ZA200307983B - N-aroyl cyclic amines. - Google Patents

Description

N-AROYL CYCLIC AMINES

This invention relates to N-aroyl cyclic amine derivatives and their use as pharmaceuticals. . Many medically significant biological processes are mediated by proteins 3 5 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; disturbed biological and circadian rhythms; 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 40 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 pain; post- operative pain; neuralgia; nausea and 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 the treatment of stroke, particularly ischemic or haemorrhagic stroke, and/or blocking the emetic response, i.e. useful in the treatment of nausea and vomiting.

International Patent Applications W099/09024, W099/58533, WO00/47577 and

WO00/47580 disclose phenyl urea derivatives and W000/47576 discloses quinolinyl ¢ cinnamide derivatives as orexin receptor antagonists. W001/96302 discloses N-aroyl cyclic " amine derivatives. © 40 According to the invention there is provided a compound of formula (I):

S

N (CH) X-(CH,) AF" : NY @ ‘ wherein:

Y represents a bond, oxygen, or a group (CH,),, wherein n represents 1,2 or 3 m represents 1, 2, or 3; p represents 0 or 1; ‘Xs NR, wherein R is H or (Cyg)alkyl;

Ar' is aryl, or a mono or bicyclic heteroaryl group containing up to 3 heteroatoms selected from N, O and S; any of which may be optionally substituted;

Ar” represents 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(Cy4 alkoxy, halo, cyano, optionally substituted(Cy.¢)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; wherein when Y is a bond Ar? can not be 2-naphthyl; when Ar! is aryl p isnot 1; or a pharmaceutically acceptable salt thereof.

X is preferably NH. m is preferably 1. p is preferably 0.

Even more preferably m is 1 when p is 0.

Preferably R is hydrogen.

Alternatively compounds of formula (J) are compounds of formula (la);

Y

N Ar

Pa © 30 (Ia) : wherein: “ Y represents a bond, oxygen, or a group (CHy),, wherein n represents 1, 2 or 3

Ar' is a mono or bicyclic heteroaryl group containing up to 3 heteroatoms selected from N, O and S; any of which may be optionally substituted;

Ar? represents 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 ’ 5 heteroatoms selected from N, O and S;

R! represents hydrogen, optionally substituted(C;.4 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; wherein when Y is a bond then Ar” can not be 2-naphthyl; or pharmaceutically acceptable salts thereof. ‘ :

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.

Y is preferably a bond, oxygen or (CHa), wherein n is 1 or 2.

Even more preferably Y is a bond, oxygen or (CHz), wherein n is 1

Alternatively R! represents hydrogen, optionally substituted(C;.4 )alkoxy, halo, optionally substituted(Cy.s)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.

Alternatively R! represents optionally substituted(C,4 )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.

Preferably R'is selected from trifluoromethoxy, methoxy, ethoxy, halo, cyano or an optionally substituted phenyl, pyridyl, pyrazolyl, pyrimidinyl, or oxadiazolyl group.

More preferably R! is selected from trifluoromethoxy, methoxy, ethoxy, halo, or an optionally substituted phenyl, pyridyl, pyrazoly), pyrimidinyl, or oxadiazolyl group. "When Ar' is optionally substituted aryl it is preferably phenyl. Ar may have up to 5, preferably 1, 2 or 3 optional substituents.

Examples of when Ar" is a mono or bicyclic heteroaryl are quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, pyridinyl, pyrimidinyl, or thiazolyl. Additionally Ar' can be selected from pyridazinyl, pyrazinyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridiyl, pyridopyrimidinyl or isoquinolinyl.

Furthermore Ar! can be furanyl or thienyl. : =

Preferably Ar' is benzoxazolyl, benzimidazolyl, quinoxalinyl, quinazolinyl, pyrimidinyl, pyridinyl, naphthyridinyl, Additionally Ar' can be quinolinyl, pyridopyrimidine, thiazolyl, oxazolylpyridinyl, benzothiazolyl, isoquinolinyl or pyrazinyl. o More preferably Ar! is benzoxazolyl, benzimidazolyl, quinoxalinyl, quinazolinyl, pyrimidinyl, pyridinyl, naphthyridinyl or oxazolyl[4,5-b]pyridinyl. i 40 When Ar? is a 5- or 6-membered heterocyclyl group containing up to 3 heteroatoms selected from N, O and S, it may be furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl or pyrazolyl.

