Indian Patents. 224402:"A N-AROYL CYCLIC AMINES COMPOUND OF FORMULA (I)"

Title of Invention	"A N-AROYL CYCLIC AMINES COMPOUND OF FORMULA (I)"
Abstract	A N-aroyl cyclic amines compound of formula (I): wherein: Y represents a bond, oxygen, or a group (CH2)n, wherein n represents 1, 2 or 3; R is H or (C1-4)alkyl; Ar1 is an aryl group and Ar2 represents phenyl or a 5- or 6-membered heterocyclyl group.

Full Text	The present invention relates to a n-aroyl cyclic amines compound of formula 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 Touretfs 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 hyperprolactmemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth hormone deficiency; dwarfism; gigantism; acromegaly; disturbed biological and circadian mythms; 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 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 neurodegenerarive disorders, which includes nosological entities such as disinhibra'on-dementia-parkinsonismamyotrophy 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 fieely-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 JV-aroyl cyclic amine derivatives which are nonpeptide antagonists of human orexin receptors, in particular orexin-1 receptors, hi 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 WO99/09024, WO99/58533, WOOO/47577and WOOO/47580 disclose phenyl urea derivatives and WOOO/47576 discloses quinolinyi cinnamide derivatives as orexin receptor antagonists. WO01/96302 discloses N-aroyl cyclic amine derivatives. According to the invention there is provided a compound of formula (I): (Figure Removed) wherein: Y represents a bond, oxygen, or a group (CHaV wherein n represents 1,2 or 3 m represents 1,2, or 3; p represents 0 or 1; X is NR, wherein R is H or (Cn)a]kyl; Ar1 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; Ar2 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 byR1 and further optional substituents; or Ar2 represents an optionally substituted bicyclic aromatic or bicyclic heteroaromatic group containing up to 3 heteroatoms selected from N, O and S; R1 represents hydrogen, optionally substituted(Ci-4 )alkoxy, halo, cyano, optionally substitated(Ci-6)allcyl, optionally substituted phenyl, or an optionally substituted 5- or 6- membered beterocyclyl group containing up to 4 heteroatoms selected from N, O and S; wherein when Y is a bond Ar2 can not be 2-naphthyl; when Ar1 is aryl p is not 1; — or a pharmaceutically acceptable salt thereof. X is preferably NHL 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 (I) are compounds of formula (la); (Figure Removed) wherein: Y represents a bond, oxygen, or a group (CH^ wherein n represents 1, 2 or 3 Ar1 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; Ar2 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 R1 and further optional substituents; or Ar2 represents an optionally substituted bicyclic aromatic or bicyclic heteroaromatic group containing up to 3 heteroatoms selected from N, O and S; R1 represents hydrogen, optionally substituted(Ci-4 )alkoxy, halo, cyano, optionally substituted(Ci^)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 Ar2 can not be 2-naphthyl; or pharmaceutically acceptable salts thereof. Preferably where Ar2 represents phenyl or a 5- or 6-membered heterocyclyl group containing up to 3 heteroatoms selected from N, O and S, the R1 group is situated adjacent to the point of attachment to the amide carbonyl. Y is preferably a bond, oxygen or (CH2)n wherein n is 1 or 2. Even more preferably Y is a bond, oxygen or (CHz)n wherein n is 1 Alternatively R1 represents hydrogen, optionally substituted(Ci.4 )alkoxy, halo, optionally substituted(Cns)alkyl, optionally substituted phenyl or an optionally substituted 5- or 6-membered heterocyclyl group containing up to 3 heteroatoms .selected from N, O andS. Alternatively R1 represents optionally substituted(CM )alkoxy, halo, optionally substinrted(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 R1 is selected from trifluoromethoxy, methoxy, ethoxy, halo, cyano or an optionally substituted phenyl, pyridyl, pyrazolyl, pyrimidinyl, or oxadiazolyl group. More preferably R1 is selected from trifluoromethoxy, methoxy, ethoxy, halo, or an optionally substituted phenyl, pyridyl, pyrazolyl, pyrimidinyl, or oxadiazolyl group. When Ar1 is optionally substituted aryl it is preferably phenyl. Ar1 may have up to 5, preferably 1,2 or 3 optional substituents. Examples of when Ar1 is a mono or bicyclic heteroaryl are qpuinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzknidazolyl, naphthyridinyl, pyridinyl, pyrimidinyl, or thiazolyl. Additionally Ar1 can be selected from pyridazinyl, pyrazinyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl, quinolinyl, benzofuranyl, indolyi, benzothiazolyl, oxazolyl[4,5-b]pyridiyl, pyridopyrimidinyl or isoquinolinyl. Furthermore Ar1 can be furanyl or thienyl. - Preferably Ar1 is benzoxazolyl, benzimidazolyl, quinoxalinyl, quinazolirryl, pyrimidinyl, pyridinyl, naphthyridinyl, Additionally Ar1 can be quinolinyl, pyridopyrimidine, thiazolyl, oxazolylpyridinyl, benzothiazolyl, isoquinoUnyl or pyrazinyl. More preferably Ar1 is benzoxazolyl, benzimidazolyl, quinoxalinyl, quinazohnyl, pyrimidinyl, pyridinyl, naphthyridinyl or oxazolyl[4,5-b]pyridinyl. When Ar2 is a 5- or 6-membered heterocyclyl group containing up to 3 heteroatoms selected from N, O and S, it may be furanyl, thienyl, pyrroryl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, miadiazolyl, pyridyl, triazolyl, triazbyl, pyridazinyl, pyrimidmyl, isothiazoryl, isoxazolyl, pyrazhiyl or pyrazolyl. When R1 is a 5- or 6-membered heterocyclyl group containing up to 4 heteroatoms selected from N, O and S, it may be fiiranyl, 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 orthiomorpholinyl. Preferably when R1 is a 5- or 6-membered heterocyclic ring containing up to 4 heteroatoms selected from N, O and S, it is fiiranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl or pyrazolyl. Preferably R1 is a 5- or 6-membered heterocyclic ring it contains up to 3 heteroatoms selected from N, 0 and S. When Ar2 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. Furthermore it can be indolyl, benzothiazolyl, or benzothiadiazoiyl. Preferably Ar2 represents optionally substituted phenyl, pyridyl, thiazolyl, pyrazolyl, benzofuryl, naphthyl, triazolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothienyl, benzotriazolyl, benzothiazolyl, indolyl or thienyl. Alternatively Ar2 represents optionally substituted phenyl, pyridyl, thiazolyl, pyrazolyl, benzofuryl, naphthyl or triazolyl. Preferably the triazolyl is 1,2,3-tfiazolyI. More preferably Ar2 represents optionally substituted thiazolyl, pyrazolyl or quinolinyl. Alternatively R1 is selected from trifluoromethoxy, methoxy, halo, or an optionally substituted phenyl, pyridyl, pyrazolyl or oxadiazolyl group Even more preferably R1 represents a trifluoromethoxy group, methoxy group, iodo, or an optionally substituted phenyl, pyridyl, or oxadiazolyl group. Optional substituents for the groups Ar1, Ar2, R and R1 include halogen, hydroxy, oxo, cyano, nitro, (CM)alkyl, (CM)alkoxy, hydroxy(Ci-4)alkyl, hydroxy^Mialkoxy, halo(CM)alkyl, halo(CM>dkoxy, aryl(CM)alkoxy, (CM)alkyltnio, hydroxy(CM)alkyl, (Ci_ 4)alkoxy(Ci4)alkyl, (C3^)cycloallcyl(CM)alkoxy, (CM)alkanoyl, (CM>lkoxycarbonyl, (Ci. 4)alkylsulfonyl, (CM>alkylsulfonyloxy, (CM)alkylsulfonyl(CM)alkyl, arylsutfonyl, arylsutfonyloxy, arylsulfonyl(Cm)alkyl, (Ci_4)alkylsulfonamido, (CM)alkylamido, (Ci- 4)a]kylsulfonamido(CM)alkyl, (Cu)alkylamido(CM)alkyl, arylsutfonamido, arylcarboxamido, arylsulfonamido(CM)alkyl, arylcarboxamido(CM)alkyl, aroyl, 4)alkyl, or aryl(C^)alkanoyl group; a group R'fc'N-, R'OCOCCH^, R'R^COCCKbX, R^^SOaCCHz), or RaSO2NRb(CH2)r ^ere each of R" and Rb independently represents a hydrogen atom or a (C^alkyl group or where appropriate R^1* forms part of a (C3^)azacyloalkane or (C3^)(2-oxo)azacycloalkane ring and r represents zero or an integer from 1 to 4. Additional substituents are (Ci-4)acyl, aryl, aryl(CM)alkyl, (CM)alkylamino(CM)alkyl, RRbN(CH2)n-, R'^'lSfCCHa^O-, wherein n represents an integer from 1 to 4. Additionally when the substituent is RaRbN(CH2)n- or RaRbN(CH2)nO, Ra with at least one CH2 of the (CH2)n portion of the group form a (Ca^azacycloalkane and Rb represents hydrogen, a (Cj^)alkyl group or with the nitrogen to which it is attached forms a second (C3-6)azacycloalkane fused to the first (C^azacycloalkane. Preferred optional substituents for Ar2 are halogen, cyano, (Ci^)alkyl. Additional preferred optional substituents are hydroxy(Ci^)aliyl, (Ci.4)alkoxy(Ci-4)alkyl, R'R^CHz)!!, R^1^. Further optional substituents for Ar2 can also be halogen, cyano, (CM)alkyl, R'R^CCH^nO or (CM)alkoxy. Preferred optional substituents for Ar1 are halogen, cyano, (Ci_4)alkanoyl. Other preferred substituents are hydroxy(Ci-4)alkyl, (Ci^)alkyl or CFa. Preferred optional substituents forR1 are halogen, (Ci-4)alkoxy(Ci-4)alkyl9 R^6!^, R^^CH^nO and RRbN(CH2)n. Other preferred substituents are (CM)alkoxy or (d. 4)alkanoyl. In the groups Ar1 and Ar2, substituents positioned ortho to one another may be linked to form a ring. Blustrative compounds of formula (T) are selected from: (Table Removed) and phannaceutically 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 (T) contains an alkyl group, whether alone or forming part of a larger group, e.g. alkoxy or alkyltbio, the alkyi 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 aromatic 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. It will be appreciated that compounds of formula (T) may exist as R or S 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 diasterepismers, 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. As used herein "pharmaceutically acceptable derivative" includes any pharmaceutically acceptable salt, ester or salt of such ester of a compound of formula (Figure Removed) 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 (1) and derivatives thereof. The following schemes detail some synthetic routes to compounds of the invention. (Figure Removed) wherein Ar1, Ar2, Y, m, p and R are as defined for formula (I), L1 and L2 are leaving groups, and P is a protecting group. Examples of suitable leaving groups L1 include halogen, hydroxy, OSC^Me, OSO2(4-tolyl). The reaction of (V) with (VT) preferably proceeds in an inert solvent such as N^f-dimethylformamide in the presence of a base such as triethylamine, sodium hydride or potassium t-butoxide. Scheme Ib (Figure Removed) Reaction of (VIS) with (IX) proceeds in an inert solvent such as dimethylformamide or xylene in the presence of a base such as potassium carbonate or diisopropylethylamine, preferably at elevated temperatures. Alternatively where m is 1 and p is 0 or 1 compounds maybe prepared as shown in scheme Ic. (Figure Removed) Reaction of (XT) with an alkylating agent (Ci-fiL1 proceeds in the presence of a base such as sodium hydride in an inert solvent such as dimethylformamide. Examples of suitable leaving groups L2 include halogen, hydroxy, QC(=O)alkyl and OC(=O)O-aIkyI. The transformation (U) to (I) may be carried out in an inert solvent such as dichloromethane, in the presence of a base such as triethyiamine. Alternatively this step may be carried out when L2 represents hydroxy, in which case reaction with (H) takes place in an inert solvent such as dichloromethane in the presence of a diimide reagent such as 1- ethyl-3-(3-dimethylaminopropyl)carbodiiniide hydrochloride, and an activator such as 1- hydroxybenzotriazole. Examples of protecting groups P include f-butyloxycarbonyl, trifluoroacetyl , optionally substitued benzyl 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), (VT) and (DQ are known in the literature or can be prepared by known methods. Compounds (VJH) can be prepared by known methods. Within the schemes above there is scope for functional group interconversion; for example in compound (V), conversion of one value of L1 to another value of L1; or hi compounds (TV) conversion of protecting group P for another protecting group P, or conversion of one compound of formula (I) to another of formula (I) by interconversion of substituents. When R1 is an aromatic group, the substituent R1 may be introduced at the final stage as illustrated in Scheme 2 by reaction of a compound of formula (VD) where L3 represents a leaving group such as halogen (preferably bromo or iodo) or trifluoromethylsulfonyloxy, and all other variables are as previously defined, with a reagent R!M, where M is the residue of an organometallic species e.g. B(OH)2 or trialkylstannyl. Such a process may be carried out in an inert solvent such as 1,2-dimethoxyethane or 1,4- dioxan, in the presence of a transition metal catalyst such as Pd(PPh3)4. (Figure Removed) Wherein Y, Ar2, m, p, AT!, R, R1 and Y are as defined for compounds of formula (I). L3 is a leaving group. The compounds of formula (I) may be prepared singly or as compound libraries comprising at least 2, e.g. 5 to 1000, preferably 10 to 100 compounds of formula (I). Compound libraries may be prepared by a combinatorial 'split and mix* approach or by multiple parallel synthesis using either solution phase or solid phase chemistry, by procedures known to those skilled in the art. Thus according to a further aspect of the invention there is provided a compound library comprising at least 2 compounds of formula (I), or phannaceutically acceptable derivatives thereof. Phannaceutically acceptable salts may be prepared conventionally by reaction with the appropriate acid or acid derivative. The compounds of formula (I) and their phannaceutically acceptable derivatives are useful for the treatment of diseases or disorders where an antagonist of a human Qrexin receptor is required such as obesity and diabetes; prolactinoma; hypoprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth hormone deficiency; Cushihgs syndrome/disease; hypothalamic-adrenal dysfunction; dwarfism; sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet-lag syndrome; sleep disturbances associated with diseases such as neurological disorders, neuropathic pain and restless leg syndrome; heart and lung diseases; 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; bulimia and hypopituitarism. Additionally the compounds of formula (I) and pharmaceutically acceptable derivatives are useful for the treatment of stroke, particularly ischemic or haemorrhagic and/or in blocking an emetic response i.e. nausea and vomiting. The compounds of formula (T) and their pharmaceutically acceptable derivatives are particularly useful for the treatment of obesity, including obesity associated with Type 2 diabetes, and sleep disorders. Additionally the compounds of formula (I) and pharmaceutically acceptable derivatives are useful for the treatment of stroke, particularly ischemic or haemorrhagic and/or hi blocking an emetic response i.e. nausea and vomiting. Other diseases or disorders which may be treated in accordance with the invention include disturbed biological and circadian rhythms; adrenohypophysis disease; hypophysis disease; hypophysis tumor /adenoma; adrenohypophysis hypofunction; functional or psychogenic amenorrhea; adrenohypophysis hyperfunction; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia and allodynia; acute pain; bum 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 pain; post-operative pain; neuralgia; and tolerance to narcotics or withdrawal from narcotics. The invention also provides a method of treating or preventing diseases or disorders where an antagonist of a human Qrexin receptor is required, which comprises administering to a subject in need thereof an effective amount of a compound of formula 0), or a pharmaceutically acceptable derivative thereof. The invention also provides a compound of formula (I), or a phannaceutically acceptable derivative thereof, for use in the treatment or prophylaxis of diseases or disorders where an antagonist of a human Qrexin receptor is required. The invention also provides the use of a compound of formula (T), or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment or prophylaxis of diseases or disorders where an antagonist of a human Orexin receptor is required For use in therapy the compounds of the invention are usually administered as a pharmaceutical composition. The invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier. The compounds of formula (T) and then- pharmaceutically acceptable derivatives may be administered by any convenient method, e.g. by oral, parenteral, buccal, sublingual, nasal, rectal or transdennal administration, and the pharmaceutical-compositions adapted accordingly. ' The compounds of formula (I) and their pharmaceutically acceptable derivatives which are active when given orally can be formulated as liquids or solids, e.g. as syrups, suspensions, emulsions, tablets, capsules or lozenges. A liquid formulation will generally consist of a suspension or solution of the active ingredient hi a suitable liquid carriers) e.g. an aqueous solvent such as water, ethanol or glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, preservative, flavouring and/or colouring agent A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose and cellulose. A composition in the form of a capsule can be prepared using routine encapsulation procedures, e.g. pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively a dispersion or suspension can be prepared using any suitable pharmaceutical carriers), e.g. aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into, a soft gelatin capsule. Typical parenteral compositions consist of a solution or suspension of the active ingredient in a sterile aqueous carrier or parenterally acceptable oil, e.g. polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration. Compositions for nasal administration may conveniently be formulated as aerosols, drops, gels and powders. Aerosol formulations typically comprise a solution or fine suspension of the active ingredient in a pharmaceutically acceptable aqueous or nonaqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container which can take the form of a cartridge or refill for use with an atomising device. Alternatively the sealed container may be a disposable dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve. Where the dosage form comprises an aerosol dispenser, it will contain a propellant which can be a compressed gas e.g. air, or an organic propellant such as a fluorochlorohydrocarbon or hydrofluorocarbon. Aerosol dosage forms can also take the form of pump-atomisers. Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles where the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter. Compositions suitable for transdermal administration include ointments, gels and patches. Preferably the composition is in unit dose form such as a tablet, capsule or ampoule. The dose of the compound of formula (I), or a pharmaceutically acceptable derivative thereof, used in the treatment or prophylaxis of the abovementioned disorders or diseases will vary in the usual way with the particular disorder or disease being treated, the weight of the subject and other similar factors. However, as a general rule, suitable unit doses may be 0.05 to 1000 mg, more suitably 0.05 to 500 mg. Unit doses may be administered more than once a day for example two or three times a day, so that the total daily dosage is in the range of about 0.01 to 100 mg/kg; and such therapy may extend for a number of weeks or months. In the case of pharmaceutically acceptable derivatives the above figures are calculated as the parent compound of formula (I). No lexicological effects are indicated/expected when a compound of formula (I) is administered in the above mentioned dosage range. Human Orexin-A has the amino acid sequence: pyroGlu Pro Leu Pro Asp Cys Cys Arg Gin Lys Thr Cys Ser Cys Arg Leu 1 5 10 1 5 Tyr Glu Leu Leu His Gly Ala Gly AsnHis Ala AlaGly Be Leu Thr 20 25 30 Leu-NH2 Orexin-A can be employed in screening procedures for compounds which inhibit the ligand's activation of the orexin-1 receptor. In general, such screening procedures involve providing appropriate cells which express the orexin-1 receptor on their surface. Such cells include cells from mammals, yeast, Drosophila or E. coll. In particular, a polynucleotide encoding the orexin-1 receptor is used to transfect cells to express the receptor. The expressed receptor is men contacted with a test compound and an orexin-1 receptor ligand to observe inhibition of a functional response. One such scieenmgprcK^ure involves the use of rnelanophores which are transfected to express the orexin-1 receptor, as described hi WO 92/01810. ~ Another screening procedure involves introducing RNA encoding the orexin-1 receptor.into Xenopus oocytes to transiently express the receptor. The receptor oocytes are then contacted with a receptor ligand and a test compound, followed by detection of inhibition of a signal hi the case of screening for compounds which are thought to inhibit activation of the receptor by the ligand. Another method involves screening for compounds which inhibit activation of the receptor by determining inhibition of binding of a labelled orexin-1 receptor ligand to cells which have the receptor on their surface. This method involves transfecting a eukaryotic cell with DNA encoding the orexin-1 receptor such that the cell expresses the receptor on its • surface and contacting the cell or cell membrane preparation with a compound in the presence of a labelled form of an orexin-1 receptor ligand. The ligand may contain a radioactive label. The amount of labelled ligand bound to the receptors is measured, e.g. by measuring radioactivity. Yet another screening technique involves the use of FLEPR equipment for high throughput screening of test compounds that inhibit mobilisation of intracellular calcium ions, or other ions, by affecting the interaction of an orexin-1 receptor ligand with the orexin-1 receptor. 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 Examples illustrate the preparation of pharmacologically active compounds of the invention. The Descriptions D1-D105 illustrate the preparation of intermediates to compounds of the invention. hi the Examples !H NMR's were measured at 250MHz in CDCk unless otherwise stated. Description 1: (S) 2-Aminomethyl-piperidine-l-carboxyIic acid tert butyl ester a)2,2-Trifluoro-N-f(S)-l-{(R)-2-hydroxy-l-phenyl-eUiyI>piperidin-2-ylmetbyl]- acetamide (R)-2-[(S)-2-Anunometiiyl-piperidin-l-yl]>2-phenyl-ethanol (20.0g) (Froelich, Olivier, Desos, Patrice; Bonin, Martine; Quirion, Jean-Charles; Husson, Henri-Philippe; Zhu, Jieping., J. Org. Chem. 1996,61,6700) and triethylamine (13.0ml) were dissolved in dichloromethane (500ml), cooled to 0°C and trifluoroacetic anhydride (12.66ml) added dropwise. The mixture was wanned to room temperature and stirred overnight The organic phase was washed with water, separated, dried and solvent removed at reduced pressure. The residue was column chromatographed [silica gel, 0^-10% (9:1 methanol/ammonia) in dichloromethane eluant] to give the title compound (28.0g) as a yellow oil. Mass Spectrum (AH): Found 331 (MH). CieHaiFjNzCb requires 330. [a]D -55°@ 28° 1% in chloroform b)22-Trifluoro-N-(S>-l-piperidin-2-yhiiethyI-acefainide 2,2,2-TrMuoro-N-[(SM^(R)-2-by (28.0g) was dissolved in ethanol (200ml) containing Pearhnans catalyst (2.0g) and shaken under a hydrogen atmosphere (SOpsi) at 50°C for 3 hours. The reaction mixture was filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 0 -10% (9:1 memanol/ammonia) in dichloromethane eluant) to give the title compound (14.18g) as a colourless oil. Mass Spectrum (API): Found 211 (MH). CjRitfjN2O requires 210. [a]D +18°@ 28° 1 % in chloroform 1H MMR 8: (d6-DMSO) 1.07 (1H, m), 1.32 (2H, m), 1.35 -1.60 (2H, m), 1.72 (1H, m), 2.54 (1H, t), 2.70 (1H, m), 3.00 (1H, d), 3.17 (3H, m), 9.30 (1H, br. s.) c) (S)-2-[(2,2^!