This invention relates to novel sulfonamide compounds having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of CNS and other disorders.

WO 98/27081, WO 99/02502, WO 99/37623, WO 99/42465 and WO 01/32646 (SmithKline Beecham plc) disclose a series of aryl sulphonamide and sulphoxide compounds that are said to be 5-HT6 receptor antagonists and which are claimed to be useful in the treatment of various CNS disorders.

A structurally novel class of compounds has now been found which possess affinity for the 5- HT6 receptor. The present invention therefore provides, in a first aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof :

wherein: R'represents hydrogen, halogen, hydroxy, cyano, nitro, trifluoromethyl, trifluoromethoxy, C-6 alkyl, trifluoromethanesulfonyloxy, pentafluoroethyl, C1-6 alkoxy, arylCI 6 alkoxy, C1-6 alkylthio, Cl 6 alkoxyCI 6 alkyl, C37 cycloalkylCI 6 alkoxy, Cl 6 alkanoyl, Cl 6 alkoxycarbonyl, C1-6 alkylsulfonyl, C1-6 alkylsulfinyl, C1-6 alkylsulfonyloxy, CX 6 alkylsulfonylCI 6 alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonylCI 6 alkyl, Cl 6 alkylsulfonamido, Cl 6 alkylamido, Cl 6 alkylsulfonamidoCI 6 alkyl, Cl 6 alkylamidoCI 6 alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamidoCI 6 alkyl, arylcarboxamidoCI 6 alkyl, aroyl, aroylCI 6 alkyl, arylCI 6 alkanoyl, or a group CONKER'* or SO2NR3R4, wherein R3 and R4 independently represent hydrogen or Cl 6 alkyl or together may be fused to form a 5-to 7-membered aromatic or non-aromatic heterocyclic ring optionally interrupted by an O or S atom; R'represents hydrogen or Cl 6 alkyl ; m represents an integer from 1 to 3; n represents an integer from 1 to 4; A represents phenyl, naphthyl or a monocyclic or bicyclic heteroaryl group each of which may be optionally substituted by one or more substituents which may be the same or different, and which are selected from those defined for R' ; or solvates thereof.

Specific groups of compounds of formula (I) which may be mentioned are those as defined above with the proviso that when A represents phenyl substituted at the 4-position, said substituent is not trifluoromethyl, trifluoromethoxy, C3-6 alkyl or Cl 6 alkoxy.

Further specific groups of compounds of formula (I) which may be mentioned are those as defined above wherein m represents 0.

Alkyl groups, whether alone or as part of another group, may be straight chain or branched and the groups alkoxy and alkanoyl shall be interpreted similarly. Alkyl moieties are more preferably Cl4 alkyl, eg. methyl or ethyl. The term'halogen'is used herein to describe, unless otherwise stated, a group selected from fluorine, chlorine, bromine or iodine.

The term"aryl"includes phenyl and naphthyl.

The term"heteroaryl"is intended to mean a 5 or 6 membered monocyclic aromatic or a fused 8- 10 membered bicyclic aromatic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur. Suitable examples of such monocyclic aromatic rings include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl and pyridyl. Suitable examples of such fused aromatic rings include benzofused aromatic rings such as quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl and the like. Heteroaryl groups, as described above, may be linked to the remainder of the molecule via a carbon atom or, when present, a suitable nitrogen atom except where otherwise indicated above.

It will be appreciated that wherein the above mentioned aryl or heteroaryl groups have more than one substituent, said substituents may be linked to form a ring, for example a carboxyl and amine group may be linked to form an amide group.

Preferably, A is substituted by 0 to 3 substituents, more preferably 0,1 or 2 substituents.

Preferably, A represents phenyl or a monocyclic heteroaryl group (such as thienyl) optionally substituted by one or more halogen (such as chlorine or bromine, eg. 3-chlorophenyl, 4- chlorophenyl, 4-bromophenyl, 5-bromophenyl, 2,3-dichlorophenyl or 3,5-dichlorophenyl), Cl 6 alkyl (such as methyl, eg. 4-methyl or ethyl, eg. 2-ethyl), C, 6 alkoxy (such as methoxy, eg. 2- methoxy), trifluoromethoxy (such as 2-trifluoromethoxy) or trifluoromethyl (such as 3- trifluoromethyl) groups.

More preferably, A represents unsubstituted phenyl or phenyl substituted by 3-trifluoromethyl, halogen (eg. 4-chloro and 4-bromo) and/or 2-trifluoromethoxy.

Most preferably, A represents phenyl di-substituted by halogen (especially 4-chloro or 4-bromo) and 2-trifluoromethoxy.

Preferably, m is 0 or 1, most preferably 0.

When m is 1, R'is preferably halogen (eg. 6-chlorine, 9-chlorine or 9-bromine) or Cl 6 alkoxy (such as methoxy, eg. 8-methoxy).

Preferably, n is 0.

Preferred compounds according to the invention include examples E1-E17 as shown below, or a pharmaceutically acceptable salt thereof.

The compounds of formula (I) can form acid addition salts thereof. It will be appreciated that for use in medicine the salts of the compounds of formula (I) should be pharmaceutically acceptable.

Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in J. Pharm. Sci. , 1977,66, 1-19, such as acid addition salts formed with inorganic acids e. g. hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; and organic acids e. g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms. Preferably, the compound of formula (I) forms an acid addition salt with hydrochloric acid.