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, pyridyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl, . isothiazolyl, isoxazolyl, pyrazinyl or pyrazolyl. Additionally it can be tetrazoyl, piperazinyl, piperidinyl, morpholinyl or thiomorpholinyl.

Preferably when R'is a 5- or 6-membered heterocyclic ring containing up to 4 ’ heteroatoms selected from N, O and S, it is furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl or pyrazolyl.

Preferably R! is a 5- or 6-membered heterocyclic ring it contains up to 3 heteroatoms selected from N, O and S. ;

When Ar is an optionally substituted bicyclic aromatic or bicyclic heteroaromatic it is selected from benzofuryl, benzimidazolyl, quinolinyl, quinoxalinyl or naphthyl.

Additionally it may be benzotriazolyl, benzothienyl, benzoxazolyl, naphthyridinyl, isoquinolinyl or quinazolinyl. F urthermore it can be indolyl, benzothiazolyl, or benzothiadiazolyl.

Preferably Ar? represents optionally substituted phenyl, pyridyl, thiazolyl, pyrazolyl, benzofuryl, naphthyl, triazolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothienyl, benzotriazolyl, benzothiazolyl, indolyl or thienyl.

Alternatively Ar” represents optionally substituted phenyl, pyridyl, thiazolyl, pyrazolyl, benzofuryl, naphthyl! or triazolyl. Preferably the triazolyl is 1,2,3-triazolyl.

More preferably Ar? represents optionally substituted thiazolyl, pyrazolyl or quinolinyl.

Alternatively R'is selected from trifluoromethoxy, methoxy, halo, or an optionally substituted phenyl, pyridyl, pyrazolyl or oxadiazolyl group

Even more preferably R! represents a trifluoromethoxy group, methoxy group, iodo, or an optionally substituted phenyl, pyridyl, or oxadiazolyl group.

Optional substituents for the groups Arl, A, R and R! include halogen, hydroxy, 0x0, cyano, nitro, (C4)alkyl, (Cr4)alkoxy, hydroxy(C.4)alkyl, hydroxy(Cis)alkoxy, halo(Ci)alkyl, halo(Cj)alkoxy, aryl(Ci)alkoxy, (Ci4)alkylthio, hydroxy(C;.4)alkyl, (C;- alkoxy(Ci4)alkyl, (Cs.¢)cycloalkyl(Cy.g)alkoxy, (Ci4)alkanoyl, (C14)alkoxycarbonyl, (C;. s)alkylsulfonyl, (Ci4)alkylsulfonyloxy, (C14)alkylsulfonyl(C;.4)alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonyl(Ci4)alkyl, (Cj4)alkylsulfonamido, (C14)alkylamido, (Ci. salkylsulfonamido(C-4)alkyl, (C;)alkylamido(Cy-s)alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamido(Ci.4)alkyl, arylcarboxamido(Cy.4)alkyl, aroyl, aroyl(C;. alkyl, or aryl(Cy_s)atkanoyl group; a group R*R°N-, R*OCO(CH,);, R®CONR*)(CHy),, ’ R*RPNCO(CH,);, R°R°NSO;(CH), or R*SO,NR®(CHz); Where each of R” and R” independently represents a hydrogen atom or a (Ci4)alkyl group or where appropriate R°R® forms part of a (Cs.¢)azacyloalkane or (Cz)(2-oxo)azacycloalkane ring and r represents 40 zero or an integer from 1 to 4. Additional substituents are (Ci.q)acyl, aryl, aryl(Ci.4)alkyl, (Ci9)alkylamino(C;.4)alkyl, R*RPN(CHa)n-, R*RPN(CH,)nO-, wherein n represents an integer from 1 to 4. Additionally when the substituent is R*R°N(CHa)n- or R*R"N(CH:)nO,

R? with at least one CH, of the (CHy)n portion of the group form a (Cs s)azacycloalkane and R® represents hydrogen, a (Cj4)alkyl group or with the nitrogen to which it is attached ! forms a second (C3.¢)azacycloalkane fused to the first (Cs)azacycloalkane.

