ZA200309293B - N-aroyl cyclic amine derivatives as orexin receptor antagonists. - Google Patents

Description

N-AROYL CYCLIC AMINE DERIVATIVES AS OREXIN RECEPTOR ANTAGONISTS

This invention relates to N-aroyl cyclic amine derivatives and their use as : pharmaceuticals. ! Many medically significant biological processes are mediated by proteins participating in signal transduction pathways that involve G-proteins and/or second messengers. . Polypeptides and polynucleotides encoding the human 7-transmembrane G-protein coupled neuropeptide receptor, orexin-1 (HFGAN72), have been identified and are disclosed in

EP-A-875565, EP-A-875566 and WO 96/34877. Polypeptides and polynucleotides encoding a second human orexin receptor, orexin-2 (HFGANP), have been identified and are disclosed in

EP-A-893498.

Polypeptides and polynucleotides encoding polypeptides which are ligands for the orexin- 1 receptor, e.g. orexin-A (Lig72A) are disclosed in EP-A-849361.

Orexin receptors are found in the mammalian host and may be responsible for many : biological functions, including pathologies including, but not limited to, depression; anxiety; addictions; obsessive compulsive disorder; affective neurosis/disorder; depressive neurosis/disorder; anxiety neurosis; dysthymic disorder; behaviour disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; sexual disorder; schizophrenia; manic depression; delerium; dementia; severe mental retardation and dyskinesias such as

Huntington's disease and Gilles de la Tourett's syndrome; disturbed biological and circadian rhythms; feeding disorders, such as anorexia, bulimia, cachexia, and obesity; diabetes; appetite/taste disorders; vomiting/nausea; asthma; cancer; Parkinson's disease; Cushing's syndrome / disease; basophil adenoma; prolactinoma; hyperprolactinemia; hypopituitarism; hypophysis tumor / adenoma; hypothalamic diseases; Froehlich's syndrome; adrenohypophysis disease; hypophysis disease; hypophysis tumor / adenoma; pituitary growth hormone; adrenohypophysis hypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism;

Kallman's syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth hormone deficiency; dwarfism; gigantism; acromegaly; and sleep disturbances associated with such diseases as neurological disorders, neuropathic pain and restless leg syndrome, heart and lung diseases; acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; ischaemic or haemorrhagic stroke; subarachnoid haemorrhage; head injury such as sub-arachnoid haemorrhage associated with traumatic head injury; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired glucose tolerance; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain, such as hyperalgesia, causalgia and allodynia; acute pain; burn pain; atypical . facial pain; neuropathic pain; back pain; complex regional pain syndromes I and II; arthritic pain; sports injury pain; pain related to infection, e.g. HIV, post-polio syndrome, and post-herpetic neuralgia; phantom limb pain; labour pain; cancer pain; post-chemotherapy pain; post-stroke 40 pain; post-operative pain; neuralgia; nausea, vomiting; conditions associated with visceral pain including irritable bowel syndrome, migraine and angina; urinary bladder incontinence e.g. urge incontinence; tolerance to narcotics or withdrawal from narcotics; sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet-lag syndrome; and neurodegenerative disorders, which includes nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex; pallido-ponto-nigral degeneration, epilepsy, and seizure disorders.

Experiments have shown that central administration of the ligand orexin-A (described in more detail below) stimulated food intake in freely-feeding rats during a 4 hour time period. This increase was approximately four-fold over control rats receiving vehicle. These data suggest that : orexin-A may be an endogenous regulator of appetite. Therefore, antagonists of its receptor may be useful in the treatment of obesity and diabetes, see Cell, 1998, 92, 573-585.

There is a significant incidence of obesity in westernised societies. According to WHO definitions a mean of 35% of subjects in 39 studies were overweight and a further 22% clinically obese. It has been estimated that 5.7% of all healthcare costs in the USA are a consequence of obesity. About 85% of Type 2 diabetics are obese, and diet and exercise are of value in all diabetics.

The incidence of diagnosed diabetes in westernised countries is typically 5% and there are estimated to be an equal number undiagnosed. The incidence of both diseases is rising, demonstrating the inadequacy of current treatments which may be either ineffective or have toxicity risks including cardiovascular effects. Treatment of diabetes with sulfonylureas or insulin can cause hypoglycaemia, whilst metformin causes GI side-effects. No drug treatment for Type 2 diabetes has been shown to reduce the long-term complications of the disease. Insulin sensitisers will be useful for many diabetics, however they do not have an anti-obesity effect.

Rat sleep/EEG studies have also shown that central administration of orexin-A, an agonist of the orexin receptors, causes a dose-related increase in arousal, largely at the expense of a reduction in paradoxical sleep and slow wave sleep 2, when administered at the onset of the normal sleep period. Therefore antagonists of its receptor may be useful in the treatment of sleep disorders including insomnia.

The present invention provides N-aroyl cyclic amine derivatives which are non-peptide antagonists of human orexin receptors, in particular orexin-1 receptors. In particular, these compounds are of potential use in the treatment of obesity, including obesity observed in Type 2 (non-insulin-dependent) diabetes patients, and/or sleep disorders Additionally these compounds are useful in stroke, particularly ischemic or haemorrhagic stroke, and/or blocking the emetic response i.e. the compounds are useful in the treatment of nausea and vomiting.

International Patent Applications W(099/09024, W099/58533, WO00/47577 and

WO00/47580 disclose phenyl urea derivatives and WO00/47576 discloses quinolinyl cinnamide derivatives as orexin receptor antagonists.(2R)-1-[3,5-bis(trifluoromethyl)benzoyl}-2-(1H-indol- 3-ylmethyl)piperazine is disclosed in EP899270 as a starting material in the preparation of compounds useful for therapy of functional and inflammatory disorders of the gastrointestinal tract. The compound is also disclosed as Example 6 in EP655442. EP655442 describes piperizine derivatives useful as Tachykinin antagonists. 1-Benzoyl-2-[(1H-indol-3-yl)methyl}piperazine is ' also disclosed therein. (2R)-1-(3.5-dichlorobenzoyl)-2-[(1H-indol-3-yl)methyl}piperazine and (2R)-1-[3,5- bis(trifluoromethyl)benzoyl}-2-[1H-indol-3-yl)methyllpiperazine are used as starting 40 materials/intermediates in W09857954. (2R)-2-[1H-indol-3-yl)methyl]-1-[3-methoxy-5-trifluoromethyl)benzoyllpiperazine, is disclosed as a prepared by preparation 42 in WO00/35915.