-Trifluoro-ethanoylaniino)-methyI]-piperidine-l-carboxylic acid ten butyl ester 2^,2-Trifluoro-N-(S)-l-piperidin-2-ylinethyl-acetamide (14.1 8g) was dissolved in dichloromethane (250ml) and treated with di-ter/-butyl dicarbonate (14.95g). The mixture was stirred for 1 6h, washed with water, 2N hydrochloric acid and saturated brine, dried and solvent removed at reduced pressure to give the title compound (1 8.3g) Mass Spectrum (APf): Found 31 1 (MH4). CjsHaiF^Oa requires 310. [ct]D -94°@ 28° 1% in chloroform 'HNMR 8: (d6-DMSO) 1J27 (1H, m), 1.36, 1.47 (9H, s),. 1.49- 1.58 (5H, m), 2.88 (1H, m), 3.22 (1H, m), 3.49 (1H, m), 3.84 (1H, m), 4.34 (1H, m) and 9.42 (1H, br. s.). d) (S) 2-Aminomethyl-piperidiiie-l-carboxylic acid tert butyl ester (S)-2-[(2,2,2-Trifluoro-ethanoylan^ acid tert butyl ester (1 8.2g) was dissolved in methanol (500ml) and treated with potassium carbonate (16.1g). After stirring for 1 6h solvent was removed at reduced pressure and the residue partitioned between dichloromethane/water. The organic phase was separated, washed with brine, dried and solvent removed at reduced pressure, the residue was column chromatographed (silica gel, 0 — 10% (9: 1 methanol/ammonia) in dichloromethane eluant) to give the title compound (8.82g) of description 1. Mass Spectrum (API): Found 215 (MFT). QiHbNaOa requires 214. [a]D -32.2°@ 28° 1% in chloroform 1H NMR 5: 1 .44 (2H, m), 1 .50 (9H, s), 2.64 - 2.80 (2H, m), 2.94 (1H, dd), 3.99 (IH, m) and 4.15 Description 2: (RS) 2-(BenzoxazoI-2-yIaminomethyI>-piperidine-l-carboxylic acid tert butyl ester (RS) 2-Aminomethyl-piperidine-l-carboxyh"c acid tert butyl ester (0.21 g) and 2- cnlorobenzoxazole (0.1 53g) and triethylamine (O.lg) were combined in tetrahydrofuran (1 Oml) and stirred at room temperature for 4 hours. The mixture was partitioned between ethyl acetate and water, the organic phase dried and solvent removed at reduced pressure to give the title compound (036g) as an oil that solidified on standing. Mass Spectrum (API1): Found 332 (MH). CigHisNaQj requires 331. Description 3: (RS)Benzozazol-2-yl-piperidin-2-ylmethyl-aniine The compound of description 2 (0.36g) was stirred in trifluoroacetic acid (1 Oml) containing water (1 drop) for 3 hours. Solvent was removed at reduced pressure and the residue column chromatographed (silica gel, 0-10% (9:1 methanol/ammonia) in dichloromethane eluant) to give the title compound (0.23g). Mass Spectrum (API): Found 232 (MH). CwH^NaO requires 231. Description 4: (R>-2-[(^2^enz»oiazoK2-ylaminomethyI)-piperidin-l-yl]-2-phenylethanol A mixture of (R>2-[(S>2rAmii»mernyl-pirx«^ (l.Og) (Froelich, Olivier; Desos, Patrice; Benin, Martine; Quirion, Jean-Charles; Husson, Henri-Philippe; Zhu, Jieping. J. Org. Chem. 1996, 61, 6700) and 2-chlorobenzoxazole (0.66g) were combined in tetrahydrofuran (40ml) containing triethylamine (0.43g) and stirred at room temperature for 1 hours. The mixture was partitioned between ethyl acetate and water, the organic phase separated, dried and solvent removed at reduced pressure, the residue was column chromatographed (silica gel, 30% pentane in ethyl acetate - ethyl acetate) to give the title compound (l.lg). JHNMRo: 1.59- 1.71 (4H,m), 1.91 (1H, t),2.73 (1H,m),2.95 (1H,m),3.71 (2H,m),4.0 (1H, m), 4.10 (1H, m), 4.26 (1H, m), 5.7 (1H, m), 7.03 (1H, m), 7.17 (1H, m), 7.23 - 7.26 (3H, m) and 7.32 - 7.40 (4H, m). Mass Spectrum (API): Found 352 (MH1). CajH^C^ requires 351. Description 5: BenzoxazoI-2-yl^S)-l-piperidm-2-ymiWhyl-amine The compound of description 4 (1.15g) in ethanol (60 ml) containing Pearlmans catalyst (0.23g) was shaken under an atmosphere of hydrogen (50psi) for 24 hours. Additional Pearlmans catalyst was added and shaking under hydrogen at 50psi continued for a further 12 hours. The reaction was filtered through kiesel guhr, the filtrate evaporated at reduced pressure and the residue column chromatographed (silica gel, ethyl acetate - ethyl acetate/methanol 1:1 eluant) to give the title compound (0.49g) as an oil. 'HNMRS: 1.16 -1.85 (7H,m), 2.64 (lH,m), 2.85-2,99 (lH,m), 3.11 (lH,m),3.31 (1H, m), 3.55 (1H, m), 7.00 (1H, dd), 7.12 (1H, m), 720 (1H, d) and 7.30 (1H, m). Mass Spectrum (API): Found 232 (MH). Ci3H17N3O requires 231. Description 6: (RS)-Benzoxa2ol-2-yl-(4-benzyl-morpholiii-3-yhnethyl)-aniine From (4-beri2yl-moiphoto-3-yl)Hmetb.ylaniine (Ig) (Morie, Toshiya; Kato, Shiro; Harada, Hiroshi; Yoshida, Naoyuki; Fujiwara, Iwao; Matsumoto, Jun-ichi., Chem. Pharm. Bull. 1995,43,1137-47) and 2-cUorobenzoxazole (0.78g), the title compound (0.77g) was prepared according to the method of D4. !H NMR 8:2.33 (1H, m), 2.73 - 2.80 (2H, m), 3.33 (1H, d), 3.51 - 3.90 (6H, m), 4.10 (1H, d), 5.58 (1H, s), 7.04 (1H, m), 7.17 (1H, m) and 724 - 7.39 (7H, m). Mass Spectrum (API): Found 324 (MH). Ci9H2iN3Q2 requires 323. Description 7: (RS)-Benzoiazol-2-yl-morpholin-3-yImethyI-amine From the compound of D6 (0.77g) the title compound (0.55g) was prepared-according to the method of D5. . " JH NMR 8:2.93 - 3.23 (2H, m), 3.46 - 4.03 (7H, m), 6.95 - 7.23 (4H, m). Mass Spectrum (APf): Found 234 (MH). Ci2Hi5N3Q2 requires 233. Description 8: (RS) 2£T-Benz»imidazoI-2-ylaminomethyI)-piperidine-l-carboxyh'c acid tert buryl ester (RS>2-Arnmomemyl-piperiduie-l-carbo^rlic acid tert butyl ester (0.25g) and 2- chlorobenzimidazole (0.15g) were combined and warmed to 100°C for 48 hours. After cooling to room temperature the mixture was column chromatographed (silica gel, ethyl acetate/pentane 1:4 — elhyl acetate/pentane 1:1 eluant) to give the title compound (0.1 g). ]H NMR 8: 1.47 (9H, m), 1.65 - 1.81 (7H, m), 2.85 (1H, t), 3.47 (2H, m), 3.91 (1H, d), 4.32 (1H, s), 5.78 (1H, s), 7.04 (3H3 m) and 7.29 (1H, s). Mass Spectrum (APf): Found 33 1 (MfT). CigHasWa requires 330. Description 9: (RS)-(lfl-Beiizoiniida2oI-2-yI)-piperidin-2-ylmethyl-amine dihydrochloride. The compound of D8 (0.39g) was stirred in a mixture of 4M HC1 in dioxan/methanol (1:1) for 4 hours. Solvent was removed at reduced pressure to give the title compound (0.28g) as a foam. Mass Spectrum (API4): Found 231 (MH1). CisHigty requires 230. Description 10: (RS) 2-(Quinolin-2-ylaminomethyI)-pliperidine-l-carboxylic acid tert butyl ester The title compound (O.lg) was prepared.from (RS) 2-ammomethyJ-piperidine-l-carboxyh"c acid tert butyl ester (0.5ml) and 2-chloroquinoline (0.5g) according to the procedure of D8. Mass Spectrum (API): Found 342 (MH). C2oH27N3Q2 requires 341 . Description 11: (RS)-Pip€ridni-2-yhnethyl-quinolin-2-yI-amine The title compound (0.29g) was prepared from the compound of D10 according to the method of D9. After removal of solvent the residue was dissolved in dichlorometnane, washed with saturated sodium hydrogen carbonate, the organic phase separated, dried and solvent removed at reduced pressure to give the title compound. 'H NMR 8: 1.20 - 1.96 (6H, m), 2.64 (1H, m), 2.85 (1H, m), 3.10 (1H, m), 3.35 (1H, m), 3.60 (1H, m), 5.17 (1H, m), 6.66 (1H, d), 7.19 (1H, dt), 7.48 - 7.58 (2H, m), 7.66 (1H, d) and 7.78 (lH,d). Mass Spectrum (API): Found 242 (MH). CisH^Na requires 24J. Description 12: (RS)-2-(Benzothiazol-2-yIaniinomethyI)-piperidine-l-carboxyIic acid tert butyl ester The title compound (1 2g) after column chromatography (silica gel, 5% diethyl ether/hexane - diethyl ether eluant) was prepared from (RS) 2-arriinornethyl-piperidine-l-carboxyUc acid tert butyl ester (2.0g) and 2-chlorobenzothiazole (l-58g) according to the method of D2. Mass Spectrum (API): Found 348 (MH). CigH^sOzS requires 347. Description 13: (RS)-BenzotbJazol-2^piperidin-2-yhiietnvi-amine The compound of D12 (1 2g) was dissolved in methanol (60ml) and treated with 4N HC1 in dioxan (12 ml), the mixture was stirred for 4h, added to water containing sodium hydrogen carbonate and extracted with ethyl acetate (x 3). The combined organic phase was dried and sol vent removed at reduced pressure to give the title compound (0.70g). Mass Spectrum (APf): Found 348 (MH). C13Hi7N3S requires 347. Description 14: 2--piperidine-l-carboxylic acid tert butyl ester The title compound (0.76g) was prepared from (RS) 2-aminomethyl-piperidine-l-carboxyIic acid tert butyl ester (1.6ml) and 1-chloroisoquinoline (0.8g) according to the method used for the preparation of the compound of D8. Mass Spectrum (API4): Found 342 (MH4). C2oH27N3O2 requires 341. Description 15: IsoquinoIin-l-yl-piperidin-2-ylmethyl-amine The title compound (0.39g) was prepared according to the method of description 13 from the compound of D14 (0.75g). Mass Spectrum (API): Found 242 (MH4). C15Hi9N3 requires 241. Description 16: (S) 2-(QuinoUn-2-ylaminomethyl)-piperidine-i-carboxylic acid tert butyl ester ' The title compound (0.1 Ig) was prepared from (S) 2-aminomethyl-piperidine-l-carboxyh"c acid tert butyl ester (1.23g) and 2-chloroquinoline (Ig) according to the procedure of D8. Mass Spectrum (APf): Found 342 (MH4). CaoH^NaQa requires 341. Description 17: (S>Piperidin-2-ylmethyl-quinolin-2-yl-amine The compound of D16 (0.1 Ig) was dissolved hi dichloromethane (10ml) and trifluoroacetic acid (1ml) added. The mixture was stirred for 4h, poured into ice containing potassium carbonate and extracted with 10% methanol/dichloromethane (x 3). The combined organic extracts were dried and solvent removed at reduced pressure to give the title compound (0.05g). Mass Spectrum (APf): Found 242 (MH4). CisHjpNa requires 241. Description 18: (RS) 2-(Quinoxalin-2-ylamuiomethyl>piperidine-l-carboxylic acid tert butyl ester The title compound (0.73g) was prepared from (RS) 2-aminomethyl-piperidine-l-carboxylic acid tert butyl ester (1ml) and 2-chloroquinoxaline (0.5g) according to the procedure of D8. Mass Spectrum (API4): Found 343 (MH4). Ci^^Cfe requires 342 Description 19: (RS)-Piperidm-2-ylmethyl-quinoxaliii-2-yl-amine The title compound (036g) was prepared from the compound of Dl 8 (0-71g) according to the method of D17. Mass Spectrum (API4): Found 243 (MH4). Cj^gty requires 242. Description 20: (RS) 2-(Pyrinudin-2-ylaminomethyl)-piperidine-l-carboiylic acid tert butyl ester A mixture of (RS) 2-aminomethyl-piperidine-l-carboxyh'c acid tert butyl ester (l-28g) and 2^bJoropyrimidine was heated at 100°C for 48 hours. After cooling to room temperature the mixture was column chromatographed (silica gel, 0 -10% (9:1 methanol/ammonia) in dichloromethane eluant) to give the title compound (0.42g) as an oil. Mass Spectrum (API4): Found 293 (MH4). CisH^Cb requires 292. Description 21: (RS)-Piperidin-2-ylmethyI-pyrimidin-2-yl-amine The title compound (0.350g) was prepared from the compound of D20 (0.4g) according to the method of D 17. Mass Spectrum (APf): Found 193 (Mtf). CioH]6N4 requires 192. Description 22: (RS) 2-{Pyrazin-2-yIaminomethyI)-piperidine-l-carboxylic acid ten butyl ester The title compound (0.1 8g) was prepared from (RS) 2-aminomethyl-piperidine-I-carboxylic acid ten butyl ester (0.54g) and 2-chloropyrazine according to the method of D20. Mass Spectrum (APf): Found 293 (MH). CisHbtN-jO^ requires 292. Description 23: (RS)-Piperidm-2-ylmethyl-pyrazin-2-iyl-ainine The title compound (0. 1 8g) was prepared from the compound of D22 (O.OSg) according to the method of D17. Mass Spectrum (API4): Found 193 (MH). CioHi^ requires 192. Description 24: (S)-2^Quina2»u^-4-ylaminomethyI)-piperiduie-l-carboxyIic acid ten butyl ester (S)-2-Aminomemyl-piperidine-l-carboxylic acid ferf-butyl ester (l.Og), 4-cbloroquinoxaIine (0.768g) and diisopropylethylamine (0.816ml) were dissolved in tetrahydrofuran (75ml) and heated to reflux for 6 hours under an atmosphere of argon. After cooling, the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with saturated sodium hydrogen carbonate solution, saturated brine, dried and evaporated. The residue was chromatographed over silica gel, eluting with a gradient of 50 to 100% ethyl acetate in hexane. The title compound was obtained as a white foam (1 .44g). 1H NMR 8: 1.40 (3H, s), 2.90 (1H, dt), 335-3.50 (1H, br.), 3.9-4,05 (1H, br.), 4.15-4.3 (1H, br.), 4.68-4.82 (1H, br.), 6.9-7.2 (1H, br.), 7.40 (1H, t), 7.65-7.85 (3H, m), 8.65(1H, s). Description 25: (S)-2-(Qiimazolin-4-yIaminomethyI)-piperidine (S)-2-(Qirinazolin^-ylaminomemyl)-piperidine-l-caiix>xylic acid ten butyl ester (1 J5g) was dissolved in trifluoroacetic acid (60ml) and stirred at room temperature for 2 hours. The solution was then evaporated and the residue chromatographed over silica gel, eluting with 0 to 10% (9:1 methanol — concentrated ammonia solution) in dichloromethane. The title compound was obtained as a white foam (0.84g), MrTi"243. Description 26: (S)-2-[(6,7-Dffluoro-3-memylquinoxahii-2-ylamino)methyI]- piperidine-1-carboxylic acid ten bury ester (S>2-Arninomethyl-piperidine-l-carboxyh'c acid /er/-butyl ester (1.14g), and 2-chloro-6,7- difluoro-3-memylqumoxamie7'e/^erfl/PCr//rf.^ff?/ (2000), WOOO/42026A 1 20000720 (1.14g) were dissolved in DMF(2ml) and heated to 90°C for 3 days under an atmosphere of argon. After cooling, the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with water, saturated brine, dried and evaporated. The residue was chromatographed over silica gel, eluting with a gradient of 10 to 50% ethyl acetate in hexane. The title compound was obtained as a pink foam (0.524g), MH~393. Description 27: (S)-2-[(6,7-Difluoro-3-methylquinoxalin-2-yIamino)methyIJ-piperidine (S)-2-[(6,7-Difluoro-3-mernylquhoxalin-2-ylan^ ten butyl ester (0.524g) was dissolved in trifluoroacetic acid (15ml) and stirred at room temperature for 3 hours. The solution was then evaporated and the residue chromatographed over silica gel, eluting with 0 to 10% (9:1 methanol — concentrated ammonia solution) in dichloromethane. The title compound was obtained as a white solid (0.289g), MH293. Description 28: (S)-2~[(6,7-Difluoroquinoxami-2-ylamMo)methyI]-piperidine-lcarborylic acid tert buty ester (S)-2-Aminomethyl-piperidine-l-carboxylic acid ter/-butyl ester (0.607g), and 2-chloro-6,7- dffluoroquinoxaline McQuaidet. al J.MedChem. (1992), 35(18), 3319-24 (0.569g) were dissolved in dimethylformamide (1ml) and heated to 90 °C for 5 days under an atmosphere of argon. After cooling, the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with water, saturated brine, dried and evaporated. The residue was chromatographed over silica gel, eluting with a gradient of 10 to 50% ethyl acetate in hexane. The title compound was obtained as a pale yellow solid (0.460g), 1^379. Description 29: (S)-2-[(6,7-DifluoroquinoxaUn-2-ylamino)niethylJ-piperidine (S>2-[(6,7-Difluoroqiu^oxalm-2-ylam acid tert butyl ester (0.460g) was dissolved in trifluoroacetic acid (10ml) and stirred at room temperature for 3 hours. The solution was then evaporated and the residue chromatographed over silica gel, eluting with 0 to 10% (9:1 methanol - concentrated ammonia solution) in dichloromethane. The title compound was obtained as a pale yellow foam (0286g), MH 279. Description 30: (R^^2-[(6 J-Duluoro^iu^oxalui-2-yIaniuio)-methylJ-pyrrolidine-l carboxylic acid tert butyl ester (R,S)-2-Ammoniethyl-pynoHdine-lKarboxylic acid terf-butyl ester (3.0g) and 2-chloro- 6,7-difluoroqumoxaline (3 .Qg) were combined in xylene (20ml). containing diisopropylethylamine (3ml) and heated at 130°C for 24 hours. Solvent was removed at reduced pressure and the residue column chromatographed (silica gel, diethyl ethenpetroleum ether 1 :1) to give the title compound (3.4g) Mass Spectrum (API): Found 365 (MH). CigKbFalSljQz requires 364. Description 31: (El^2-[(6,74>ifluoroqiiinoxalin-2-ylaiijino)methyl]-pyjTolidine The compound of D30 (3.4g) was dissolved in dichloromethane (100ml) and treated with trifluoroacetic acid (15ml). After 3h additional trifluoroacetic acid (40ml) and dichloromethane (100ml) was added. The mixture was stirred for 48h, poured into excess aqueous sodium hydrogen carbonate, the organic phase separated, dried and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 5% (9:1 methanol/ammonia)/ dichloromethane to give the title compound (0.9g) Mass Spectrum (API): Found 265 (MH). Ci3Hi4F2N4 requires 264. 1H NMR 6: 1 .56 (IH, m), 1.72 - 1.93 (3H, m), 2.96 (2h, m), 3.28 (IH, m), 3.49 (IH, m), 3.64 (IH, m), 7.39 (IH, dd), 7.591H,dd)and8.16(lH,s). Description 32: (S)-2-(quinazoIin-2-ylamino)methyl-piperidiJie-l-carboxylic acid tert butyl ester The title compound (0.6g) was prepared from (S)-2-aminomethyl-piperidine-l-carboxylic acid /erf-butyl ester (0.68g) and 2-chloroquinazoline (0.53g) according to the method of D30. Mass Spectrum (AH): Found 343 (MH). CnHadWh requires 342. Description 33: (S)-l-Piperidin-2-yltnethyI-quinazoIin-2-yl-amine The title compound (0.384g) was prepared from the compound of D32 (0.6g) according to the method of D31 Mass Spectrum (API): Found 243 (MH). C14HigN4 requires 242. 'HNMR 6: 1.18 - 1.65 6H, m), 2.66 (IH, m), 3.08 - 323 (2H, m), 3.50 (IH, m), 3.69 (IH, m), 6.16 (Ih, br. s), 720 (1H, t), 7.54 - 7.69 (3H, m) and 8.91 (IH, s). Description 34: (S)-2-([l^]Naphthyridin-2-yIaminomethyl)-piperidine-l-carboxylic acid tert butyl ester The title compound (0.48g) was prepared from (S)-2-aminomethyl-piperidme-l-carboxylic acid /erf-butyl ester (0.59g) and 2K;hIoro-l^-naphmvridmeJZfl3w?por/>, etal J. Org. Chem. (1971), 36(3), 450-4 (OAOg) according to the method of D30. , Mass Spectrum (API): Found 343 (MH). Ci^^Ch requires 342. Description 35: [l^i]Naphthyridin-2-yl-{S)-l-piperidin-2-yImemyl-amiiie The title compound (0.30g) was prepared from the compound of D34 (0.48g) according to the method of D31. Mass Spectrum (APf): Found 243 (MH). CwHigty requires 242. NMR 8: 1 25 - 1.88 (6H, m), 2.68 (IH, m), 2.98 (IH, m), 3.16 (IH, m), 337 - 3.50 (IH, m), 3.66 (IH, m), 6.85 (IH, d), 7.41 IH, dd), 7.95 (IH, t) and 8.58 (IH, m). " Description 36: (S)-2^1,8-NaphmyridJm-2-ylaniino)methyl-piperidine-l-carboxyh'c acid tert butyl ester The title compound (0.28g) was prepared from (S)-2-aminomemyl-piperidme-l-carboxyHc acid tert-batyl ester (0.35g) and 2-chloro-l,8-naphthyridine (0.19g) according to the method of D30. Mass Spectrum (API): Found 343 (MH). Ci9H26N4O2requues 342. Description 37: [l,8]Naphthyridin-2-yl-(S)-l-piperidin-2-yhnerhyI-amine The title compound (0.1 Ig) was prepared from the compound of D36 (0.28g) according to the method of D31. Mass Spectrum (API): Found 243 (MH). CiiHjgty requires 242. Description 38: (RS) 2-(4-Azabenzooxazol-2-ylaminomethyl)-piperidine-l-carboxyUc acid tert butyl ester The title compound (0.7g) was prepared from (RS)-2-aminomethyl-piperidine-l-carboxylic acid tert-butyl ester (0.64g) and 2-methylthio-4-azabenzoxazole Chu-Moyeret al J. Org. Chem. (1995), 60(17), 5721-5. (0.5g) according to the method of D30. Mass Spectrum (API): Found 333 (MH). CnH^Os requires 332. Description 39: (RS)-Oxazolo[4^-b]]pyridin-2-yl-pipferidin-2-ylinethyl-amine The title compound (0.55g) was prepared from the compound of D38 (0.7g) according to the method of D31. Mass Spectrum (API4): Found 233 (MH). CizHi^O requires 232. Description 40: ((S)-l-{l-[2-(3-Methyl-[lt2,4]-oxadiazoI-5-yl)-phenyI]-methanoyI}- piperidin-2-ylmethyI)-carbamic acid tert butyl ester A mixture of (S)-l-piperidin-2-ylmethyl-carbamic acid tert butyl ester (2.0g) and 2-(3- memyl-[l,2,4]oxadiazol-5-yl)-benzoic acid (1.9) in dimethylformaide (10ml containing diisopropylethylamine (2.4ml) was treated with [O-(7-azabenzotriazol-l-yl)-l,l,3^- tetramethyluronium hexafluorophosphate] (3.55g) and stirred at 90°C for 16 hours. Solvent was removed at reduced pressure and the residue column chromatographed (silica gel, diethyl ether eluant) to give the title compound (3.4g). Mass Spectrum (APf): Found 401 (MH). CziEfeg^CU requires 400. Description 41: l-((S>2-Aminomethyl-piperidin-l-yI)-l-[2- 5-yI)-phenyl]-methanone The title compound (0.53g) was prepared from the compound of D40 according to the method of D13. Mass Spectrum (API4); Found 301 (MH1). Ci6H2oN4Q2 requires 300. Description 42: MethyH(S>l-{l-[2-(3-methyl-[l^,4]oiadiazol-S-yl>-phenyl]- methanoyl}-piperidin-2-ylmethyl)-carbanuc acid dimethyl-ethyl ester ((SH-{H2^3-Merayl-[i;2,4]oxa&azol-5-yl>phen^ carbamie acid tert butyl ester (0.4g) in tetrahydrofuran (5ml) was treated with sodium hydride (0. 1 g). After evolution of hydrogen had ceased iodomethane (0. 1ml) was added and the reaction stirred for 1 6 hours. The reaction was quenched with ice/water, extracted with diethyl ether (x 3), the combined organic extracts dried and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, diethyl ether) to give the title compound (0.2g). Mass Spectrum (API): Found 415 (MH4). CzaHaoN^ requires 414. Description 43: l-[(R)-2-Methylaminomethyl-piperidin-l-ylJ)-l-[2-(3-methyl- [l^,4Joxadiazol-5-yl)-phenyIJ-methanone The title compound (0.1 5g) was prepared from the compound of D42 according to the method of D13. Mass Spectrum (API1): Found 315 (MH4). CnHi2N4 requires 314. Description 44: (S)-2-[(6,7-Difluoro-quino3:aIin-2-yJamino)-methyIJ-pyrroIidine-lcarboxylic acid tert butyl ester The title compound (0.53g) was prepared from (S)-2-aminomemyl-pyrroh"dme-l-caiboxylic acid ter/-butyl ester (0.5g) and 2-chloro-6,7-difmoroquinoxaline (0.5g) according to the method of D30. Mass Spectrum (API4): Found 365 (MH). CigHbfoN^ requires 364. Description 45: (S>2-[(6,7-DifluoroquinoxaIin-2-ylamino)methyl]-pyrroIidine The title compound (038g) was prepared from the compound of D44 (0.53g) according to the method of D31. Mass Spectrum (API): Found 265 (MH). Ci3H]4F2N4 requires 264. Description 46: (RS)-3-[(6,7-Difluoro^uinoxalin-2-ylamino)-methylJ-morphoIine-4- carboxylic acid tert butyl ester The title compound (0.58g) was prepared from 2-aminomethyhnorphohiie-4-carboxylic acid tert-butyl ester (0.82g) and 2-chloro-6,7-difIuoroquinoxaline (0.76g) according to the method of D30. Mass Spectrum (API4): Found 381 (MH). CigHzzFztyOa requires 380. Description 47: (6,74)iQuoro^umoxaIur2~yI)-morpboIm-3-yImethyI-amine The compound of D46 ((X58g) was dissolved in trifhioroacetic acid and stirred for 3hours. Solvent was removed at reduced pressure and the residue partitioned between aqueous sodium hydrogen carbonate and ethyl acetate. The organic phase was separated dried, solvent removed at reduced pressure and the residue column chromatographed ( silica gel, 0 - 10% (9: 1 methanol/ammonia) in dichloromethane, eluant ) to give the title compound (0-327g). Mass Spectrum (API4): Found 281 (MH). Ci3Hi4F2N4O requires 280. Description 48: 2-iylic acid tert butyl ester and 2-(Pyrido[2^A]-pyrazin-3-ylaminomerliyl)-piperidine-lcarborylic acid tert butyl ester A mixture of (S>2-aminomethyl-piperidine-l-carboxylic acid tert butyl ester (I.Og) and a 2:1 mixture of 2K;Uoro-pyrido[23-b]pyrazine and 3K5Uoro-pyrido[23-b]pyrazine (0.8g) was combined and wanned to 90°C for 18 hours. The mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and water, the organic phase dried and solvent was removed at reduced pressure. The residue was column chromatographed (silica gel, dichloromethane 0 to 6% ethanol in dichloromethane, 1% increments) to give as the faster running component 2-(pyrido[2,3-6]pyrazin-2- ylaminomethyl)-piperidine-l-carboxylic acid tert butyl ester (0.48g). mass spectrum (API); Found 344 (MfV). C17H25N5O2 requires 343 and 2-(pyrido[2,3-£]pyrazin-3- y]arninometbyl)-piperidine-l-carboxylic acid tert butyl ester (0.3g) mass spectrum (API): Found 344 (ME). C,7H25N5O2 requires 343. Description 49: Piperidin-2-ylmethyl-pyrido[23-A]pyrazin-2-yI-aiixuie trifluoroacetate salt 2-(Pyrido[23-6]pyrazm-2-ylammomemyl)-piperidine-l-carboxyh"c acdd tert butyl ester (0.48g) was dissolved in dichloromethane (3ml), cooled (ice bath) and treated with trifluoroacetic acid (2ml). The mixture was stirred for 3hours at room temperature, solvent removed at reduced pressure and the residue co-evaporated with toluene to give the title compound (0.45g). Mass spectrum (APf)-' Found 244 (MH> C\|3Hi7N5 requires 243. . Description SO: Piperidin-2-ylmethyl-pyrido[23-^]pyrazin-3-yl-amine trifluoroacetate salt The title compound (0.3g) was prepared from 2^yrido[23-i]pyrazin-3-ylaminomethyl)- piperidine-1-carboxylic