrazol-5-vn -phenvPι-1 - methylethyl amine

Prepared following the procedure of Example 1 Step 2, using the above 3-{l-ethyl-3- [2-(4-fluorophenyl)-ethyl]-lH-pyrazol-5-yl}-benzonitrile (380 mg, 1.19 mmol), CeCL, (1.76 g, 7.15 mmol) and MeLi (1.6 M in Et₂O, 4.45 mL, 7.15 ihmol) to yield, after purification by column chromatography on deactivated alumina using 1-5 %

MeOΗ/CΗ₂Cl_2, the amine (133 mg, 32 %). Η NMR (CDC1₃, 360 MHz) δ 7.58-7.50 (2H, m), 7.40 (IH, t, J= 1.1 Hz), 7.25 (3H, m), 6.97 (2H, t, J= 8.7 Hz), 6.04 (IH, s), 4.10 (2H, q, J= 7.2 Hz), 3.00-2.87 (4H, m), 1.52 (6H, s), 1.37 (3H, t, J- 7.2 Hz).

Step 4: N-ri-r3-{l-Ethyl-3-r2-r4-fluorophenyl)ethyll-lH-pyrazol-5-vnphenyl -l- methyl ethyl! -N-(2,2,2-trifluoroethyl)sulfamide

Prepared by the procedure of Example 1 Step 3. The amine from Step 3 (67 mg, 0.19 mmol), Et₃ (80 DL, 0.57 mmol) and 2,2,2-trifluoroethylsulfamoyl chloride (75 mg, 0.38 mmol) were reacted to yield after purification by column chromatography on silica using 80% Et₂O/wo-hexanes the title sulfamide (25 mg, 26 %). ^lH NMR

(CDCI₃, 500 MHz) δ 7.57-7.49 (2H, m), 7.45 (IH, t, J= 7.8 Hz), 7.30 (IH, d, J= 7.8 Hz), 7.19 (2H, dd, J= 8.7, 5.6 Hz,), 6.97 (2H, tJ= 8.7 Hz), 6.03 (IH, s), 4.69 (IH, s), 4.39 (IH, t, J= 5.4 Hz), 4.10 (2H, q, J= 7.2 Hz), 3.57 (2H, quintet, J= 5.4 Hz), 3.03- 2.90 (4H, m), 1.78 (6H, s), 1.39 (3H, t, J= 7.2 Hz). MS (ES⁺) C₂₄H₂₈F₄N₄O₂S requires: 512, found: 513 (M+Ef^1", 100%).

Example 7

N-ri-(3-n-Ethyl-5-r2-(4-fluorophenyl)ethyll-lH-pyrazol-3-yl>phenyl)-l- methylethyll-N-(2,2,2-trifluoroethyl)sulfamide

Prepared from the by-product of Example 6 Step 2, following the procedures of Example 6 Steps 3 and 4. Purified by column chromatography on silica using 70% EtzO/wø-hexanes. 1H NMR (CDC1₃, 500 MHz) δ 7.97 (IH, s), 7.67-7.63 (IH, m), 7.44-7.38 (2H, m), 7.14 (2H, dd, J= 8.4, 5.5 Hz), 6.99 (2H, t, J= 8.5 Hz), 6.33 (IH, s), 4.70 (IH, s), 4.28 (IH, t, J= 7.1 Hz), 4.02 (2H, q, J= 7.2 Hz), 3.52 (2H, quintet, J = 7.1 Hz), 2.99 (2H, t, J= 7.7 Hz), 2.92 (2H, t, /= 7.7 Hz), 1.80 (6H, s), 1.39 (3H, t, J = 7.2Hz). MS (ES⁺) C₂₄H₂₈F₄N₄0₂S requires: 512, found: 513 (M+H⁺, 100%).

Example 8

N-ri-(3-{3-r2-(4-Fluorophenyl)ethyll-l,4-dimethyl-lH-pyrazol-5-yl|phenyl -l- methylethyll-N-(2,2,2-trifluoroethyl sulfamide

Step 1 : 3-r5-f4-Fluorophenyl)-2-methyl-3-oxo-pentanoyll-benzonitrile

A mixture of 3-[5-(4-fluorophenyl)-3-oxo-pentanoyl]-benzonitrile (Example 6 Step 1) (1.0 g, 3.39 mmol), K₂CO₃ (469 mg, 3.39 mmol), Mel (264 μL, 4.23 mmol) and acetone (25 mL) was heated at 60°C for 36 hours and then concentrated under reduced pressure. The residue was partitioned between Η₂O (20 mL) and Et₂0 (80 mL) and acidified to pH = 3 using 2 M HC1 solution. The organics were separated and concentrated under reduced pressure. The residue was purified by column chromatography on silica using 30 % EtOAc/wo-hexanes to yield the alkylated product (0.63 g, 60 %). 1H ΝMR (CDC1₃, 360 MHz) δ 8.14 (IH, s), 8.04 (IH, d, J= 8.0 Hz), 7.83 (IH, d, J= 1.1 Hz), 7.57 (IH, J= 7.8 Hz), 7.08-7.00 (2H, m), 6.87 (2H, t, J- 8.6 Hz), 4.38 (IH, q, J= 7.0 Hz), 2.85-2.70 (4H, m), 1.43 (3H, d, J= 7.0 Hz). MS (ES^") C_]9H₁₆FNO₂ requires: 309, found: 308 (M+H⁺, 100%).