The compounds of formula (I) may be prepared in crystalline or non-crystalline form, and, if crystalline, may optionally be solvated, eg. as the hydrate. This invention includes within its scope stoichiometric solvates (eg. hydrates) as well as compounds containing variable amounts of solvent (eg. water).

Certain compounds of formula (I) are capable of existing in stereoisomeric forms (e. g. diastereomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates. The different stereoisomeric forms may be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis. The invention also extends to any tautomeric forms and mixtures thereof.

The present invention also provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof, which process comprises: (a) reacting a compound of formula (II) wherein R', R2, m and n are hereinbefore defined and P'is a suitable protecting group such as acetyl, trifluoroacetyl, t-butyloxycarbonyl, 2', 2', 2'-trichloroethoxycarbonyl, benzyl or methyl, with a compound of formula (III)

wherein A is as hereinbefore defined and L is a suitable leaving group, such as a halogen atom (eg. fluorine or chlorine) and thereafter deprotecting the resultant compound; or (b) deprotecting a compound of formula (I) which is protected; and optionally thereafter (c) interconversion to other compounds of formula (I).

Process (a) typically comprises the use of a suitable base such as pyridine or triethylamine in an inert solvent such as dichloromethane or tetrahydrofuran.

In process (b), examples of protecting groups and the means for their removal can be found in T.

W. Greene'Protective Groups in Organic Synthesis' (J. Wiley and Sons, 1991). Suitable amine protecting groups include sulphonyl (e. g. tosyl), acyl (e. g. acetyl, 2', 2', 2'-trichloroethoxycarbonyl, benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e. g. benzyl), which may be removed by hydrolysis (e. g. using an acid such as hydrochloric acid) or reductively (e. g. hydrogenolysis of a benzyl group or reductive removal of a 2', 2', 2'-trichloroethoxycarbonyl group using zinc in acetic acid) as appropriate. Other suitable amine protecting groups include trifluoroacetyl (-COCF3) which may be removed by base catalysed hydrolysis or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker), which may be removed by acid catalysed hydrolysis, for example with trifluoroacetic acid.

Process (c) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic or electrophilic aromatic substitution, ester hydrolysis or amide bond formation. Examples of process (c) include interconversions of the groups R', R2 and A.

Compounds of formula (II) and (hui) are known in the literature or can be prepared by analogous methods.

Pharmaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative.

Compounds of formula (I) and their pharmaceutically acceptable salts have affinity for the 5-HT6 receptor and are believed to be of potential use in the treatment of certain CNS disorders such as anxiety, depression, epilepsy, obsessive compulsive disorders, migraine, cognitive memory disorders (e. g. Alzheimers disease, age related cognitive decline and mild cognitive impairment), Parkinsons Disease, ADHD (Attention Deficit Disorder/Hyperactivity Syndrome), sleep disorders (including disturbances of Circadian rhythm), feeding disorders such as anorexia and bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, schizophrenia, and also disorders associated with spinal trauma and/or head injury such as hydrocephalus. Compounds of the invention are also expected to be of use in the

treatment of certain GI (gastrointestinal) disorders such as IBS (Irritable Bowel Syndrome).

Compounds of the invention are also expected to be of use in the treatment of obesity.

Thus the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use as a therapeutic substance, in particular in the treatment or prophylaxis of the above disorders. In particular the invention provides for a compound of formula (1) or a pharmaceutically acceptable salt thereof, for use in the treatment of depression, anxiety, obesity and cognitive memory disorders The invention further provides a method of treatment or prophylaxis of the above disorders, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment or prophylaxis of the above disorders.

In order to use the compounds of formula (I) in therapy, they will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. The present invention also provides a pharmaceutical composition, which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

A pharmaceutical composition of the invention, which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusable solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.

Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents. The tablets may be coated according to methods well known in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colourants.

For parenteral administration, fluid unit dosage forms are prepared utilising a compound of the invention or pharmaceutically acceptable salt thereof and a sterile vehicle. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the

vehicle. In preparing solutions, the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The composition may contain from 0. 1 % to 99% by weight, preferably from 10 to 60% by weight, of the active material, depending on the method of administration.

The dose of the compound used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors. However, as a general guide suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 200 mg, for example 20 to 40 mg; and such unit doses will preferably be administered once a day, although administration more than once a day may be required; and such therapy may extend for a number of weeks or months.

All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

The following Descriptions and Examples illustrate the preparation of compounds of the invention.

Description 1 3-t-Butyloxycarbonyl-7-nitro-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine (Dl) A solution of di-t-butyl dicarbonate (19.3g, 88.2mmol) in dichloromethane (150ml) was added over 0. 5h to a stirred, ice-cooled solution of 7-nitro-2,3, 4, 5-tetrahydro-lH-benzo [d] azepine (11.3g, 58. 8mmol) (for synthesis see Pecherer et al., J. Het. Chem., 1971,8, 779) and triethylamine (12. 3ml, 88. 2mmol) in dichloromethane (150ml) under argon. The solution was warmed to ambient temperature and stirred for 18h. The reaction mixture was then washed with water (2 x 400ml), dried (MgS04) and concentrated in vacuo to an oily solid. The solid was purified by chromatography over silica gel eluting with a solvent gradient of ethyl acetate/hexane to afford the title compound (Dl) as a colourless solid (9. 1g, 31. 1mmol, 53%). 8H (CDC13, 400MHz) 1.49 (9H, s), 3.00 (4H, br s), 3.58 (4H, br s), 7.27-7. 29 (1H, br d), 7. 98- 8. 00 (2H, br, m).