Preferred optional substituents for Ar are halogen, cyano, (Ci)alkyl. Additional ¢ preferred optional substituents are hydroxy(Cj.4)alkyl, (Ci4)alkoxy(Ci4)alkyl,

R®R°N(CH>)n, R®R®N . Further optional substituents for Ar” can also be halogen, cyano, (Ci1a)alkyl, R*RPN(CH)nO or (Cj.4)alkoxy.

Preferred optional substituents for Ar' are halogen, cyano, (C;.s)alkanoyl. Other preferred substituents are hydroxy(Ci4)alkyl, (Ci4)alkyl or CFs.

Preferred optional substituents for R! are halogen, (Cy4)alkoxy(Cia)alkyl, RRPN,

R*R°N(CH2)nO and R°RPN(CH,)n. Other preferred substituents are (Ci4)alkoxy or (Ci. s)alkanoyl.

In the groups Ar! and AF, substituents positioned ortho to one another may be linked to form a ring.

Tustrative compounds of formula (I) are selected from: thiazol-4-yl)-methanone. methanone 1-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl}-1-[2-(3-methyl- [1,2,4)Joxadiazol-5-y1)-phenyl}-methanone 1-[2-(Benzooxazol-2-ylaminomethyl)-piperidin-1-yl]-1-(2-trifluoromethoxy- phenyl)-methanone methanone + ma methanone methanone : ~

BU iii— phenyl)-methanone a ¢ 1,2,4]oxadiazol-5-y1)-phenyl]-methanone « methanone methanone phenyl)-2-methyl-thiazol-4-yl]-methanone 1,2,4]oxadiazol-5-yl)-phenyl]-methanone 1,2,4Joxadiazol-5-yl)-phenyl]-methanone phenyl)-methanone methanone - thiazol-4-yl)-methanone ylaminomethyl)-piperidin-1-yl]-methanone 1,2 4Joxadiazol-5-yl)-phenyl]-methanone phenyl)-methanone : methanone methanone phenyl)-methanone phenyl)-methanone methanone ylaminomethyl)-piperidin-1-yl}-methanone ylaminomethyl)-piperidin-1-yl]-methanone ylaminomethyl)-piperidin-1-yl]-methanone .

. ylaminomethyl)-piperidin-1-yl]-methanone ylaminomethyl)-piperidin-1-yl]-methanone 2-methyl-thiazol-4-yl]-methanone [1,2,4]oxadiazol-5-y)-phenyl]-methanone piperidin-1-yl}-methanone piperidin-1-yl]-methanone

’ methanone methanone ylaminomethyl)-piperidin-1-yl]-methanone - ylaminomethyl)-piperidin-1-yl]-methanone ylaminomethyl)-piperidin-1-yl]-methanone piperidin-1-yl]-methanone ylaminomethyl)-piperidin-1-yl]-methanone

: piperidin-1-yl]-methanone ylaminomethyl)-piperidin-1-yl]-methanone ylaminomethyl)-piperidin-1-yl}-methanone ylaminomethyl)-piperidin-1-yl}-methanone : ylaminomethy!)-piperidin-1-yl]-methanone ylaminomethyl)-piperidin-1-yl]-methanone methanone Co piperidin-1-yl]-methanone .

. ylaminomethyl)-piperidin-1-yl}-methanone phenyl)-methanone y1}-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone y1}-1-[5-(4-fluoro-phenyl)-thiazol-4-yl]-methanone y1}-1-{4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-ylj-methanone 1-{(S)-2-[(6,7-Difluoro-3-methyl-quinoxalin-2-ylamino)-methyl]-piperidin-1- yl}-1-[4-(4-fluoro-phenyl)-1 H-pyrazol-3-yl]-methanone 1-{(S)-2-[(6,7-Difluoro-3-methyl-quinoxalin-2-ylamino)-methyl}-piperidin-1- y1}-1-[2~(4-fluoro-phenyl)-5-methyl-2H-pyrazol-3-yl}-methanone y1}-1-{4-(4-fluoro-phenyl)-2-methyl-2H-pyrazol-3-yl]-methanone yl}-1-naphthalen-1-yl-methanone -