Ste^p 2: 3-{3-r2-(4-Fluoro^phenvDethyll- 4-dimethyl-lH-^ρyrazol-5-yl}-benzonitrile

EtOΗ (20mL) and methyl hydrazine (162 μL, 3.05 mmol) were added to the product of Step 1 (630 mg, 2.04 mmol) and the mixture heated at reflux for 90 min. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica eluting with 40% EtOAc/zso-hexanes to yield first 3-{5-[2- (4-fluorophenyl)-ethyl]-l,4-dimethyl-lH-pyrazol-3-yl}-benzonitrile(213 mg, 33 %) (byproduct) and then the desired 3-{3-[2-(4-fluorophenyl)-ethyl]-l,4-dimethyl-lH- pyrazol-5-yl}-benzonitrile (250 mg, 38 %).

3-{5-[2-(4-Fluorophenyl)-ethyl]-l,4-dimethyl-lH-pyrazol-3-yl}-benzonitrile: 1H NMR (CDC1₃, 500 MHz) δ 7.94 (IH, s), 7.88 (IH, d, J= 7.8 Hz), 7.57 (IH, d, J= 7.8 Hz), 7.49 (IH, t, J= 7.8 Hz), 7.02 (2H, dd, J= 8.5, 5.7 Hz), 6.97 (2H, t, J= 8.5 Hz), 3.64 (3H, s), 2.89 (2H, t, J= 6.7 Hz), 2.83 (2H, t, J= 6.7 Hz), 2.01 (3H, s). 3 - {3 - [2-(4-Fluorophenyl)-ethyl] - 1 ,4-dimethyl- 1 H-pyrazol-5 -yl } -benzonitrile : ' Η NMR (CDCI₃, 500 MHz) δ 7.71 (IH, d, J= 7.7 Hz), 7.63-7.55 (2H, m), 7.53 (IH, d, J= 7.7 Hz), 7.18 (2H, dd, J- 8.5, 5.5 Hz), 6.98 (2H, t, J= 8.5 Hz), 3.73 (3H, s), 2.97-2.92 (2H, m), 2.88-2.82 (2H, m), 1.84 (3H, s).

Step 3: l-(3-(3-r2-f4-Fluorophenyl)ethyll-1.4-dimethyl-lH-pyrazol-5-vU-phenyl)-l- methytethyl amine

Prepared by the procedure of Example 1 Step 2 using 3-{3-[2-(4-fluorophenyl)-ethyl]- l,4-dimethyl-lH-pyrazol-5-yl}-benzonitrile (250 mg, 0.81 mmol), CeCl₃ (1.2 g, 4.9 mmol) and MeLi (1.6 M in Et₂0, 3.05 mL, 4.9 mmol) to yield, after purification by column chromatography on deactivated alumina using 2-5 % MeOH/CH₂Cl_2; the title amine (72 mg, 26 %). 1H NMR (CDC1₃, 500 MHz) δ 7.56 (IH, d, J= 8.0 Hz), 7.45- 7.36 (2H, m), 7.20-7.13 (3H, m), 6.97 (2H, t, J= 8.6 Hz), 3.74 (3H, s), 3.03-2.95 (2H, m), 2.90-2.85 (2H, m), 1.87 (3H, s), 1.53 (6H, s). MS (ES⁺) C₂₂H₂₆FN₃ requires: 351, found: 352 (M+H⁺, 30%).

Step 4: N-n-(3-{3-r2-r4-Fluorophenvnethvn-1.4-diinethyl-lH-pyrazol-5-vUphenyl - l-methylethvn-N- ^^-trifluoroethvDsulfamide

Prepared by the procedure of Example 1 Step 3 using the amine from Step 3 (72 mg, 0.20 mmol), Et₃Ν (114 μL, 0.82 mmol) and 2,2,2-trifluoroethylsulfamoyl chloride (121 mg, 0.61 mmol) to yield, after purification by column chromatography on silica using 80-100% Et₂O/z5o-hexanes the title sulfamide (23 mg, 22 %). 1H NMR (CDC1₃, 500 MHz) δ 7.54 (IH, d, J- 7.8 Hz), 7.48 (IH, t, J= 7.8 Hz), 7.42 (IH, s), 7.23 (IH, d, J= 7.5 Hz), 7.19 (2H, dd, J- 8.5, 5.6 Hz), 6.97 (2H, t, J= 8.5 Hz), 4.71 (IH, s), 4.43 (IH, t, J= 7.4 Hz), 3.74 (3H, s), 3.57 (2H, quintet, J= 7.4 Hz), 2.98-2.92 (2H, m), 2.87-2.82 (2H, m), 1.87 (3H, s), 1.79 (6H, s). MS (ES⁺) C₂₄H₂₈F₄N₄O₂S requires: 512, found: 513 (M+H⁺, 100%).

Examples 9-15 The following were prepared by the procedure of Example 6, using the appropriate hydrazine in the second step and the appropriate sulfamoyl chloride in the final step:

Example 16

N-π-(3-{5-r2-(^'4-Fluorophenyl ethyll-l-methyl-lH-pyrazol-3-vUphenyl ethyll-N- (2,2,2-trifluoroethyl sulfamide

Step 1 : 3-{5-r2-(4-Fluorophenyl -ethvn-l-methyl-lΗ-pyrazol-3-yl>-benzonitrile

Prepared by the procedures of Example 6 Steps 1 and 2, using methylhydrazine in the second step and retaining the 1 -methyl- lH-pyrazol-3-yl isomer.