acid tert butyl ester (0.3g) according to the method of description Mass spectrum (API4): Found 244 (MH). CisHnNs requires 243. Description 51: 2-Thioureidomethyl-piperidine-l-carboxylic acid tert butyl ester Benzoyl chloride (1 -2ml) was added dropwise to sodium thiocyanate (0.90g) in acetone (50ml). When the addition was complete the mixture was refluxed for 1 5 minutes, cooled to room temperature and (RS) 2-aminomethyl-piperidine-l-carboxylic acid tert butyl ester (2.0g) in acetone (5ml) added. The mixture was refluxed for 2 hours, cooled to room temperature and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, 0 — 10% (9:1 methanol/ammonia) in dichloromethane eluant) to give the title product (1 .95g). Mass spectrum (API): Found 274 (MH). CnHbNaCbS requires 273. Description 52: 2-[(4-Phenyl-thiazol-2-ylamino)-niethyl]-piperidine-l-carborylic acid tert butyl ester The compound of description 51 (1.95g) was dissolved in ethanol (100ml) containing triethylamine (0.99ml). Phenacyl bromide (1.42g) was added and the mixture stirred for 16 hours. Solvent was removed at reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was separated and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, dichloromethane eluant) to give the title compound (2.42g). Mass spectrum (API): Found 274 (MH). C^yNsOaS requires 273. Description 53: (4-Phenyl-thiazol-2-yI>-piperidin-2-ylniethyl-aniine The title compound (1 .55g) was prepared from the compound of D52 (2.42g) according to the method of D47. Mass spectrum (API): Found 174 (MH4). CjsH^NsOaS requires 173. Description 54: 2-[(5-Cyano-pyridin-2-ylamino)-methyl]-piperidine-l-carboxylic acid tert butyl ester. The title compound (1 .54g) was prepared from (S)-2-arainomethyl-piperidine-l-carboxyh"c acid terf-butyl ester (2.0g) and 2-chloro-5-cyanopyridine (1.29g) in the presence of diisopropylethylamine (1.21g) according to the method of D28. Mass spectrum (API): Found 317 (MH4). CnHa^Oi requires 316. Description 55: 6-[(Piperidin-2-ylmethyl)-amino]-nicotinonitriIe The title compound (1 .56g) was prepared from the compound of D54 (1 .53g) and trifluoroacetic acid according to the method of D29. Mass spectrum (API): Found 217 (MH1). Ci2Hi$N4 requires 216. Description 56: 2-[(4-Trifluoromethyl-pyrimidin-2-ylamino)-niethylJ-piperidine-lcarboxylic acid tert butyl ester The title compound (0.298g) was prepared from (S)-2-aminomethyl-piperidine-l-carboxyh"c acid ter/-butyl ester (1 .Og) and 2s±loro^trifluoropyrirnidine (0.85g) according to the method of D28. Mass spectrum (API4): Found 361 (MH4). CieH^F^Qz requires 360. Description 57: Piperidm-2-yhiiethyH^t1^uorometbyl-pyriniidin-2-yI)-amine. The title compound (0.25g) was prepared from the compound of D56 (OJ29g) and trifluoroacetic acid according to the method of D29. Mass spectrum (API1): Found 261 (MH). CnHisFaty requires 260. Description 58: ((S)-l-{l-[4-(4-Fluoro-phenyl)-l-mettiyl-LH— pyrazoI-3-yI]-methanoyl}- piperidin-2-ylmethyI)-carbamic acid tert butyl ester The title compound (3.96g) was prepared from (S)-l-piperidin-2-yhnethyl-carbamic acid tert butyl ester (2.14g) and 4^4-fluoro^henyl)-l-rnethyl-l/r-pyrazol-3-yl carboxyh'c acid (220g) according to the method of D40. Mass spectrum (API4): Found 417 (MH4). CzjHjjjF^Os requrres 416. Description 59: ((S)-l-{l-[4^4-Fluoi^phenyI)-l-metbyl-lH-pyrazol-3-yl]-methanoyI}- piperidin-2-ykaethyI)-methyI-carbamic acid dimethyl-ethyl ester. The title compound (2.0g) was prepared from the compound of description 58 (3.85g) according to the method of D42. Mass spectrum (API): Found 431 (MH4). C^iFNA requires 430 Description 60: l-[4-(4-Fluoro-phenyl)-l-methyl-Lff-pyrazol-3-yl]-l-((S>-2- methylaniinomethyl-piperidin-l-yi>-methanone -40- The title compound (0.1 5g) was prepared for the compound of D59 (0.50g) according to the method of D29. Description 61 : (S)-2-[(3-Cyano-pyridin-2-yIamino)-methyl]-piperidine-l-carboxyIic acid lert butyl ester The title compound (0.66g) was prepared from (S)-2-aniinomethyl-piperidine-l-carboxylic acid terr-butyl ester (1 .55g) and 2-chloro-3-cyanopyridine (1 .Og) according to the method of D28. Mass spectrum (APf): Found 317 (MET1). CiyKWSLA requires 316 Description 62: 2-[((S)-l-Piperidin-2-yunethyI)-amino]-nicotinonitriIe The title compound (0.53g) was prepared from me compound of D61 (0.663g) and trifluoroacetic acid according to the method of D29. Mass spectrum (API): Found 217 (MH4)- Ci2Hi6N4 requires 216 Description 63: (S)-2-[(4-C^ano-pyridm-2-ylamino)-methyIJ-piperidine-l-carboxyIic acid tert butyl ester The title compound (0.24g) was prepared from (S)-2-aminomethyl-piperidine-l-carboxylic acid fe/f -butyl ester (1 . 14g) and 2-chloro-4-cyanopyridine (0.74g) according to the method ofD28. Mass spectrum (API4): Found 317 (MH4). CnfkdWh requires 316 Description 64: 4-Cyano-2-[((S)-l-Piperidui-2-ybnethyI)-aminoJ-pyridine The title compound (0.1 7g) was prepared from the compound of D63 (0.243g) and trifluoroacetic acid according to the method of D29. Mass spectrum (API4): Found 217 (MH4). CuHuNi requires 216 Description 65: (S)2-[(5-Bromo-pyrmudto-2-ylamino)-methyl]-piperidine-l-carboxyuc acid tert butyl carbonate. (S>2-Aminomemyl-piperidine-l-carboxylic acid tert butyl ester (Ig), 5-bromo-2- chloropyrimidine (0.9g) were combined in xylene (20ml) containing potassium carbonate (1 .29g) and diisopropylethylamine (2.43g) and wanned to reflux for 48k The mixture was cooled to room temperature, filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, pentane - 25% ethyl acetate/pentane). The appropriate fractions were collected, solvent removed at reduced pressure to give the title compound (1.43g) as a colourless gum Mass spectrum (API4): Found 272 (Mrf-tert BOG). CioHW^UBr requires 371 Description 66: (S) (5-Bromo-pyrimidin-2-yl)-piperidin-2-ybaiethyl-amine The title compound (1 .40g) was prepared from the compound of D65 (2.1 g) according to the method of D9. Mass spectrum (API4): Found 272 (MH4). CioHi4N4Br requires 271. Description 67: (S) 2-[(3- 1-carboxylic acid tert butyl ester. (S)-2-Aminomemyl-piperidine-l-carboxytic acid tert-butyl ester (l.lg) and 2-chloro-3- cyano-5,6-difluoroquinoIine (1 .12g) according to the method of D28 were combined in xylene (1 5ml) containing potassium carbonate (4.0g) and diisopropylethylamine (4ml) and boiled for 20 hours. The reaction mixture was cooled to room temperature, filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, dichloromethane eluant) to give after combining appropriate fiactions the title compound Mass spectrum (API4): Found 403 (MH). C21H24F2N Description 68: (S) 6,7-Difluoro-2-[(piperidin-2-ylmethyI)-amino]-quinoline-3- carbonitrile The title compound (1 .40g) was prepared from the compound of D67 (1 .8g) according to the method of D9. Mass spectrum (API4): Found 303 (MH). CieHieFaty requires 302 Description 69: (S)2-[(5-Bromo-pyriinidm-2-ylammo)-methyl]-pyrrolidin-l-carboxyIic acid tert butyl carbonate. (S)-2-Aminomethyl-pvrrolidhie-l-carboxylic acid tert butyl ester (2g), 5-bromo-2- chloropyrimidine (1.93g) were combined hi xylene (4Qml) containing potassium carbonate (2.76g) and diisopropylemylamine (5.23ml) and wanned to reflux for 20h. The mixture was cooled to room temperature, filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, pentane — 25% ethyl acetate/pentane). The appropriate tractions were collected, solvent removed at reduced pressure to give the title compound (l-78g) as a colourless gum Mass spectrum (API): Found 257 (MlT-tertBOC). C14H21BrN4O2 requires 357 Description 70: (S) (5-Bromo-pyrunidm-2-yI)-pyrTOu"din-2-yImethyl-amhie The title compound (1 .40g) was prepared from the compound of D69 (1 .78 g) according to the method of D9. Mass spectrum (API): Found 258 (MH). Cj>Hi2N4Br requires 257. Description 71: 3^1-{(S)-2-[(6,7-Duluoro^umox:alin-2-yIamino>rnethyI]-piperidin-lyl}- methanoyl)-benzoic add benzoic acid methy ester (0.5g) was dissolved in methanol (1 5ml) and treated with 1M sodium hydroxide (1 .7ml). The reaction mixture was stirred for 12 h, additional 1M sodium hydroxide (1 .7ml) added and stirring continued for a further 24k The reaction mixture was diluted with water and washed with ethyl acetate. The aqueous phase was acidified with 2M hydrochloric acid and extracted with ethyl aceate (x 3). the combined organic phase was dried (MgSOl), fioltered and solvent removed at reduced pressure to give the title compound (0.463g) as a yellow solid. Mass spectrum (APf): Found 427 (MHT). C^H^HiOa requires 426. Description 72: 1,1,1-Trifluoromethanesulphonic acid, 5-bromo-pyridin-2-yl ester To a solution of 5-bromo-2-pyridone (3g) in dichloromethane (60ml) andpyridine (60ml) at 0°C under argon was added dropwise trifluoromethane sulphonic anhydride (5.4g). The resulting mixture was warmed to ambient temperature and after 20h was evaporated and the residue chromatographed on silica gel eluting with ethyl acetate to afford the title product (3.5g) as a yellow oil. JH NMR 8: 7.1 0 (1H, d, J = 8 Hz), 8.00 (1H, dd, 2.4 and 8 Hz), 8.46 (lH,d,J = 2.4 Hz). Description 73: (S)-2-[(5-Bromopyridin-2-ylamino>-niethyIJ-pyrTolidine-l-carboxyIic acid tert-butyl ester > The title product (0.22g) was obtained from (S)-2-aminomethyl-pyrrolidine-l-carboxylic acid tert butyl ester (Ig) and the compound of D72 (1.7g) according to the method of D69. Mass Spectrum (Electrospray LC/MS), APf: Found 356 (MET). QsH^^rNaOa requires 355. Description 74: (5-Bromo-pvridin-2-yl)-(S)-l-pyrrolJdui-2-ylmethylamine To a solution of the compound from D73 (0.49g) in dichloromethane (40ml) at ambient temperature was added trifluoroacetic acid (5ml). After 48h, the reaction mixture was evaporated and partitioned between chloroform and 1M sodium hydroxide. The aqueous layer was extracted with chloroform and the combined organic extracts dried and evaporated to afford the title compound (0.33g) as an orange oil. JH NMR 8: 1 .44 - 1 .48 (1H, m), 1 .71 - 1.81 (3H, m), 2.05 (1H, br s), 2.93 (2H, m), 3.09 - 3.13 (1H, m), 3.35 - 3.41 (2H, m), 4.99 (1H, br s), 6.32 (1H, d, J = 9 Hz), 7.43 (1H, dd, J = 3 and 9 Hz), 8.08 (1H, d, J = 3 Hz). Description 75: A'-(4-Benzyl-inorpholui-3-yhTaethyI)-2J2r2-trifluoroacetamide To (4-benzyl-morphoh^-3-yl)rmemylamine (734g) in dichloromethane (240ml) was added triethylamine (5.83ml), followed by dropwise addition of trifluoroacetic anhydride (823g) over 25 min at 0°C under argon. The reaction mixture was allowed to reach ambient temperature and after stirring for 1 8h, was diluted in dichloromethane and washed with saturated aqueous sodium hydrogencarbonate. The organic phase was separated, dried and evaporated to afford a brown gum that was purified on silica gel, eluting with ethyl acetatepentane mixtures to afford the title product (5. 1 7g) as an orange gum. Mass Spectrum (API): Found 303 (MH4). C14Hi7F3N2O2 requires 302. Description 76: l^^Trifluoro-TV-morphoIin-S-ylmetfayl acetamide To the compound from D75 (1.62g) in methanol (40ml) was added paUadhim black (0.45g) and formic acid (10 drops) and the mixture stirred at ambient temperature for 1 6h, Further palladium black (0.225g) and formic acid (10 drops) were added and after Ih, the reaction mixture was filtered through kieselguhr and the filtrate evaporated to an orange gum. Re- evaporation from dichloromethane provided the title compound (1.4g) as a pink solid. Mass Spectrum (APf): Found 213 (MH). CvHuFaNzCfe requires 212. Description 77: 3-[(2^^-Trifluoro-ethanoylammo)-methyl]-morpholine-4-carboxylic acid fert-butyl ester A mixture of the compound from D76 (1.75g), triethylamine (225ml) and di-tert-butyl dicarbonate (3.59g) in dichloromethane (75ml) was stirred at ambient temperature for 18h. The reaction mixture was diluted with dichloromethane and washed successively with 2M hydrochloric acid, water and brine, dried and evaporated to a gum. Chromatography on silica gel eluting with ethyl acetate-pentane mixtures afforded the title compound (1.70g) as apale yellow solid. Mass Spectrum (AW1): Found 213 (MH-lBoc)+. CnHigFjNaOj requires 312. ' Description 78:3-Aminomethyl-morpholine-4-carborylic acid tert-bntyl ester A mixture of the compound from D77 (1.7g) and potassium carbonate (3.77g) in methanol (80 ml) and water (27 ml) was stirred at ambient temperature for 4h and then heated at 50°C for a further 2h. The reaction mixture was concentrated to remove methanol, diluted with water and extracted with ethyl acetate (x3) and dichloromethane (x4). The combined extracts were dried and evaporated to afford the title product (0.97g) as a yellow gum. Mass Spectrum (API): Found 116 (MH-'Boc) CioHytvfcQj requires 216. Description 79:3-[(5-Bromo-pyrimidm-2-ylamino)-methyl]-morpholme-4-carboxylic acid tot-butyl ester The title compound (1.19g) was obtained from the compound of D78 (0.97g) and 5-bromo- 2-cUoropyrimidine (0.87g) according to the method of D30. Mass spectrum (API): Found 273 (MH^'Boc). Ci^i^rN^ requires 372. Description 80: (5-Bromo-pyrimidin-2-yl)-morpholm-3-ylmetliyl amine To the compound of D79 (1.15g) in dichloromethane (45 ml) at 0°C was added trifluoroacetic acid (5 ml) and the reaction mixture then stirred at ambient temperature for 2h. The resulting solution was poured onto ice and saturated aqueous potassium carbonate solution, and then extracted with dichloromethane (x2). The organic extracts were dried and evaporated to afford the title product (0.85g) as an off white solid. Mass Spectrum (Art): Found 273 (MH). CyHu^rN^ requires 272. Description 81: (S>2-[(4X^ano-2,6^iflnoro-phenyIamino)-methyI]-piperidine-lcarboxylic acid terf-butyl ester (S>2-Aminomethyl-piperidme-l-carboxyh'c acid /erf-butyl ester (136g) and 3,4,5- trifluorobenzonitrile (1 .OOg) were heated under argon in xylene (10 ml) containing diisopropylethylamine (33 ml) for 16h. The reaction mixture was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried and evaporated to give a solid which was triturated with pentane-ether to afford the title product (0.16 g) as an off white powder. Chromatography of the mother liquors on silica gel eluting with ethyl acetate-pentane mixtures afforded further title product (0.92 g). Mass Spectrum (API): Found 252 (MHVBoc). C]SH23F2N302 requires 351 . Description 82: 3^-Difluoro-4-[((S)-l-piperidin-2-ylmethyl)-amino]-benzonitrile Trifluoroacetic acid (3 ml) was added to a solution of D81 (1.05 g) in dichloromethane (27 ml) at 0 °C. The reaction was allowed to reach ambient temperature, stirred for 4 h and then poured into saturated aqueous potassium carbonate. The aqueous phase was extracted with dichloromethane and the combined extracts dried and evaporated to afford the title compound (0.59g) as an off white solid. Mass Spectrum (API1): Found 252 (MH). a requires 25 1 . Description 83: (S)-2-[(4-Cyano-2,6-diiluoro-phenyIamino)-methylJ-pyrrolidine-lcarboxylic acid /erf-butyl ester The title compound (0.295g) was obtained from (S)-2-aminomet:hyl-pyrroliduie-lcarboxylic acid tert-batyl ester (0.402g) and 3,4,5-trifluorobenzonitrile (0.3 14g) using a similar procedure to that described in Description 8 1 . Mass Spectrum (API): Found 238 (MH^'Boc) Ci7H2iF2N3O2 requires 337. Description 84: 3^Difluoro^[((S)-l-pyrrolidin-2-yhiiethyI)-aniinoJ-benzonrtriIe The title compound (0.1 9g) was obtained from the compound of D83 (0.28g) using a similar procedure to that described in Description 82. Description 85: (S)-2-l(5-Ethyl-pyrinudin-2-ylaniino)-methyI]-pyrrolidine-l-carboxylic acid tert-butyl ester The title compound (0.1 Og) was obtained from (S)-2-aminomethyl-pyrrolidine-l-carboxylic acid tert-butyl ester (0.75g) and 2-chloro-5-ethyl pyrimidine (0.53g) using a similar procedure to that described in description 81 . Mass Spectrum (Electrospray LC/MS): Found 307 (MH1). CieHa^Cb requires 306. Description 86: (5-Ethyl-pyrimidin-2-ylH^l-pyn"olidin-2-yImefliylamine The title compound (0.07g) was obtained from the compound of D85 (0. 1 Og) using the method of D9. Mass Spectrum (Electrospray LC/MS): Found 207 (MH). CuHigN4 requires 206. Description 87: (S)-2-[(2^^-Trifluoro-ethanoylamino>-methyl]-pyrroIidine-lcarboxyjic acid tert-buryl ester To a solution of (S)-2-aminometiiyl pyrrolidine-1-carboxylic acid tert-batyl ester (l-3g) in dichloromethane (50 ml) containing triethylamine (1 .4 ml) was added trifluoroacetic anhydride ( 1 .6g) dropwjse under argon. After 1 6h at ambient temperature the reaction mixture was diluted with dichloromethane and washed with brine. The aqueous layer was extracted with dichloromethane and the combined extracts dried and evaporated. Chromatography of the residue on silica gel eluting with pentane-emyl acetate mixtures afforded the title compound (1 .43g) as an orange oil. !H NMR 5: 1 .30 - 1 .50 (1H, ra), 1 .47 (9H,s), 1.60- 1.75(1 H,m), 1.80- 1.95 (2H,m), 2.00- 2.10 (lH,m), 3.22 -3.30 (lH5m), 3.30 - 3.55 (3H, in), 9.03 (1H, br s). Description 88: (S)-2-{[MethyH2^-trifluoro-ethanoyl)-ainino]-methyl}-pyrroIidinel- carborylic acid tert-butyl ester Sodium hydride (0 .23g, 60 % dispersion in oil) was added to a solution of the compound of D87 (1.4g) in dimethylformamide (30 ml) under argon. After Ih, iodomethane (0.32 ml) was added and the reaction mixture stirred for a further 1 6h before being partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined extracts washed with brine, dried and evaporated to give the title compound (1.6g) as an orange oil. Mass Spectrum (API): Found 311 (MET); C13H2iF3N2O3 requires 310. » Description 89: (S)-2-MethyIanunomethyl-pyrrolidine-l-carbojylic acid tert-bvtyl ester A mixture of the compound of D88 (1.47g) and 1M potassium carbonate (20 ml) in methanol (50 ml) was stirred at ambient temperature for 20 h. After removal of the methanol in vacuo, the residue was partitioned between chlorofonn and water. The aqueous layer was extracted with chlorofonn and the combined extracts dried and evaporated to afford the title product (0.82g) as an orange oil. Description 90: (S>-2-{[(5-Bromo-pyrimidin-2-yI)-mefliyI-anunoJ-mettiyl}-pyrrolidinel- carboxylic acid tert-bntyl ester The title product (0.85g) was obtained from the compound of D89 (0.82g) and 5-bromo-2- chloro pyrimidine (0.77g) in a similar manner to that described in the procedure of description 81 . Mass Spectrum (API): Found 371 (MH). CisHb^nNkOa requires 370. Description 91: (5-Bromo-pyrimidin-2-yI>-methyl-(S)-l-pyrrolidin-2-yr)memylamuie A solution of the compound from D90 (0.82g) in dichloromethane (50 ml) and trifluoroacetic acid (10 ml) was stirred at ambient temperature for 20 h. evaporated and partitioned between ethyl acetate and 1M sodium hydroxide. The organic phase was separated, dried and evaporated to afford the tMe product as an orange oil (0.54g). Mass Spectrum (API4): Found 271 (MH). Ci0Hi5 79BrN4 requires 270. Description 92: (S)-2-[(5rAceryl-pvrimidm-2-ylamino)-methyIJ-pyrrolidine-lcarboiylic acid tert-butyl ester The title compound (0.57g) was prepared from the compound of D69 (1.06g) (1- ethoxyvinyl)triburyl tin (13. ml) and tetrakis (triphenylphosphine)palladium (0) (0.1 72g) according to the method of Example 171. Mass Spectrum (API): Found 321 (MH). requires 320. Description 93: !-{2-[((S)-l-PyrroUdm-2-ymiethyI>ammo]-pvriniidin-S-yl}-ethanone trifluoroacetate To a solution of the compound of D92 (0.57g) in dichloromethane (18ml) at 0°C was added trifluoroacetic acid (2ml) dropwise. The reaction mixture was stirred at ambient temperature for 2h, and evaporated to afford the title compound as a yellow gum (1.13g). Mass Spectrum (API4): Found 221 (MJT). CnHi6N4O requires 220. Description 94: (S)-2-f(5-CiIoro-pyrimidinr2-ylamino)-iiiethyIJ-pyrro]idine-lcarboxylic acid tert-butyl ester (S)-2-Aminomethyl pyrrolidine-1-carboxyIic acid tert-bvctyl ester (3.38g), 2,5- dichloropyrimidine (2.50g), potassium carbonate (4.67g) and diisopropylethylamine (8.79ml) were heated in xylene (60 ml) at 100°C for 3.75h. The cooled reaction mixture was filtered and the filtrate evaporated to a gum which was chromatographed on silica gel, eluting with ethyl acetate-pentane fractions, to afford the title compound as a pale yellow solid (2.55g). Mass Spectrum (API): Found 213 (MH^Boc). C]4H2i35ClN4Q2 requires 312. Description 95: (5-CUort>-pyrimidm-2-yI)-(S)-l-pyrTolidin-2-yhBethyIaniine The compound of D94 (2.5g) was dissolved in dichloromethane (63 ml), cooled to 0°C and trifluoroacetic acid (7 ml) added dropwise. The reaction mixture was stirred at ambient temperature for 2h, recooled to 0°C and further trifluoroacetic acid (3 ml) added. After 2h at ambient temperature the mixture was carefully poured into ice-saturated potassium carbonate and the organic layer separated. The aqueous phase was extracted with dichloromethane (x4) and the combined extracts dried and evaporated to afford the title product (1.74g) as an orange solid. Mass Spectrum (Electrospray LC/MS): Found 213 (MH). C9HU 35CIN4 requires 212. Description 96: (S)-2-[(5-Cyano-pyridin-2-ylamino)-methyI]-pyrTolidine-l-carboxyIic acid tert-butyl ester (S)-2-Aminomethyl pyjrolidine-l-carboxyh"c acid tert-butyl ester (0.3g), 6- chloronicotinonitrile (021g), potassium carbonate (0.41g) and diisopropylethylamine (0.78 ml) were heated in xylene at 130°C for 26h, cooled and the mixture filtered through kieselguhr. The filtrate was evaporated and the residue chromatographed on silica gel, eluting with ethyl acetate-hexane mixtures to afford the title compound (0.2g). Mass Spectrum (API1): Found 303 (MH). CigkMk requires 302. . Description 97: 6-[((S)-l-Pyrrolidin-2-yhnethyr)-amino]-nicotinonitriIe A solution of the compound of D% (0.2g) in dichloromethane (20 ml) and trifluoroacetic acid (2.5 ml) was stirred at ambient temperature for 2h., evaporated and partitioned between dichloromethane and 1M sodium hydroxide. The aqueous phase was extracted with dichloromethane and the combined extracts dried and evaporated to afford the title compound as a gum (0.137g). Mass Spectrum (Electrospray LC/MS): Found 203 (MH). CnHi4N4 requires 202. Description 98:1,1,1-Trifluoromethanesulfonic acid 6-methyl~2-methylsulfanyIpyrimidin- 4-yl ester To a solution of 6^mefeyl-2-methylsuLfanyl-pyrimidin-4-ol (Ig) in dichloromethane (40 ml) containing triethylamine (1.35 ml) at 0°C under argon was added trifluoromethanesulphonic anhydride (1.46 ml) dropwise. The resulting solution was allowed to reach ambient temperature and stirred for 16h. before being partitioned between dichloromethane and saturated aqueous sodium hydrogen carbonate solution. The organic phase was washed with brine, dried and evaporated and the residue chromatpgraphed on silica gel, eluting with ethyl acetate-pentane mixtures, to afford the title compound (0.8g). JH NMR S: 2.53 (3H, s), 2.55 (3H,s), 6.63 (lH,s). Description 99:2^^2-Trifluoro-Ar-(S>l-pyrrolidin-2-ylmethyI-acetamide The title compound (2.3Ig) was obtained from the compound of D87 (5.5g) using the method of D97. JH NMR 8:130 -1.50 (IH, m), 1.70 - 1.95 (3H, m), 2.20 (IH, br s), 2.85 - 2.90 (IH, m), 2.94 - 2.97 (IH, m), 3.07 - 3.12 (IH, m), 3.37 - 3 39 (IH, m), 3.44 - 3.48 (IH, m),7.15(lH,brs). Description 100:2^r2-Trifluoro-A^-((S)-l-{l-[5-(4-fluoroplienyi)-2-metiiyl- ylJ-methanoyI}-pyrroIidin-2-yIinethyI>-acetamide The title compound (3.84g) was obtained from the compound of D99 (2.3 Ig) and 5-(4- fluorophenyl)-2-methyl-miazole-4-carboxyhrc acid (3.08g) using the method of Example 229. Mass Spectrum (EleetrosprayLC/MS): Found 416 (MH). CigHi7F4N3O2S requires 415. Description 101: H(S)-2-AminomefhyI-pyrTolidin-l-yI)-l-f5-(4-fluoro-phenyr)-2- methyl-thiazol-4-yl]-methanone The title compound (2.45g) was obtained from the compound of D100 (3.84g) using a similar procedure to mat described in D78. Mass Spectrum (Electrospray LC/MS): Found 320 (MH). CisH^sOS requires 319. Description 102:3-[(2^^-Trifluoro^manoylamino)-methyIJ-morpholine-4-carboxyIic acid fert-bnryl ester The title compound (0.56g) was obtained from me compound of D77 (0.55g) and iodomethane (0.12 ml) using a method similar to mat of Description 88. Mass Spectrum (API4): Found 227 (MHVBoc). CisHjiFsNaCU requires 326. Description 103:3-Methylaminomethyl~morphoUne-4-carbo3cyUc acid tert-butyl ester The title compound (0.29g) was obtained from the compound of D102 (0.56g) using the method of Description 89. Description 104: 3-{[(5-Bromo-pyrimidin-2-yI)-methyl-amino]-methyl}-morpholine-4- carboxylic acid tert-butyl ester The title compound (0.3g) was obtained from the compound of D103 (0.29g) and 5-bromo- 2-chloropyrimidine (0.26g) using the method of Description 81. Mass Spectrum (Electrospray LC/MS): Found 287 (MHV&oc). Ci5H2379BrN4O3 requires 386. Description 105: (5-Bromo-pyrimidin-2-yl)-niethyI-niorphoIin-3-ylmethyI-amine The title compound (0.19g) was obtained from the compound of D104 (0.3g) according to the method of Description 91. Mass Spectrum (API): Found 287 (MH4). CioHi5 79BrN4O requires 286. Example 1: !