RR quinolin-4-yl-methanone fluoro-phenyl)-2-methyl-oxazol-4-yl}-methanone fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone methyl-{1,2 4Joxadiazol-5-yl)-phenyl]-methanone triflucromethoxy-pheny!)-methanone piperidin-1-yl}-methanone me a methyl]-piperidin-1-yl}-methanone fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl}-methanone

Eh fluoro-phenyl)-2-methyl-2H-pyrazol-3-yl}-methanone

Ma fluoro-phenyl)-2-methyl-2H-[1,2,3}triazol-4-yl]-methanone naphthalen-1-yl-methanone fluoro-phenyl)-thiazol-4-yl}-methanone . ylaminomethyl)-piperidin-1-yl])-methanone 73 |1-[2-(3-Methyl-[1,2,4Joxadiazol-5-yl)-phenyl]-1-[2-(oxazolo[4,5-b]pyridin-2-

I FE trifluoromethoxy-phenyl)-methanone ylaminomethyl)-piperidin-1-yl]-methanone yl}-methanone fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone ’ fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone fluoro-phenyl)-2-methyl-2H-pyrazol-3-yl]-methanone rr ylaminomethyl)-piperidin-1-yl]-methanone - ylaminomethyl)-piperidin-1-yl]-methanone ylamino)-methyl]-piperidin-1-y1}-methanone fluoro-phenyl)-2H-pyrazol-3-yl}-methanone fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone fluoro-phenyl)-5-methyl-2H-pyrazol-3-yl]-methanone } fluoro-pheny!)-2-methyl-2H-[1,2,3]triazol-4-yl]-methanone methanoyl)-benzonitrile et naphthalen-1-yl-methanone :

Be ia methyl}-pyrrolidin-1-y1} -methanone : methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-methanone fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone : fluoro-phenyl)-thiazol-4-yl}-methanone . methyl-]1,2,4Joxadiazol-5-yl)-phenyl]-methanone 1 fluoro-phenyl)-1H-pyrazol-3-yl]-methanone 2-ylaminomethyl)-piperidin-1-yl]-methanone

EE b]pyridin-2-yl-amino)-methyl]-piperidin-1-yl}-methanone quinoxalin-2-yl-methanone quinolin-3-yl-methanone isoquinolin-3-yl-methanone

EE i methoxy-pyridin-3-yl)-methanone quinoxalin-6-yl-methanone - piperidin-2-ylmethyl)-amino]-nicotinonitrile

Br Uo pyrimidin-2-ylamino)-methyl}-piperidin-1-yl}-methanone 1-(1H-Benzoimidazol-5-y1)-1-[(S)-2-(pyrido[2,3-b]pyrazin-2-ylaminomethyl)- piperidin-1-yl}-methanone 7 pe dimethylamino-5-(4-fluoro-phenyl)-thiazol-4-yl}-methanone dimethylamino-propoxy)-phenyl]-methanone piperidin-2-ylmethyl)-methyl-amino]-nicotinonitrile 1-((S)-2-{[(6.7-Difluoro-quinoxalin-2-yl)-methyl-amino}-methyl}-piperidin-1- y1)-1-[4-(4-fluoro-phenyl)-1-methyl-1H-pyrazol-3-yl]-methanone and pharmaceutically acceptable salts thereof. :

Additional compounds of formula (I) are selected from: fluoro-benzofuran-2-yl)-methanone 2-ylmethyl)-amino]-nicotinonitrile . pe /1)-amino}-nicotinonitrile 2-ylmethyl)-amino]-isonicotinonitrile 112 be -piperidin-1-y1}-methanone methyl]-piperidin-1-yl}-methanone