Step 2: N-ri-(3-{5-r2-(4-Fluorophenyl ethyll-l-methyl-lH-pyrazol-3- yl}phenyl)ethyll-N-f2,2,2-trifluoroethyl)sulfamide

A solution of the nitrite from Step 1 (50 mg, 0.16 mmol) in TΗF (5 mL) was treated with MeMgl in Et₂0 (3.0 M, 0.32 mL, 0.96 mmol). A milky solution formed, which was stirred at RT for 30mins, then further MeMgl was added (1.0 mL, 3 mmol) and stirred for 1 hour. A solution of LiAUEL; in TΗF (1.0 M, 2.5 mL, 2.5 mmol) was added and stirred at RT for 1 hour. The reaction was quenched by addition of Η₂O and the solvent evaporated under reduced pressure. The residue was partitioned between CH₂C1₂ and H₂O, the CH2CI₂ layer was separated and the aqueous layer re-extracted with CH2CI2. The combined organic extracts were washed with brine, dried (MgSO ) and concentrated to give crude l-(3-{5-[2-(4-fluorophenyl)-ethyl]-l-methyl-lH- pyrazol-3-yl}-phenyl)-ethylamine as a yellow gum (50 mg). This amine was dissolved in CΗ₂C1₂ (5 mL) and treated with 2,2,2- trifluoroethylsulfamoyl chloride (91 mg, 0.45 mmol) and Et₃Ν (63 μL, 0.45 mmol) and stined at RT for 30 min. The solvent was evaporated under reduced pressure and the residue purified by silica chromatography eluting with 2% MeOH/CH₂Cl₂ to yield the title sulfamide as a colourless gum (18 mg, 23% over 2 steps). 1H NMR (CDC1₃, 500 MHz) δ 7.80-7.76 (IH, s), 7.65 (IH, d, J= 7.8 Hz), 7.38 (IH, t, J= 7.8 Hz), 7.23 (IH, d, J= 7.8 Hz), 7.18-7.10 (2H, m), 6.98 (2H, t, J= 8.7 Hz), 6.35 (IH, s), 4.66- 4.56 (2H, m), 4.38-4.28 (IH, m), 3.69 (3H, s), 3.53-3.42 (IH, m), 3.42-3.30 (IH, m), 3.02-2.84 (4H, m), 1.62-1.52 (3H, m). MS (ES⁴) C₂₂H₂₄F₄N₄O₂S requires: 484, found: 485 (M+H ).

Example 17 N-Cvclobutyl-N-(l-(3-r3-r4-fluorobenzyl -l-methyl-lH-pyrazol-5-yl1phenyll-l- methylethvDsulfamide

Step 1: 3-(4-Fluorobenzyl)-5-(3-iodophenyl)-l-methyl-lΗ-pyrazole

A solution of ¹Pr₂ΝH (11.2 mL, 80 mmol) in THF (100 mL) was cooled in an ice/salt bath and "BuLi (80mmol) in hexanes (1.6M, 50 mL) was added dropwise. The solution was stined for lh, then cooled to -78°C. A solution of 3-iodoacetophenone

(19.7 g, 80 mmol) in THF (30 mL) was added dropwise and stirred for 1 h at -78°C, then a solution of methyl 4-fluorophenylacetate (13.4 g, 80 mmol) in THF (30 mL) was added. The mixture was stined for 24 h while wanning to RT. Acetic acid (9

^' mL) and EtOH (100 mL) were added, followed by MeNHNH₂ (4.2mL, 80 mmol).

The mixture was heated to 60°C for lh and, after cooling, the solvent was removed under reduced pressure. The residue was partitioned between CH₂C1₂ and H₂O, the CH₂C1₂ layer was separated and retained and the aqueous layer re-extracted with CH₂C1₂. The combined organic extracts were washed with brine, dried (MgSO₄), and evaporated. The residue was purified by silica chromatography eluting with 50-80% CH₂Cl₂/z5O-hexane to yield 3-(4-fluorobenzyl)-5-(3-iodophenyl)-l-methyl-lH- pyrazole, as the second of two pyrazole isomers, as a brown oil (4.5 g, 15 %). 1H NMR (CDCI₃, 500 MHz) δ 7.72 (IH, s), 7.69 (IH, d, J= 8.0 Hz), 7.31 (IH, d, J= 8.0 Hz), 7.26-7.20 (2H, m), 7.13 (IH, t, J= 8.0 Hz), 6.96 (2H, t, J= 8.8 Hz), 6.01 (IH, s), 3.93 (2H, s), 3.81 (3H, s). MS (ES⁺) C,₇Hι₄FIN₂ requires: 392, found: 393 (M+H⁴).

Step 2: 3-r3-(4-Fluorobenzyl -l-methyl-lH-pyrazol-5-vn-benzonitrile

A solution of the iodophenyl derivative from Step 1 (2 g, 5.1 mmol) inNMP (10 mL) was treated with zinc cyanide (418 mg, 3.5 mmol) and Pd(PPh₃) (400 mg, 0.35 mmol) and heated at 170°C in a preheated oil bath for 30 min. Further Pd(PPli₃)₄ (400 mg, 0.35 mmol) was added and heating continued for a further 30 min. The cooled reaction mixture was diluted with CΗ₂C1₂ and loaded onto a silica column which was eluted with 100% CH₂C1₂. The product was collected, concentrated and further purified in the same way to yield 3-[3-(4-fluorobenzyl)-l-methyl-lH-pyrazol-5-yl]- benzonitrile as a yellow oil (600 mg, 41 %). 1H NMR (CDCI₃, 360 MHz) δ 7.70-7.58 (3H, m), 7.55 (IH, t, J= 8.0 Hz), 7.29-7.20 (2H, m), 6.98 (2H, t, J= 8.7 Hz), 6.07 (IH, s), 3.96 (2H, s), 3.85 (3H, s). MS (ES⁺) Cι₈Hι₄FN₃ requires 291: found: 292 (M+H⁺).