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

X

(ne ® wherein:

X represents a bond, oxygen, NR’ or a group (CH,),, wherein n represents 1, 2 or 3; :

Y represents CH,, CO, CH(OH), or CH,CH(OH);

Het is an optionally substituted bicyclic heteroaryl group containing up to 4 heteroatoms selected from N, O and S;

Ar’ represents an optionally substituted phenyl or a 5- or 6-membered heterocyclyl group containing up to 3 heteroatoms selected from N, O and S, wherein the phenyl or heterocyclyl group is substituted by R' and further optional substituents; or Ar represents an optionally substituted bicyclic aromatic or bicyclic heteroaromatic group containing up to 3 heteroatoms selected from N, O and S;

R' represents hydrogen, optionally substituted(C, , )alkoxy, halo, cyano, optionally substituted(C,.)alkyl, optionally substituted phenyl, or an optionally substituted 5- or 6- membered heterocyclyl group containing up to 4 heteroatoms selected from N, O and S;

R’represents hydrogen or an optionally substituent (C, )alkyl other than when Het is indolyl where R? represents hydrogen or (C4) alkyl; or a pharmaceutically acceptable salt thereof. with the proviso that; when X is NH, Y is CH, and Het is indolyl, Ar” is not 3,5-bis(trifluoromethyl)phenyl; or the compound is not (2R)-1-(3,5-dichlorobenzoyl)-2-[(1H-indol-3-yl)methyl]piperazine; (2R)-2-] 1H-indol-3-yDmethyl]-1-[3-methoxy-5-trifluoromethyl)benzoyllpiperazine; or 1-benzoly!l-2-[1H-indol-3-ymethyl]piperazine.

Preferably where Ar’ represents phenyl or a 5- or 6-membered heterocyclyl group containing up to 3 heteroatoms selected from N, O and S, the R' group is situated adjacent to the point of attachment to the amide carbonyl.

X is preferably a bond, oxygen or CH, , NH or NMe, more preferably CH; NH or NMe, most preferably CH,.

Alternatively X is preferably a bond, oxygen or (CHz)n wherein n is 1 or 2.

Y is preferably CH, ' Preferably R is hydrogen or a (C, alkyl. : Het may have up to 5, preferably 1, 2 or 3 optional substituents. ' 35 Examples of when Het is an optionally substituted bicyclic heteroaryl group are quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothienyl, benzofuranyl, benzimidazolyl, naphthyridiny] or benzothiazolyl. Additionally Het may be indolyl, triazolopyridinyl, furopyridinyl, pyridopyrimidinyl, isoquinolinyl or quinolinyl. Furthermore Het can be oxazolylpyridinyl or tetrahydrobenzimidazolyl, tetrahydrobenzofuranyl, or tetrahydrotriazolopyridinyl.

Preferably Het is benzofuranyl, benzoxazolyl, benzimidazolyl, furopyridinyl, benzothiazolyl, indolyl, benzothienyl, triazolopyridinyl, quinolinyl and tetrahydrotriazolopyryidinyl, more preferably benzimidazolyl, benzofuranyl, benzoxazolyl, even i more preferably benzofuranyl or benzimidazolyl.

When Ar’ is a 5- or 6-membered heteroaryl group containing up to 3 heteroatoms selected from N, O and S, it may be furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, triazinyl, pyridazinyl, pyridinyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl or pyrazolyl. :

More specifically, examples of Ar” are thiazolyl, pyrazolyl, triazolyl, pyridazinyl, oxazolyl, pyridinyl, pyrimidinyl, isoxazolyl and thienyl.

When R' is a 5- or 6-membered heterocyclyl group containing up to 4 heteroatoms selected from N, O and S, it may be furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl or pyrazolyl. Additional heterocyclyl groups can be morpholinyi, piperazinyl and thiomorpholinyl. Furthermore it can be tetrazolyl, piperidinyl or pyrrolidinyl.

Preferably when R is a 5- or 6-membered heterocyclyl group containing up to 4 heteroatoms selected from N, O and S, it may be oxadiazolyl, pyridinyl, pyrimidinyl, morpholinyl pyrazolyl or pyrrolyl.

Examples of where Ar’ represents an optionally substituted bicyclic aromatic or bicyclic heteroaromatic include naphthyl, quinolinyl, napththyridinyl, benzofuranyl, benzimidazolyl, quinoxalinyl or quinazolinyl. Additionally Ar’ may be isoquinolinyl or benzoxazolyl.

Furthermore it can benzotriazolyl, benzothienyl, indolyl, benzothiazolyl, or benzothiadiazolyl.

Preferably Ar’ represents optionally substituted phenyl, pyridinyl, thiazolyl, pyrazolyl, pyridazinyl, thienyl, naphthyl, triazolyl, isoxazolyl, quinolinyl, or isoquinolinyl. '

More preferably Ar’ represents optionally substituted phenyl, pyridinyl, thiazolyl, pyrazolyl, thienyl, triazolyl, quinolinyl, or isoquinolinyl.

Even more preferably Ar’ represents optionally substituted phenyl, pyridinyl, thiazolyl, pyrazolyl, thienyl, or 1,2,3-triazolyl.

Alternatively R’ represents hydrogen, optionally substituted(C, , )alkoxy, halo, optionally substituted(C,.¢)alkyl, optionally substituted phenyl, or an optionally substituted 5- or 6- membered heterocyclyl group containing up to 3 heteroatoms selected from N, O and S.