Description 2 7-Amino-3-t-butyloxycarbonyl-2, 3,4, 5-tetrahydro-lH-benzo Idl azepine (D2)

A solution of 3-t-butyloxycarbonyl-7-nitro-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine (D1) (8. 0g, 27.4mmol) in ethanol (250ml) was stirred with 10% palladium on carbon (1.3g) for 20h under one atmosphere of hydrogen at ambient temperature. The reaction mixture was filtered to remove the catalyst and the filtrate was evaporated in vacuo to yield the title compound (D2) as a colourless oil (7. 0g, 26.6mmol, 97%). 8H (CDC13, 400MHz) 1.48 (9H, s), 2.78 (4H, br s), 3.51 (6H, br s), 6.45-6. 48 (2H, m), 6.89 (1H, d, J = 7. 5Hz).

Description 3 3-t-Butyloxycarbonyl-7- (3-trinuoromethyl) phenylsulfonamido-2, 3,4, 5-tetrahydro-lH- benzo [djazepine (D3) A solution of 7-amino-3-t-butyloxycarbonyl-2, 3,4, 5-tetrahydro-lH-benzo [duazepine (D2) (512mg, 1. 95mmol) in dichloromethane (20ml) was treated successively with pyridine (lml) and 3-trifluoromethylbenzenesulfonyl chloride [Lancaster] (2.15 mmol, 520mg) with stirring. After 2 hours, water (lml) was added, and the mixture stirred vigorously for a further 2h then the solvents evaporated. The residue was dissolved in ethyl acetate (100ml) and washed successively with 5% aq. citric acid (50ml), water (50ml) and brine (50ml) then dried (MgS04) and evaporated in vacuo. The residue was purified by flash chromatography (gradient of ethyl acetate/hexane) on silica gel to afford the title compound (D3) as a clear oil (910mg, 99%).

8H (CDC13, 400MHz) 1.47 (9H, s), 2.77-2. 83 (4H, m), 3.48-3. 49 (4H, m), 6.8 (1H, br s), 6.9 (1H, br s), 6.99 (lH, d), 7.23 (1H, s), 7.60 (1H, app. t), 7.79 (1H, d), 7.95 (1H, d), 7.98 (1H, s).

Description 4 3-t-Butyloxycarbonyl-7-phenylsulfonamido-2, 3,4, 5-tetrahydro-lH-benzo [0 azepine (D4) The title compound (D4) was prepared in 72% yield as described in Description 3, by treatment of 7-amino-3-t-butyloxycarbonyl-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine (D2) with phenyl sulfonyl chloride.

8H (D6-DMSO), 400MHz) 1.37 (9H, s), 2.70 (4H, br, s), 3.36 (4H, br, s), 6.83-6. 85 (2H, m), 6.97 (1H, d, J = 8.3 Hz), 7.52-7. 60 (3H, m), 7.75 (2H, d, J = 7. 2Hz), 10.2 (1H, s).

Description 5 7-Nitro-3-trifluoroacetyl-2, 3,4, 5-tetrahydro-lH-benzo [dJazepine (D5) To a stirred, ice-cooled solution of 7-nitro-2, 3,4, 5-tetrahydro-lH-benzo [dlazepine (29g, O. 15mol) (for synthesis see Pecherer et al., J. Het. Chem., 1971,8, 779) in dichloromethane (1 litre) was slowly added triethylamine (41. 8ml, 0. 30mol) followed by dropwise addition of trifluoroacetic anhydride (42. 4ml, 0. 30mol). The resulting mixture was allowed to stir and warm to ambient temperature over 18h before being poured onto ice. The organic phase was separated and the aqueous layer extracted with dichloromethane (200ml). The combined organic phases were then washed with saturated aqueous sodium hydrogen carbonate (600ml), brine (600ml) and then dried (MgS04) and evaporated in vacuo. The crude residue (59g) was purified by column chromatography on silicagel eluting with ethyl acetate/hexane (1: 4) to afford the title compound (D5) as a yellow solid (37g, 0. 128mol, 86%).

8H (CDC13, 400MHz) 3.08-3. 13 (4H, m), 3.74-3. 84 (4H, m), 7.31-7. 36 (1H, m), 8. 03- 8. 07 (2H, m).

Description 6 7-Amino-3-trifluoroacetyl-2, 3,4, 5-tetrahydro-lH-benzo [< azepine (D6) A mixture of 7-nitro-3-trifluoroacetyl-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine (D5) (37g, 0. 128mmol) and 10% palladium on carbon (5g) in ethanol (200ml) and 1,4-dioxane (600ml) was stirred with hydrogen at atmospheric pressure and room temperature for 18h. The mixture was filtered and the filtrate concentrated in vacuo to a solid which was stirred with hexane (200ml) for lh. Filtration of the mixture gave the title compound (D6) as a solid (32.5g, 0.126mmol, 98%).

8H (CDC13, 400MHz) 2.84-2. 89 (4H, m), 3.05 (2H, br, s), 3.63-3. 68 (2H, m), 3.71-3. 76 (2H, m), 6.48-6. 51 (2H, m), 6.91-6. 95 (IH, m).