-[2-(BenzoxazoI-2-ylaminomethyI)-piperidin-l-yl]-l-(2-methyI-5-phenyltbiazol- 4~yl)-methanone The amine of D3 (0.1 Ig), triethylamine (O.OSg) and 2-meuiyl-5-phenyl-thiazole-4-carbonyl chloride (0.12g) were combined in dichloromethane (5ml) and shaken for 16 hours. The organic phase was washed with water, filtered through a Whatman phase-separation filter tube, solvent removed at reduced pressure to give after column chromatography (silica gel, 0-10% (9:1 methanol/ammonia) in dichloromethane eluant) the title compound (0.13g). Mass Spectrum (APf): Found 433 (MH). C24H24N4O2S requires 432. The compounds of the Examples below were prepared from the appropriate amine and acid chloride using a similar procedure to that described in Example. 1. NHAr1 Example Amine Y AS Ar1 Mass Spectrum (Electrospray LC/MS) (Figure Removed) Example 32: l-[(S)-2-(Benzoxazol-2-ylanimomethyI)-piperidin-l-yl]-l-[S-(4-fluorophenyI)- 2-niethyI-thiazol-4-ylJ-iiierhanone A mixture of amine D5 (O.OSg), 2-methyl-5-phenyl-trdazoleH^carboxylic acid (0.026g) and diisopropylethylamine (0.06ml) in dimethylfonnarnide (5rnl) was treated with [0-(7- a2abenzotriazol-l-yl>1433-tfitramethyluronium hexafluorophosphate] (0.042g) and the mixture stirred for 48 hours. The mixture was diluted with ethyl acetate, washed with sodium hydrogen carbonate and water, dried, solvent removed at reduced pressure and the residue column chromatographed (silica gel, dichloromethane - 1% methanol/dichloromethane) to give the title compound (O.OSg). Mass Spectrum (API1): Found 451 (MH). C24H23FN4O2S requires 450. The compounds of the Examples below were prepared from the appropriate amine and acid using similar procedures to that described in Example 32. NHAr1 (Table Removed) Example 93: l-{2-[(6,7-Diflnoro^umoxa^ (4-flaoro-phenyI)-2-H-pyrazoI-3-ylI-methajione The amine of D31 (0.085^ in dmiethyu^imamide (3ml) was treated with 4-(4-fluorophmyl> 2^-pyrazole-3-carboxylic acid (0.125g), diisopropylethyianiine (0.07ml) and [O- (7-azabenzotriazol-l-ylH»l^-tetr^ (0-llg). the mixture was shaken for 48 hours. Solvent was removed at reduced pressure and the residue extracted with dichloromethane. The filtrate was evaporated under reduced pressure and the residue column chromatographed (silica gel, 3% methanol/diethyl ether) to give the title compound (O.lg). Mass Spectrum (APf): Found 453 (MH4). QoH^sNeO requires 452. iHAr1 residue column chromatographed (silica gel, 3% methanol/diethyl ether) to give the title compound (O.lg). Mass Spectrum (APT): Found 453 (MH). C^H^NeO requires 452. NHAr1 Example (Table Removed) Example 105: l-[2-(3-Methyl-[M,4]oiadiazol-5-yI>phenyI]-l-[(S>2-{oxazolo[4^- b]]pyridin-2-yIaminoinethyI)-piperidin-l-yI]-methanone The compound of D41 (0.51g) and 2-methylsulfenyl-oxazolo[4,5-6]pyridine (O^ZSg) were combined and heated under argon at 90°C for 1 8 hours The mixture was column chromatographed (5% methanol, diethyl ether eluant) to give the title compound (0.26g) Mass Spectrum (API): Found 419 (MH4). C^zHzzNeOs requires 418. Example 106: l-fX3-MethyHlA4]oxadiazol-5-yI)-phenylI~l-{(R)-2-f(metIiyIoiazolo[ 4^b]pyridm-2-yI-amino)-methylJpiperidin-l-yl}-methanone The title compound (O.OlSg) was prepared fiom the compound of D43 (0. 15g) according to the method of Example 105. Mass Spectrum (APf): Found 433 (MH4). CzsHa^NeOs requires 432. Example 107: 6-[((S)-l-{l-[4-(4-Fluoro-phenyI>-l-methyl-lH-pyrazoI-3-yl]- methanoyl}-piperidm-2-ylmethy^methyl-amino]-nicotinonitrile . - . . The title compound (0.078g) was prepared from the compound of D60 (0.45g) and 2- chloro-5-cyanopyridine (0. 1 89g) according to the method of D26 Mass Spectrum (API4): Found 433 (MH). Cz^HasFNgO requires 432. Example 108: l^(S>2-{[(6,7-DiflnoroHjumoxaIm-2-yI>-methyl-amino]-methyl}- piperidin-l-y^l-[4^4-fliioro-pheny^l-me&vl-lH-pyrazol-3-y5^ The title compound (0.03 Ig) was prepared fiom the compound of D60 (0. 1 5g) and 2- chloro-6,7-difluoK)quiiioxamie (0.091g) according to the method of D26 Mass Spectrum (API): Found 495 (MH1). CasHzsFaNeO requires 494. Example 171: !-{2-[((S)-l-{l-[4-(4-FIuoro-phenyI)-l-methyl-lH-pyrazol-3-ylJmethanoyl}- piperidin-2-yIinethyl)-amino]-pyrimidin-5-yl}-ethanone A mixture of l-{(S)-2-[(5-Bromo-pyriiiudin-2-ylaniino>methyl]-piperidin-l-yl}-l-[4-(4- fluoro-phenyl)-l-methyl-lS-pyrazol-3-yl]-methanone (0.5g) and l-ethoxyvinyl)tributyltin (0.42ml) tetrakis(triphenylphosphine)palladium[0} (0.06g) was boiled in dioxane (8ml) for 1 6h. 2N Hydrochloric acid was added, the mixtrue stirred for 90 min, water was added and the mixture extracted (x3) with ethyl acetate. The combined ethyl acetate extracts were dried, solvent removed at reduced pressure and the residue column chromatographed (silica gel, ethyl acetate -> 2% methanol ethyl acetate to give the title compound (0.3g) as a yellow foam. Mass Spectrum (API): Found 437 (MH4). CzjH^FNsCb requires 436. i Example 172: !-[4-(4-FIuoro-phenyI)-l-methyl-lH-pvraaM>l-3-yII-l-((S)-2-{[5-(lhydroxy^ thyI)-pyriinidin-2-ylamino]-methyl}-piperidin-l-yI)-methanone l-{2-[((S>l-{l-[4^4-Fluoro-phenyl)-l-memyl-lH-pyra2»l-3-yl]-methanoyl}-piperi ymiethyl)-ammo]-pyrimidin-5-yl}-ethanone (0.2g) was dissolved in methanol 20ml) and sodium borohydride (0.4g) added. The reaction was stirred overnight, water was added and stirring continued for 30min. The reaction mixture was extracted with ethyl acetate (x3), the organic extracts combined, dried (MgSC^) and solvent removed at reduced pressure to give the title compound as a colourless foam. Mass Spectrum (API): Found 439 (MET). Ca^yFNeOa requires 438. Example 173: 2-[((S)-l-{l-[4-(4-H»oro-phenyI)-l-methyl-lH-pyrazol-3-yl]- methanoyl}-piperidm-2-yhiiethyI)-amino]-pyrimidine-5-carbonitrile !-{(S)-2-[(5-Brom0-pyrimidrn-2~ylamrno l-methyl-l#-pyrazol-3-yl]-methanone (035g) in N-methylpyrrolidinone (10ml) containing copper(I)cyanide (0. 1 3g) was heated to reflux for 5h. The reaction mixture was diluted with water, filtered (Kieselguhr) and the filtrate extracted with ethyl acetate. The ethyl acetate phase was washed with water and brine, dried (MgSO4), filtered and solvent removed at reduced pressure. The residue was column chromatographed (silica gel; ethyl acetaterpentane 1 :1 -» ethyl acetate eluant), the appropriate fractions combined and solvent removed at reduced pressure to give the title compound (0.01 9g). Mass Spectrum (API): Found 420 (MET). CjaHbFNTO requires 419. Example 174: 3^1-{ ylJ-methanoyiy-N— methyl-benzamide The compound of description 71 (0.1 Og) was dissolved in dimetbylfonnamide (5ml) containing HATU (0.095g) and diisopropylethylamine (0.131ul) and stirred for 30 in. Methylamine (1M in tetrahydrofuran, 0.125ml) was added and stirring continued for 16. The reaction mixture was diluted with diethyl ether, washed with water (x3), saturated brine and dried (MgSO4). Solvent was removed at reduced pressure and the residue column chromatographed (silica gel; ethyl acetate — » 1 0% metbanol:ethyl acetate to give the title compound (0.01 8g). Mass Spectrum (API): Found 440 (MH). CasK^NsOa requires 439. Example 194: l-{(S>2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrroIidin-l-yl}-l-[5- (4-fluoro-phenyI)-2-methyl-thiazoI-4-yl]-methanone A mixture of the amine of D70 (0.070g), 5-(4-fluoro-phenyI)-2-methyl-thiazole-4- carboxylic acid (0.065g), H3- (EDC) (0.042g) and 1-hydroxybenzotriazole hydrate (0.037g) in dimethylfonnamide (2ml) was stirred at ambient temperature for 18h, evaporated in vacua and the residue partitioned between ethyl acetate and water. The organic layer was dried (Na2SO4), evaporated and the residue chromatographed on silica gel eluting with a 30% - 100% ethyl acetate in pentane gradient to afford the title product (0.083g) as a white solid. Mass-Spectrum (Electrospray LCMS), APf: Found 476 (MEf). Example 195: !-{(S)-[(5-Bromo-pvrimJdm-2-ylajiimo>methylJ-pyrToIidin-l-yl}-l-[2- (3-methyl-[l^,4]oxadiazoI-5-yl)-phenyl]-methanone The title compound (0.053g) was obtained from the amine of D70 (0.070g) and 2-(3-methyl-[l^,4]oxadiazol-5-yl>benzoic acid (0.056g) using the method of Example 194. Mass Spectrum (Electrospray LC/MS) : Found 443 (MH4). CwH^rNeOa requires 442. Example 196: !-{(S)-2-[5-Bromo-pyrimidin-2-ylamino)-methyl]-pvrrolidin-l-yI}-l-[5- (4-chloro-phenyI)-2-methyl-thiazol-4-yl]-methanone The title compound (0.078g) was obtained from the amine of D70 (0.077g) and 5-(4-chlorophenyl)- 2-methyl-thiazole-4-carboxyUc acid (0.076g) according to the method of Example 32. Mass spectnim(mectrospray LC/MS), APf: Found 492 (MH). CaoHw^r^ONsOS requires 491. Example 197: !-{(S)-2-[(5-Brom{>-pyridin-2-ylamino)-niethyl]-pyTrolidin-l-yl}-l-[5-(4- fluoro-phenyl)-2-methyl-miazoI-4-ylJ-inethanone The title compound (0.135g) was obtained from the amine of D74 (0.1 Ig) and 5-{4-fluorophenyl> 2-memyl-thiazole-4-carboxylic acid (0.12g) according to the method of Example 32. Mass Spectrum APf: Found 475 (MH1). C2iH2o79BrFN4OS requires 474. Example 198: !-{(S)-2-K5rBromo-pyridra-2-yI^ fluoro-pheny!)-l-methyl-lHr-pyrazol-3-yl]-methanone The title compound (0. 1 Og) was obtained from the amine of D74 (0. 1 Ig) and 4-(4-fluorophenyl)- J-memyl-l/f-pyrazole-3-carboxylic acid (0.12g) according to the method of Example 32. Mass Spectrum APf: Found 458 (MH). C2iH2i79BrFN5O requires 457. Example 200: !-{3-[(5-Brom(Hpyrimidm-2-ylammo>methyIJ-morpholin-4-yl}-l-[4-(4- fluoro-phenyl)-l-mediyl-l£r-pyrazoI-3-yl]-methanone The title compound (0.393g) was obtained from the compound of D80 (0 Jg) and 4-(4- fluorophenyl>l-memyl--l/f-pyrazole-3-carboxylic acid (0^42g) according to the method of Example 32. Mass Spectrum (API): Found 475 (MH). C^M^BrFNeOa requires 474. Example 203: 3,5-Difluoro-4-f((S)-l-{l-f5-{4-fluoroplienyJ)-2-inethyl-thiazoI-4-yI]- methanoyl}-piperidin-2-ylmethyI)-amino]-benzonitrile The title compound (0.090g) was obtained from the compound of D82 (0.073g) and 5-(4- fluorophenyl)-2-methyl-thiazole-4-caii)oxylic acid (0.069g) according to the method of Example 32. Mass Spectrum (Electrospray LC/MS): Found 471. C24H2iF3N4OS requires 470. Example 208: 3^-Difluoro-4-I((S)-l-{l-[5-(4-fluoro-phenyI)-2-methyl-thiazol-4-yl]- methanoyl}-pyrrolidin-2-ylmethy!)-amino]-benzonitrile The title compound (0.09g) was obtained from the compound of D84 and 5-(4-fluorophenyl)- 2-niethyl-thia2»le-4-carboxylic acid (0.095g) according to the method of Example 32. Mass Spectrum (Electrospray LC/MS): Found 457 (MH4). QoHpF^OS requires 456. Example 216: !-{(S)-2-[(5-Ethyl-pyriniidm-2-yIaniino>methyl]-pyrTolidin-l-yl}-l-f5- (4-fluoro-phenyI)-2-methyl-thiazol-4-yI]-methanone The title compound (0.05g) was obtained from the compound of D86 (0.07g) and 5-{4- fluoro-phenyl)-2-memyl-thiazole-4-carboxylic acid (0.068g) according to the method of Example 32. Mass Spectrum (Electrospray LC/MS): Found 426 (MH4). C22H24FN5OS requires 425. Example 217: l^(S)-2-{[(5-Bromo-pyrimidin-2-yl>-methyl-amino]-methyl}-pyrrolidinl- yl)-l-[5-(4-fluoro-phenyI)-2-methyl-thiazol-4-yI]-methanone The title compound (O.lg) was obtained from the compound of D91 (0.275g) and 5-(4- fluoro-phenyl)-2-nMJthyl-thiazole-4-carboxylic acid (0.285g) according to the method of Example 32. Mass Spectrum (Electrospray LC/MS): Found 490 (MH4). C2]H2i79BrFN5OS requires 489. Example 218: l^(S)-2-{[(5-Bromo-pyrimidm-2-yl)-methyl-ainino]-methyl}-pyiTolidinl- y!)-l-[4-{4-fluoro-phenyI)-l-methyI-LEr-pyrazol-3-yIJ-inethaiione The title compound (0.02g) was obtained from the compound of D91. (0.275g) and 4-(4- fluoro-phenyl)-lrmethyl-l/frpyrazole-3-carboxyUc acid (0.260g) according to-fhe method of Example 32. Mass Spectrum (Electrospray LC/MS): Found 473 (MH4). CaiHb^BrFNfiO requires.472. Example 225: !-{2-[((S)-l-{l-[5-(4-Chloro-phenyl>-2-methyl-thiazol-4-yI]-methanoyI}- pyrroUdm-2-ylmethyl)-ammo]-pyrimidin-5-yl}-ethanone The title product (0.04g) was obtained from me compound of D93 (0.133g) and 5-(4-chlorophenyl)- 2-metbyl-thiazole-4-carboxyh"c acid (0.076g) using a similar procedure to that described in Example 32. Mass Spectrum (Electrospray LC/MS): Found 456 (MH4). ONsChS requires 455. Example 226: l-{(S>2-[(5-Chloro-pyrixnidin-2-ylamino)-methyI]-pyrrolidin-l-yI}-l-[5- (4-fluoro-phenyl)-2-methyl-thia2ol-4-yl]-methanoBe The title product (0.095g) was obtained from the amine of D95 (0.064g) and 5-{4- fluorophenyl)-2-methyl-thiazole-4-carboxylic acid (0.071g) using the method of Example 32. Mass Spectrum (Electrospray LC/MS): Found 432 (MH4). C2oHi935ClFN5OS requires 431. Example 227: l-{(S>2-[(5^hloro-pyrimidin-2-ylamino)-niethylJ-pyrroHdin-l-yI}-l-[2- (3-methyI-[l^,4]oxadiazol-5-yI)-phenyl]-memanone The title compound (0.052g) was obtained from the amine of D95 (0.064g) and 2-(3- memyi-[l^,4]oxadiazol-5-yl)-benzoic acid (0.061g) according to the method of Example 32. Mass Spectrum (Electrospray LOMS): Found 399 (MH). CjpHw^ClNfiCb requires 398. Example 228: l-[5-{4-FIuoro-phenyl)-2-metliyl-thiazol-4-yl]-l-{(S)-2-[(5-methylpyrimidin- 2-ylamino)-methyl]-pyrrolidin-l-yl}-methanone To the compound of Example 194 (0.36g) in dunethylformarnide was added lithium chloride (0.096g), tetramethyl tin (0.126 ml) and dicUorobis(triphenyjtphosphine) palladium (0) (0.035g) and the resulting mixture heated at 100°C under argon for 18h. The reaction was men evaporated, diluted with dichloromethane, filtered and the filtrate washed with water, dried and evaporated. Chromatography of the residue on silica gel, eluting with raethanol-dichloromethane mixtures, afforded the title product (0_2g) as a yellow amorphous solid. Mass Spectrum (API4): Found 412 (MH4). CaiHzaFNsOS requires 411. Example 229: 6-f((S)-l-{l-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yIJ-uiethanoyI)- pyrroUdin-2-ylmethyl)'amino]-nicotuionirrile A mixture of the amine of D97 (0.134g), 5-(4-fluoro-phenyl)-2-niethyl-tiiiazole-4- carboxylic acid (0.172g), EDC (0.139g) and 1-hydroxybenzottiazole (O.Olg) in dichloromethane (8 ml) was stirred at ambient temperature for 7 days. The reaction was washed with saturated aqueous sodium bicarbonate solution, dried and evaporated. Chromatography of the residue on silica gel, eluting with ethyl acetate - hexane mixtures afforded the title product (0.196g), Mass Spectrum (Electrospray LC/MS): Found 422 (MH4). C22H2oFN5OS requires 421. Example 234: l-[5-{4-Flnoro-phenyl)-2-inethyl-thiazol-4-y]J-l-{(S)-2-[(6-inethyl-2- methykutfanyl-pyriniidm^ylammo)-merhyl]-pyrTolidin-l-yl}-methanone The title product (0.095g) was obtained from the amine of D101 (0.15g) and the compound of D98 (0.14g) using a similar method to mat described in D69. Mass Spectrum (Electrospray LC/MS): Found 458 (MH4). CzzHMFNsC^ requires 457. Example 235: l-[5-(4-Fluoro-phenyI)-2-methyI-thiazol-4-yl]-l-{(S>-2-[(2- methylsiih^nyl-pyrimidm^ylariimo)-memyl]-pyrroh"diii-l-yl}-methanone -84- The title compound (O.OSg) was obtained from the amine of D101 (0.15g) and 4-chloro-2- methylsulfanyl-pyrimidine (0.076g) using a similar method to that described in D69. Mass Spectrum (Electrospray LC/MS): Found 444 (MH4). C2iH22FN5OS2 requires 443. The following compounds were prepared using methods similar to that described in Examples 234 and 235. Ar' Example Amin Ar1 Mass spectrum (Electrospray LCMS),APf 236 D101 Bond Found 494 (MH4). requires 493. Me 237 D101 Bond Found 426 (MET)- requires 425. Me 238 D101 Bond Found 466 (MET). C2,H,9F4N5OS requires 465. Example 239: 1^3-{[(5-Bromo-pyrimidin-2-y^methyl-ainino]-methyI}-moi^holin-^ yI)-l-[5-{4-fluoro-phenyI)-2-niethyl-thiazol-4-yl]-methanone The title compound (0.056g) was obtained from the compound of D105 (0.095g) and 5-(4-fluorophenyl)-2- methyl-thiazole-4-catbo3(ylic acid (0.1 Og) according to the method of Example 32. Mass Spectrum (Electrospray LC/MS): Found 506 (MH4). C2iH21 79BrFN5O2S requires 505. Example 240: 1^3-{[(5-Bromo-pyrimidm-2-yl>-methyl-ammo]-me^yl}-morpholin-4- yl)-l-[2-(4-fluoro-phenyI)-thiophen-3-yI]-methanone To the compound of D105 (0.095g) in dichloromethane (8ml) containing triethylamine (0.06ml>was added 2-(4-fluorophenyl)-thiophene-3-carbonyl chloride (0.084g). After 72h at ambient temperature the reaction mixture was washed with brine, dried and evaporated; the residue was chromatographed on silica gel, eluting with ethyl acetate-pentane mixtures to afford the title product (0.093g). Mass Spectrum (Electrospray LC/MS): Found 491 (MH4). C2iH2o79BrFN402S requires 490. Example 249: l-[5-(4-Flttoro-phenyl)-2-methyl-thiazol-4-yl]-l-{(S)-2-[(5- trifluoromethyl-pyrimidm-2-ylamino)-methyl]-pyrrolidin-l-yI}-methanone Example 249: l-I5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yI]-l-{(S)-2-[(5- trifluoromethyl-pyrimidm-2-ylammo)-methyl]-pyrroIidin-l-yI}-methanone To the compound from Example 194 (0.36g) in dimemylformamide (5ml) was added potassium trifluoroacetate (0.23g), copper iodide (0.3g) and toluene (5ml) and the resulting mixture heated at reflux under Dean-Stark conditions for 3h, before refluxing for a further 20L The reaction mixture was cooled, poured into water/ether and filtered through kieselguhr. The aqueous layer from the filtrate was extracted with ether, and the combined ether extracts washed with water, dried and evaporated. The aqueous was re-extracted with dichloromethane and the extract evaporated. The combined extracts were chromatographed on silica gel, eluting with methanol-dichloromethane mixtures, to afford the title product (O.OOlg). Mass Spectrum (Electrospray LGMS): Found 466 (MH). requires 465. The compounds in the table below -wereprepared using methods described above Example R Ar2 Mass Spectrum (Electrospray 267 CH2 H Found 486 (MH^). requires 485. 268 CH2 H Found 526 (MH). requires 525. 269 CH2 H Found 540 (MH), requires 539. 270 CH2 Me (Figure Removed) It is understood that the present invention covers all combinations of particular and preferred groups described herein above. Determination of Orexin-1 Receptor Antagonist Activity The orexin-1 receptor antagonist activity of the compounds of formula (T) was determined in accordance with the following experimental method. Experimental Method CHO-DG44 cells expressing the human orexin-1 receptor were grown in cell medium (MEM medium with Earl's salts) containing 2 mM L-Glutamine, 0.4 mg/mL G418 Sulphate from GEBCO BRL and 10% heat inactivated fetal calf serum from Gibco BRL. The cells were seeded at 20,000 cells/100 /tlAvell into 96-well black clear bottom sterile plates from Costar which had been pre-coated with 10 /tg/well of poly-L-Iysine from SIGMA. The seeded plates were incubated overnight at 37C in 5% COa- Agonists were prepared as 1 mM stocks in watenDMSO (1:1). EC50 values (the concentration required to produce 50% maximal response) were estimated using 1 Ix half log unit dilutions (Biomek 2000, Beckman) in Tyrode's buffer containing probenecid (10 mM HEPES with 145mM NaCl, lOmM glucose, 2.5 mM KC1,1.5 mM CaCl2,1.2 mM MgCl2 and 2.5mM probenecid; pH7.4). Antagonists were prepared as 10 mM stocks in DMSO (100%). Antagonist IC50 values (the concentration of compound needed to inhibit 50% of the agonist response) were determined against 3.0 nM human orexin-A using 1 Ix half log unit dilutions in Tyrode's buffer containing 10% DMSO and probenecid. On the day of assay 50 fd of cell medium containing probenecid (Sigma) and FluoS AM (Texas Fluorescence Laboratories) was added (Quadra, Tomtec) to each well to give final concentrations of 25 mM and 4 /iM, respectively. The 96-well plates were incubated for 60 min at 37C in 5% CO2. The loading solution containing dye was then aspirated and cells were washed with 4x150 /il Tyrode's buffer containing probenecid and 0.1% gelatin (Denley Cell Wash). The volume of buffer left in each well was 125 jil. Antagonist or buffer (25 /il) was added (Quadra) the cell plates gently shaken and incubated at 37C in 5% CQz for 30 minutes. Cell plates were then transferred to the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices) instrument Prior to drug addition a single image of the cell plate was taken (signal test), to evaluate dye loading consistency. The run protocol used 60 images taken at 1 second intervals followed by a further 24 images at 5 second intervals. Agonists were added (by the FLIPR) after 20 seconds (during continuous reading). From each well, peak fluorescence was determined over the whole assay period and me mean of readings 1-19 inclusive was subtracted from this figure. The peak increase in fluorescence was plotted against compound concentration and iteranVely curve fitted using a four parameter logistic fit (as described by Bowen and Jerman, TIPS, 1995,16,413-417) to generate a concentration effect value. Antagonist Kb values were calculated using the equation: Kb= IC50/(l+([3/EC50]) where EC50 was the potency of human orexin-A detennined in the assay (in nM terms) and IC50 is expressed in molar terms. Compounds of Examples tested according to mis method had pKb values hi the range 6.7 - 9.7 at the human cloned orexiri-1 receptor. The orexin-2 receptor antagonist activity of me compounds of formula (I) was detennined in accordance with the following experimental method. Experimental Method CHO-DG44 cells expressing the human orexin-2 receptor were grown hi cell medium (MEM medium with Earl's salts) containing 2 mM L-Glutamine, 0.4 mg/mL G418 Sulphate from GIBCO BRL and 10% heat inactivated fetal calf serum from Gibco BRL. The cells were seeded at 20,000 cells/100 /ilAvell into 96-well black clear bottom sterile plates from Costar which had been pre-coated with 10 /tg/well of poly-I/-lysine from SIGMA. The seeded plates were incubated overnight at 37C in 5% CC^. Agonists were prepared as 1 mM stocks in watenDMSO (1:1). EC50 values (the concentration required to produce 50% maximal response) were estimated using 1 Ix half log unit dilutions (Biomek 2000, Beckman) hi Tyrode's buffer containing probenecid (10 mM HEPES with 145mM NaCL lOmM glucose, 2.5 mM KCL. 1 -5 mM CaCl2,1.2 mM MgCl2 and 2.5mM probenecid; pH7.4). Antagonists were prepared as 10 mM stocks in DMSO (100%). Antagonist IC50 values (the concentration of compound needed to inhibit 50% of the agonist response) were determined against 10.0 nM human orexin-A using 1 Ix half log unit dilutions in Tyrode's buffer containing 10% DMSO and probenecid. On the day of assay 50 /il of cell medium containing probenecid (Sigma) and FluoSAM (Texas Fluorescence Laboratories) was added (Quadra, Tomtec) to each well to give final concentrations of 2.5 mM and 4 /iM, respectively. The 96-well plates were incubated for 60 min at 37C hi 5% CQj. The loading solution containing dye was then aspirated and cells were washed with 4x150 [A Tyrode's buffer containing probenecid and 0.1% gelatin (Denley Cell Wash). The volume of buffer left in each well was 125 fd. Antagonist or buffer (25 /d) was added (Quadra) the cell plates gently shaken and incubated at 37C in 5% COa for 30 min. Cell plates were then transferred to the Fluorescent Imaging Plate Reader (FLIPR, Molecular Devices) instrument Prior to drug addition a single image of the cell plate was taken (signal test), to evaluate dye loading consistency. The run protocol used 60 images taken at 1 