Preferably R' represents optionally substituted(C, , alkoxy, halo, optionally substituted(Cy.¢)alkyl, optionally substituted phenyl, or an optionally substituted 5- or 6- membered heterocyclyl group containing up to 3 heteroatoms selected from N, O and S. ‘ Even more preferably R' represents an optionally substituted phenyl, pyridinyl, pyrazolyl pyrimidinyl or oxadiazolyl group. ) Optional substituents for the groups Het, Ar’, R'and R’ include halogen, hydroxy, oxo, 40 cyano, nitro, (Cia)alkyl, (C,4)alkoxy, hydroxy(Ci4)alkyl, hydroxy(C,4)alkoxy, halo(C,4)alkyl, halo(C,4)alkoxy, aryl(C alkoxy, (Cy4)alkylthio, hydroxy(C,.)alkyl, (Cy4)alkoxy(C,4)alkyl, (Csg)cycloalkyl(Cy4)alkoxy, (Cy4)alkanoyl, (Ci4)alkoxycarbonyl, (Ci4)alkylsulfonyl, (C.. salkylsulfonyloxy, (C;4)alkylsulfonyl(C;4)alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonyl(C;. . _4-

»alkyl, (Cy4)alkylsulfonamido, (C,4)alkylamido, (C;.4)alkylsulfonamido(C;)alkyl, (C,. aalkylamido(C,.)alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamido(C;)alkyl, ' arylcarboxamido(C,.¢)alkyl, aroyl, aroyl(C;4)alkyl, or aryl(C,4)alkanoyl group; a group R*R°N-,

R*OCO(CH,),, R*CON(R*}(CHy),, R*'RPNCO(CH,),, R*RYNSO,(CHy), or R®SONR®(CH,), where . 5 each of R* and R” independently represents a hydrogen atom or a (C,4)alkyl group or where appropriate R’R® forms part of a (Cs.s)azacyloalkane or (Cs.s)(2-0x0)azacycloalkane ring and r represents zero or an integer from 1 to 4. Additional substituents are (C, )acyl, aryl, aryiC,

Dalkyl, (Ci4)alkylamino(Ci)alkyl, RR'N(CH,)n-, R'R'N(CH,)nO-, wherein n represents an interger from 1 to 4. Additionally when the substituent is RR'N(CH,)n- or RR’N(CH,)nO, R* . with at least one CH, of the (CH,)n portion of the group form a (C, Jazacycloalkane and R" represents hydrogen, a (C, )alkyl group or with the nitrogen to which it is attached forms a second (C, ,Jazacycloalkane fused to the first (C, )azacycloalkane.

Preferred optional substituents for Ar? are halogen, cyano, (Cy4)alkyl, hydroxy(Cy)alkyl, (C, )alkoxy(C, alkyl, RR'N(CH,)n or R'R'N, more preferably halogen, cyano and (C, alkyl.

Additional substituents are (Ci.4)acyl, RR'N(CH,)nO, (C, )alkoxy, phenyl, and (C,,)alkylamido.

More preferred substituents for Ar” are (C;)alkyl, hydroxy(C alkyl, RR'N, (C,

Jalkoxy, RR'N(CH,)n, (C, acyl, and (C, )alkylamido.

Preferred optional substituents for Het are halogen, cyano, (C.4)alkyl, hydroxy(C;.4)alkyl, (C, acyl, (C, Dalkoxy(C, Jalkyl, RR*NCO(CH,), R'R"N(CH,)n, R'R"N(CH,)nO or R'R’N.

Additional optional substituents are (C,4)alkoxy or CF,

More preferred substituents for Het are halogen, RR'NCO(CH,), cyano, (C, )alkoxy, (Ciw)alkyl, RRN(CH,)n, hydroxy(C;_4)alkyl, (C,Dacyl or (C, )alkoxy(C, )alkyl. .

Preferred optional substituents for R' are halogen, (C,)alkoxy(C, alkyl, RR'N,

R'R°N(CH,)nO or R'R'N(CH,)n. Additional optional sustituents are (C, )alkyl, (C, Jalkoxy and (C acyl

More preferred substituents for R' are halogen, RR'N(CH,)nO, (C, alkyl, and (C,.

Jalkoxy.

Prefered optional substituents for R’ may be selected from halogen, hydroxy, cyano, (C;. salkoxy, RR'N(CH,)nO or R'R'N.

In the groups Hetand Ar’, substituents positioned ortho to one another may be linked to form a ring.

Illustrative compounds of formula (I) can be selected from: carbonyl)-piperidine methyl-thiazol-4-yI]-methanone [1,2,4]Joxadiazol-5-yl)-phenyl]-methanone and pharmaceutical acceptable salts thereof.

Additional compounds of formula (I) can be selected from: ' (RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-[4-(4-fluoro-pheny1)-1-methyl- 1-H-pyrazol-3-y{}-methane (RS)-1-[2-(5-Fluoro-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-

N phenyl)-2-methyl-thiazol-4-yl}-methanone (RS)-1-[2-(5-Fluoro-benzofuran-2-ylmethyl)-piperidin-1-yI]-1-(5-pyridin-2-yl- _ thiazol-4-y1)-methanone 3 (RS)-1-[2-(5-Fluoro-benzofuran-2-ylmethyl)-piperidin-1-yl}-1-quinolin-4-yl- methanone s (RS)-1-{2-(5-Fluoro-benzofuran-2-ylmethyl)-piperidin-1-yl}-1-quinolin-5-yl- methanone

BN (RS)-1-[2-(5-Fluoro-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-(2-methoxy-pyridin- (RS)-1-[2-Dimethylamino-5-(4-fluoro-phenyl)-thiazol-4-yl}-1-[2~(5-fluoro- benzofuran-2-ylmethyl)-piperidin-1-yl}-methanone (RS)-1-[2-(5-Fluoro-benzofuran-2-ylmethyl)-piperidin-1-yl]- 1-(2-morpholin-4-yl- phenyl)-methanone (RS)-1-{2~(5-Fluoro-benzofuran-2-ylmethyl)-piperidin-1-y1]-1-(2- trifluoromethoxy-phenyl)-methanone (RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-{2~(2-dimethylamino-ethoxy)- phenyl]-methanone (RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-y1)- 1-(2-pyrimidin-2-yl-phenyl)- methanone (RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-y1)-1-[5-(4-fluoro-phenyl)-2H- 1,2,31triazol-4-yl}-methanone (RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-y1)-1-[4-(4-fluoro-phenyl)-1H- pyrazol-3-yl]-methanone (RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-[5-(4-fluoro-phenyl)-2- hydroxymethyl-thiazol-4-yl]-methanone : (RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-{5-[3-(3-dimethylamino- propoxy)-phenyl]-2-methyl-thiazol-4-yl} -methanone (RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-{5-[3-(4-dimethylamino- butoxy)-phenyl]-2-methyl-thiazol-4-yl}-methanone (RS)-1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-(2-furo[2,3-b]pyridin-2-