Description 7 7- (4-Bromo-2-trifluoromethoxy) phenylsulfonamido-3-t-butyloxycarbonyl-2, 3,4, 5- tetrahydro-lH-benzo [dJazepine (D7) To a stirred solution of 7-amino-3-t-butyloxycarbonyl-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine (D2) (23.4g, 89. 3mmol) in pyridine (60ml) and dichloromethane (140ml) at 5°C was added 2-trifluoromethoxy-4-bromo-benzenesulfonyl chloride (33.4g, 98. 2mmol) in dichloromethane (20ml) over 30 mins. The solution was then stirred at room temperature for 18 hours. The solvents were removed and the residue purified by chromatography on silica using 20% ethyl acetate in hexane. The crude product was recrystallised from ethyl acetate/hexane to afford the title compound (D7) as a pale yellow solid (30. 5g, 60%).

8H (CDC13, 400MHz), 1.46 (9H, s), 2.79 (4H, m), 3.48 (4H, m), 6.63 (1H, s), 6.80 (1H, br s), 6.84 (1H, s), 6.96 (1H, d, J=8.08 Hz), 7.47 (1H, dd J=8.4, 1.6 Hz), 7.52 (1H, s), 7.79 (1H, d J=8.4Hz).

Description 8 7- (4-Bromo-2-trifluoromethoxy) phenylsulfonamido-3-trifluoroacetyl-2, 3,4, 5-tetrahydro- 1H-benzo [d] azepine (D8) A solution of 4-bromo-2-trifluoromethoxybenzene sulfonyl chloride (42.4g, 125mmol) in dichloromethane (100ml) was added over 20 minutes to a stirred solution of 7-amino-3- trifluoroacetyl-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine (D6) (32.3g, 125mmol) and pyridine (30. 2ml, 375mmol) in dichloromethane (150ml) at room temperature under argon. After 18h the solution was diluted with dichloromethane (750ml) and washed successively with water (1 litre), 1M hydrochloric acid (2 x 1 litre) and brine (1 litre). The organic extract was dried (MgS04) and concentrated in vacua to a red oil which was purified by column chromatography over silicagel eluting with a gradient of ethyl acetate/hexane to afford the title compound (D8) as a colourless oil (56g, 100mmol, 80%) 8H (CDC13, 400MHz) 2. 87-2. 91 (4H, m), 3.62-3. 65 (2H, m), 3.70-3. 73 (2H, m), 6.67 ( ! H, br, s), 6.83-6. 86 (1H, m), 6.91 (1H, d, J = 2.2Hz), 6.99-7. 03 (1H, m), 7.48-7. 58 (2H, m), 7.79-7. 82 (1H, m).

Found [MH] + 561/563 (CgHsBrF6N204S)

Description 9 7- (4-Chloro-2-trifluoromethoxy) phenylsulfonamido-3-trifluoroacetyl-2, 3,4, 5-tetrahydro- lH-benzo [dlazepine (D9) An efficiently stirred mixture of 7- (4-bromo-2-trifluoromethoxy) phenylsulfonamido-3- trifluoroacetyl-2,3, 4, 5-tetrahydro-1H-benzo [d] azepine (D8) (55g, 98mmol) and copper (I) chloride (193g, 1. 94mol) in dry N, N-dimethylformamide (540ml) was heated at 120°C for 24h under argon. The mixture was cooled to ambient temperature then the solid filtered, and washed with dry N, N-dimethylformamide (2 x 100ml). To the filtrate and washings was added fresh copper (1) chloride (48g, 485mmol) and the stirred mixture reheated at 120°C for 18h under argon. The mixture was cooled to ambient temperature and the solid was filtered and washed with dichloromethane (6 x 200ml). The filtrate and washings were concentrated in vacuo and the residue re-concentrated with toluene (2 x 750ml). The residue was then stirred with dichloromethane (250ml) and the whole mixture filtered through kieselguhr. The filtrate was concentrated in vacuo and the residue partially purified by column chromatography over silicagel eluting with dichloromethane to afford crude title product (D9) as a foam (42.8g). This material was crystallised by dissolving in diethyl ether (150ml) at room temperature and adding hexane (150ml) with stirring and leaving to fully crystallize for 2 days. The colourless crystals were filtered off and identified as the title compound (D9) (24g, 46.4mmol, 47%). A second crop of the product (D9) (7.4g, total yield = 31.4g, 60.7mmol, 62%) was isolated from the filtrate by concentrating the filtrate and re-chromatographing the residue over silicagel (acetone/toluene gradient) followed by crystallisation from diethyl ether/hexane.

8H (CDC13, 400MHz) 2.87-2. 91 (4H, m), 3.62-3. 65 (2H, m), 3.70-3. 73 (2H, m), 6.71 (1H, s), 6.83-6. 87 (1H, m), 6.90 (1H, d, J = 2.3Hz), 6.99-7. 03 (1H, m), 7.31-7. 39 (2H, m), 7.87-7. 90 (1H, m).

Found [MH] + 517/519 (ClgHlsclF6N2o4s) Description 10 7-Amino-6-chloro-1, 2,4, 5-tetrahydro-benzo [d] azepine-3-carboxylic acid tert-butyl ester (DIG) 7-Amino-3-t-butyloxycarbonyl-2, 3,4, 5-tetrahydro-I H-benzo [dlazepine (D2) (1. 57g, 6mmol) was dissolved in acetonitrile (30ml) and treated with N-chlorosuccinimide (895mg, 6. 5mmol) at 0°C and the stirred. mixture allowed to warm to room temperature for 14 hours. Saturated aqueous sodium sulphite (5ml) was added and the mixture evaporated. The residue was triturated with diethyl ether (2 x 100ml), and the combined organic phase dried (MgS04), filtered and evaporated. The residue was subjected to flash chromatography on silica gel, eluting with a mixture of ethyl acetate and hexane to afford the title compound (D10) as a white solid; yield 305mg.