second intervals followed by a further 24 images at 5 second intervals. Agonists were added (by the FUPR) after 20 sec (during continuous reading). From each well, peak fluorescence was determined over the whole assay period and the mean of readings 1-19 inclusive was subtracted from this figure. The peak increase in fluorescence was plotted against compound concentration and iteratively curve fitted using a four parameter logistic fit (as described by Bowen and Jerman, TiPS, 1995,16,413- 417) to generate a concentration effect value. Antagonist Kb values were calculated using the equation: Kb=IC50/(l+([3/BC50]) where EC50 was the potency of human orexin-A determined in the assay (in nM terms) and IC50 is expressed in molar terms. Compounds of Examples tested according to this method had pKb values in the range - 9.1 at the human cloned orexin-2 receptor. The application of which this description and claims forms part maybe used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation the following claims: We Claims: 1. A N-aroyl cyclic amines compound of formula (I): (Formula Removed) wherein: Y represents a bond, oxygen, or a group (CH2)n, wherein n represents 1, 2 or 3; R is H or (C1-4)alkyl; Ar1 is an aryl group selected from phenyl, quinoxalinyl, quinazolinyl, pyridopyrazinyl, baazoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, pyridinyl, pyrimidinyl, thiazolyl, pyridazinyl, pyrazinyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl, quinolinyl, benzofuranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridiyl, pyridopyrimidinyl, isoquinolinyl, furanyl or thienyl, which aryl is optionally substituted with 1, 2 or 3 optional substituents; Ar2 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 R1 and further optional substituents; or Ar2 represents an optionally substituted bicyclic aromatic or bicyclic heteroaromatic group containing up to 3 heteroatoms selected from N, O and S; R1 represents hydrogen, optionally substituted(C1-4 jalkoxy, halo, cyano, optionally substituted(Ci-6)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 the optional substituents for the groups Ar1, Ar2, R and R1 are selected from halogen, hydroxy, oxo, cyano, nitro, (C1-4)alkyl, (C1-4)alkoxy, hydroxy(C1-4)alkyl, hydroxy(C1-4)alkoxy, halo(C1-4)alkyl, halo(C1-4)alkoxy, aryl(C1-4)alkoxy, (C1-4)alkylthio, hydroxy(C1-4)alkyl, (C1-4)alkoxy(C1-4)alkyl, (C3-6)cycloalkyl(C1-4)alkoxy, (C1-4)alkanoyl, (C1-4)alkoxycarbonyl, (C1-4)alkylsulfonyl, (C1-4)alkylsulfonyloxy, (C1-4)alkylsulfonyl(C1-4)alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonyl(C1-4)alkyl, (C1- 4)alkylsulfonamido (C1-4)aikylamido, (C1-4)alkylsulfonamido(C1-4)alkyl, (C1-4alkylamido(C1-4)alkyl, arylcarboxamido, arylcarboxamido(C1-4)alkyl, aroyl, aroyl(C1-4)alkyl, or aryl(C1-4)alkanoyl group; a group RaRbN, RaOCO(CH2)r, RaCON(Ra)(CH2)r, RaRbNCO(CH2)r or RaS02NRb(CH2)r where each of Ra and Rb independently represents a hydrogen atom or a (C1-4)alkyi group or where appropriate RaRb forms part of a (C3-6)azacyloalkane or (C3-6)(2-oxo)azacycloalkane ring and r represents zero or an integer from 1 to 4, (C1-4)acyl, aryl, aryl(C1-4)alkyl, (C1-4)alkylamino(C1-4)alkyl, RaRbN(CH2)n-, RaRbN(CH2)nO-, wherein n represents an integer from 1 to 4; wherein when Y is a bond Ar2 can not be 2-naphthyl; or a pharmaceutical^ acceptable salt thereof; with the proviso that the compound is not: (2S)- l-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5methylpyrazolo[ 1,5- a]pyrimidin-6 -yl] carbonyl] -2 - [ (phenylamino) methyl] pyrrolidine; or (2-bromophenyl){[l-(phenylcarbonyl)-2-pyrrolidinyl]methyl} amine. 2. A compound as claimed in claim 1 wherein R is H. 3. A compound as claimed in claim 1 or 2 wherein Y is a bond, oxygen or (CH2)n where n is 1 or 2. 4. A compound as claimed in any preceding claim wherein Ar2 represents an optionally substituted phenyl, pyridyl, thiazolyl, pyrazolyl, benzofuryl, naphthyl, triazolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothienyl, benzotriazolyl, benzothiazolyl, indolyl or thienyl. 5. A compound as claimed in any preceding claim wherein Ar1 represents an optionally substituted benzoxazolyl, benzimidazolyl, quinoxalinyl, quinazolinyl, pyrimidinyl, pyridinyl, naphthyridinyl, quinolinyl, pyridopyrimidine, thiazolyl, oxazolylpyridinyl, benzothiazolyl, isoquinolinyl or pyrazinyl. 6. A compound as claimed in any preceding claim wherein R1 is selected from trifluoromethoxy, methoxy, ethoxy, halo, cyano or an optionally substituted phenyl, pyridyl, pyrazolyl, pyrimidinyl, or oxadiazolyl group. 7. A compound as claimed in claim 1 selected from: (Table Removed) or a pharmaceutically acceptable salt thereof. 8. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

Full Text

The present invention relates to a n-aroyl cyclic amines compound of formula
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 Touretfs 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 hyperprolactmemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth hormone deficiency; dwarfism; gigantism; acromegaly; disturbed biological and circadian mythms; 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 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 neurodegenerarive
disorders, which includes nosological entities such as disinhibra'on-dementia-parkinsonismamyotrophy
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 fieely-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 JV-aroyl cyclic amine derivatives which are nonpeptide
antagonists of human orexin receptors, in particular orexin-1 receptors, hi
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 WO99/09024, WO99/58533, WOOO/47577and
WOOO/47580 disclose phenyl urea derivatives and WOOO/47576 discloses quinolinyi
cinnamide derivatives as orexin receptor antagonists. WO01/96302 discloses N-aroyl cyclic
amine derivatives.
According to the invention there is provided a compound of formula (I):
(Figure Removed)
wherein:
Y represents a bond, oxygen, or a group (CHaV wherein n represents 1,2 or 3
m represents 1,2, or 3;
p represents 0 or 1;
X is NR, wherein R is H or (Cn)a]kyl;
Ar1 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;
Ar2 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 byR1 and further optional substituents; or Ar2 represents an optionally
substituted bicyclic aromatic or bicyclic heteroaromatic group containing up to 3
heteroatoms selected from N, O and S;
R1 represents hydrogen, optionally substituted(Ci-4 )alkoxy, halo, cyano, optionally
substitated(Ci-6)allcyl, optionally substituted phenyl, or an optionally substituted 5- or 6-
membered beterocyclyl group containing up to 4 heteroatoms selected from N, O and S;
wherein when Y is a bond Ar2 can not be 2-naphthyl;
when Ar1 is aryl p is not 1; —
or a pharmaceutically acceptable salt thereof.
X is preferably NHL
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 (I) are compounds of formula (la);
(Figure Removed)
wherein:
Y represents a bond, oxygen, or a group (CH^ wherein n represents 1, 2 or 3
Ar1 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;
Ar2 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 R1 and further optional substituents; or Ar2 represents an optionally
substituted bicyclic aromatic or bicyclic heteroaromatic group containing up to 3
heteroatoms selected from N, O and S;
R1 represents hydrogen, optionally substituted(Ci-4 )alkoxy, halo, cyano, optionally
substituted(Ci^)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 Ar2 can not be 2-naphthyl;
or pharmaceutically acceptable salts thereof.
Preferably where Ar2 represents phenyl or a 5- or 6-membered heterocyclyl group
containing up to 3 heteroatoms selected from N, O and S, the R1 group is situated adjacent
to the point of attachment to the amide carbonyl.
Y is preferably a bond, oxygen or (CH2)n wherein n is 1 or 2.
Even more preferably Y is a bond, oxygen or (CHz)n wherein n is 1
Alternatively R1 represents hydrogen, optionally substituted(Ci.4 )alkoxy, halo,
optionally substituted(Cns)alkyl, optionally substituted phenyl or an optionally substituted
5- or 6-membered heterocyclyl group containing up to 3 heteroatoms .selected from N, O
andS.
Alternatively R1 represents optionally substituted(CM )alkoxy, halo, optionally
substinrted(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 R1 is selected from trifluoromethoxy, methoxy, ethoxy, halo, cyano or an
optionally substituted phenyl, pyridyl, pyrazolyl, pyrimidinyl, or oxadiazolyl group.
More preferably R1 is selected from trifluoromethoxy, methoxy, ethoxy, halo, or an
optionally substituted phenyl, pyridyl, pyrazolyl, pyrimidinyl, or oxadiazolyl group.
When Ar1 is optionally substituted aryl it is preferably phenyl. Ar1 may have up to 5,
preferably 1,2 or 3 optional substituents.
Examples of when Ar1 is a mono or bicyclic heteroaryl are qpuinoxalinyl,
quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzknidazolyl,
naphthyridinyl, pyridinyl, pyrimidinyl, or thiazolyl. Additionally Ar1 can be selected from
pyridazinyl, pyrazinyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl, quinolinyl, benzofuranyl,
indolyi, benzothiazolyl, oxazolyl[4,5-b]pyridiyl, pyridopyrimidinyl or isoquinolinyl.
Furthermore Ar1 can be furanyl or thienyl. -
Preferably Ar1 is benzoxazolyl, benzimidazolyl, quinoxalinyl, quinazolirryl,
pyrimidinyl, pyridinyl, naphthyridinyl, Additionally Ar1 can be quinolinyl,
pyridopyrimidine, thiazolyl, oxazolylpyridinyl, benzothiazolyl, isoquinoUnyl or pyrazinyl.
More preferably Ar1 is benzoxazolyl, benzimidazolyl, quinoxalinyl, quinazohnyl,
pyrimidinyl, pyridinyl, naphthyridinyl or oxazolyl[4,5-b]pyridinyl.
When Ar2 is a 5- or 6-membered heterocyclyl group containing up to 3 heteroatoms
selected from N, O and S, it may be furanyl, thienyl, pyrroryl, oxazolyl, thiazolyl,
imidazolyl, oxadiazolyl, miadiazolyl, pyridyl, triazolyl, triazbyl, pyridazinyl, pyrimidmyl,
isothiazoryl, isoxazolyl, pyrazhiyl or pyrazolyl.
When R1 is a 5- or 6-membered heterocyclyl group containing up to 4 heteroatoms
selected from N, O and S, it may be fiiranyl, 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 orthiomorpholinyl.
Preferably when R1 is a 5- or 6-membered heterocyclic ring containing up to 4
heteroatoms selected from N, O and S, it is fiiranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,
imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl,
isothiazolyl, isoxazolyl, pyrazinyl or pyrazolyl.
Preferably R1 is a 5- or 6-membered heterocyclic ring it contains up to 3
heteroatoms selected from N, 0 and S.
When Ar2 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. Furthermore it can be indolyl, benzothiazolyl, or
benzothiadiazoiyl.
Preferably Ar2 represents optionally substituted phenyl, pyridyl, thiazolyl, pyrazolyl,
benzofuryl, naphthyl, triazolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzimidazolyl,
benzothienyl, benzotriazolyl, benzothiazolyl, indolyl or thienyl.
Alternatively Ar2 represents optionally substituted phenyl, pyridyl, thiazolyl,
pyrazolyl, benzofuryl, naphthyl or triazolyl. Preferably the triazolyl is 1,2,3-tfiazolyI.
More preferably Ar2 represents optionally substituted thiazolyl, pyrazolyl or
quinolinyl.
Alternatively R1 is selected from trifluoromethoxy, methoxy, halo, or an optionally
substituted phenyl, pyridyl, pyrazolyl or oxadiazolyl group
Even more preferably R1 represents a trifluoromethoxy group, methoxy group, iodo,
or an optionally substituted phenyl, pyridyl, or oxadiazolyl group.
Optional substituents for the groups Ar1, Ar2, R and R1 include halogen, hydroxy,
oxo, cyano, nitro, (CM)alkyl, (CM)alkoxy, hydroxy(Ci-4)alkyl, hydroxy^Mialkoxy,
halo(CM)alkyl, halo(CM>dkoxy, aryl(CM)alkoxy, (CM)alkyltnio, hydroxy(CM)alkyl, (Ci_
4)alkoxy(Ci4)alkyl, (C3^)cycloallcyl(CM)alkoxy, (CM)alkanoyl, (CM>lkoxycarbonyl, (Ci.
4)alkylsulfonyl, (CM>alkylsulfonyloxy, (CM)alkylsulfonyl(CM)alkyl, arylsutfonyl,
arylsutfonyloxy, arylsulfonyl(Cm)alkyl, (Ci_4)alkylsulfonamido, (CM)alkylamido, (Ci-
4)a]kylsulfonamido(CM)alkyl, (Cu)alkylamido(CM)alkyl, arylsutfonamido,
arylcarboxamido, arylsulfonamido(CM)alkyl, arylcarboxamido(CM)alkyl, aroyl,
4)alkyl, or aryl(C^)alkanoyl group; a group R'fc'N-, R'OCOCCH^,
R'R^COCCKbX, R^^SOaCCHz), or RaSO2NRb(CH2)r ^ere each of R" and Rb
independently represents a hydrogen atom or a (C^alkyl group or where appropriate R^1*
forms part of a (C3^)azacyloalkane or (C3^)(2-oxo)azacycloalkane ring and r represents
zero or an integer from 1 to 4. Additional substituents are (Ci-4)acyl, aryl, aryl(CM)alkyl,
(CM)alkylamino(CM)alkyl, R*RbN(CH2)n-, R'^'lSfCCHa^O-, wherein n represents an
integer from 1 to 4. Additionally when the substituent is RaRbN(CH2)n- or RaRbN(CH2)nO,
Ra with at least one CH2 of the (CH2)n portion of the group form a (Ca^azacycloalkane
and Rb represents hydrogen, a (Cj^)alkyl group or with the nitrogen to which it is attached
forms a second (C3-6)azacycloalkane fused to the first (C^azacycloalkane.
Preferred optional substituents for Ar2 are halogen, cyano, (Ci^)alkyl. Additional
preferred optional substituents are hydroxy(Ci^)aliyl, (Ci.4)alkoxy(Ci-4)alkyl,
R'R^CHz)!!, R^1^. Further optional substituents for Ar2 can also be halogen, cyano,
(CM)alkyl, R'R^CCH^nO or (CM)alkoxy.
Preferred optional substituents for Ar1 are halogen, cyano, (Ci_4)alkanoyl. Other
preferred substituents are hydroxy(Ci-4)alkyl, (Ci^)alkyl or CFa.
Preferred optional substituents forR1 are halogen, (Ci-4)alkoxy(Ci-4)alkyl9 R^6!^,
R^^CH^nO and R*RbN(CH2)n. Other preferred substituents are (CM)alkoxy or (d.
4)alkanoyl.
In the groups Ar1 and Ar2, substituents positioned ortho to one another may be
linked to form a ring.
Blustrative compounds of formula (T) are selected from:
(Table Removed)
and phannaceutically 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 (T) contains an alkyl group, whether alone or
forming part of a larger group, e.g. alkoxy or alkyltbio, the alkyi 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 aromatic 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.
It will be appreciated that compounds of formula (T) may exist as R or S
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 diasterepismers, 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.
As used herein "pharmaceutically acceptable derivative" includes any
pharmaceutically acceptable salt, ester or salt of such ester of a compound of formula (Figure Removed)

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 (1) and derivatives thereof. The following schemes
detail some synthetic routes to compounds of the invention.
(Figure Removed)
wherein Ar1, Ar2, Y, m, p and R are as defined for formula (I), L1 and L2 are leaving groups,
and P is a protecting group.
Examples of suitable leaving groups L1 include halogen, hydroxy, OSC^Me,
OSO2(4-tolyl). The reaction of (V) with (VT) preferably proceeds in an inert solvent such as
N^f-dimethylformamide in the presence of a base such as triethylamine, sodium hydride or
potassium t-butoxide.
Scheme Ib
(Figure Removed)
Reaction of (VIS) with (IX) proceeds in an inert solvent such as dimethylformamide
or xylene in the presence of a base such as potassium carbonate or diisopropylethylamine,
preferably at elevated temperatures.
Alternatively where m is 1 and p is 0 or 1 compounds maybe prepared as shown in
scheme Ic.
(Figure Removed)
Reaction of (XT) with an alkylating agent (Ci-fiL1 proceeds in the presence of a base
such as sodium hydride in an inert solvent such as dimethylformamide.
Examples of suitable leaving groups L2 include halogen, hydroxy, QC(=O)alkyl and
OC(=O)O-aIkyI. The transformation (U) to (I) may be carried out in an inert solvent such as
dichloromethane, in the presence of a base such as triethyiamine. Alternatively this step
may be carried out when L2 represents hydroxy, in which case reaction with (H) takes place
in an inert solvent such as dichloromethane in the presence of a diimide reagent such as 1-
ethyl-3-(3-dimethylaminopropyl)carbodiiniide hydrochloride, and an activator such as 1-
hydroxybenzotriazole.
Examples of protecting groups P include f-butyloxycarbonyl, trifluoroacetyl ,
optionally substitued benzyl 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), (VT) and (DQ are known in the literature or can be
prepared by known methods. Compounds (VJH) can be prepared by known methods.
Within the schemes above there is scope for functional group interconversion; for
example in compound (V), conversion of one value of L1 to another value of L1; or hi
compounds (TV) conversion of protecting group P for another protecting group P, or
conversion of one compound of formula (I) to another of formula (I) by interconversion of
substituents.
When R1 is an aromatic group, the substituent R1 may be introduced at the final
stage as illustrated in Scheme 2 by reaction of a compound of formula (VD) where L3
represents a leaving group such as halogen (preferably bromo or iodo) or
trifluoromethylsulfonyloxy, and all other variables are as previously defined, with a reagent
R!M, where M is the residue of an organometallic species e.g. B(OH)2 or trialkylstannyl.
Such a process may be carried out in an inert solvent such as 1,2-dimethoxyethane or 1,4-
dioxan, in the presence of a transition metal catalyst such as Pd(PPh3)4.
(Figure Removed)
Wherein Y, Ar2, m, p, AT!, R, R1 and Y are as defined for compounds of formula (I).
L3 is a leaving group.
The compounds of formula (I) may be prepared singly or as compound libraries
comprising at least 2, e.g. 5 to 1000, preferably 10 to 100 compounds of formula (I).
Compound libraries may be prepared by a combinatorial 'split and mix* approach or by
multiple parallel synthesis using either solution phase or solid phase chemistry, by
procedures known to those skilled in the art.
Thus according to a further aspect of the invention there is provided a compound
library comprising at least 2 compounds of formula (I), or phannaceutically acceptable
derivatives thereof.
Phannaceutically acceptable salts may be prepared conventionally by reaction with
the appropriate acid or acid derivative.
The compounds of formula (I) and their phannaceutically acceptable derivatives are
useful for the treatment of diseases or disorders where an antagonist of a human Qrexin
receptor is required such as obesity and diabetes; prolactinoma; hypoprolactinemia;
hypothalamic disorders of growth hormone deficiency; idiopathic growth hormone
deficiency; Cushihgs syndrome/disease; hypothalamic-adrenal dysfunction; dwarfism; sleep
disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet-lag syndrome; sleep
disturbances associated with diseases such as neurological disorders, neuropathic pain and
restless leg syndrome; heart and lung diseases; 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; bulimia and hypopituitarism. Additionally the compounds of formula
(I) and pharmaceutically acceptable derivatives are useful for the treatment of stroke,
particularly ischemic or haemorrhagic and/or in blocking an emetic response i.e. nausea and
vomiting.
The compounds of formula (T) and their pharmaceutically acceptable derivatives are
particularly useful for the treatment of obesity, including obesity associated with Type 2
diabetes, and sleep disorders. Additionally the compounds of formula (I) and
pharmaceutically acceptable derivatives are useful for the treatment of stroke, particularly
ischemic or haemorrhagic and/or hi blocking an emetic response i.e. nausea and vomiting.
Other diseases or disorders which may be treated in accordance with the invention
include disturbed biological and circadian rhythms; adrenohypophysis disease; hypophysis
disease; hypophysis tumor /adenoma; adrenohypophysis hypofunction; functional or
psychogenic amenorrhea; adrenohypophysis hyperfunction; migraine; hyperalgesia; pain;
enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia and allodynia;
acute pain; bum 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 pain; post-operative pain; neuralgia; and
tolerance to narcotics or withdrawal from narcotics.
The invention also provides a method of treating or preventing diseases or disorders
where an antagonist of a human Qrexin receptor is required, which comprises administering
to a subject in need thereof an effective amount of a compound of formula 0), or a
pharmaceutically acceptable derivative thereof.
The invention also provides a compound of formula (I), or a phannaceutically
acceptable derivative thereof, for use in the treatment or prophylaxis of diseases or disorders
where an antagonist of a human Qrexin receptor is required.
The invention also provides the use of a compound of formula (T), or a
pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the
treatment or prophylaxis of diseases or disorders where an antagonist of a human Orexin
receptor is required
For use in therapy the compounds of the invention are usually administered as a
pharmaceutical composition. The invention also provides a pharmaceutical composition
comprising a compound of formula (I), or a pharmaceutically acceptable derivative thereof,
and a pharmaceutically acceptable carrier.
The compounds of formula (T) and then- pharmaceutically acceptable derivatives
may be administered by any convenient method, e.g. by oral, parenteral, buccal, sublingual,
nasal, rectal or transdennal administration, and the pharmaceutical-compositions adapted
accordingly. '
The compounds of formula (I) and their pharmaceutically acceptable derivatives
which are active when given orally can be formulated as liquids or solids, e.g. as syrups,
suspensions, emulsions, tablets, capsules or lozenges.
A liquid formulation will generally consist of a suspension or solution of the active
ingredient hi a suitable liquid carriers) e.g. an aqueous solvent such as water, ethanol or
glycerine, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation
may also contain a suspending agent, preservative, flavouring and/or colouring agent
A composition in the form of a tablet can be prepared using any suitable
pharmaceutical carrier(s) routinely used for preparing solid formulations, such as
magnesium stearate, starch, lactose, sucrose and cellulose.
A composition in the form of a capsule can be prepared using routine encapsulation
procedures, e.g. pellets containing the active ingredient can be prepared using standard
carriers and then filled into a hard gelatin capsule; alternatively a dispersion or suspension
can be prepared using any suitable pharmaceutical carriers), e.g. aqueous gums, celluloses,
silicates or oils and the dispersion or suspension then filled into, a soft gelatin capsule.
Typical parenteral compositions consist of a solution or suspension of the active
ingredient in a sterile aqueous carrier or parenterally acceptable oil, e.g. polyethylene glycol,
polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be
lyophilised and then reconstituted with a suitable solvent just prior to administration.
Compositions for nasal administration may conveniently be formulated as aerosols,
drops, gels and powders. Aerosol formulations typically comprise a solution or fine
suspension of the active ingredient in a pharmaceutically acceptable aqueous or nonaqueous
solvent and are usually presented in single or multidose quantities in sterile form in
a sealed container which can take the form of a cartridge or refill for use with an atomising
device. Alternatively the sealed container may be a disposable dispensing device such as a
single dose nasal inhaler or an aerosol dispenser fitted with a metering valve. Where the
dosage form comprises an aerosol dispenser, it will contain a propellant which can be a
compressed gas e.g. air, or an organic propellant such as a fluorochlorohydrocarbon or
hydrofluorocarbon. Aerosol dosage forms can also take the form of pump-atomisers.
Compositions suitable for buccal or sublingual administration include tablets,
lozenges and pastilles where the active ingredient is formulated with a carrier such as sugar
and acacia, tragacanth, or gelatin and glycerin.