Imethyl-piperidin-1-yl)-methanone (RS)-1-{4-(4-Fluoro-phenyl)-1-methyl-1 H-pyrazole-3-yl](2-furof2,3-b]pyridin-2- ylmethyl-piperidin-1-yl)methanone (RS)-1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-y1]-1-(2-quinolin-2-ylmethyl- piperidin-1-yl)-methanone (RS)-1-Benzofuran-2-yl-1-(1-{ 1-[5-(4-flucro-phenyl)-2-methyl-thiazol-4-y1]- methanoy!}-piperidin-2-yl)-methanone (RS)-1-[2-(1 H-benzoimidazol-2-ylmethyl)-piperidin-1-y1]-1-[5-(4-fluoro-phenyl)- ’ 2-methyl-thiazol-4-yl]-methanone (RS)-1-[2-(5-Chloro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro- 8 phenyl)-2-methyl-thiazol-4-yl)-methanone : (RS)-1-[2-(5-Fluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl}-1-{5-(4-fluoro- phenyl)-2-methyl-thiazol-4-yl]-methanone (RS)-1-[2-(5-Chloro-6-fluoro-1H-benzoimidazol-2-yImethyl)-piperidin-1-yl}-1-[5- (4-fluoro-phenyl)-2-methyl-thiazol-4-yl}-methanone (RS)-1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-y1]-1-[2-(4-methyl-1H- benzoimidazol-2-ylmethyl)-piperidin-1-yl]-methanone

__| fluoro-phenyl)-2-methyl-thiazol-4-yll-methanone (RS)-1-[2-(4-Dimethylaminomethyl-1H-benzoimidazol-2-ylmethyl)-piperidin-1- : 1}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl}-methanone (RS)-1-[2-(5-Bromo-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl}-1-[5-(4-fluoro- phenyl)-2-methyl-thiazol-4-y1]-methanone (RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yi}-1-[5-(4- fluoro-phenyl)-2-methyl-thiazol-4-yl}-methanone (RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-y1]-1-[5-(4- fluoro-phenyl)-2-methyl-thiazol-4-yll-methanone (RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethy!)-piperidin-1-yl]-1-[5-(4- _ fluoro-phenyl)-2-hydroxymethyl-thiazol-4-yl}-methanone (RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-y1]-1-[5-(4- fluoro-phenyl)-2-hydroxymethyl-thiazol-4-yl]-methanone (RS)-1-[2-(5,6-Difluoro-1 H-benzoimidazol-2-ylmethy1)-piperidin-1-yl}-1-[4-(4- fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone (RS)-1-[2-(5-Methoxy-1 H-benzoimidazol-2-ylmethyl)-piperidin-1-yl}-1-[5-(4- fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone (RS)-1-[2-(6,7-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-y1]-1-(2- methyl-5-phenyl-thiazol-4-yl)-methanone (RS)-1-[2-(6,7-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-y1}-1-[4-(4- fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl}-methanone (RS)-1-[2-(6,7-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl}-1-[4-(4- fluoro-phenyl)-1H-pyrazol-3-yl]-methanone (RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yi}-1-{5-[3-(2- dimethylamino-ethoxy)-phenyl}-2-methyl-thiazol-4-yl}-methanone os | (RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-y1]-1-[5-(2- fluoro-phenyl)-2-methyl-thiazol-4-yl}-methanone 46 | (RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-y1}-1-[5-(3- fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone (RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-y1]-1-(2- trifluoromethoxy-phenyl)-methanone (RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yi]-1-(2- ethoxy-phenyl)-methanone 49 | (RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-y1]-1-(2,6- i dimethoxy-phenyl)-methanone (RS)-1-[2-(6,7-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-y1]-1-(2- pyrazol-1-yl-phenyl)-methanone (RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl}-1-[4-(4- fluoro-phenyl)-1H-pyrazol-3-yl}-methanone (RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin- L-yl}- 1-[2-(3- methyl-[1,2 4Joxadiazol-5-yl)-phenyl]-methanone (RS)-1-[2-(Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-i-yl}-1-[1-(2- dimethylamino-ethyl)-4-(4-fluoro-phenyl)-1H-pyrazol-3-yl}-methanone (RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl}-1-[5-(4- fluoro-phenyl)-2-methyl-2H-[1,2,3 Jtriazol-4-yI]-methanone (RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-{2-[3-(3- dimethylamino-propoxy)-phenyl]-thiophen-3-yl}-methanone (RS)-1-[2-(5,6-Difluoro-1-methyl-1H-benzoimidazol-2-ylmethyl)-piperidin-1-y1}- . 1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone 1-[(S)-2-(1 H-Benzoimidazol-2-ylmethyl)-pyrrolidin-1-y1}- 1-{5-(4-fluoro-phenyl)- 2-methyl-thiazol-4-yl]-methanone : . 1-[(8)-2-(5,6-Difluoro-1 H-Benzoimidazol-2-ylmethyl)-pyrrolidin-1-y1}-1-[5-(4- fluoro-phenyl)-2-methyl-thiazol-4-yl}-methanone 1-[(S)-2-(5,6-Difluoro-1 H-Benzoimidazol-2-ylmethyl)-pyrrolidin-1-yi]-1-[4-(4- fluoro-phenyl)-1-methyl-1H-pyrazol-3-yljmethanone

EN (RS)-1-(2-Benzothiazol-2-ylmethylpiperidin-1-yl)-1-[ 5-(4-fluorophenyl)-2- methylthiazol-4-yl]-methanone [61 _[ (RS)-1-(2-Benzothiazol-2-ylmethylpiperidin-1-yl)-1-[4-(4-fluorophenyl)-1-methyl-