1-(1H-Benzotriazol-5-y1)-1-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)- methyl]-piperidin-1-yl}-methanone piperidin-1-yl }-methanone ' piperidin-1-yl}-methanone dimethoxy-phenyl)-methanone yl]-methanone - yl]-methanone vl-methanone fluoro-phenyl)-1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-methanone dimethyl-thiazol-5-yl)-methanone : fluoro-phenyl)-1-methyl-1H-[1,2,3]triazol-4-yl]-methanone methanoyl}-piperidin-2-ylmethy})-amino]-nicotinonitrile fluoro-phenyl)-2-methyl-thiazol-4-yl}-methanone fluoro-phenyl)-1H-pyrazol-3-yl]-methanone : fluoro-phenyl)-2H-[1,2,3]triazol-4-yl]-methanone yl-methanone fluoro-phenyl)-1-methyl-1H-[1,2,3]triazol-4-yl]-methanone - fluoro-phenyl)-2-hydroxymethyl-thiazol-4-yl}-methanone methyl-[1,2,4Joxadiazol-5-yl)-phenyl}-methanone yl-methanone } 6,7-difluoro-quinoline-3-carbonitrile amino }-quinoline-3-carbonitrile

Claims (13)

1. A compound of formula (J): CL N (CH,),-X-(CH,) Ar’ oo Ny ® wherein: Y represents a bond, oxygen, or a group (CHz),, wherein n represents 1, 2 or 3 m represents 1, 2, or 3; p represents O or 1; X is NR, wherein R is H or (Cj4)alkyl; Ar! is aryl, or a mono or bicyclic heteroaryl group containing up to 3 heteroatoms selected from N, O and S; any of which may be optionally substituted; Ar? represents phenyl or a 5- or 6- membered heterocyclyl group containing upto3 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,4 )alkoxy, halo, cyano, optionally substituted(C,g)alkyl, optionally substituted phenyl, or an optionally substituted 5- or 6- membered heterocyclyl group containing up to 4 heteroatoms selected from N,O and SS; wherein when Y is a bond Ar? can not be 2-naphihyl; when Ar’ is aryl pisnot 1; or a pharmaceutically acceptable salt thereof. :

2. A compound of formula (la);

Y. (J N Sar Ny (a) wherein: Y represents a bond, oxygen, or a group (CH>),, wherein n represents 1, 2 or 3 Ar' is a mono or bicyclic heteroaryl group containing up to 3 heteroatoms selected ‘ from N, O and S; any of which may be optionally substituted;

AY represents phenyl or a 5- or 6-membered heterocyclyl group containing upto3 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;4 alkoxy, halo, cyano, optionally substituted(C1.¢)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; wherein when Y is a bond then Ar? can not be 2-naphthyi; or a pharmaceutically acceptable salt thereof,

3. A compound according to claim 1 or 2 wherein Yis a bond, oxygen or (CH), wherenis 1 or 2.

4. A compound according to any preceding claim wherein Ar? represents an optionally substituted phenyl, pyridyl, thiazolyl, pyrazolyl, benzofuryl, naphthyl, triazolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothienyl, benzotriazolyl, benzothiazolyl, indolyl or thienyl.

5. A compound according to any preceding claim wherein Ar' represents an optionally substituted is benzoxazolyl, benzimidazolyl, quinoxalinyl, quinazolinyl, pyrimidiny, pyridinyl, naphthyridinyl, quinolinyl, pyridopyrimidine, thiazolyl, oxazolylpyridinyl, benzothiazolyl, isoquinolinyl or pyrazinyl.

6. A compound according to any preceding claim wherein R! is selected from trifluoromethoxy, methoxy, ethoxy, halo, cyano or an optionally substituted phenyl, pyridyl, pyrazolyl, pyrimidinyl, or oxadiazolyl group.

7. A compound of formula (J) as defined in any one of Examples 1 to 275, ora oo pharmaceutically acceptable salt of any one thereof

8. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

:

9. A compound of formula (I) as defined in anyone of claims 1 to 7, 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. 40 -91- AMENDED SHEET

10. Use of a compound of formula (I) as defined in anyone of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in treating or preventing diseases or disorders where an antagonist of a human orexin receptor is required.

11. A compound according to anyone of claims 1, 2, 7 and 9 substantially as herein described and exemplified.

12. A pharmaceutical composition according to claim 8, substantially as herein described and exemplified.

13. Use according to claim 10, substantially as herein described and exemplified. AMENDED SHEET :