Step 3: N-Cvclobutyl-N-(l-{3-r3-(4-fluorobenzyl -l-methyl-lH-pyrazol-5- vUphenyl} - 1 -methylethvDsulfamide Crushed CeCl₃ (630 mg, 2.6 mmol) was dried under vacuum at 170°C for lh, then cooled and the flask filled with Ν₂. THF (20 mL) was added and the resultant milky solution cooled to -78°C. A solution of MeLi in Et O (1.6 M, 1.6 mL, 2.6 mmol) was added and the temperature maintained at -78°C for lh. A solution of 3-[3-(4- fluorobenzyl)-l-methyl-lH-pyrazol-5-yl]-benzonitrile in TΗF (10 mL) was added and after 5 min the cooling bath was removed and the reaction stined overnight gradually warming to RT. The reaction was quenched by the addition of MeOH, and the solvents evaporated under reduced pressure. The residue was triturated with CH C1₂, then filtered and the solid washed well with CH₂C1 . The combined organics were washed with NaHCO₃ solution, then brine, dried (MgS0 ) and evaporated under reduced pressure to give crude l-{3-[3-(4-fluorobenzyl)-l-methyl-lH-pyrazol-5-yl]- phenyl}-l-methylethylamine as a yellow gum (70 mg).

The crude amine was dissolved in CΗ₂C1₂ (5 mL) and Et₃N (222 μL, 1.6 mmol) and crude cyclobutylsulfamoyl chloride (136 mg, ca. 0.8 mmol) were added and the reaction was stined at RT for 30 min. The reaction was evaporated under reduced pressure and diluted with MeCN:DMSO (1:1, 2mL) and filtered. The filtrate was injected on to a reverse phase HPLC system and the title compound was isolated, after basic workup, as a yellow gum (4 mg, 1 % over 2 steps). 1H NMR (CDC1₃, 500MHz) δ 7.52-7.48 (2H, m), 7.41 (IH, t, J= 8.6 Hz), 7.31-7.23 (3H, m), 6.98 (2H, t, J= 8.8 Hz), 6.02 (IH, s), 4.49 (IH, s), 4.10 (IH, d, J= 8.4 Hz), 3.96 (2H, s), 3.85 (3H, s),

3.82-3.73 (IH, m), 2.30-2.21 (2H, m), 1.90-1.79 (2H, m), 1.73 (6H, s), 1.72-1.63 (2H, m). MS (ES⁺) C₂₄H₂₉FN₄O₂S requires 456: found: 457 (M+H⁺).

Example 18 N-(l-{3-r5-(4-Fluoroρhenvπ-l-methyl-lH-pyrazol-3-yl1phenyl}-l-methylethyl)-N- (2.2,2-trifluoroethyl sulfamide

Step 1 : 5 -(4-Fluorophenyl)- 1 -methyl- 1 ,2-dihydro-p yrazol-3 -one and 5-(4-Fluorophenyl)-2-methyl- 1 ,2-dihydro-pyrazol-3-one

A suspension of (4-fluorophenyl)propynoic acid methyl ester (1.6 g, 9.0 mmol) in MeOΗ (10 mL) and Η₂O (10 mL) was heated at 60°C and MeΝHΝH₂ (0.5 mL, 9.4 mmol) was added. The reaction mixture was stined at 60°C for 20 min. then filtered. The residue was washed with H₂O (10 mL) and MeOH (5 mL) and dried to give 5-(4- fluorophenyl)-l-methyl-.l,2-dihydro-pyrazol-3-one (0.63 g, 36 %). The filtrate was then concentrated under reduced pressure and the residue dissolved in EtOAc (20 ml) and washed with H₂O (3 x 15 mL). The aqueous layer was acidified to pH 5.5 with 2 M citric acid solution (3 x 15 mL) and extracted with EtOAc (3 x 20 mL). The extracts were dried (MgSO₄) and concentrated under reduced pressure to give 5-(4- fluoro-phenyl)-2-methyl-l,2-dihydro-pyrazol-3-one (0.2 g, 12 %). 5-(4-Fluorophenyl)-l-methyl-l,2-dihydro-pyrazol-3-one: 1H NMR (δ₆-DMSO, 360 MHz) δ 11.01 (IH, s), 7.69-7.73 (2H, m), 7.16 (2H, t, J= 8.9 Hz), 5.77 (IH, s), 3.55 (3H, s). MS (ES⁺) C₁₀H₉FN₂O requires: 192, found: 193 (M+H^4", 100%). 5-(4-Fluorophenyl)-2-methyl-l,2-dihydro-pyrazol-3-one: 1H NMR (d₆-DMSO, 360 MHz) δ 9.65 (IH, s), 7.54-7.50 (2H, m), 7.30 (2H, t, J= 8.9 Hz), 5.61 (IH, s), 3.60 (3H, s). MS (ES⁺) CιoH₉FN₂0 requires: 192, found: 193 (M+H^4", 100%).