__| I-Hpyrazol-3-yl-methanone (RS)-1-(2-Benzothiazol-2-ylmethylpiperidin-1-y1)-1-[2-(3-methyl- 1,2,4Joxadiazol-5-y)phenyl)-methanone : (RS)-1-[5-(4-Fluorophenyl)-2-methyithiazol-4-yI]-1-[2~(5,6,7,8-tetrahydro-[1,2,4]- triazolo[1,5-a]pyridin-2-ylmethyl)-piperidin-1-yl]-methanone (RS)-1-[5-(4-Fluorophenyl)-2-methyithiazol-4-y1}-1-(2-[1,2,4]triazolo[1,5- a]pyridin-2-ylmethylpiperidin-1-yl)-methanone ' 1-[(RS)2-((RS)-2-Benzofirran-2-yl-2-hydroxy-ethyl)-piperidin-1-y1}-1-[5-(4- fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone (as separate diastereoisomers 66 | (RS)-1-[2-(4-Bromo-1H-benzoimidazol-2-ylmethy})-piperidin-1-y1}-1-[5-(4- ] (RS)-1-[2-(4-Cyano-1H-benzoimidazol-2-ylmethyl)-piperidin-1-y1]-1-[5-(4- fluorophenyl)-2-methylthiazol-4-yl}methanone 6s | (RS)-1-[2-(4-Acetyl-1 H-benzoimidazol-2-ylmethyl)-piperidin-1-y1]-1-[5-(4- fluorophenyl)-2-methylthiazol-4-ylJmethanone

Ex (RS)-2-(1-{ 1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-y1}-methanoyl} -piperidin-2-

Imethyl)-1H-benzoimidazole-5-carbonitrile (RS)-1-[2-(5,6-Difluoro- 1-propyl-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl}- 1-{5-(4-fluoro-phenyl)-2-methyl-thiazol-4-ylj-methanone (RS)-1-{2-[5,6-Difluoro-1-(2-methoxy-ethyl)-1H-benzoimidazol-2-ylmethyl}- piperidin-1-yl1}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone (RS)-1-{2-[1-(2-Dimethylamino-ethyl)-5,6-difluoro-1 H-benzoimidazol-2- ylmethyl]-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-y1]- methanone (RS)-1-{2-[5,6-difluoro-1~(2-hydroxy-ethyl)-1 H-benzoimidazol-2-ylmethyl]- piperidin-1-yl1}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yi]-methanone (RS)-1-[2-(6,7-Difluoro-1-methyl-1 H-benzoimidazol-2-ylmethyl)-piperidin-1-y1]- 1-[5-(4-fluorophenyl)-2-methyl-thiazol-4-yl]-methanone (RS)-1-[2-(4,5-Difluoro-1-methyl-1 H-benzoimidazol-2-ylmethyl)-piperidin-1-y1}- 1-[5-(4-fluorophenyl)-2-methyl-thiazol-4-yl]-methanone (RS)-2-(1-{1-[5-(4-Fluorophenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-

Imethyl)-benzofuran-3-carboxylic acid amide 7 (RS)-2-(1-{1-[4-(4-Fluorophenyl)-1-methyl- 1 H-pyrazol-3-yl}-methanoyl}- . piperidin-2-ylmethyl)-benzofuran-3-carboxylic acid amide (RS)-1-[3-(4,5-Difluoro-1 H-benzoimidazol-2-ylmethyl)-morpholin-4-y1]-1-[5-(4- fluoro-phenyl)-2-methyl-thiazol-4-y!]-methanone (RS)-1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl}-1-(2-furo[3,2-b]-pyridin-2-

Imethyl-piperidin-1-yl)methanone (RS)-1-[4-(4-Fluoro-phenyl)-1-methyl-1 H-pyrazole-3-yl)-(2-furo[3,2-b]pyridin-2- yimethyl-piperidin-1-yl)methanone (RS)-1-[2-(3-Bromo-benzofuran-2-ylmethyl)-piperidin-1-y1}-1-[5-(4-fluoro- phenyl)-2-methyl-thiazol-4-yl]-methanone (RS)-2-(1-{1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanoyl}-piperidin-2-

Imethyl)-benzofuran-3-carbonitrile (RS)-1-[2-(5-Fluorobenzofuran-2-ylmethyl)-4-methylpiperazin-1-yl1}-1-[5-(4- fluorophenyl)-2-methythiazol-4-ylimethanone 34 (RS)-1-(2-Benzofuran-2-ylmethyl-4-methyl-piperazin-1-yl)-1-[5-(4-fluoro-phenyl)- : 2-methyl-thiazol-4-yl)}-methanone (RS)-1-(2-Benzofuran-2-ylmethyl-piperazin-1-yl)-1-[5-(4-fluorophenyl)-2-methyl- thiazol-4-yl]-methanone ' 56 | 1-{(RS)-2-[(RS)-1-(5-Fluoro-benzofurany-2-yl)-1-hydroxy-methyl]-4-methyl- piperazin-1-y1}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-y1}-methanone : 1-{(RS)-2-[(RS)-1-(5-Fluoro-benzofurany-2-yl)-1-hydroxy-methyl]-4-methyl- (RS)-1-[2-(1-{1-[5~(4-fluoro-phenyl)-2-methyl-thiazol-4-yl}-methanoyl } -piperidin-

(R)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl}-1-[ 5-(4- fluoro-phenyl)-2-methyl-thiazol-4-y1}-methanoneand(S)-1-[2-(5,6-Difluoro-1H- benzoimidazol-2-ylmethyl)-piperidin-1-yl}-1-[5-(4-fluoro-phenyl)-2-methyl- thiazol-4-yl]-methanone . and pharmaceutically acceptable salts thereof. ! Further compounds of formula (I) can be selected from 00 | (RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-[5-(4-methoxy-phenyl)-2- methyl-thiazol-4-yl]-methanone . (RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-{5-[3-(2-dimethylamino- etho phenyl}-2-methyl-thiazol-4-yl}-methanone (RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-y1]-1-(5- methyl-3-phenyl-isoxazol-4-yl)-methanone 1-[3-(2,6-Dichloro-phenyl)-5-methyl-isoxazol-4-y1]-1-[2-(4,5-difluoro-1H- benzoimidazol-2-ylmethyD)-piperidin-1-yl}-methanone (RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-y1}-1-[4-(4- fluoro-phenyl)-2-methyl-2H-pyrazol-3-yl}-methanone (RS)-1-[3-(2-Chloro-6-fluoro-phenyl)-5-methyl-isoxazol-4-yl}-1-[2-(4,5-difluoro- 1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-methanone