8H (CDCl3, 400MHz) 1.46 (9H, s), 2.82 (2H, m), 3.12 (2H, m), 3.53 (4H, m), 4.02 (2H, s), 6.56 (1H, d), 6.82 (1H, d).

Description 11 3-Acetyl-6-iodo-8-nitro-2, 3,4, 5-tetrahydro-lH-benzo [dl azepine (D11)

To a stirred solution of 3-acetyl-7-nitro-2, 3,4, 5-tetrahydro-lH-benzo [dlazepine [J. Heterocyl. Chem. (1971), 8 (5), 779-783] (2.71g, 11. 6mmol) in trifluoromethane-sulfonic acid (1 5ml) at room temperature was added N-iodosuccinimide (3. 38g, 15mmol), portionwise over 1 hour, then the mixture stirred for 2 days. The mixture was poured onto ice and extracted with dichloromethane. After separating, the organic layer was washed with sodium thiosulfate solution, then brine and dried over magnesium sulfate. After filtration, the solvent was evaporated in vacuo to afford the title compound (D11), (2.74g, 69%).

5H (CDC13, 400MHz), 2.17, 2.16 (3H, 2s), 3.10 (2H, m), 3.30 (2H, m), 3.65 (2H, m), 3.76 (2H, m), 8.00 (1H, 2d, J = 2.2Hz), 8.60 (1H, 2d, J = 2.2Hz).

Description 12 6-Iodo-8-nitro-2, 3,4, 5-tetrahydro-lH-benzo [dl azepine (D12) A mixture of 3-acetyl-6-iodo-8-nitro-2, 3,4, 5-tetrahydro-lH-benzo [dlazepine (D11) (2.74g, 7.59mmol) and hydrochloric acid (36%, 250ml) was heated at reflux for 2 days, cooled, filtered and evaporated to dryness. The residue was redissolved in water, treated with sodium bicarbonate and extracted with dichloromethane. The organic layer was dried, filtered and evaporated to afford the title compound (D12) (2.2g, 91%).

6H (DMSO-d6, 400MHz), 2.50 (4H, m), 3.04 (2H, m), 3.22 (2H, m), 8.02 (1H, d, J=2.4Hz), 8.40 (1H, d, J=2.4Hz).

Description 13 6-Iodo-8-nitro-3-trifluoroacetyl-2, 3,4, 5-tetrahydro-lH-benzo [dl azepine (D13) To a stirred solution of 6-iodo-8-nitro-2, 3,4, 5-tetrahydro-1H-benzo [d] azepine (D12) (2. 2g, 6. 9mmol) in dichloromethane (40ml), was added 2 equivalents of polymer supported Hunig's base [Argonault Tech. ] (3. 83mmol/g ; 3.6g, 13. 8mmol). After cooling to 5°C, trifluoroacetic anhydride (1.6g, 7. 61mmol) was added dropwise, then stirred at room temperature for 18 hours.

After filtration, the solution was washed with water then dried over magnesium sulfate. After filtration, the solvent was removed and the residue purified by chromatography on silica using 25% diethyl ether in hexane to afford the title compound (D13) (2.56g 90%).

AH (CDC13, 400MHz) 3.17 (2H, m), 3.38 (2H, m), 3.75 (4H, m) 8.01 (1H, m) 8.61 (1H, m).

Description 14 6-Chloro-8-nitro-3-trifluoroacetyl-2, 3,4, 5-tetrahydro-lH-benzo [dg azepine (D14) A mixture of 6-iodo-8-nitro-3-trifluoroacetyl-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine (D13) (222mg, 0. 5mmol), copper (I) chloride (362mg, 3. 65mmol) and dimethyl formamide (5ml) were heated to 110 °C for 18 hours with stirring. The solvent was removed and the residue purified by chromatography on silica using 25% diethyl ether in hexane to afford the title compound (D14), (130mg, 75%) 8H (CDC13, 400MHz) 3.15 (2H, m), 3.48 (2H, m), 3.76 (2H, m), 3.82 (2H, m), 7.95 (1H, m) 8.19 (1H, m).

Description 15 6-Bromo-8-nitro-3-trifluoroacetyl-2, 3,4, 5-tetrahydro-lH-benzo [dJazepine (D15)

Prepared from 6-iodo-8-nitro-3-trifluoroacetyl-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine (D13) and copper (t) bromide in a similar manner to Description 14, in 41% yield.

8H (CDC13, 400MHz) 3.18 (2H, m), 3.37 (2H, m), 3.60-3. 85 (4H, m), 7.97-8. 06 (1H, m), 8.36- 8.37 (1H, m).

Description 16 8-Amino-6-chloro-3-trifluoroacetyl-2, 3,4, 5-tetrahydro-lH-benzo [dl azepine (D16) 6-Chloro-8-nitro-3-trifluoroacetyl-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine (D14) (1.7g, 5. 27mmol), was dissolved in methanol (20ml) and treated with 6 equivalents of titanium trichloride (30% solution in 2N HCI, 12. 3ml, 5. 27mmol) at room temperature with stirring, which was continued for a further hour. The reaction was treated with dropwise 30% hydrogen peroxide until the purple colour was extinguished, toluene added and the solvent removed. A saturated solution of sodium acetate in methanol was added until the pH rose to-5 then the solvent was removed. The residue was purified by chromatography on silica using 20-50% diethyl ether in hexane to afford the title compound (D16) (975mg, 63%).