Step 2: Trifluoromethanesulfonic acid 5 -(4-fluorophenyl)- 1 -methyl- lH-pyrazol-3-yl ester

A suspension of 5-(4-fluorophenyl)-l-methyl-l,2-dihydro-pyrazol-3-one (0.63 g, 3.3. mmol) in dry pyridine (6 ml) was cooled to -10°C and triflic anhydride (0.58 mL, 3.4 mmol) was added. The reaction mixture was gradually warmed to RT and stined for 2 hours, then poured into 2 N HC1 (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with 2 N HC1 (ca. 40 mL), until washings were pH 1, and then washed with brine (15 mL) and saturated NaHCO₃ solution (15 mL), dried (MgSO ) and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with 35% CH₂Cl₂/ώo-hexane to give the triflate (0.91 g, 86 %). 1H NMR (CDC1₃, 360 MHz) δ 7.41-7.38 (2H, m), 7.18 (2H, t, J = 8.5 Hz), 6.16 (IH, s), 3.80 (3H, s). MS (ES⁺) C_nH₈F₄N₂O₃S requires: 324, found: 325 (M+H , 100%). Step 3 : 3-r5-(4-Fluorophenyl)-l-methyl-lH-pyrazol-3-vn-benzonitrile

3-Cyanophenylboronic acid (60 mg, 0.4 mmol) and 2M Na₂CO₃ solution (0.4 mL, 0.8 mmol) were added to a solution of the triflate from Step 2 (0.2 g, 0.6 mmol) in toluene (5 mL). The reaction mixture was degassed with a flow of N₂ for 5 min and then Pd(PPh₃)₄ (50 mg, 0.06 mmol) was added. The mixture was heated at reflux for 8 hours and cooled to RT. 4N NaOH solution (20 mL) and EtOAc (30 mL) were added, and the organic layer separated, dried (MgSO ), and concentrated under reduced pressure. The residue was purified by column chromatography on silica eluting with 20% EtOAc/ wo-hexane to give the title compound (53 mg, 48 %). 1H NMR (CDC1₃, 360 MHz) δ 8.11 (IH, s), 8.03 (IH, d, J = 7.8 Hz), 7.58 (IH, d, J= 7.8 Hz ), 7.50 (IH, t, J= 7.8 Hz ), 7.46-7.42 (2H, m), 7.19 (2H, t, J= 8.4 Hz), 6.60 (IH, s), 3.91 (3H, s). MS (ES ) Cι₇Hι₂FN₃ requires: 277, found: 278 (M+H^4" 100%).

Step 4: 1 - (3 - r5-(4-Fluorophenyl)- 1 -methyl- lH-p yrazol-3 -yll -phenyl } - 1 -methylethyl amine

Prepared by the procedure of Example 1 Step 2 using the nitrite from Step 3 (100 mg, 0.4 mmol), CeCl₃ (0.7 g, 2.9 mmol) and MeLi (1.6 M in Et₂O, 1.8 mL, 2.9 mmol) to yield, after purification by column chromatography on deactivated alumina using 2 % MeOΗ/CΗ₂Cl₂₎ the amine (50 mg, 45 %). MS (ES⁴) C₁₉H₂₀FN₃ requires: 309, found: 310 (M+H^4"). Step 5: N-d-f3-r5-(4-Fluorophenyl -l-methyl-lH-pyrazol-3-vnphenyll-l- methylethyl -N-(2.2,2-trifluoroethyl)sulfamide

2,2,2-Trifluoroethylsulfamoyl chloride (53 mg, 0.3 mmol) was added dropwise to a stirred solution of the amine from Step 4 (50 mg, 0.2 mmol) and Et₃Ν (37 μL, 0.3 mmol) in CH₂CI2 (2 mL) at RT under N₂. The mixture was stirred at RT overnight and then diluted with CH C1₂ (25 mL), washed with NaHCO₃ solution (20 mL), dried (MgSO₄) and concentrated under reduced pressure. The crude product was purified by column chromatography on silica eluting with 20% EtOAc/t5<?-hexane to yield the title sulfamide (5 mg, 6 %). Η NMR (CDCI₃, 500 MHz) δ 8.02 (IH, s), 7.69 (IH, d, J= 6.6 Hz), 7.45-7.42 (4H, m), 7.18 (2H, t, J= 8.6 Hz), 6.58 (IH, s), 4.70 (IH, s), 4.30- 4.27 (IH, m), 3.90 (3H, s), 3.57-3.53 (2H, m), 1.80 (6H, s). MS (ES⁴) C₂ιH₂₂F₄N₄O₂S requires: 470, found: 471 (M+H⁴, 100%).

Example 19

N-(l-{3-r3-f4-Fluorophenyl)-l-methyl-lH-pyrazol-5-yllphenyl}-l-methylethyl)-N- (2,2,2-trifluoroethyl sulfamide

Prepared by the procedure of Example 18, using the isomeric 5-(4-fluorophenyl)-2- methyl-l,2-dihydro-pyrazol-3-one in Step 2.