EN (RS)-1-[3-(2-Chloro-phenyl)-5-methyl-isoxazol-4-y1}-1-[2-(4,5-difluoro-1H- benzoimidazol-2-ylmethyl)-piperidin-1-yl}-methanone (RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl}-1-(2- propoxy-phenyl)-methanone (RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-y1}-1-(2-

El isopropoxy-phenyl)-methanone

EN (RS)-1-(2-Benzyloxy-phenyl)-1-[2-(4,5-difluoro-1H-benzoimidazol-2-ylmethyl)- piperidin-1-yl]-methanone 100 | (RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-y1}-1-(2- 100 ethoxy-6-methoxy-phenyl)-methanone (RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-y1]-1-(2- ethoxy-6-methyl-phenyl)-methanone (RS)-1-(2,6-Diethoxy-phenyl)-1-[2-(4,5-difluoro-1H-benzoimidazol-2-ylmethyl)- piperidin-1-yl}-methanone 1-(3-{1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]- methanoyl}-4-ethoxy-phenyl)-ethanone (RS)-1-{2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethy!)-piperidin-1-y1}-1-(2- ethoxy-naphthalen-1-yl)-methanone 105 | (RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-y1]-1-(2- 105 poh nyridin-2-yl-phenyl)-methanone 106 1-[2-(6,7-Difluoro-1H-benzoimidazol-2-ylmethyl}-piperidin-1-yi]-1-(2-pyrrol-1-yi- : phenyl)-methanone (RS)-1-[2-(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-y1}-1-{5-[3-(3- dimethylamino-propoxy)-phenyl]-2-methyl-thiazol-4-yl}-methanone (RS)-1-[2~(4,5-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl1}-1-{5-[3-(4- 105 | mitts phon 3 my oso 31) manne (RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-y1}-1-{5-(4- fluoro-phenyl)-2-methoxy-thiazol-4-yl]-methanone : 10 | (RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]- 1-[2-ethyl- 5-(4-flucro-phenyl)-thiazol-4-y1}-methanone (RS)-1-[2~(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(2- . flvoro-phenyl)-2-methyl-thiazol-4-y1]-methanone (RS)-1-[2-(5,6-Difluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-y1}-1-{5-(3- fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone (RS)-1-[2-(4-Fluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro- phenyl)-2-methyl-thiazol-4-yl}-methanone (RS)-1-[2~(4-Fluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[4-(4-fluoro- rhenyl)-1-methyl-1H-pyrazol-3-yl]-methanone

(RS)-1-{2-(4-Fluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-1-y1]-1-[4~(4-fluoro- phenyl)-1H-pyrazol-3-yl]-methanone 116 | (RS)-1-[2-(4-Fluore-1H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]-1-[4-(4-fluoro- , phenyl)-2-methyl-2H-pyrazol-3-yl]-methanone

117 (RS)-~1-(2-Ethoxy-phenyl)-1-[2-(4-fluoro-1H-benzoimidazol-2-ylmethyl)-piperidin-

1-yl}-methanone : , (RS)-1-[2-(4-Fluoro-1H-benzoimidazol-2-ylmethyl)-piperidin- 1-yl}- 1-[5-(4-fluoro-

phenyl)-2-hydroxymethyl-thiazol-4-yI}-methanone (RS)-1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-y1]-1-{2-[4-(1-hydroxy-ethyl)-1H- benzoimidazol-2-ylmethyl}-piperidin-1-yl}-methanone i : (RS)- 1-(2-Benzofuran-2-yimethyl-piperidin-1-yi)-1-[5-(4-chioro-phenyl)-2-

120 methyl-thiazol-4-yl}-methanone

121 RS)-1-[2-(3 -Chloro-furo {3,2-b]pyridin-2-ylmethyl)-piperidin-1-yl}-1-[5-(4-fluoro-

: phenyl)-2-methyl-thiazol-4-yI]-methanone : :

122 (RS)-1-[2-(5,6-Difluoro- 1-methyl- { H-benzoimidazol-2-ylmethyl)-piperidin-1-yl]- 1-[5-(4-fluoro-phenyl)-2-hydroxymethyl-thiazol-4-yl]-methanone (RS)-1-{2-(5-Chloro-benzofuran-2-ylmethyl)-4-methyl-piperazin-1-y1}-1-[5-(4-

123 fluoro-phenyl)-2-methyl-thiazol-4-yl}-methanone

124 (RS)-1-[2-(5-Chloro-benzofuran-2-ylmethyl)-piperazin-1-yl1}-1-[5-(4-fluoro- phenyl)-2-methyl-thiazol-4-yl]- methanone

125 (RS)-1-{2-(5,7-Dichloro-benzofuran-2-ylmethyl)-4-methyl-piperazin-1-y1]-1-[5-(4- fluoro-phenyl)-2-methyl-thiazol-4-yl}-methanone ~~ -

126 (RS)-1-[2-(5,7-Dichloro-benzofuran-2-ylmethyl)-piperazin- 1-yl]-1-{5-(4-fluoro- phenyl)-2-methyl-thiazol-4- yl}J-methanone

127 (RS)-1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4~yl}-1-[2-(1H-indol-2-ylmethyl)- piperidin-1-yl]-methanone

128 (RS)-5-{1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-methanoyl]-4 H- benzo[1,4]oxazin-3-one

129 (RS)-1-[2-(5-Bromo-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro- : phenyl)-2-methyl-thiazol-4-yl}-methanone (RS)-1-[2-(5-Cyano-benzofuran-2-ylmethyl)-piperidin-1-y1}-1-[5-(4-fluoro-

130 phenyl)-2-methyl-thiazol-4-yl}-methanone (RS)-1-[2-(4-Bromo-benzofuran-2-ylmethyl)-piperidin-1-y1}-1-[5-(4-fluoro-

131 phenyl)-2-methyl-thiazol-4-yl]-methanone (RS)-1-[2-(4-Cyano-benzofuran-2-ylmethyl)-piperidin-1-yi}-1-[5-(4-fluoro-