Compositions for rectal administration are conveniently in the form of suppositories
containing a conventional suppository base such as cocoa butter.
Compositions suitable for transdermal administration include ointments, gels and
patches.
Preferably the composition is in unit dose form such as a tablet, capsule or ampoule.
The dose of the compound of formula (I), or a pharmaceutically acceptable
derivative thereof, used in the treatment or prophylaxis of the abovementioned disorders or
diseases will vary in the usual way with the particular disorder or disease being treated, the
weight of the subject and other similar factors. However, as a general rule, suitable unit
doses may be 0.05 to 1000 mg, more suitably 0.05 to 500 mg. Unit doses may be
administered more than once a day for example two or three times a day, so that the total
daily dosage is in the range of about 0.01 to 100 mg/kg; and such therapy may extend for a
number of weeks or months. In the case of pharmaceutically acceptable derivatives the
above figures are calculated as the parent compound of formula (I).
No lexicological effects are indicated/expected when a compound of formula (I) is
administered in the above mentioned dosage range.
Human Orexin-A has the amino acid sequence:
pyroGlu Pro Leu Pro Asp Cys Cys Arg Gin Lys Thr Cys Ser Cys Arg Leu
1 5 10 1 5
Tyr Glu Leu Leu His Gly Ala Gly AsnHis Ala AlaGly Be Leu Thr
20 25 30
Leu-NH2
Orexin-A can be employed in screening procedures for compounds which inhibit the
ligand's activation of the orexin-1 receptor.
In general, such screening procedures involve providing appropriate cells which
express the orexin-1 receptor on their surface. Such cells include cells from mammals,
yeast, Drosophila or E. coll. In particular, a polynucleotide encoding the orexin-1 receptor
is used to transfect cells to express the receptor. The expressed receptor is men contacted
with a test compound and an orexin-1 receptor ligand to observe inhibition of a functional
response. One such scieenmgprcK^ure involves the use of rnelanophores which are
transfected to express the orexin-1 receptor, as described hi WO 92/01810. ~
Another screening procedure involves introducing RNA encoding the orexin-1
receptor.into Xenopus oocytes to transiently express the receptor. The receptor oocytes are
then contacted with a receptor ligand and a test compound, followed by detection of
inhibition of a signal hi the case of screening for compounds which are thought to inhibit
activation of the receptor by the ligand.
Another method involves screening for compounds which inhibit activation of the
receptor by determining inhibition of binding of a labelled orexin-1 receptor ligand to cells
which have the receptor on their surface. This method involves transfecting a eukaryotic
cell with DNA encoding the orexin-1 receptor such that the cell expresses the receptor on its
• surface and contacting the cell or cell membrane preparation with a compound in the
presence of a labelled form of an orexin-1 receptor ligand. The ligand may contain a
radioactive label. The amount of labelled ligand bound to the receptors is measured, e.g. by
measuring radioactivity.
Yet another screening technique involves the use of FLEPR equipment for high
throughput screening of test compounds that inhibit mobilisation of intracellular calcium
ions, or other ions, by affecting the interaction of an orexin-1 receptor ligand with the
orexin-1 receptor.
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 Examples illustrate the preparation of pharmacologically active
compounds of the invention. The Descriptions D1-D105 illustrate the preparation of
intermediates to compounds of the invention.
hi the Examples !H NMR's were measured at 250MHz in CDCk unless otherwise
stated.
Description 1: (S) 2-Aminomethyl-piperidine-l-carboxyIic acid tert butyl ester
a)2,2-Trifluoro-N-f(S)-l-{(R)-2-hydroxy-l-phenyl-eUiyI>piperidin-2-ylmetbyl]-
acetamide
(R)-2-[(S)-2-Anunometiiyl-piperidin-l-yl]>2-phenyl-ethanol (20.0g) (Froelich, Olivier,
Desos, Patrice; Bonin, Martine; Quirion, Jean-Charles; Husson, Henri-Philippe; Zhu,
Jieping., J. Org. Chem. 1996,61,6700) and triethylamine (13.0ml) were dissolved in
dichloromethane (500ml), cooled to 0°C and trifluoroacetic anhydride (12.66ml) added
dropwise. The mixture was wanned to room temperature and stirred overnight The
organic phase was washed with water, separated, dried and solvent removed at reduced
pressure. The residue was column chromatographed [silica gel, 0^-10% (9:1
methanol/ammonia) in dichloromethane eluant] to give the title compound (28.0g) as a
yellow oil.
Mass Spectrum (AH*): Found 331 (MH*). CieHaiFjNzCb requires 330.
[a]D -55°@ 28° 1% in chloroform
b)22-Trifluoro-N-(S>-l-piperidin-2-yhiiethyI-acefainide
2,2,2-TrMuoro-N-[(SM^(R)-2-by
(28.0g) was dissolved in ethanol (200ml) containing Pearhnans catalyst (2.0g) and shaken
under a hydrogen atmosphere (SOpsi) at 50°C for 3 hours. The reaction mixture was filtered
and solvent removed at reduced pressure. The residue was column chromatographed (silica
gel, 0 -10% (9:1 memanol/ammonia) in dichloromethane eluant) to give the title compound
(14.18g) as a colourless oil.
Mass Spectrum (API*): Found 211 (MH*). CjRitfjN2O requires 210.
[a]D +18°@ 28° 1 % in chloroform
1H MMR 8: (d6-DMSO) 1.07 (1H, m), 1.32 (2H, m), 1.35 -1.60 (2H, m), 1.72 (1H, m),
2.54 (1H, t), 2.70 (1H, m), 3.00 (1H, d), 3.17 (3H, m), 9.30 (1H, br. s.)
c) (S)-2-[(2,2^!-Trifluoro-ethanoylaniino)-methyI]-piperidine-l-carboxylic acid ten
butyl ester
2^,2-Trifluoro-N-(S)-l-piperidin-2-ylinethyl-acetamide (14.1 8g) was dissolved in
dichloromethane (250ml) and treated with di-ter/-butyl dicarbonate (14.95g). The mixture
was stirred for 1 6h, washed with water, 2N hydrochloric acid and saturated brine, dried and
solvent removed at reduced pressure to give the title compound (1 8.3g)
Mass Spectrum (APf): Found 31 1 (MH4). CjsHaiF^Oa requires 310.
[ct]D -94°@ 28° 1% in chloroform
'HNMR 8: (d6-DMSO) 1J27 (1H, m), 1.36, 1.47 (9H, s),. 1.49- 1.58 (5H, m), 2.88 (1H, m),
3.22 (1H, m), 3.49 (1H, m), 3.84 (1H, m), 4.34 (1H, m) and 9.42 (1H, br. s.).
d) (S) 2-Aminomethyl-piperidiiie-l-carboxylic acid tert butyl ester
(S)-2-[(2,2,2-Trifluoro-ethanoylan^ acid tert butyl ester
(1 8.2g) was dissolved in methanol (500ml) and treated with potassium carbonate (16.1g).
After stirring for 1 6h solvent was removed at reduced pressure and the residue partitioned
between dichloromethane/water. The organic phase was separated, washed with brine,
dried and solvent removed at reduced pressure, the residue was column chromatographed
(silica gel, 0 — 10% (9: 1 methanol/ammonia) in dichloromethane eluant) to give the title
compound (8.82g) of description 1.
Mass Spectrum (API*): Found 215 (MFT*). QiHbNaOa requires 214.
[a]D -32.2°@ 28° 1% in chloroform
1H NMR 5: 1 .44 (2H, m), 1 .50 (9H, s), 2.64 - 2.80 (2H, m), 2.94 (1H, dd), 3.99 (IH, m) and
4.15
Description 2: (RS) 2-(BenzoxazoI-2-yIaminomethyI>-piperidine-l-carboxylic acid tert
butyl ester
(RS) 2-Aminomethyl-piperidine-l-carboxyh"c acid tert butyl ester (0.21 g) and 2-
cnlorobenzoxazole (0.1 53g) and triethylamine (O.lg) were combined in tetrahydrofuran
(1 Oml) and stirred at room temperature for 4 hours. The mixture was partitioned between
ethyl acetate and water, the organic phase dried and solvent removed at reduced pressure to
give the title compound (036g) as an oil that solidified on standing.
Mass Spectrum (API1): Found 332 (MH*). CigHisNaQj requires 331.
Description 3: (RS)Benzozazol-2-yl-piperidin-2-ylmethyl-aniine
The compound of description 2 (0.36g) was stirred in trifluoroacetic acid (1 Oml) containing
water (1 drop) for 3 hours. Solvent was removed at reduced pressure and the residue
column chromatographed (silica gel, 0-10% (9:1 methanol/ammonia) in dichloromethane
eluant) to give the title compound (0.23g).
Mass Spectrum (API*): Found 232 (MH*). CwH^NaO requires 231.
Description 4: (R>-2-[(^2^enz»oiazoK2-ylaminomethyI)-piperidin-l-yl]-2-phenylethanol
A mixture of (R>2-[(S>2rAmii»mernyl-pirx«^ (l.Og) (Froelich,
Olivier; Desos, Patrice; Benin, Martine; Quirion, Jean-Charles; Husson, Henri-Philippe;
Zhu, Jieping. J. Org. Chem. 1996, 61, 6700) and 2-chlorobenzoxazole (0.66g) were
combined in tetrahydrofuran (40ml) containing triethylamine (0.43g) and stirred at room
temperature for 1 hours. The mixture was partitioned between ethyl acetate and water, the
organic phase separated, dried and solvent removed at reduced pressure, the residue was
column chromatographed (silica gel, 30% pentane in ethyl acetate - ethyl acetate) to give
the title compound (l.lg).
JHNMRo: 1.59- 1.71 (4H,m), 1.91 (1H, t),2.73 (1H,m),2.95 (1H,m),3.71 (2H,m),4.0
(1H, m), 4.10 (1H, m), 4.26 (1H, m), 5.7 (1H, m), 7.03 (1H, m), 7.17 (1H, m), 7.23 - 7.26
(3H, m) and 7.32 - 7.40 (4H, m). Mass Spectrum (API*): Found 352 (MH1). CajH^C^
requires 351.
Description 5: BenzoxazoI-2-yl^S)-l-piperidm-2-ymiWhyl-amine
The compound of description 4 (1.15g) in ethanol (60 ml) containing Pearlmans catalyst
(0.23g) was shaken under an atmosphere of hydrogen (50psi) for 24 hours. Additional
Pearlmans catalyst was added and shaking under hydrogen at 50psi continued for a further
12 hours. The reaction was filtered through kiesel guhr, the filtrate evaporated at reduced
pressure and the residue column chromatographed (silica gel, ethyl acetate - ethyl
acetate/methanol 1:1 eluant) to give the title compound (0.49g) as an oil.
'HNMRS: 1.16 -1.85 (7H,m), 2.64 (lH,m), 2.85-2,99 (lH,m), 3.11 (lH,m),3.31 (1H,
m), 3.55 (1H, m), 7.00 (1H, dd), 7.12 (1H, m), 720 (1H, d) and 7.30 (1H, m). Mass
Spectrum (API*): Found 232 (MH*). Ci3H17N3O requires 231.
Description 6: (RS)-Benzoxa2ol-2-yl-(4-benzyl-morpholiii-3-yhnethyl)-aniine
From (4-beri2yl-moiphoto-3-yl)Hmetb.ylaniine (Ig) (Morie, Toshiya; Kato, Shiro; Harada,
Hiroshi; Yoshida, Naoyuki; Fujiwara, Iwao; Matsumoto, Jun-ichi., Chem. Pharm. Bull.
1995,43,1137-47) and 2-cUorobenzoxazole (0.78g), the title compound (0.77g) was
prepared according to the method of D4.
!H NMR 8:2.33 (1H, m), 2.73 - 2.80 (2H, m), 3.33 (1H, d), 3.51 - 3.90 (6H, m), 4.10 (1H,
d), 5.58 (1H, s), 7.04 (1H, m), 7.17 (1H, m) and 724 - 7.39 (7H, m).
Mass Spectrum (API*): Found 324 (MH*). Ci9H2iN3Q2 requires 323.
Description 7: (RS)-Benzoiazol-2-yl-morpholin-3-yImethyI-amine
From the compound of D6 (0.77g) the title compound (0.55g) was prepared-according to the
method of D5. . "
JH NMR 8:2.93 - 3.23 (2H, m), 3.46 - 4.03 (7H, m), 6.95 - 7.23 (4H, m). Mass Spectrum
(APf): Found 234 (MH*). Ci2Hi5N3Q2 requires 233.
Description 8: (RS) 2£T-Benz»imidazoI-2-ylaminomethyI)-piperidine-l-carboxyh'c
acid tert buryl ester
(RS>2-Arnmomemyl-piperiduie-l-carbo^rlic acid tert butyl ester (0.25g) and 2-
chlorobenzimidazole (0.15g) were combined and warmed to 100°C for 48 hours. After
cooling to room temperature the mixture was column chromatographed (silica gel, ethyl
acetate/pentane 1:4 — elhyl acetate/pentane 1:1 eluant) to give the title compound (0.1 g).
]H NMR 8: 1.47 (9H, m), 1.65 - 1.81 (7H, m), 2.85 (1H, t), 3.47 (2H, m), 3.91 (1H, d), 4.32
(1H, s), 5.78 (1H, s), 7.04 (3H3 m) and 7.29 (1H, s).
Mass Spectrum (APf): Found 33 1 (MfT). CigHasWa requires 330.
Description 9: (RS)-(lfl-Beiizoiniida2oI-2-yI)-piperidin-2-ylmethyl-amine
dihydrochloride.
The compound of D8 (0.39g) was stirred in a mixture of 4M HC1 in dioxan/methanol (1:1)
for 4 hours. Solvent was removed at reduced pressure to give the title compound (0.28g) as
a foam.
Mass Spectrum (API4): Found 231 (MH1). CisHigty requires 230.
Description 10: (RS) 2-(Quinolin-2-ylaminomethyI)-pliperidine-l-carboxylic acid tert
butyl ester
The title compound (O.lg) was prepared.from (RS) 2-ammomethyJ-piperidine-l-carboxyh"c
acid tert butyl ester (0.5ml) and 2-chloroquinoline (0.5g) according to the procedure of D8.
Mass Spectrum (API*): Found 342 (MH*). C2oH27N3Q2 requires 341 .
Description 11: (RS)-Pip€ridni-2-yhnethyl-quinolin-2-yI-amine
The title compound (0.29g) was prepared from the compound of D10 according to the
method of D9. After removal of solvent the residue was dissolved in dichlorometnane,
washed with saturated sodium hydrogen carbonate, the organic phase separated, dried and
solvent removed at reduced pressure to give the title compound.
'H NMR 8: 1.20 - 1.96 (6H, m), 2.64 (1H, m), 2.85 (1H, m), 3.10 (1H, m), 3.35 (1H, m),
3.60 (1H, m), 5.17 (1H, m), 6.66 (1H, d), 7.19 (1H, dt), 7.48 - 7.58 (2H, m), 7.66 (1H, d)
and 7.78 (lH,d).
Mass Spectrum (API*): Found 242 (MH*). CisH^Na requires 24J.
Description 12: (RS)-2-(Benzothiazol-2-yIaniinomethyI)-piperidine-l-carboxyIic acid
tert butyl ester
The title compound (1 2g) after column chromatography (silica gel, 5% diethyl ether/hexane
- diethyl ether eluant) was prepared from (RS) 2-arriinornethyl-piperidine-l-carboxyUc acid
tert butyl ester (2.0g) and 2-chlorobenzothiazole (l-58g) according to the method of D2.
Mass Spectrum (API*): Found 348 (MH*). CigH^sOzS requires 347.
Description 13: (RS)-BenzotbJazol-2^piperidin-2-yhiietnvi-amine
The compound of D12 (1 2g) was dissolved in methanol (60ml) and treated with 4N HC1 in
dioxan (12 ml), the mixture was stirred for 4h, added to water containing sodium hydrogen
carbonate and extracted with ethyl acetate (x 3). The combined organic phase was dried and
sol vent removed at reduced pressure to give the title compound (0.70g).
Mass Spectrum (APf): Found 348 (MH*). C13Hi7N3S requires 347.
Description 14: 2--piperidine-l-carboxylic acid
tert butyl ester
The title compound (0.76g) was prepared from (RS) 2-aminomethyl-piperidine-l-carboxyIic
acid tert butyl ester (1.6ml) and 1-chloroisoquinoline (0.8g) according to the method used
for the preparation of the compound of D8.
Mass Spectrum (API4): Found 342 (MH4). C2oH27N3O2 requires 341.
Description 15: IsoquinoIin-l-yl-piperidin-2-ylmethyl-amine
The title compound (0.39g) was prepared according to the method of description 13 from
the compound of D14 (0.75g).
Mass Spectrum (API*): Found 242 (MH4). C15Hi9N3 requires 241.
Description 16: (S) 2-(QuinoUn-2-ylaminomethyl)-piperidine-i-carboxylic acid tert
butyl ester '
The title compound (0.1 Ig) was prepared from (S) 2-aminomethyl-piperidine-l-carboxyh"c
acid tert butyl ester (1.23g) and 2-chloroquinoline (Ig) according to the procedure of D8.
Mass Spectrum (APf): Found 342 (MH4). CaoH^NaQa requires 341.
Description 17: (S>Piperidin-2-ylmethyl-quinolin-2-yl-amine
The compound of D16 (0.1 Ig) was dissolved hi dichloromethane (10ml) and trifluoroacetic
acid (1ml) added. The mixture was stirred for 4h, poured into ice containing potassium
carbonate and extracted with 10% methanol/dichloromethane (x 3). The combined organic
extracts were dried and solvent removed at reduced pressure to give the title compound
(0.05g).
Mass Spectrum (APf): Found 242 (MH4). CisHjpNa requires 241.
Description 18: (RS) 2-(Quinoxalin-2-ylamuiomethyl>piperidine-l-carboxylic acid
tert butyl ester
The title compound (0.73g) was prepared from (RS) 2-aminomethyl-piperidine-l-carboxylic
acid tert butyl ester (1ml) and 2-chloroquinoxaline (0.5g) according to the procedure of D8.
Mass Spectrum (API4): Found 343 (MH4). Ci^^Cfe requires 342
Description 19: (RS)-Piperidm-2-ylmethyl-quinoxaliii-2-yl-amine
The title compound (036g) was prepared from the compound of Dl 8 (0-71g) according to
the method of D17.
Mass Spectrum (API4): Found 243 (MH4). Cj^gty requires 242.
Description 20: (RS) 2-(Pyrinudin-2-ylaminomethyl)-piperidine-l-carboiylic acid tert
butyl ester
A mixture of (RS) 2-aminomethyl-piperidine-l-carboxyh'c acid tert butyl ester (l-28g) and
2^bJoropyrimidine was heated at 100°C for 48 hours. After cooling to room temperature
the mixture was column chromatographed (silica gel, 0 -10% (9:1 methanol/ammonia) in
dichloromethane eluant) to give the title compound (0.42g) as an oil.
Mass Spectrum (API4): Found 293 (MH4). CisH^Cb requires 292.
Description 21: (RS)-Piperidin-2-ylmethyI-pyrimidin-2-yl-amine
The title compound (0.350g) was prepared from the compound of D20 (0.4g) according to
the method of D 17.
Mass Spectrum (APf): Found 193 (Mtf). CioH]6N4 requires 192.
Description 22: (RS) 2-{Pyrazin-2-yIaminomethyI)-piperidine-l-carboxylic acid ten
butyl ester
The title compound (0.1 8g) was prepared from (RS) 2-aminomethyl-piperidine-I-carboxylic
acid ten butyl ester (0.54g) and 2-chloropyrazine according to the method of D20.
Mass Spectrum (APf): Found 293 (MH*). CisHbtN-jO^ requires 292.
Description 23: (RS)-Piperidm-2-ylmethyl-pyrazin-2-iyl-ainine
The title compound (0. 1 8g) was prepared from the compound of D22 (O.OSg) according to
the method of D17.
Mass Spectrum (API4): Found 193 (MH*). CioHi^ requires 192.
Description 24: (S)-2^Quina2»u^-4-ylaminomethyI)-piperiduie-l-carboxyIic acid ten
butyl ester
(S)-2-Aminomemyl-piperidine-l-carboxylic acid ferf-butyl ester (l.Og), 4-cbloroquinoxaIine
(0.768g) and diisopropylethylamine (0.816ml) were dissolved in tetrahydrofuran (75ml) and
heated to reflux for 6 hours under an atmosphere of argon. After cooling, the reaction
solution was partitioned between ethyl acetate and water. The organic layer was washed
with saturated sodium hydrogen carbonate solution, saturated brine, dried and evaporated.
The residue was chromatographed over silica gel, eluting with a gradient of 50 to 100%
ethyl acetate in hexane. The title compound was obtained as a white foam (1 .44g).
1H NMR 8: 1.40 (3H, s), 2.90 (1H, dt), 335-3.50 (1H, br.), 3.9-4,05 (1H, br.), 4.15-4.3 (1H,
br.), 4.68-4.82 (1H, br.), 6.9-7.2 (1H, br.), 7.40 (1H, t), 7.65-7.85 (3H, m), 8.65(1H, s).
Description 25: (S)-2-(Qiimazolin-4-yIaminomethyI)-piperidine
(S)-2-(Qirinazolin^-ylaminomemyl)-piperidine-l-caiix>xylic acid ten butyl ester (1 J5g) was
dissolved in trifluoroacetic acid (60ml) and stirred at room temperature for 2 hours. The
solution was then evaporated and the residue chromatographed over silica gel, eluting with
0 to 10% (9:1 methanol — concentrated ammonia solution) in dichloromethane. The title
compound was obtained as a white foam (0.84g), MrTi"243.
Description 26: (S)-2-[(6,7-Dffluoro-3-memylquinoxahii-2-ylamino)methyI]-
piperidine-1-carboxylic acid ten bury ester
(S>2-Arninomethyl-piperidine-l-carboxyh'c acid /er/-butyl ester (1.14g), and 2-chloro-6,7-
difluoro-3-memylqumoxamie7'e/^erfl/PCr//rf.^ff?/ (2000), WOOO/42026A 1 20000720
(1.14g) were dissolved in DMF(2ml) and heated to 90°C for 3 days under an atmosphere of
argon. After cooling, the reaction solution was partitioned between ethyl acetate and water.
The organic layer was washed with water, saturated brine, dried and evaporated. The
residue was chromatographed over silica gel, eluting with a gradient of 10 to 50% ethyl
acetate in hexane. The title compound was obtained as a pink foam (0.524g), MH*~393.
Description 27: (S)-2-[(6,7-Difluoro-3-methylquinoxalin-2-yIamino)methyIJ-piperidine
(S)-2-[(6,7-Difluoro-3-mernylquhoxalin-2-ylan^
ten butyl ester (0.524g) was dissolved in trifluoroacetic acid (15ml) and stirred at room
temperature for 3 hours. The solution was then evaporated and the residue
chromatographed over silica gel, eluting with 0 to 10% (9:1 methanol — concentrated
ammonia solution) in dichloromethane. The title compound was obtained as a white solid
(0.289g), MH*293.
Description 28: (S)-2~[(6,7-Difluoroquinoxami-2-ylamMo)methyI]-piperidine-lcarborylic
acid tert buty ester
(S)-2-Aminomethyl-piperidine-l-carboxylic acid ter/-butyl ester (0.607g), and 2-chloro-6,7-
dffluoroquinoxaline McQuaidet. al J.MedChem. (1992), 35(18), 3319-24 (0.569g)
were dissolved in dimethylformamide (1ml) and heated to 90 °C for 5 days under an
atmosphere of argon. After cooling, the reaction solution was partitioned between ethyl
acetate and water. The organic layer was washed with water, saturated brine, dried and
evaporated. The residue was chromatographed over silica gel, eluting with a gradient of 10
to 50% ethyl acetate in hexane. The title compound was obtained as a pale yellow solid
(0.460g), 1^379.
Description 29: (S)-2-[(6,7-DifluoroquinoxaUn-2-ylamino)niethylJ-piperidine
(S>2-[(6,7-Difluoroqiu^oxalm-2-ylam acid tert butyl
ester (0.460g) was dissolved in trifluoroacetic acid (10ml) and stirred at room temperature
for 3 hours. The solution was then evaporated and the residue chromatographed over silica
gel, eluting with 0 to 10% (9:1 methanol - concentrated ammonia solution) in
dichloromethane. The title compound was obtained as a pale yellow foam (0286g), MH*
279.
Description 30: (R^^2-[(6 J-Duluoro^iu^oxalui-2-yIaniuio)-methylJ-pyrrolidine-l
carboxylic acid tert butyl ester
(R,S)-2-Ammoniethyl-pynoHdine-lKarboxylic acid terf-butyl ester (3.0g) and 2-chloro-
6,7-difluoroqumoxaline (3 .Qg) were combined in xylene (20ml). containing
diisopropylethylamine (3ml) and heated at 130°C for 24 hours. Solvent was removed at
reduced pressure and the residue column chromatographed (silica gel, diethyl
ethenpetroleum ether 1 :1) to give the title compound (3.4g)
Mass Spectrum (API*): Found 365 (MH*). CigKbFalSljQz requires 364.
Description 31: (El^2-[(6,74>ifluoroqiiinoxalin-2-ylaiijino)methyl]-pyjTolidine
The compound of D30 (3.4g) was dissolved in dichloromethane (100ml) and treated with
trifluoroacetic acid (15ml). After 3h additional trifluoroacetic acid (40ml) and
dichloromethane (100ml) was added. The mixture was stirred for 48h, poured into excess
aqueous sodium hydrogen carbonate, the organic phase separated, dried and solvent
removed at reduced pressure. The residue was column chromatographed (silica gel, 5%
(9:1 methanol/ammonia)/ dichloromethane to give the title compound (0.9g) Mass
Spectrum (API*): Found 265 (MH*). Ci3Hi4F2N4 requires 264. 1H NMR 6: 1 .56 (IH, m),
1.72 - 1.93 (3H, m), 2.96 (2h, m), 3.28 (IH, m), 3.49 (IH, m), 3.64 (IH, m), 7.39 (IH, dd),
7.591H,dd)and8.16(lH,s).
Description 32: (S)-2-(quinazoIin-2-ylamino)methyl-piperidiJie-l-carboxylic acid tert
butyl ester
The title compound (0.6g) was prepared from (S)-2-aminomethyl-piperidine-l-carboxylic
acid /erf-butyl ester (0.68g) and 2-chloroquinazoline (0.53g) according to the method of
D30.