The crude product was purified by column chromatography on silica eluting with 30% EtOAc/ώo-hexane to yield the title sulfamide. 1H NMR (CDC1₃, 500 MHz) δ 7.80- 7.77 (2H, m), 7.59-7.55 (2H, m), 7.49 (IH, t, J= 7.6 Hz), 7.40 (IH, d, J= 7.6 Hz), 7.10 (2H, t, J= 8.7 Hz), 6.56 (IH, s), 4.73 (IH, s), 4.46-4.43 (IH, m), 3.92 (3H, s), 3.61-3.58 (2H, m), 1.80 (6H, s). MS (ES⁴) C₂₁H₂2F₄N₄0₂S requires: 470, found: 471 (M+H⁺, 100%). Example 20

N-{l-r3-(l-Ethyl-3-{r4-(trifluoromethyl -3,6-dihvdropyridin-ir2H)-vnmethyl>-lH- pyrazol-5-yl)phenyll-l-methylethyl}-2,2,2-trifluoroethanesulfonamide

Step l: N-(l-{3-r3-rChloromethyl)-l-ethyl-lH-pyrazol-5-yllphenvn-l-methylethvn- 2,2,2-trifluoroethanesulfonamide

The procedure of Example 1 steps 1-5 was repeated using ethyl hydrazine in step 1. The resulting alcohol (0.136mg, 0.33mmol) in dichloromethane (5ml) was treated with thionyl chloride (0.073ml, Immol) at room temperature and stined for 2 hours. The organic phase was washed with water (10ml) and brine (10ml), dried over MgS0₄, filtered and evaporated, to give 0.13g. MS (ES⁴) 423 (M+Η , 100%).

Step 2: N-{l-r3-(l-Ethyl-3-(r4-(trifluoromethyl)-3.6-dihvdropyridin-l(2H)- yllmethylj - lH-pyrazol-5-yl phenyll - 1 -methylethyl) -2,2,2-trifluoroethanesulfonamide

The chloride from Step 1 (45mg, 0.106mmol) was dissolved in dimethylformamide (3ml) and treated with triethylamine (0.03ml, 0.212mmol) and the appropriate amine (20mg, 0.108mmol). The reaction was then heated to 80°C for 16 hours. The reaction was then diluted with water (20ml) and the products extracted into ethyl acetate (2x 20ml). The combined organic phase was washed with brine, dried over MgSO and evaporated to dryness. The product was isolated using silica gel chromatography eluting with hexane-ethyl acetate mixtures to give 0.06g. 1H NMR (CDC1₃, 360 MHz) δ 7.57-7.54 (2H, m), 7.48 (lh, t, J = 7.6Hz), 7.35 (IH, d, J= 7.5Hz), 6.26 (IH, s), 6.29 (IH, m), 5.01 (IH, brs), 4.15-4.11 (2H, q, J= 7.1, 14 Hz), 3.70 (2H, s), 3.49-3.43 (2H, q, J= 8.7, 17.6Hz), 3.20 (2H, m), 2.74 (2H, t, J = 5.6Hz), 2.32 (2H, m), 1.82 (6H, s) and 1.39 (3H, t, J= 7.2Hz). MS (ES ) 539 (M+H , 100%).

Example 21

N-ri-(3-{3-r(4,4-Difluoropiperidin-l-yl)methyll-l-ethyl-lH-pyrazol-5-yl>phenyl -l- methylethyll-2,2,2-trifluoroethanesulfonamide

Following the procedure as outlined in Example 20 using 4,4-difluoropiperidine as amine; 0.04g isolated. 1H ΝMR (CDC1₃, 360 MHz) δ 7.56-7.54 (2H, m), 7.48 (IH, m), 7.35 (IH, d, J= 7.5Hz), 6.22 (IH, s), 5.02 (IH, brs), 4.15-4.11 (2H, q, J=7.1, 14Hz), 3.62 (2H, s), 3.48-3.43 (2H, q, J= 8.7, 17.5Hz), 2.64-2.62 (4H, m), 2.06-1.97 (4H, m), 1.82 (6H, s) and 1.38 (3H, t, J= 7.1Hz). MS (ES⁺) 509 (M+H⁴, 100%).

Example 22

N-{l-r3-(l-Ethyl-3-{r(3,3,3-trifluoropropyl)aminolmethyl>-lH-pyrazol-5-yl)phenyll- 1 -methylethyl) -2,2,2-trifluoroethanesulfonamide

Following the procedure as outlined in Example 20 using 3,3,3-trifluoropropylamine as amine; 0.04g isolated. 1H ΝMR (CDC1₃, 360 MHz) δ 7.51-7.46 (3H, m), 7.36-7.33 (IH, m,), 6.21 (IH, s), 4.91 (IH, brs), 4.13-4.09 (2H, q, J= 6.5, 13Hz), 3.85 (2H, s), 3.48-3.44 (2H, q, J=7.8, 15.8Hz), 2.97 (2H, t, J=6.5Hz), 2.40-2.32 (2H, m), 1.82 (6H, s), 1.65 (IH, brs) and 1.40 (3H, t, J=6.4Hz). MS (ES⁴) 501(M+H⁺). Example 23

N-{l-r3-(l-Ethyl-5-{r4-(trifluoromethyl)piρeridin-l-yllmethyl>-lH-pyrazol-3- vDphenyll- 1 -methylethyl} -2,2,2-trifluoroethanesulfonamide