132 phenyl)-2-methyl-thiazol-4-yl}-methanone (RS)-1-{5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-y1}-1-[2-(3-methyl-benzofuran-2-

133 ylmethyl)-piperidin-1-yl}-methanone : (RS)-1-(2-(4-Fluoro-benzofuran-2-ylmethyl)-piperidin-1-yI}-1-[5-(4-fluoro-

134 phenyl)-2-methyl-thiazol-4-yl}-methanone (RS)-1-[2-(4-Fluoro-benzofuran-2-ylmethyl)-piperidin-1-yl}-1-[4-(4-fluoro-

’ 135 phenyl)-1-methyl-1H- pyrazol-3 -yl}-methanone (RS)-1-[2-(4,6-Dichloro-benzofuran-2-ylmethyl)-4-methyl-piperazin-1-yl]-1-[5-(4-

136 fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone (RS)-1-[2-(4,6-Dichloro-benzofuran-2-ylmethyl)-piperazin- 1 -y1}-1-[5-(4-fluoro-

137 phenyl)-2-methyl-thiazol-4- yl}-methanone (RS)-1-(2-Benzofuran-2-ylmethyl-pyrrolidin-1-y1)-1-{ 5-(4-fluoro-phenyl)-2-

138 methyl-thiazol-4-yl]-methanone methyl-1H-pyrazol-3-yl}-methanone . methyl-thiazol-4-y{]-methanone : (RS)-1-(2-Benzo{b}thiophen-2-ylmethyl-piperidin-1-y1)-1-[4-(4-fluoro-phenyl)-1- (RS)-1-(2-Benzofuran-2-ylmethyl-piperidin-1-yl)-1-(2-methyl-5-phenyl-thiazol-4- 1-[(S)-2-(5,6-Difluoro-1 H-benzoimidazol-2-ylmethyl)-pyrrolidin-1-yl}-1-[5-(4- 5-yD-phenyl]-methanone : (R)-1-[2-(4,6-Difluoro-1 H-benzoimidazol-2-ylmethyl)-piperidin-1-y1}-1-[5~(4- benzoimidazol-2-ylmethyl)-piperidin-1-yi}-1-[5-(4-fluoro-phenyl)-2-methyl- thiazol-4-yl]-methanone and pharmaceutically acceptable salts thereof.

When a halogen atom is present in the compound of formula (I) it may be fluorine, chlorine, bromine or iodine.

When the compound of formula (I) contains an alkyl group, whether alone or forming part of a larger group, e.g. alkoxy or alkylthio, the alkyl group may be straight chain, branched or cyclic, or combinations thereof, it is preferably methyl or ethyl.

When used herein the term aryl means a 5- to 6- membered ring for example phenyl, or a 7- to 12 membered bicyclic ring system where at least one of the rings is aromatic for example naphthyl.

When used herein the term bicyclic hetero aryl means a 7- to 12 membered bicyclic ring system where at least one of the rings is aromatic for example benzimidazoyl, or ' tetrahydrobenzimidazolyl.

Tt will be appreciated that compounds of formula (I) may exist as R or § enantiomers. The present invention includes within its scope all such isomers, including mixtures. Where additional chiral centres are present in compounds of formula (I), the present invention includes within its scope all possible diastereoismers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.

It will be understood that the invention includes pharmaceutically acceptable derivatives of compounds of formula (I) and that these are included within the scope of the invention. : Particular compounds according to the invention include those mentioned in the examples and their pharmaceutically acceptable derivatives. , 25 As used herein "pharmaceutically acceptable derivative” includes any pharmaceutically acceptable salt, ester or salt of such ester of a compound of formula (I) which, upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (I) or an active metabolite or residue 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 acid addition salts formed with inorganic acids e.g. hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid; and organic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or : naphthalenesulfonic acid. Other salts e.g. oxalates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention. Also included within the scope of the invention are solvates and hydrates of compounds of formula (I). :

Certain of the compounds of formula (I) may form acid addition salts with one or more equivalents of the acid. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions.

According to a further feature of the invention there is provided a process for the preparation of compounds of formula (I) and salts thereof. The following schemes detail some synthetic routes to compounds of the invention. ‘Scheme 1

X X X.

Oras OUT 2 Ol

Nf | “OMe Het N pO P O pO (0)

W

® | Reduction (ii) | and

Deprotection

X N

Om dom (1, ye wy

Ar 0]

U] an . wherein, X, Het, and Ar” are as defined for compounds of formula (I), P is a protecting group and M is a metal for example lithium.

Examples of suitable leaving groups L; include halogen, OC(=0)alkyl and OC(=0)0- alkyl. The transformation (II) to (I) may be carried out in an inert solvent such as dichloromethane, in the presence of a base such as triethylamine. Alternatively this step may be carried out when L' represents hydroxy, in which case reaction with (II) takes place in an inert solvent such as dichloromethane in the presence of a diimide reagent such as 1-ethyl-3-(3-

dimethylaminopropyl)carbodiimide hydrochloride, and an activator such as 1- ‘hydroxybenzotriazole.

Examples of protecting groups P include #-butyloxycarbonyl, trifluoroacetyl and benzyloxycarbonyl. Deprotection conditions are respectively, acid (e.g. trifluoroacetic acid in dichloromethane), base (e.g. sodium hydroxide in a solvent such as aqueous methanol) and : catalytic hydrogenolysis in an inert solvent (e.g using palladium on charcoal in a lower alcohol or ethyl acetate).

Compounds of formula (V) are known in the literature or can be prepared by known methods.

Scheme 2

X

X

X o o () EDC, 2-aminophenol N N (ii) H+ N 3 P ZH P NT,

X x C (i) zZ

N AY MW be ew

AZ ° ArcocL, 0, wherein, X, and Ar® are as defined for compounds of formula (I), Zis S, or O,and Pisa protecting group.

Scheme 3

JO e

X X. (A, - (LK aay

N OH N N

] H [ X X ©

N N

CL 4 CX $ J 2

I N ArRCOL, N N wherein, X, and Ar” are as defined for compounds of formula (I) and P is a protecting group.