Mass Spectrum (AH*): Found 343 (MH*). CnHadWh requires 342.
Description 33: (S)-l-Piperidin-2-yltnethyI-quinazoIin-2-yl-amine
The title compound (0.384g) was prepared from the compound of D32 (0.6g) according to
the method of D31
Mass Spectrum (API*): Found 243 (MH*). C14HigN4 requires 242.
'HNMR 6: 1.18 - 1.65 6H, m), 2.66 (IH, m), 3.08 - 323 (2H, m), 3.50 (IH, m), 3.69 (IH,
m), 6.16 (Ih, br. s), 720 (1H, t), 7.54 - 7.69 (3H, m) and 8.91 (IH, s).
Description 34: (S)-2-([l^]Naphthyridin-2-yIaminomethyl)-piperidine-l-carboxylic
acid tert butyl ester
The title compound (0.48g) was prepared from (S)-2-aminomethyl-piperidme-l-carboxylic
acid /erf-butyl ester (0.59g) and 2K;hIoro-l^-naphmvridmeJZfl3w?por/>, etal J. Org. Chem.
(1971), 36(3), 450-4 (OAOg) according to the method of D30. ,
Mass Spectrum (API*): Found 343 (MH*). Ci^^Ch requires 342.
Description 35: [l^i]Naphthyridin-2-yl-{S)-l-piperidin-2-yImemyl-amiiie
The title compound (0.30g) was prepared from the compound of D34 (0.48g) according to
the method of D31.
Mass Spectrum (APf): Found 243 (MH*). CwHigty requires 242.
NMR 8: 1 25 - 1.88 (6H, m), 2.68 (IH, m), 2.98 (IH, m), 3.16 (IH, m), 337 - 3.50 (IH,
m), 3.66 (IH, m), 6.85 (IH, d), 7.41 IH, dd), 7.95 (IH, t) and 8.58 (IH, m). "
Description 36: (S)-2^1,8-NaphmyridJm-2-ylaniino)methyl-piperidine-l-carboxyh'c
acid tert butyl ester
The title compound (0.28g) was prepared from (S)-2-aminomemyl-piperidme-l-carboxyHc
acid tert-batyl ester (0.35g) and 2-chloro-l,8-naphthyridine (0.19g) according to the
method of D30.
Mass Spectrum (API*): Found 343 (MH*). Ci9H26N4O2requues 342.
Description 37: [l,8]Naphthyridin-2-yl-(S)-l-piperidin-2-yhnerhyI-amine
The title compound (0.1 Ig) was prepared from the compound of D36 (0.28g) according to
the method of D31.
Mass Spectrum (API*): Found 243 (MH*). CiiHjgty requires 242.
Description 38: (RS) 2-(4-Azabenzooxazol-2-ylaminomethyl)-piperidine-l-carboxyUc
acid tert butyl ester
The title compound (0.7g) was prepared from (RS)-2-aminomethyl-piperidine-l-carboxylic
acid tert-butyl ester (0.64g) and 2-methylthio-4-azabenzoxazole Chu-Moyeret al J. Org.
Chem. (1995), 60(17), 5721-5. (0.5g) according to the method of D30.
Mass Spectrum (API*): Found 333 (MH*). CnH^Os requires 332.
Description 39: (RS)-Oxazolo[4^-b]]pyridin-2-yl-pipferidin-2-ylinethyl-amine
The title compound (0.55g) was prepared from the compound of D38 (0.7g) according to
the method of D31.
Mass Spectrum (API4): Found 233 (MH*). CizHi^O requires 232.
Description 40: ((S)-l-{l-[2-(3-Methyl-[lt2,4]-oxadiazoI-5-yl)-phenyI]-methanoyI}-
piperidin-2-ylmethyI)-carbamic acid tert butyl ester
A mixture of (S)-l-piperidin-2-ylmethyl-carbamic acid tert butyl ester (2.0g) and 2-(3-
memyl-[l,2,4]oxadiazol-5-yl)-benzoic acid (1.9) in dimethylformaide (10ml containing
diisopropylethylamine (2.4ml) was treated with [O-(7-azabenzotriazol-l-yl)-l,l,3^-
tetramethyluronium hexafluorophosphate] (3.55g) and stirred at 90°C for 16 hours. Solvent
was removed at reduced pressure and the residue column chromatographed (silica gel,
diethyl ether eluant) to give the title compound (3.4g).
Mass Spectrum (APf): Found 401 (MH*). CziEfeg^CU requires 400.
Description 41: l-((S>2-Aminomethyl-piperidin-l-yI)-l-[2- 5-yI)-phenyl]-methanone
The title compound (0.53g) was prepared from the compound of D40 according to the
method of D13.
Mass Spectrum (API4); Found 301 (MH1). Ci6H2oN4Q2 requires 300.
Description 42: MethyH(S>l-{l-[2-(3-methyl-[l^,4]oiadiazol-S-yl>-phenyl]-
methanoyl}-piperidin-2-ylmethyl)-carbanuc acid dimethyl-ethyl ester
((SH-{H2^3-Merayl-[i;2,4]oxa&azol-5-yl>phen^
carbamie acid tert butyl ester (0.4g) in tetrahydrofuran (5ml) was treated with sodium
hydride (0. 1 g). After evolution of hydrogen had ceased iodomethane (0. 1ml) was added and
the reaction stirred for 1 6 hours. The reaction was quenched with ice/water, extracted with
diethyl ether (x 3), the combined organic extracts dried and solvent removed at reduced
pressure. The residue was column chromatographed (silica gel, diethyl ether) to give the
title compound (0.2g).
Mass Spectrum (API*): Found 415 (MH4). CzaHaoN^ requires 414.
Description 43: l-[(R)-2-Methylaminomethyl-piperidin-l-ylJ)-l-[2-(3-methyl-
[l^,4Joxadiazol-5-yl)-phenyIJ-methanone
The title compound (0.1 5g) was prepared from the compound of D42 according to the
method of D13.
Mass Spectrum (API1): Found 315 (MH4). CnHi2N4 requires 314.
Description 44: (S)-2-[(6,7-Difluoro-quino3:aIin-2-yJamino)-methyIJ-pyrroIidine-lcarboxylic
acid tert butyl ester
The title compound (0.53g) was prepared from (S)-2-aminomemyl-pyrroh"dme-l-caiboxylic
acid ter/-butyl ester (0.5g) and 2-chloro-6,7-difmoroquinoxaline (0.5g) according to the
method of D30.
Mass Spectrum (API4): Found 365 (MH*). CigHbfoN^ requires 364.
Description 45: (S>2-[(6,7-DifluoroquinoxaIin-2-ylamino)methyl]-pyrroIidine
The title compound (038g) was prepared from the compound of D44 (0.53g) according to
the method of D31.
Mass Spectrum (API*): Found 265 (MH*). Ci3H]4F2N4 requires 264.
Description 46: (RS)-3-[(6,7-Difluoro^uinoxalin-2-ylamino)-methylJ-morphoIine-4-
carboxylic acid tert butyl ester
The title compound (0.58g) was prepared from 2-aminomethyhnorphohiie-4-carboxylic acid
tert-butyl ester (0.82g) and 2-chloro-6,7-difIuoroquinoxaline (0.76g) according to the
method of D30.
Mass Spectrum (API4): Found 381 (MH*). CigHzzFztyOa requires 380.
Description 47: (6,74)iQuoro^umoxaIur2~yI)-morpboIm-3-yImethyI-amine
The compound of D46 ((X58g) was dissolved in trifhioroacetic acid and stirred for 3hours.
Solvent was removed at reduced pressure and the residue partitioned between aqueous
sodium hydrogen carbonate and ethyl acetate. The organic phase was separated dried,
solvent removed at reduced pressure and the residue column chromatographed ( silica gel, 0
- 10% (9: 1 methanol/ammonia) in dichloromethane, eluant ) to give the title compound
(0-327g).
Mass Spectrum (API4): Found 281 (MH*). Ci3Hi4F2N4O requires 280.
Description 48: 2-iylic
acid tert butyl ester and 2-(Pyrido[2^A]-pyrazin-3-ylaminomerliyl)-piperidine-lcarborylic
acid tert butyl ester
A mixture of (S>2-aminomethyl-piperidine-l-carboxylic acid tert butyl ester (I.Og) and a
2:1 mixture of 2K;Uoro-pyrido[23-b]pyrazine and 3K5Uoro-pyrido[23-b]pyrazine (0.8g)
was combined and wanned to 90°C for 18 hours. The mixture was diluted with ethyl
acetate, washed with aqueous sodium hydrogen carbonate and water, the organic phase
dried and solvent was removed at reduced pressure. The residue was column
chromatographed (silica gel, dichloromethane 0 to 6% ethanol in dichloromethane, 1%
increments) to give as the faster running component 2-(pyrido[2,3-6]pyrazin-2-
ylaminomethyl)-piperidine-l-carboxylic acid tert butyl ester (0.48g). mass spectrum (API*);
Found 344 (MfV). C17H25N5O2 requires 343 and 2-(pyrido[2,3-£]pyrazin-3-
y]arninometbyl)-piperidine-l-carboxylic acid tert butyl ester (0.3g) mass spectrum (API*):
Found 344 (ME*). C,7H25N5O2 requires 343.
Description 49: Piperidin-2-ylmethyl-pyrido[23-A]pyrazin-2-yI-aiixuie trifluoroacetate
salt
2-(Pyrido[23-6]pyrazm-2-ylammomemyl)-piperidine-l-carboxyh"c acdd tert butyl ester
(0.48g) was dissolved in dichloromethane (3ml), cooled (ice bath) and treated with
trifluoroacetic acid (2ml). The mixture was stirred for 3hours at room temperature, solvent
removed at reduced pressure and the residue co-evaporated with toluene to give the title
compound (0.45g).
Mass spectrum (APf)-' Found 244 (MH*> C|3Hi7N5 requires 243. .
Description SO: Piperidin-2-ylmethyl-pyrido[23-^]pyrazin-3-yl-amine trifluoroacetate
salt
The title compound (0.3g) was prepared from 2^yrido[23-i]pyrazin-3-ylaminomethyl)-
piperidine-1-carboxylic acid tert butyl ester (0.3g) according to the method of description
Mass spectrum (API4): Found 244 (MH*). CisHnNs requires 243.
Description 51: 2-Thioureidomethyl-piperidine-l-carboxylic acid tert butyl ester
Benzoyl chloride (1 -2ml) was added dropwise to sodium thiocyanate (0.90g) in acetone
(50ml). When the addition was complete the mixture was refluxed for 1 5 minutes, cooled
to room temperature and (RS) 2-aminomethyl-piperidine-l-carboxylic acid tert butyl ester
(2.0g) in acetone (5ml) added. The mixture was refluxed for 2 hours, cooled to room
temperature and solvent removed at reduced pressure. The residue was column
chromatographed (silica gel, 0 — 10% (9:1 methanol/ammonia) in dichloromethane eluant)
to give the title product (1 .95g).
Mass spectrum (API*): Found 274 (MH*). CnHbNaCbS requires 273.
Description 52: 2-[(4-Phenyl-thiazol-2-ylamino)-niethyl]-piperidine-l-carborylic acid
tert butyl ester
The compound of description 51 (1.95g) was dissolved in ethanol (100ml) containing
triethylamine (0.99ml). Phenacyl bromide (1.42g) was added and the mixture stirred for 16
hours. Solvent was removed at reduced pressure and the residue partitioned between ethyl
acetate and water. The organic phase was separated and solvent removed at reduced
pressure. The residue was column chromatographed (silica gel, dichloromethane eluant) to
give the title compound (2.42g).
Mass spectrum (API*): Found 274 (MH*). C^yNsOaS requires 273.
Description 53: (4-Phenyl-thiazol-2-yI>-piperidin-2-ylniethyl-aniine
The title compound (1 .55g) was prepared from the compound of D52 (2.42g) according to
the method of D47.
Mass spectrum (API*): Found 174 (MH4). CjsH^NsOaS requires 173.
Description 54: 2-[(5-Cyano-pyridin-2-ylamino)-methyl]-piperidine-l-carboxylic acid
tert butyl ester.
The title compound (1 .54g) was prepared from (S)-2-arainomethyl-piperidine-l-carboxyh"c
acid terf-butyl ester (2.0g) and 2-chloro-5-cyanopyridine (1.29g) in the presence of
diisopropylethylamine (1.21g) according to the method of D28.
Mass spectrum (API*): Found 317 (MH4). CnHa^Oi requires 316.
Description 55: 6-[(Piperidin-2-ylmethyl)-amino]-nicotinonitriIe
The title compound (1 .56g) was prepared from the compound of D54 (1 .53g) and
trifluoroacetic acid according to the method of D29.
Mass spectrum (API*): Found 217 (MH1). Ci2Hi$N4 requires 216.
Description 56: 2-[(4-Trifluoromethyl-pyrimidin-2-ylamino)-niethylJ-piperidine-lcarboxylic
acid tert butyl ester
The title compound (0.298g) was prepared from (S)-2-aminomethyl-piperidine-l-carboxyh"c
acid ter/-butyl ester (1 .Og) and 2s±loro^trifluoropyrirnidine (0.85g) according to the
method of D28.
Mass spectrum (API4): Found 361 (MH4). CieH^F^Qz requires 360.
Description 57: Piperidm-2-yhiiethyH^t1^uorometbyl-pyriniidin-2-yI)-amine.
The title compound (0.25g) was prepared from the compound of D56 (OJ29g) and
trifluoroacetic acid according to the method of D29.
Mass spectrum (API1): Found 261 (MH*). CnHisFaty requires 260.
Description 58: ((S)-l-{l-[4-(4-Fluoro-phenyl)-l-mettiyl-LH— pyrazoI-3-yI]-methanoyl}-
piperidin-2-ylmethyI)-carbamic acid tert butyl ester
The title compound (3.96g) was prepared from (S)-l-piperidin-2-yhnethyl-carbamic acid
tert butyl ester (2.14g) and 4^4-fluoro^henyl)-l-rnethyl-l/r-pyrazol-3-yl carboxyh'c acid
(220g) according to the method of D40.
Mass spectrum (API4): Found 417 (MH4). CzjHjjjF^Os requrres 416.
Description 59: ((S)-l-{l-[4^4-Fluoi^phenyI)-l-metbyl-lH-pyrazol-3-yl]-methanoyI}-
piperidin-2-ykaethyI)-methyI-carbamic acid dimethyl-ethyl ester.
The title compound (2.0g) was prepared from the compound of description 58 (3.85g)
according to the method of D42.
Mass spectrum (API*): Found 431 (MH4). C^iFNA requires 430
Description 60: l-[4-(4-Fluoro-phenyl)-l-methyl-Lff-pyrazol-3-yl]-l-((S>-2-
methylaniinomethyl-piperidin-l-yi>-methanone
-40-
The title compound (0.1 5g) was prepared for the compound of D59 (0.50g) according to the
method of D29.
Description 61 : (S)-2-[(3-Cyano-pyridin-2-yIamino)-methyl]-piperidine-l-carboxyIic
acid lert butyl ester
The title compound (0.66g) was prepared from (S)-2-aniinomethyl-piperidine-l-carboxylic
acid terr-butyl ester (1 .55g) and 2-chloro-3-cyanopyridine (1 .Og) according to the method of
D28.
Mass spectrum (APf): Found 317 (MET1). CiyKWSLA requires 316
Description 62: 2-[((S)-l-Piperidin-2-yunethyI)-amino]-nicotinonitriIe
The title compound (0.53g) was prepared from me compound of D61 (0.663g) and
trifluoroacetic acid according to the method of D29.
Mass spectrum (API*): Found 217 (MH4)- Ci2Hi6N4 requires 216
Description 63: (S)-2-[(4-C^ano-pyridm-2-ylamino)-methyIJ-piperidine-l-carboxyIic
acid tert butyl ester
The title compound (0.24g) was prepared from (S)-2-aminomethyl-piperidine-l-carboxylic
acid fe/f -butyl ester (1 . 14g) and 2-chloro-4-cyanopyridine (0.74g) according to the method
ofD28.
Mass spectrum (API4): Found 317 (MH4). CnfkdWh requires 316
Description 64: 4-Cyano-2-[((S)-l-Piperidui-2-ybnethyI)-aminoJ-pyridine
The title compound (0.1 7g) was prepared from the compound of D63 (0.243g) and
trifluoroacetic acid according to the method of D29.
Mass spectrum (API4): Found 217 (MH4). CuHuNi requires 216
Description 65: (S)2-[(5-Bromo-pyrmudto-2-ylamino)-methyl]-piperidine-l-carboxyu*c
acid tert butyl carbonate.
(S>2-Aminomemyl-piperidine-l-carboxylic acid tert butyl ester (Ig), 5-bromo-2-
chloropyrimidine (0.9g) were combined in xylene (20ml) containing potassium carbonate
(1 .29g) and diisopropylethylamine (2.43g) and wanned to reflux for 48k The mixture was
cooled to room temperature, filtered and solvent removed at reduced pressure. The residue
was column chromatographed (silica gel, pentane - 25% ethyl acetate/pentane). The
appropriate fractions were collected, solvent removed at reduced pressure to give the title
compound (1.43g) as a colourless gum
Mass spectrum (API4): Found 272 (Mrf-tert BOG). CioHW^UBr requires 371
Description 66: (S) (5-Bromo-pyrimidin-2-yl)-piperidin-2-ybaiethyl-amine
The title compound (1 .40g) was prepared from the compound of D65 (2.1 g) according to
the method of D9.
Mass spectrum (API4): Found 272 (MH4). CioHi4N4Br requires 271.
Description 67: (S) 2-[(3- 1-carboxylic acid tert butyl ester.
(S)-2-Aminomemyl-piperidine-l-carboxytic acid tert-butyl ester (l.lg) and 2-chloro-3-
cyano-5,6-difluoroquinoIine (1 .12g) according to the method of D28 were combined in
xylene (1 5ml) containing potassium carbonate (4.0g) and diisopropylethylamine (4ml) and
boiled for 20 hours. The reaction mixture was cooled to room temperature, filtered and
solvent removed at reduced pressure. The residue was column chromatographed (silica gel,
dichloromethane eluant) to give after combining appropriate fiactions the title compound
Mass spectrum (API4): Found 403 (MH*). C21H24F2N Description 68: (S) 6,7-Difluoro-2-[(piperidin-2-ylmethyI)-amino]-quinoline-3-
carbonitrile
The title compound (1 .40g) was prepared from the compound of D67 (1 .8g) according to
the method of D9.
Mass spectrum (API4): Found 303 (MH*). CieHieFaty requires 302
Description 69: (S)2-[(5-Bromo-pyriinidm-2-ylammo)-methyl]-pyrrolidin-l-carboxyIic
acid tert butyl carbonate.
(S)-2-Aminomethyl-pvrrolidhie-l-carboxylic acid tert butyl ester (2g), 5-bromo-2-
chloropyrimidine (1.93g) were combined hi xylene (4Qml) containing potassium carbonate
(2.76g) and diisopropylemylamine (5.23ml) and wanned to reflux for 20h. The mixture was
cooled to room temperature, filtered and solvent removed at reduced pressure. The residue
was column chromatographed (silica gel, pentane — 25% ethyl acetate/pentane). The
appropriate tractions were collected, solvent removed at reduced pressure to give the title
compound (l-78g) as a colourless gum
Mass spectrum (API*): Found 257 (MlT-tertBOC). C14H21BrN4O2 requires 357
Description 70: (S) (5-Bromo-pyrunidm-2-yI)-pyrTOu"din-2-yImethyl-amhie
The title compound (1 .40g) was prepared from the compound of D69 (1 .78 g) according to
the method of D9.
Mass spectrum (API*): Found 258 (MH*). Cj>Hi2N4Br requires 257.
Description 71: 3^1-{(S)-2-[(6,7-Duluoro^umox:alin-2-yIamino>rnethyI]-piperidin-lyl}-
methanoyl)-benzoic add
benzoic acid methy ester (0.5g) was dissolved in methanol (1 5ml) and treated with 1M
sodium hydroxide (1 .7ml). The reaction mixture was stirred for 12 h, additional 1M sodium
hydroxide (1 .7ml) added and stirring continued for a further 24k The reaction mixture was
diluted with water and washed with ethyl acetate. The aqueous phase was acidified with
2M hydrochloric acid and extracted with ethyl aceate (x 3). the combined organic phase
was dried (MgSOl), fioltered and solvent removed at reduced pressure to give the title
compound (0.463g) as a yellow solid.
Mass spectrum (APf): Found 427 (MHT*). C^H^HiOa requires 426.
Description 72: 1,1,1-Trifluoromethanesulphonic acid, 5-bromo-pyridin-2-yl ester
To a solution of 5-bromo-2-pyridone (3g) in dichloromethane (60ml) andpyridine (60ml) at
0°C under argon was added dropwise trifluoromethane sulphonic anhydride (5.4g). The
resulting mixture was warmed to ambient temperature and after 20h was evaporated and the
residue chromatographed on silica gel eluting with ethyl acetate to afford the title product
(3.5g) as a yellow oil. JH NMR 8: 7.1 0 (1H, d, J = 8 Hz), 8.00 (1H, dd, 2.4 and 8 Hz), 8.46
(lH,d,J = 2.4 Hz).
Description 73: (S)-2-[(5-Bromopyridin-2-ylamino>-niethyIJ-pyrTolidine-l-carboxyIic
acid tert-butyl ester >
The title product (0.22g) was obtained from (S)-2-aminomethyl-pyrrolidine-l-carboxylic
acid tert butyl ester (Ig) and the compound of D72 (1.7g) according to the method of D69.
Mass Spectrum (Electrospray LC/MS), APf: Found 356 (MET*). QsH^^rNaOa requires
355.
Description 74: (5-Bromo-pvridin-2-yl)-(S)-l-pyrrolJdui-2-ylmethylamine
To a solution of the compound from D73 (0.49g) in dichloromethane (40ml) at ambient
temperature was added trifluoroacetic acid (5ml). After 48h, the reaction mixture was
evaporated and partitioned between chloroform and 1M sodium hydroxide. The aqueous
layer was extracted with chloroform and the combined organic extracts dried and
evaporated to afford the title compound (0.33g) as an orange oil. JH NMR 8: 1 .44 - 1 .48
(1H, m), 1 .71 - 1.81 (3H, m), 2.05 (1H, br s), 2.93 (2H, m), 3.09 - 3.13 (1H, m), 3.35 - 3.41
(2H, m), 4.99 (1H, br s), 6.32 (1H, d, J = 9 Hz), 7.43 (1H, dd, J = 3 and 9 Hz), 8.08 (1H, d, J
= 3 Hz).
Description 75: A'-(4-Benzyl-inorpholui-3-yhTaethyI)-2J2r2-trifluoroacetamide
To (4-benzyl-morphoh^-3-yl)rmemylamine (734g) in dichloromethane (240ml) was added
triethylamine (5.83ml), followed by dropwise addition of trifluoroacetic anhydride (823g)
over 25 min at 0°C under argon. The reaction mixture was allowed to reach ambient
temperature and after stirring for 1 8h, was diluted in dichloromethane and washed with
saturated aqueous sodium hydrogencarbonate. The organic phase was separated, dried and
evaporated to afford a brown gum that was purified on silica gel, eluting with ethyl acetatepentane
mixtures to afford the title product (5. 1 7g) as an orange gum. Mass Spectrum
(API*): Found 303 (MH4). C14Hi7F3N2O2 requires 302.
Description 76: l^^Trifluoro-TV-morphoIin-S-ylmetfayl acetamide
To the compound from D75 (1.62g) in methanol (40ml) was added paUadhim black (0.45g)
and formic acid (10 drops) and the mixture stirred at ambient temperature for 1 6h, Further
palladium black (0.225g) and formic acid (10 drops) were added and after Ih, the reaction
mixture was filtered through kieselguhr and the filtrate evaporated to an orange gum. Re-
evaporation from dichloromethane provided the title compound (1.4g) as a pink solid. Mass
Spectrum (APf): Found 213 (MH*). CvHuFaNzCfe requires 212.
Description 77: 3-[(2^^-Trifluoro-ethanoylammo)-methyl]-morpholine-4-carboxylic
acid fert-butyl ester
A mixture of the compound from D76 (1.75g), triethylamine (225ml) and di-tert-butyl
dicarbonate (3.59g) in dichloromethane (75ml) was stirred at ambient temperature for 18h.
The reaction mixture was diluted with dichloromethane and washed successively with 2M
hydrochloric acid, water and brine, dried and evaporated to a gum. Chromatography on
silica gel eluting with ethyl acetate-pentane mixtures afforded the title compound (1.70g) as
apale yellow solid. Mass Spectrum (AW1): Found 213 (MH-lBoc)+. CnHigFjNaOj
requires 312. '
Description 78:3-Aminomethyl-morpholine-4-carborylic acid tert-bntyl ester
A mixture of the compound from D77 (1.7g) and potassium carbonate (3.77g) in methanol
(80 ml) and water (27 ml) was stirred at ambient temperature for 4h and then heated at 50°C
for a further 2h. The reaction mixture was concentrated to remove methanol, diluted with
water and extracted with ethyl acetate (x3) and dichloromethane (x4). The combined
extracts were dried and evaporated to afford the title product (0.97g) as a yellow gum. Mass
Spectrum (API*): Found 116 (MH-'Boc)* CioHytvfcQj requires 216.
Description 79:3-[(5-Bromo-pyrimidm-2-ylamino)-methyl]-morpholme-4-carboxylic
acid tot-butyl ester
The title compound (1.19g) was obtained from the compound of D78 (0.97g) and 5-bromo-
2-cUoropyrimidine (0.87g) according to the method of D30. Mass spectrum (API*): Found
273 (MH^'Boc). Ci^i^rN^ requires 372.
Description 80: (5-Bromo-pyrimidin-2-yl)-morpholm-3-ylmetliyl amine
To the compound of D79 (1.15g) in dichloromethane (45 ml) at 0°C was added
trifluoroacetic acid (5 ml) and the reaction mixture then stirred at ambient temperature for
2h. The resulting solution was poured onto ice and saturated aqueous potassium carbonate
solution, and then extracted with dichloromethane (x2). The organic extracts were dried
and evaporated to afford the title product (0.85g) as an off white solid. Mass Spectrum
(Art): Found 273 (MH*). CyHu^rN^ requires 272.