Steps 1-4 of Example 1 were repeated, using ethyl hydrazine in place of methyl hydrazine, and using 3-(5-dimethoxymethyl-l-ethyl-lΗ-pyrazol-3-yl)-benzonitrile from the first step. The resulting aldehyde (50 mg, 0.13 mmol) in 1,2-dichloroethane (5 ml) was treated with 4-trifluoromethylpiperidine (21 mg, 0.14 mmol), triethylamine (35 μl, 0.26 mmol) and sodium triacetoxyborohydride (40 mg, 0.20 mmol). The mixture was stined for 4 h and diluted with dichloromethane, washed with saturated aqueous sodium hydrogencarbonate, water, brine, dried (MgS0 ), filtered and evaporated. The crude product was purified by flash chromatography (2:1 ώo-hexane/ethyl acetate) to give a white foam (45 mg). 1H ΝMR (ppm) (CDC1₃) δ 1.38 (3 H, t, J = 7.2Hz), 1.82 (6 H, s), 2.55 (4 H, s), 3.39-3.49 (2 H, q, J=8.2 Hz), 3.58 (2 H, s), 3.74 (4 H, t, J = 4.6Hz), 4.15 (2 H, q, J = 7.1Hz), 5.30 (1 H, br s), 6.24 (1 H, s), 7.35 (1 H, d, J = 7.7Hz), 7.48 (1 H, t, J = 7.7Hz), 7.55 (2 H, m). MS(MH⁴) 475.

Example 24

N-(l - (3-r 1 -Ethyl-3-(morpholin-4-ylmethyl)- lH-pyrazol-5-yllphenyl> - 1 -methylethyl)-

2,2,2-trifluoroethanesulfonamide

Prepared as in Example 23, using the aldehyde obtained as in Example 1 (steps 1-4), using ethyl hydrazine in Step 1 and taking forward the isomer 3-(3-dimethoxymethyl- l-ethyl-lH-pyrazol-5-yl)-benzonitrile. The final step, following the method of Example 23, was carried out using morpholine as amine. 1H NMR (ppm) (CDC1₃) δ 1.38 (3 H, t, J = 7.2Hz), 1.82 (6 H, s), 2.55 (4 H, s), 3.39-3.49 (2 H, q, J=8.2 Hz), 3.58 (2 H, s), 3.74 (4 H, t, J = 4.6Hz), 4.15 (2 H, q, J = 7.1Hz), 5.30 (1 H, br), 6.24 (1 H, s), 7.35 (1 H, d, J = 7.7Hz), 7.48 (1 H, t, J = 7.7Hz), 7.55 (2 H, m). MS(MH+) 475.

Examples 25-35

Prepared by the procedure described in Example 1 (using ethyl hydrazine in place of methyl hydrazine in step 1) using the appropriate phenols in Step 6.

Examples 36-46

Prepared by the procedure of Example 6, using methyl hydrazine in Step 2, and the appropriate sulfamoyl or sulfonyl chloride in Step 4.

methylethyll-2,2,2-trifluoroethanesulfonamide

Step 1 : 2-Bromo-6-(lH-imidazol-l-ylcarbonyl)pyridine

6-Bromopicolinic acid (4.015g 19.8mmol) was mixed with dichloromethane (16ml), and carbonyl diimidazole (5.147g, 31.7 mmole) was added to the suspension. After stirring overnight, the solution was washed with saturated sodium hydrogen carbonate solution (25ml) and water (15ml), dried over MgSO and evaporated to a brown oil (3.91g 78%). The resulting activated acid was used directly in the next step.

Step 2: l-(6-Bromopyridin-2-yl^')-4.4-dimethoxybutane- 3-dione

Diisopropylamine (4.6ml, 30 mmol) in TΗF (25ml) was cooled to 0°C, n-butyllithium (1.6 M in hexane, 20.6ml, 33 mmol) was added, and the mixture cooled in dry ice/acetone with stirring for 1 hr. 1,1-Dimethoxy acetone (3.9g, 33 mmol) in TΗF (20ml) was added, and stirring continued for lhr. The activated acid (step 1) (3.9g, 15 mmol) was suspended in THF (35ml), added to the reaction, and stirring continued for 40 mins. After warming to room temperature, citric acid (1 M solution in water, 50ml) was added and the product extracted with ether (2 x 50ml). Drying over MgSO₄ and evaporation yielded 4.44g product, used in the next step without further purification.

Step 3 : 2-Bromo-6-r3-(dimethoxymethyl)-l-ethyl-lH-pyrazol-5-yllpyridine

Prepared from the product of Step 2 using the procedure of Example 6 Step 2 to give the titled product, 2.75g.

1H NMR (CDC1₃, 360MHz) 7.59 (IH, t, J=7.2Hz), 7.53 (IH, d, J=7.2 Hz),7.42 (IH, d, J-7.7Hz), 6.65 (IH, s), 5.49 (IH, s), 4.67 (2H, q, J=7.1 Hz), 3.41 (6H, s), 1.45 (3H, t, J=7.1 Hz)

Step 4: 6-r3-(Dimethoxymethyl)-l-ethyl-lH-pyrazol-5-yllpyridine-2-carbonitrile

2-Bromo-6-[3-(dimethoxymethyl)-l-ethyl-lH-pyrazol-5-yl]ρyridine from Step 3 (2.7g,

8 mmol), Pd(PPh₃)₄ (0.36g, 0.3 mmol) and zinc cyanide (544mg, 4.6 mmol) in NMP

(80ml) were heated at 170°C for lhr. After cooling to room temperature, water (30ml) was added and the mixture extracted with ether (2x50ml). The combined organic layers were washed with brine (30ml), dried over MgS0₄ and evaporated.

Chromatography of the residue on silica gel eluting with 5:1 isohexane : ethyl acetate yielded desired product (1.50g 66%).