Examples of protecting groups P include t-butyloxycarbonyl, trifluoroacetyl and benzyloxycarbonyl. Deprotection conditions are respectively, acid (e.g. trifluoroacetic acid in dichloromethane), base (e.g. sodium hydroxide in a solvent such as aqueous methanol) and catalytic hydrogenolysis in an inert solvent (e.g using palladium on charcoal in a lower alcohol or ethyl acetate). } : The transformation of A to B can be carried out at elevated temperature in the absence of solvent or in the presence of an acid such as sulfuric acid or polyphosphoric acid, usually at elevated temperature. Deprotection can occur in situ under acidic conditions, if for example P is t-butoxycarbony] to afford C directly.

Examples of suitable leaving groups L; include halogen, OC(=0)alky! and OC(=0)0- alkyl. The transformation C to D may be carried out in an inert solvent such as dichloromethane, in the presence of a base such as triethylamine. Alternatively this step may be carried out when

L1 represents hydroxy, in which case reaction with C takes place in an inert solvent such as dichloromethane in the presence of a diimide reagent such as 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride, and an activator such as 1- : hydroxybenzotriazole. Also when L ; represents hydroxy the reaction can be effected using O-(7- azabenzotrazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) with a base such as triethylamine or N,N-diisopropylethylamine.

Scheme 4

X. reduction and X 2 X deprotection ( Ar’COL, (Ay oe N Het

H

PO OH 0

JEN 0 Ho i reduction x : deprotection ~~ ArZCOL, X

N Het Het

N \

P O

0] o ar So ©

Wherein Het, X and Ar” are as defined for formula land P is a protecting group. Suitable reducing agents include sodium borohydride which can be used at ambient temperature in methanol.

Scheme 5

Claims (16)

1. ' 1. A compound of formula (I): CL Het NT YT NY ~ wherein X represents a bond, oxygen, NR? or a group (CH,),, wherein n represents 1, 2 or 3; Y represents CH,, CO, CH(OH), or CH,CH(OH); Het is an optionally substituted bicyclic heteroaryl group containing up to 4 heteroatoms selected from N, O and S; Ar’represents an optionally substituted phenyl or a 5- or 6-membered heterocyclyl group containing up to 3 heteroatoms selected from N, O and S, wherein the phenyl or heterocyclyl group is substituted by R' and further optional substituents; or Ar’represents an optionally substituted bicyclic aromatic or bicyclic heteroaromatic group containing up to 3 heteroatoms selected from N, O and S; R' represents hydrogen, optionally substituted(C, , )alkoxy, halo, cyano, optionally substituted(C,.s)alkyl, optionally substituted phenyl, or an optionally substituted 5- or 6-. membered heterocyclyl group containing up to 4 heteroatoms selected from N, O and S; R’represents hydrogen or an optionally substituent (C, )alkyl other than when Het is indolyl where R? represents hydrogen or (C4) alkyl; or a pharmaceutically acceptable salt thereof. with the proviso that; when X is NH, Y is CH, and Het is indolyl, Ar’ is not 3,5-bis(trifluoromethyl)phenyl; or the compound is not (2R)-1-(3,5-dichlorobenzoyl)-2-[(1H-indol-3-y)methyl] piperazine; (2R)-2-[1H-indol-3-yl)methyl]-1-[3-methoxy-5-trifluoromethyl)benzoyl]piperazine; 1-benzolyl-2-[1H-indol-3-yDmethyl}piperazine.
2. 2. A compound according to claim 1 wherein X is CH,
3. 3. A compound according to claim 1 or 2 wherein Ar’ represents optionally substituted , 35 phenyl, pyridinyl, thiazolyl, pyrazolyl, pyridazinyl, thienyl, naphthyl, triazolyl isoxazolyl, quinolinyl, or isoquinolinyl.
4. 4. A compound according to any one of claims 1 to 3 wherein R' represents optionally substituted phenyl, pyridinyl, pyrazolyl pyrimidinyl or oxadiazolyl group.
5. 5. A compound according to any one of claims 1 to 4 wherein Ar” is optionally substituted by Ciu)alkyl, hydroxy(Ci.4)alkyl, RR'N, (C, alkoxy, RR'N(CH,)n, (Cl acyl, and (C, Jalkylamido.
6. 6. A compound according to any one of claims 1 to 5 wherein Het is benzimidazolyl, benzofurany! or benzoxazolyl.
7. 7. A compound according to any one of claims 1 to 6 wherein Y represents CH,.
8. 8. A compound of formula (I) as defined in any one of Examples 1 to 146, ora pharmaceutically acceptable salt of any one thereof.
9. 9. A pharmaceutical composition comprising a compound of formula (D as defined in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. :
10. 10. Use of a compound of formula (I) as defined in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing diseases or disorders where an antagonist of a human orexin receptor is required.
11. 11. Use of a compound selected from (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H- indol-3-ylmethyl)piperazine, (2R)-1-(3,5-dichlorobenzoyl)-2-[(1H-indol-3- ylmethyl]piperazine,(2R)-2-[ 1H-indol-3-yl)methyl]-1-[3-methoxy-5- trifluioromethyl)benzoyl]piperazine; or 1-benzolyl-2-[1H-indol-3 -yl)methyl]piperazine in the manufacture of a medicament for treating or preventing diseases or disorders where an antagonist of a human orexin receptor is required.
12. 12. A compound of formula (I) as defined in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof for use in treating or preventing diseases or disorders where an antagonist of a human orexin receptor is required.
13. 13. A compound selected from (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1 H-indol-3- ylmethyl)piperazine, (2R)-1-(3,5-dichlorobenzoyl)-2-[(1H-indol-3 -yl)methyl]piperazine,(2R)-2- [1H-indol-3-yl)methyl]-1-[3-methoxy-5-trifluoromethyl)benzoyl piperazine; or 1-benzolyl-2- [1H-indol-3-yl)methyl]piperazine for use in treating or preventing diseases or disorders where an antagonist of a human orexin receptor is required. -68- AMENDED SHI
14. 14. A compound according to any one of claims 1, 8, 12 or 13, substantially as herein described and exemplified.
15. 15. A pharmaceutical composition according to claim 9, substantially as herein described and exemplified.
16. 16. Use according to claim 10 or 11, substantially as herein described and exemplified. - 68A - AMENDED gir