6H (CDC13, 400MHz) 2.89 (2H, m), 3.11 (2H, m), 3.5 (2H br. s), 3.63-3. 76 (4H, m), 6.38 (1H, m), 6.62 (1H, m).

Description 17 8-Amino-6-bromo-3-trifluoroacetyl-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine (D17) Prepared from 6-bromo-8-nitro-3-trifluoroacetyl-2,3, 4, 5-tetrahydro-lH-benzo [d] azepine (D15) in a similar manner to Description 16, in 34% yield.

8H (CDC13, 400MHz) 2.0 (2H, br. s) 2.89 (2H, m), 3.16 (2H, m), 3.64-3. 76 (4H, m), 6.42 (1H, m) 6.81 (1H, m).

Description 18 7-Hydroxy-8-nitro-1, 2,4, 5-tetrahydro-benzo [d] azepine-3-carboxylic acid tert-butyl ester (D18) 7-Hydroxybenzazepine [WO 00/21951] (40g, 0.15 mol), was dissolved in glacial acetic acid (400ml) and added dropwise to a mixture of glacial acetic acid (200ml), acetic anhydride (20ml) and 70% nitric acid (16g). The reaction temperature was maintained at 10°C using an ice bath.

Following addition, the mixture was allowed to warm to ambient and stirrer for a further 2 hours.

The mixture was poured into ice/water (1 litre) and dichloromethane (2 litres) added. The organic phase was separated and neutralised to pH6 by addition of saturated sodium bicarbonate solution. The organic phase was separated, dried (MgS04) and purified by chromatography [Biotage Flash 75,2Kg silica cartridge] using ethyl acetate and hexane as eluents to give the title compound (D18) in 52% yield.

8H (CDC13, 400MHz) 1.48 (9H, s), 2.89 (4H, m), 3.56 (4H, m), 6.92 (1H, s), 7.84 (1H, s), 10.5 (1 H, br. s).

Description 19 7-Methoxy-8-nitro-1, 2,4, 5-tetrahydro-benzo [d] azepine-3-carboxylic acid tert-butyl ester (D19)

A mixture of 7-hydroxy-8-nitro-1, 2,4, 5-tetrahydro-benzo [d] azepine-3-carboxylic acid tert-butyl ester (D18) (49g, 0.16 mol), methyl iodide (12. 4ml), potassium carbonate (27.4g) in N, N- dimethylformamide (400ml) was stirred at room temperature for 16 hours. The mixture was poured into water (300ml) and extracted with diethyl ether (3 x 300ml), the combined organic phases washed with brine (50ml) and dried over MgS04 to afford the title compound (D19) in 96% yield. bH (CDC13, 400MHz) 1.49 (9H, s), 2.88 (2H, m), 2.94 (2H, m), 3.57 (4H, m), 3.94 (3H, s), 6.84 (1H, s), 7.67 (1H, s).

Description 20 8-Amino-7-methoxy-1, 2,4, 5-tetrahydro-benzo [dlazepine-3-carboxylic acid tert-butyl ester (D20) A solution of 7-methoxy-8-nitro-1, 2,4, 5-tetrahydro-benzo [d] azepine-3-carboxylic acid tert-butyl ester (D19) (25g, 78mmol) in ethanol (700ml) was treated with 5% palladium on charcoal (5g) and hydrogenated at 50psi for 1 hour. The catalyst was removed by filtration under argon and the solution evaporated to give the title compound (D20) as a white solid in 96% yield.

SH (CDC13, 400MHz) 1.48 (9H, s), 2.76 (4H, m), 3.51 (4H, m), 3.65 (2H, brs), 3.82 (3H, s), 6.50 (1H, s), 6.55 (1H, s).

Description 21 7- (3, 5-Dichloro-2-methoxy-benzenesulfonylamino)-8-methoxy-1, 2,4, 5-tetrahydro- benzo [dJazepine-3-carboxylic acid tert-butyl ester (D21) 8-Amino-7-methoxy-1, 2,4, 5-tetrahydro-benzo [d] azepine-3-carboxylic acid tert-butyl ester (D20) (80mg) was dissolved in pyridine (0. 5ml), cooled to 0°C and treated with 3,5-dichloro-2-methoxy-benzenesulfonyl chloride (110mg, 0. 41mmol). After 16 hours, the solution was treated with methanol-water 1: 1 (lml) and evaporated. The residue was subjected to chromatography on silicagel, eluting with hexane and diethyl ether to give the title compound (D21) in 87% yield.

8H (CDC13, 400MHz) 1.46 (9H, s), 2.78 (4H, m), 3.48 (4H, m), 3.71 (3H, s), 3.87 (3H, s), 6.53 (1H, brs), 7.22 (1H, s), 7.46 (2H, app. s), 7.49 (1H, s).

Description 22 7- (4-Bromo-2-trifluoromethoxy-benzenesulfonylamino)-6-chloro-1 , 2,4, 5-tetrahydro- benzo [d] azepine-3-carboxylic acid tert butyl ester (D22) A solution of 7-amino-6-chloro-1, 2,4, 5-tetrahydro-benzo [d] azepine-3-carboxylic acid tert-butyl ester (D10) (0. 25mmol, 75mg) in dichloromethane (2ml) was treated with 4-bromo-2- trifluoromethoxy-benzenesulfonyl chloride (135mg 0. 4mmol) in dichloromethane (2ml) and pyridine (0. 2ml). After 14 hours, the solution was treated with water (O. 5ml) and evaporated then the residue purified by flash chromatography on silicagel, eluting with diethyl ether and hexane to afford the title compound (D22) as a white solid.