1H NMR (CDCI₃, 360MHz) 7.89(1H, t, J=7.2Hz), 7.80 (IH, d, J=7.2Hz), 7.63 (IH, d, J=7.2Hz), 6.73 (IH, s), 5.49 (IH, s), 4.69 (2H, q, J=7.1Hz), 3.42 (6H, s), 1.25 (3H, t,

J=7.1Hz). Step 5 : N-f 1 -(6- { l-Ethyl-3-r(4-fluoroρhenoxy)methyll- lH-ρyrazol-5-yl>pyridin-2-yl)- l-methvtethyll-2,2,2-trifluoroethanesulfonamide

Prepared from the product of Step 4 by the procedure of Example 1 Steps 2-6. 1H ΝMR (CDC1₃, 500MΗz) 7.83 (IH, t, J=7.9Hz), 7.53 (IH, d, J=7.7Hz), 7.41 (IH, d, J=7.8Hz), 6.97 (4H, s), 6.66 (lH,s), 6.53 (lH,s), 5.08 (2H, s), 4.59 (2H, q, J=7.2Hz), 3.79 (2H, q, J=8.8Hz), 1.83 (6H, s), 1.51 (3H, t, J=7.2Hz). MS (ES+) C₂₂H₂₄F₄Ν₄O₃S requires 500 found 501

Examples 48-50

Using the procedure of Example 47 the following were prepared:

Glossary

RT room temperature

DIAD - diisopropylazodicarboxylate GDI - 1 , 1 '-carbonyldiimidazole TFA - trifluoroacetic acid

AcOH - acetic acid

NMP - N-methylpynolidone

Claims

CLAIMS:

A compound of formula I:

wherein :

A represents CH or N;

X represents a bond, O or NR ;

Y represents a bond, (CHR⁸)_n, CR⁸=CR⁸, O-CHR⁸, CHR⁸-O or CHR⁸-NR⁸, where n is 1 or 2 and each R⁸ is independently H or

Z represents Ar or N(R⁹)₂, with the proviso that when Z represents N(R⁹)₂, Y represents a bond or (CHR )_n;

R¹ represents a hydrocarbon group of 1-10 carbon atoms which is optionally substituted with up to 3 halogen atoms, or heteroaryl of 5 or 6 ring atoms optionally bearing up to 3 substituents independently selected from halogen, CF₃, CHF₂, CH₂F, NO₂, CN, OCF₃, -ealkyl and Cι_₆alkoxy; or when X represents NR², R¹ and R² together may complete a heterocyclic ring of up to 6 members which optionally bears up to 3 substituents independently selected from halogen, CF₃, CHF , CH₂F, NO₂, CN, OCF₃, Cι-₆alkyl and d-ealkoxy;

completes a heterocyclic ring as defined above;

R³ represents H or

R⁴ represents Ci.₆alkyl, R⁵ represents H or Cι-₆alkyl; R⁶ is bonded to one of the nitrogen atoms of the pyrazole ring and represents a hydrocarbon group of 1-5 carbon atoms which is optionally substituted with up to 3 halogen atoms; R⁷ represents H or Cι-₆alkyl;

R⁹ represents H or a hydrocarbon group of 1-10 carbon atoms which is optionally substituted with up to 3 halogen atoms, provided that at least one R⁹ is not H; or the two R⁹ groups complete a heterocyclic ring of 5 or 6 members which is optionally substituted with CF₃ or up to 3 halogen atoms; and

Ar represents phenyl or 6-membered heteroaryl, either of which bears 0-3 substituents independently selected from halogen, CF₃, CHF₂, CH₂F, NO₂, CN, OCF₃, Cι.₆alkyl and Cι-₆alkoxy; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein X is a bond and R¹ represents Cι_₆alkyl which is optionally substituted with up to 3 fluorine atoms, or phenyl, benzyl or 5- or 6-membered heteroaryl, any of which is optionally substituted with chlorine or fluorine.

3. A compound according to claim 2 wherein R¹ is selected from n- propyl, n-butyl, 2,2,2-trifluoroethyl, benzyl, 4-fluorophenyl, 2-thienyl, 5-chloro-2- thienyl, 5-isothiazolyl and 6-chloro-pyridin-3-yl.

4. A compound according to claim 1 wherein X is O and R¹ represents alkyl, alkenyl, cycloalkyl or cycloalkylalkyl of up to 6 carbon atoms which is optionally substituted with up to 3 fluorine atoms.

5. A compound according to claim 1 wherein X is NH or NMe and R¹ represents alkyl, alkenyl, cycloalkyl or cycloalkylalkyl of up to 6 carbon atoms which is optionally substituted with up to 3 fluorine atoms.

6. A compound according to claim 5 wherein R¹ is selected from ethyl, n- propyl, isopropyl, n-butyl, 2,2-dimethylpropyl, t-butyl, 2,2,2-trifluoroethyl, 3,3,3- trifluoropropyl, cyclobutyl, cyclopentyl and cyclopropylmethyl.

7. A compound according to any previous claim wherien Z is Ar and Y is selected from CH₂, OCH₂, CH₂CH₂ and CH₂O.

8. A pharmaceutical composition comprising a compound according to any previous claim and a pharmaceutically acceptable carrier.

9. A compound according to any of claims 1-7 for use in a method of treatment of the human body.

10. Use of a compound according to any of claims 1 -7 for the manufacture of a medicament for treating or preventing Alzheimer's disease.