8H (CDC13, 400MHz) 1.42 (9H, s), 2.85 (2H, m), 3.08 (2H, m), 3.48 (4H, m), 6.94 (1H, d), 7.33 (2H, m), 7.48 (2H, m), 7.85 (1H, d).

Example 1 2,3, 4, 5-Tetrahydro-7-(3-trifluoromethyl) phenylsulfonamido-lH-benzo [dl azepine, hydrochloride (El)

A suspension of 3-t-butyloxycarbonyl-7- (3-trifluoromethyl) phenylsulfonamido-2, 3,4, 5- tetrahydro-1H-benzo[d]azepine (D3) (910mg, 1.93 mmol) in hydrochloric acid (40ml, 4M in 1: 1 water: 1,4-dioxane) was warmed to 60°C for 1 hour. The now clear solution was concentrated in vacuo and the residue crystallised from methanol/ether to afford the title compound (E1) as a pale brown solid (700mg, 89%).

6H (MeOH, 400MHz) 3.05-3. 09 (4H, m), 3.22-3. 26 (4H, m), 6.94 (1H, dd, J = 2.1, 8.1 Hz), 7.03 (1 H, d, J = 2. 1 Hz), 7.12 (1H, d, J = 8. 1 Hz), 7.73 (1H, app. t, J= 7. 9Hz), 7.91 (1 H, d, J = 7. 8 Hz), 7.98 (1H, s), 8.03 (1H, d, J = 7.9Hz).

Found [MH] (Cl7Hl7F3N202S)- Example 2 7-Phenylsulfonamido-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine, hydrochloride (E2) The title compound (E2) was prepared in 90% yield as described in Example 1, from 3-t- butyloxycarbonyl-7-phenylsulfonamido-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine (D4).

8H (D6-DMSO, 400MHz) 2.98 (4H, br, s), 3.08 (4H, br, s), 6.87-6. 93 (2H, m), 7.04 (1H, d, J = 8. 1Hz), 7.53-7. 63 (3H, m), 7.77 (1H, d, J= 7.3Hz), 930 (2H, br, s), 10.35 (1H, br, s).

Found [MH] + 303 (Cl6Hl8N202S).

Examples 3-5 (E3-E5) Examples E3-E5 were prepared by a two step process, using the appropriate aryl sulfonyl chloride with 7-amino-3-t-butyloxycarbonyl-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine (D2) in a similar manner to that described in Description 3, followed by a deprotection step in a similar manner to that described in Example 1. Exam le MH + Formula E3 3-chlorophenyl 337/339 C16Hl7CIN202S E4 5-bromo-2-thienyl 387/389 C, 4H, 5BrN202S2 E5 4-methylphenyl 317 C17H20N2O2S Example 6 7- (4-Bromo-2-trifluoromethoxy) phenylsulfonamido-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine (E6)

Prepared in an analogous procedure to E1 from 7- (4-bromo-2- trifluoromethoxy) phenylsulfonamido-3-t-butyloxycarbonyl-2, 3,4, 5-tetrahydro-1H- benzo [d] azepine (obtained in an analogous manner to that of D3 using 4-bromo-2- trifluoromethoxybenzenesulfonyl chloride).

Found [MH]+ 465/467 (C17H16BrF3N2O3S).

Examples 7-9 (E7-E9)

Examples E7-E9 were prepared by a two step process, using the appropriate aryl sulfonyl chloride with 7-amino-3-t-butyloxycarbonyl-2,3, 4, 5-tetrahydro-1H-benzo[d] azepine (D2) in a similar manner to that described in Description 3, followed by a deprotection step in a similar manner to that described in Example 1. E7 2, 3-dichlorophenyl 371/373 C, 6H, 6Cl2N2O2S E8 3, 5-dichloro-2-methoxyphenyl 401/403 l Cl 7H, 8CI2N203S E9 4-bromo-2-ethylphenyl 409/411 C18H21BrN2O2S

Example 10 7- (4-Chloro-2-trifluoromethoxy) phenylsulfonamido-2, 3,4, 5-tetrahydro-lH-benzo [dJazepine (E10)

Prepared from 7- (4-bromo-2-trifluoromethoxy) phenylsulfonamido-3-trifluoroacetyl-2,3, 4,5- tetrahydro-1H-benzo[d]azepine (obtained by treatment of E6 with trifluoroacetic anhydride in the presence of pyridine as a base) by reaction with copper (1) chloride in N, N-dimethylformamide at reflux, followed by removal of the trifluoroacetyl group using aqueous ammonia.

Found [MH] + 421/423 (Cl7Hl6CIF3N203S).

Example 11 7- (4-Bromo-2-trifluoromethoxy) phenylsulfonamido-2, 3,4, 5-tetrahydro-lH-benzo [d] azepine, hydrochloride (Ell)

7- (4-Bromo-2-trifluoromethoxy) phenylsulfonamido-3-t-butyloxycarbonyl-2, 3,4, 5-tetrahydro-1H- benzo [d] azepine (D7) (30.2g, 53. 5mmol) in dioxane (175ml) and 4N hydrochloric acid (175ml) was heated to 90°C with stirring. After 90 mins a solution was formed and the solvents were removed in vacuo. The residue was recrystallised from isopropanol to afford the title compound (E11) (23.6g, 88%).

8H (MeOd4, 400MHz) 3.04 (4H, m), 3.22 (4H, m), 6.92 (1H, dd, J=2.4Hz, 8Hz), 7.01 (1H, d, J=2.4Hz), 7.08 (lH, d, J=8Hz), 7.64, (2H, m), 7.88, (1H, d, J=8.8Hz).

Found [MH] + 465/467 (C, 7H, 6BrF3N203S) m. p. 231 - 233 °C Example 12 7- (4-Chloro-2-trifluoromethoxy) phenylsulfonamido-2, 3,4, 5-tetrahydro-lH- benzo [dlazepine, hydrochloride (E12) To a stirred suspension of 7- (4-chloro-2-trifluoromethoxy) phenylsulfonamido-3-trifluoroacetyl- 2,3, 4, 5-tetrahydro-lH-benzo [d] azepine (D9) (30.3g, 58. 6mmol) in methanol (750ml) was added 32% ammonia solution (75ml) and the resulting solution stirred at room temperature for 24h. The reaction mixture was then evaporated in vacuo, then the residue was suspended in toluene (800ml) and solvent evaporated in vacuo. The residue was again suspended in toluene (800ml) and solvent evaporated in vacuo. To the resulting colourless residue was added diethyl ether (400ml) and the mixture stirred for 30 minutes before being filtered and dried in vacuo at 50 °C.

To a suspension of this material in dichloromethane (250ml) was added 1M HCI/diethyl ether (123ml) followed by methanol (50ml). The resulting solution was concentrated to an oil and to this added dichloromethane (100ml)/diethyl ether (300ml) to give fine white crystals. The crystals were filtered, washed with dichloromethane/diethyl ether (1 : 3) (2x75ml) and diethyl ether (2x75ml) before being dried in vacuo. The material was then recrystallised from iso- propanol to afford the desired compound as a white solid (21.8g, 81%).

AH (DMSO-d6, 400MHz) 2.99-3. 01 (4H, m), 3.08 (4H, br s), 6.86 (1H, dd, J = 8. 1Hz, 2.3Hz), 6.94 (1H, d, J = 2.2Hz), 7.07 (1H, d, J = 8.2Hz), 7.66-7. 70 (2H, m), 7.97 (1H, d, J = 8. 5Hz), 9.37 (2H, br s), 10.70 (1H, br s).

Found [MH] + 420/422 (C, 7HI6CIF3N203S) m. p. 210-211 °C.

Examples 13-15 (E13-E15)

Examples E13-E15 were prepared by treatment of the appropriate trifluoroacetyl protected aminobenzo [d] azepine derivative (D16 for E13 and E14 and D17 for E15) with the required arylsulfonyl chloride in an analogous manner to the process described in D8, followed by treatment of the product with aqueous ammonia (2M), and subsequent purified by recrystallisation of their respective hydrochlorides. Example R'A [MH] + Formula El3 9-C1 phenyl 337 C16H17ClN2O2S E14 9-Cl (3-trifluoromethyl)phenyl 405 C H C1F N O S E15 9-Br phenyl 381/383C C16H17BrN2O2S

Example 16 7- (4-Bromo-2-trifluoromethoxy-benzenesulfonylamino)-6-chloro-1 , 2,4, 5-tetrahydro- benzo [d] azepine Hydrochloride (E16)

Prepared from 7- (4-bromo-2-trifluoromethoxy-benzenesulfonylamino)-6-chloro-1 , 2,4, 5- tetrahydro-benzo [dlazepine-3-carboxylic acid tert butyl ester (D22) by an analogous method to that described for Example 1.

AH (MeOH-d4, 400MHz) 3.15-3. 47 (8H, m), 7.15 (1H, d), 7.39 (1H, d), 7.65, (2H, m), 7.89, (1H, d).

8H (MeOH d4, 400MHz) 3.15-3. 47 (8H, m), 7.17 (1H, d), 7. 37 (1H, d), 7.65, (2H, m), 7.82, (1H, d).

Found [MH] + 499,501, 503 (C, 7H, 5BrCIF3N203S) Example 17 3, 5-Dichloro-2-methoxy-N-(8-methoxy-2, 3,4, 5-tetrahydro-1H-benzo[d]azepin-7-yl)- benzenesulfonamide hydrochloride (E17)

Prepared from 7- (3, 5-dichloro-2-methoxy-benzenesulfonylamino)-8-methoxy-1, 2,4, 5-tetrahydro- benzo [d] azepine-3-carboxylic acid tert-butyl ester (D21) by an analogous method to that described for Example 1.

8H (MeOD, 400MHz) 2.99 (m, 4H), 3.14 (m, 4H), 3.55 (3H, s), 3.74 (3H, s), 6.70 (1H, s), 7.18 (1H, s), 7.52 (1H, s), 7.57 (1H, s) Found [MH] + 431, 433, 435 (C, 8H20CI2N204S) Pharmacological data Compounds can be tested following the procedures outlined in W098/27081.

The compounds of Examples E1-E17 were tested and showed good affinity for the 5-HT6 receptor, having pKi values > 8 at human cloned 5-HT6 receptors. More specifically, the compounds of Examples 6 and 10 demonstrated pKi values > 8.5 at human cloned 5-HT6 receptors.