Description 81: (S>2-[(4X^ano-2,6^iflnoro-phenyIamino)-methyI]-piperidine-lcarboxylic
acid terf-butyl ester
(S>2-Aminomethyl-piperidme-l-carboxyh'c acid /erf-butyl ester (136g) and 3,4,5-
trifluorobenzonitrile (1 .OOg) were heated under argon in xylene (10 ml) containing
diisopropylethylamine (33 ml) for 16h. The reaction mixture was cooled and partitioned
between ethyl acetate and water. The organic phase was washed with brine, dried and
evaporated to give a solid which was triturated with pentane-ether to afford the title product
(0.16 g) as an off white powder. Chromatography of the mother liquors on silica gel eluting
with ethyl acetate-pentane mixtures afforded further title product (0.92 g). Mass Spectrum
(API*): Found 252 (MHVBoc). C]SH23F2N302 requires 351 .
Description 82: 3^-Difluoro-4-[((S)-l-piperidin-2-ylmethyl)-amino]-benzonitrile
Trifluoroacetic acid (3 ml) was added to a solution of D81 (1.05 g) in dichloromethane (27
ml) at 0 °C. The reaction was allowed to reach ambient temperature, stirred for 4 h and then
poured into saturated aqueous potassium carbonate. The aqueous phase was extracted with
dichloromethane and the combined extracts dried and evaporated to afford the title
compound (0.59g) as an off white solid. Mass Spectrum (API1): Found 252 (MH*).
a requires 25 1 .
Description 83: (S)-2-[(4-Cyano-2,6-diiluoro-phenyIamino)-methylJ-pyrrolidine-lcarboxylic
acid /erf-butyl ester
The title compound (0.295g) was obtained from (S)-2-aminomet:hyl-pyrroliduie-lcarboxylic
acid tert-batyl ester (0.402g) and 3,4,5-trifluorobenzonitrile (0.3 14g) using a
similar procedure to that described in Description 8 1 . Mass Spectrum (API*): Found 238
(MH^'Boc) Ci7H2iF2N3O2 requires 337.
Description 84: 3^Difluoro^[((S)-l-pyrrolidin-2-yhiiethyI)-aniinoJ-benzonrtriIe
The title compound (0.1 9g) was obtained from the compound of D83 (0.28g) using a similar
procedure to that described in Description 82.
Description 85: (S)-2-l(5-Ethyl-pyrinudin-2-ylaniino)-methyI]-pyrrolidine-l-carboxylic
acid tert-butyl ester
The title compound (0.1 Og) was obtained from (S)-2-aminomethyl-pyrrolidine-l-carboxylic
acid tert-butyl ester (0.75g) and 2-chloro-5-ethyl pyrimidine (0.53g) using a similar
procedure to that described in description 81 . Mass Spectrum (Electrospray LC/MS):
Found 307 (MH1). CieHa^Cb requires 306.
Description 86: (5-Ethyl-pyrimidin-2-ylH^l-pyn"olidin-2-yImefliylamine
The title compound (0.07g) was obtained from the compound of D85 (0. 1 Og) using the
method of D9. Mass Spectrum (Electrospray LC/MS): Found 207 (MH*). CuHigN4
requires 206.
Description 87: (S)-2-[(2^^-Trifluoro-ethanoylamino>-methyl]-pyrroIidine-lcarboxyjic
acid tert-buryl ester
To a solution of (S)-2-aminometiiyl pyrrolidine-1-carboxylic acid tert-batyl ester (l-3g) in
dichloromethane (50 ml) containing triethylamine (1 .4 ml) was added trifluoroacetic
anhydride ( 1 .6g) dropwjse under argon. After 1 6h at ambient temperature the reaction
mixture was diluted with dichloromethane and washed with brine. The aqueous layer was
extracted with dichloromethane and the combined extracts dried and evaporated.
Chromatography of the residue on silica gel eluting with pentane-emyl acetate mixtures
afforded the title compound (1 .43g) as an orange oil. !H NMR 5: 1 .30 - 1 .50 (1H, ra), 1 .47
(9H,s), 1.60- 1.75(1 H,m), 1.80- 1.95 (2H,m), 2.00- 2.10 (lH,m), 3.22 -3.30 (lH5m),
3.30 - 3.55 (3H, in), 9.03 (1H, br s).
Description 88: (S)-2-{[MethyH2^-trifluoro-ethanoyl)-ainino]-methyl}-pyrroIidinel-
carborylic acid tert-butyl ester
Sodium hydride (0 .23g, 60 % dispersion in oil) was added to a solution of the compound of
D87 (1.4g) in dimethylformamide (30 ml) under argon. After Ih, iodomethane (0.32 ml)
was added and the reaction mixture stirred for a further 1 6h before being partitioned
between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the
combined extracts washed with brine, dried and evaporated to give the title compound
(1.6g) as an orange oil. Mass Spectrum (API*): Found 311 (MET); C13H2iF3N2O3 requires
310. »
Description 89: (S)-2-MethyIanunomethyl-pyrrolidine-l-carbojylic acid tert-bvtyl
ester
A mixture of the compound of D88 (1.47g) and 1M potassium carbonate (20 ml) in
methanol (50 ml) was stirred at ambient temperature for 20 h. After removal of the
methanol in vacuo, the residue was partitioned between chlorofonn and water. The aqueous
layer was extracted with chlorofonn and the combined extracts dried and evaporated to
afford the title product (0.82g) as an orange oil.
Description 90: (S>-2-{[(5-Bromo-pyrimidin-2-yI)-mefliyI-anunoJ-mettiyl}-pyrrolidinel-
carboxylic acid tert-bntyl ester
The title product (0.85g) was obtained from the compound of D89 (0.82g) and 5-bromo-2-
chloro pyrimidine (0.77g) in a similar manner to that described in the procedure of
description 81 . Mass Spectrum (API*): Found 371 (MH*). CisHb^nNkOa requires 370.
Description 91: (5-Bromo-pyrimidin-2-yI>-methyl-(S)-l-pyrrolidin-2-yr)memylamuie
A solution of the compound from D90 (0.82g) in dichloromethane (50 ml) and
trifluoroacetic acid (10 ml) was stirred at ambient temperature for 20 h. evaporated and
partitioned between ethyl acetate and 1M sodium hydroxide. The organic phase was
separated, dried and evaporated to afford the tMe product as an orange oil (0.54g). Mass
Spectrum (API4): Found 271 (MH*). Ci0Hi5
79BrN4 requires 270.
Description 92: (S)-2-[(5rAceryl-pvrimidm-2-ylamino)-methyIJ-pyrrolidine-lcarboiylic
acid tert-butyl ester
The title compound (0.57g) was prepared from the compound of D69 (1.06g) (1-
ethoxyvinyl)triburyl tin (13. ml) and tetrakis (triphenylphosphine)palladium (0) (0.1 72g)
according to the method of Example 171. Mass Spectrum (API*): Found 321 (MH*).
requires 320.
Description 93: !-{2-[((S)-l-PyrroUdm-2-ymiethyI>ammo]-pvriniidin-S-yl}-ethanone
trifluoroacetate
To a solution of the compound of D92 (0.57g) in dichloromethane (18ml) at 0°C was added
trifluoroacetic acid (2ml) dropwise. The reaction mixture was stirred at ambient
temperature for 2h, and evaporated to afford the title compound as a yellow gum (1.13g).
Mass Spectrum (API4): Found 221 (MJT*). CnHi6N4O requires 220.
Description 94: (S)-2-f(5-CiIoro-pyrimidinr2-ylamino)-iiiethyIJ-pyrro]idine-lcarboxylic
acid tert-butyl ester
(S)-2-Aminomethyl pyrrolidine-1-carboxyIic acid tert-bvctyl ester (3.38g), 2,5-
dichloropyrimidine (2.50g), potassium carbonate (4.67g) and diisopropylethylamine
(8.79ml) were heated in xylene (60 ml) at 100°C for 3.75h. The cooled reaction mixture
was filtered and the filtrate evaporated to a gum which was chromatographed on silica gel,
eluting with ethyl acetate-pentane fractions, to afford the title compound as a pale yellow
solid (2.55g). Mass Spectrum (API*): Found 213 (MH^Boc). C]4H2i35ClN4Q2 requires
312.
Description 95: (5-CUort>-pyrimidm-2-yI)-(S)-l-pyrTolidin-2-yhBethyIaniine
The compound of D94 (2.5g) was dissolved in dichloromethane (63 ml), cooled to 0°C and
trifluoroacetic acid (7 ml) added dropwise. The reaction mixture was stirred at ambient
temperature for 2h, recooled to 0°C and further trifluoroacetic acid (3 ml) added. After 2h
at ambient temperature the mixture was carefully poured into ice-saturated potassium
carbonate and the organic layer separated. The aqueous phase was extracted with
dichloromethane (x4) and the combined extracts dried and evaporated to afford the title
product (1.74g) as an orange solid. Mass Spectrum (Electrospray LC/MS): Found 213
(MH*). C9HU
35CIN4 requires 212.
Description 96: (S)-2-[(5-Cyano-pyridin-2-ylamino)-methyI]-pyrTolidine-l-carboxyIic
acid tert-butyl ester
(S)-2-Aminomethyl pyjrolidine-l-carboxyh"c acid tert-butyl ester (0.3g), 6-
chloronicotinonitrile (021g), potassium carbonate (0.41g) and diisopropylethylamine (0.78
ml) were heated in xylene at 130°C for 26h, cooled and the mixture filtered through
kieselguhr. The filtrate was evaporated and the residue chromatographed on silica gel,
eluting with ethyl acetate-hexane mixtures to afford the title compound (0.2g). Mass
Spectrum (API1): Found 303 (MH*). CigkMk requires 302. .
Description 97: 6-[((S)-l-Pyrrolidin-2-yhnethyr)-amino]-nicotinonitriIe
A solution of the compound of D% (0.2g) in dichloromethane (20 ml) and trifluoroacetic
acid (2.5 ml) was stirred at ambient temperature for 2h., evaporated and partitioned between
dichloromethane and 1M sodium hydroxide. The aqueous phase was extracted with
dichloromethane and the combined extracts dried and evaporated to afford the title
compound as a gum (0.137g). Mass Spectrum (Electrospray LC/MS): Found 203 (MH*).
CnHi4N4 requires 202.
Description 98:1,1,1-Trifluoromethanesulfonic acid 6-methyl~2-methylsulfanyIpyrimidin-
4-yl ester
To a solution of 6^mefeyl-2-methylsuLfanyl-pyrimidin-4-ol (Ig) in dichloromethane (40 ml)
containing triethylamine (1.35 ml) at 0°C under argon was added trifluoromethanesulphonic
anhydride (1.46 ml) dropwise. The resulting solution was allowed to reach ambient
temperature and stirred for 16h. before being partitioned between dichloromethane and
saturated aqueous sodium hydrogen carbonate solution. The organic phase was washed
with brine, dried and evaporated and the residue chromatpgraphed on silica gel, eluting with
ethyl acetate-pentane mixtures, to afford the title compound (0.8g). JH NMR S: 2.53 (3H,
s), 2.55 (3H,s), 6.63 (lH,s).
Description 99:2^^2-Trifluoro-Ar-(S>l-pyrrolidin-2-ylmethyI-acetamide
The title compound (2.3Ig) was obtained from the compound of D87 (5.5g) using the
method of D97. JH NMR 8:130 -1.50 (IH, m), 1.70 - 1.95 (3H, m), 2.20 (IH, br s), 2.85 -
2.90 (IH, m), 2.94 - 2.97 (IH, m), 3.07 - 3.12 (IH, m), 3.37 - 3 39 (IH, m), 3.44 - 3.48 (IH,
m),7.15(lH,brs).
Description 100:2^r2-Trifluoro-A^-((S)-l-{l-[5-(4-fluoroplienyi)-2-metiiyl- ylJ-methanoyI}-pyrroIidin-2-yIinethyI>-acetamide
The title compound (3.84g) was obtained from the compound of D99 (2.3 Ig) and 5-(4-
fluorophenyl)-2-methyl-miazole-4-carboxyhrc acid (3.08g) using the method of Example
229. Mass Spectrum (EleetrosprayLC/MS): Found 416 (MH*). CigHi7F4N3O2S requires
415.
Description 101: H(S)-2-AminomefhyI-pyrTolidin-l-yI)-l-f5-(4-fluoro-phenyr)-2-
methyl-thiazol-4-yl]-methanone
The title compound (2.45g) was obtained from the compound of D100 (3.84g) using a
similar procedure to mat described in D78. Mass Spectrum (Electrospray LC/MS): Found
320 (MH*). CisH^sOS requires 319.
Description 102:3-[(2^^-Trifluoro^manoylamino)-methyIJ-morpholine-4-carboxyIic
acid fert-bnryl ester
The title compound (0.56g) was obtained from me compound of D77 (0.55g) and
iodomethane (0.12 ml) using a method similar to mat of Description 88. Mass Spectrum
(API4): Found 227 (MHVBoc). CisHjiFsNaCU requires 326.
Description 103:3-Methylaminomethyl~morphoUne-4-carbo3cyUc acid tert-butyl ester
The title compound (0.29g) was obtained from the compound of D102 (0.56g) using the
method of Description 89.
Description 104: 3-{[(5-Bromo-pyrimidin-2-yI)-methyl-amino]-methyl}-morpholine-4-
carboxylic acid tert-butyl ester
The title compound (0.3g) was obtained from the compound of D103 (0.29g) and 5-bromo-
2-chloropyrimidine (0.26g) using the method of Description 81. Mass Spectrum
(Electrospray LC/MS): Found 287 (MHV&oc). Ci5H2379BrN4O3 requires 386.
Description 105: (5-Bromo-pyrimidin-2-yl)-niethyI-niorphoIin-3-ylmethyI-amine
The title compound (0.19g) was obtained from the compound of D104 (0.3g) according to
the method of Description 91. Mass Spectrum (API*): Found 287 (MH4). CioHi5
79BrN4O
requires 286.
Example 1: !-[2-(BenzoxazoI-2-ylaminomethyI)-piperidin-l-yl]-l-(2-methyI-5-phenyltbiazol-
4~yl)-methanone
The amine of D3 (0.1 Ig), triethylamine (O.OSg) and 2-meuiyl-5-phenyl-thiazole-4-carbonyl
chloride (0.12g) were combined in dichloromethane (5ml) and shaken for 16 hours. The
organic phase was washed with water, filtered through a Whatman phase-separation filter
tube, solvent removed at reduced pressure to give after column chromatography (silica gel,
0-10% (9:1 methanol/ammonia) in dichloromethane eluant) the title compound (0.13g).
Mass Spectrum (APf): Found 433 (MH*). C24H24N4O2S requires 432.
The compounds of the Examples below were prepared from the appropriate amine and acid
chloride using a similar procedure to that described in Example. 1.
NHAr1
Example Amine Y AS Ar1 Mass Spectrum
(Electrospray LC/MS)
(Figure Removed)
Example 32: l-[(S)-2-(Benzoxazol-2-ylanimomethyI)-piperidin-l-yl]-l-[S-(4-fluorophenyI)-
2-niethyI-thiazol-4-ylJ-iiierhanone
A mixture of amine D5 (O.OSg), 2-methyl-5-phenyl-trdazoleH^carboxylic acid (0.026g) and
diisopropylethylamine (0.06ml) in dimethylfonnarnide (5rnl) was treated with [0-(7-
a2abenzotriazol-l-yl>1433-tfitramethyluronium hexafluorophosphate] (0.042g) and the
mixture stirred for 48 hours. The mixture was diluted with ethyl acetate, washed with
sodium hydrogen carbonate and water, dried, solvent removed at reduced pressure and the
residue column chromatographed (silica gel, dichloromethane - 1%
methanol/dichloromethane) to give the title compound (O.OSg).
Mass Spectrum (API1): Found 451 (MH*). C24H23FN4O2S requires 450.
The compounds of the Examples below were prepared from the appropriate amine and acid
using similar procedures to that described in Example 32.
NHAr1
(Table Removed)
Example 93: l-{2-[(6,7-Diflnoro^umoxa^
(4-flaoro-phenyI)-2-H-pyrazoI-3-ylI-methajione
The amine of D31 (0.085^ in dmiethyu^imamide (3ml) was treated with 4-(4-fluorophmyl>
2^-pyrazole-3-carboxylic acid (0.125g), diisopropylethyianiine (0.07ml) and [O-
(7-azabenzotriazol-l-ylH»l^-tetr^ (0-llg). the
mixture was shaken for 48 hours. Solvent was removed at reduced pressure and the residue
extracted with dichloromethane. The filtrate was evaporated under reduced pressure and the
residue column chromatographed (silica gel, 3% methanol/diethyl ether) to give the title
compound (O.lg).
Mass Spectrum (APf): Found 453 (MH4). QoH^sNeO requires 452.
iHAr1
residue column chromatographed (silica gel, 3% methanol/diethyl ether) to give the title
compound (O.lg).
Mass Spectrum (APT*): Found 453 (MH*). C^H^NeO requires 452.
NHAr1
Example
(Table Removed)
Example 105: l-[2-(3-Methyl-[M,4]oiadiazol-5-yI>phenyI]-l-[(S>2-{oxazolo[4^-
b]]pyridin-2-yIaminoinethyI)-piperidin-l-yI]-methanone
The compound of D41 (0.51g) and 2-methylsulfenyl-oxazolo[4,5-6]pyridine (O^ZSg) were
combined and heated under argon at 90°C for 1 8 hours The mixture was column
chromatographed (5% methanol, diethyl ether eluant) to give the title compound (0.26g)
Mass Spectrum (API*): Found 419 (MH4). C^zHzzNeOs requires 418.
Example 106: l-fX3-MethyHlA4]oxadiazol-5-yI)-phenylI~l-{(R)-2-f(metIiyIoiazolo[
4^b]pyridm-2-yI-amino)-methylJpiperidin-l-yl}-methanone
The title compound (O.OlSg) was prepared fiom the compound of D43 (0. 15g) according to
the method of Example 105.
Mass Spectrum (APf): Found 433 (MH4). CzsHa^NeOs requires 432.
Example 107: 6-[((S)-l-{l-[4-(4-Fluoro-phenyI>-l-methyl-lH-pyrazoI-3-yl]-
methanoyl}-piperidm-2-ylmethy^methyl-amino]-nicotinonitrile . - . .
The title compound (0.078g) was prepared from the compound of D60 (0.45g) and 2-
chloro-5-cyanopyridine (0. 1 89g) according to the method of D26
Mass Spectrum (API4): Found 433 (MH*). Cz^HasFNgO requires 432.
Example 108: l^(S>2-{[(6,7-DiflnoroHjumoxaIm-2-yI>-methyl-amino]-methyl}-
piperidin-l-y^l-[4^4-fliioro-pheny^l-me&vl-lH-pyrazol-3-y5^
The title compound (0.03 Ig) was prepared fiom the compound of D60 (0. 1 5g) and 2-
chloro-6,7-difluoK)quiiioxamie (0.091g) according to the method of D26
Mass Spectrum (API*): Found 495 (MH1). CasHzsFaNeO requires 494.
Example 171: !-{2-[((S)-l-{l-[4-(4-FIuoro-phenyI)-l-methyl-lH-pyrazol-3-ylJmethanoyl}-
piperidin-2-yIinethyl)-amino]-pyrimidin-5-yl}-ethanone
A mixture of l-{(S)-2-[(5-Bromo-pyriiiudin-2-ylaniino>methyl]-piperidin-l-yl}-l-[4-(4-
fluoro-phenyl)-l-methyl-lS-pyrazol-3-yl]-methanone (0.5g) and l-ethoxyvinyl)tributyltin
(0.42ml) tetrakis(triphenylphosphine)palladium[0} (0.06g) was boiled in dioxane (8ml) for
1 6h. 2N Hydrochloric acid was added, the mixtrue stirred for 90 min, water was added and
the mixture extracted (x3) with ethyl acetate. The combined ethyl acetate extracts were
dried, solvent removed at reduced pressure and the residue column chromatographed (silica
gel, ethyl acetate -> 2% methanol ethyl acetate to give the title compound (0.3g) as a yellow
foam.
Mass Spectrum (API*): Found 437 (MH4). CzjH^FNsCb requires 436.
i
Example 172: !-[4-(4-FIuoro-phenyI)-l-methyl-lH-pvraaM>l-3-yII-l-((S)-2-{[5-(lhydroxy^
thyI)-pyriinidin-2-ylamino]-methyl}-piperidin-l-yI)-methanone
l-{2-[((S>l-{l-[4^4-Fluoro-phenyl)-l-memyl-lH-pyra2»l-3-yl]-methanoyl}-piperi
ymiethyl)-ammo]-pyrimidin-5-yl}-ethanone (0.2g) was dissolved in methanol 20ml) and
sodium borohydride (0.4g) added. The reaction was stirred overnight, water was added and
stirring continued for 30min. The reaction mixture was extracted with ethyl acetate (x3),
the organic extracts combined, dried (MgSC^) and solvent removed at reduced pressure to
give the title compound as a colourless foam.
Mass Spectrum (API*): Found 439 (MET). Ca^yFNeOa requires 438.
Example 173: 2-[((S)-l-{l-[4-(4-H»oro-phenyI)-l-methyl-lH-pyrazol-3-yl]-
methanoyl}-piperidm-2-yhiiethyI)-amino]-pyrimidine-5-carbonitrile
!-{(S)-2-[(5-Brom0-pyrimidrn-2~ylamrno
l-methyl-l#-pyrazol-3-yl]-methanone (035g) in N-methylpyrrolidinone (10ml) containing
copper(I)cyanide (0. 1 3g) was heated to reflux for 5h. The reaction mixture was diluted with
water, filtered (Kieselguhr) and the filtrate extracted with ethyl acetate. The ethyl acetate
phase was washed with water and brine, dried (MgSO4), filtered and solvent removed at
reduced pressure. The residue was column chromatographed (silica gel; ethyl
acetaterpentane 1 :1 -» ethyl acetate eluant), the appropriate fractions combined and solvent
removed at reduced pressure to give the title compound (0.01 9g).
Mass Spectrum (API*): Found 420 (MET). CjaHbFNTO requires 419.
Example 174: 3^1-{
ylJ-methanoyiy-N— methyl-benzamide
The compound of description 71 (0.1 Og) was dissolved in dimetbylfonnamide (5ml)
containing HATU (0.095g) and diisopropylethylamine (0.131ul) and stirred for 30 in.
Methylamine (1M in tetrahydrofuran, 0.125ml) was added and stirring continued for 16.
The reaction mixture was diluted with diethyl ether, washed with water (x3), saturated brine
and dried (MgSO4). Solvent was removed at reduced pressure and the residue column
chromatographed (silica gel; ethyl acetate — » 1 0% metbanol:ethyl acetate to give the title
compound (0.01 8g).
Mass Spectrum (API*): Found 440 (MH*). CasK^NsOa requires 439.
Example 194: l-{(S>2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrroIidin-l-yl}-l-[5-
(4-fluoro-phenyI)-2-methyl-thiazoI-4-yl]-methanone
A mixture of the amine of D70 (0.070g), 5-(4-fluoro-phenyI)-2-methyl-thiazole-4-
carboxylic acid (0.065g), H3- (EDC) (0.042g) and 1-hydroxybenzotriazole hydrate (0.037g) in dimethylfonnamide (2ml)
was stirred at ambient temperature for 18h, evaporated in vacua and the residue partitioned
between ethyl acetate and water. The organic layer was dried (Na2SO4), evaporated and the
residue chromatographed on silica gel eluting with a 30% - 100% ethyl acetate in pentane
gradient to afford the title product (0.083g) as a white solid. Mass-Spectrum (Electrospray
LCMS), APf: Found 476 (MEf).
Example 195: !-{(S)-[(5-Bromo-pvrimJdm-2-ylajiimo>methylJ-pyrToIidin-l-yl}-l-[2-
(3-methyl-[l^,4]oxadiazoI-5-yl)-phenyl]-methanone The title compound (0.053g) was
obtained from the amine of D70 (0.070g) and 2-(3-methyl-[l^,4]oxadiazol-5-yl>benzoic
acid (0.056g) using the method of Example 194. Mass Spectrum (Electrospray LC/MS) :
Found 443 (MH4). CwH^rNeOa requires 442.
Example 196: !-{(S)-2-[5-Bromo-pyrimidin-2-ylamino)-methyl]-pvrrolidin-l-yI}-l-[5-
(4-chloro-phenyI)-2-methyl-thiazol-4-yl]-methanone
The title compound (0.078g) was obtained from the amine of D70 (0.077g) and 5-(4-chlorophenyl)-
2-methyl-thiazole-4-carboxyUc acid (0.076g) according to the method of Example
32. Mass spectnim(mectrospray LC/MS), APf: Found 492 (MH*). CaoHw^r^ONsOS
requires 491.
Example 197: !-{(S)-2-[(5-Brom{>-pyridin-2-ylamino)-niethyl]-pyTrolidin-l-yl}-l-[5-(4-
fluoro-phenyl)-2-methyl-miazoI-4-ylJ-inethanone
The title compound (0.135g) was obtained from the amine of D74 (0.1 Ig) and 5-{4-fluorophenyl>
2-memyl-thiazole-4-carboxylic acid (0.12g) according to the method of Example
32. Mass Spectrum APf: Found 475 (MH1). C2iH2o79BrFN4OS requires 474.
Example 198: !-{(S)-2-K5rBromo-pyridra-2-yI^
fluoro-pheny!)-l-methyl-lHr-pyrazol-3-yl]-methanone
The title compound (0. 1 Og) was obtained from the amine of D74 (0. 1 Ig) and 4-(4-fluorophenyl)-
J-memyl-l/f-pyrazole-3-carboxylic acid (0.12g) according to the method of
Example 32. Mass Spectrum APf: Found 458 (MH*). C2iH2i79BrFN5O requires 457.
Example 200: !-{3-[(5-Brom(Hpyrimidm-2-ylammo>methyIJ-morpholin-4-yl}-l-[4-(4-
fluoro-phenyl)-l-mediyl-l£r-pyrazoI-3-yl]-methanone
The title compound (0.393g) was obtained from the compound of D80 (0 Jg) and 4-(4-
fluorophenyl>l-memyl--l/f-pyrazole-3-carboxylic acid (0^42g) according to the method of
Example 32. Mass Spectrum (API*): Found 475 (MH*). C^M^BrFNeOa requires 474.
Example 203: 3,5-Difluoro-4-f((S)-l-{l-f5-{4-fluoroplienyJ)-2-inethyl-thiazoI-4-yI]-
methanoyl}-piperidin-2-ylmethyI)-amino]-benzonitrile
The title compound (0.090g) was obtained from the compound of D82 (0.073g) and 5-(4-
fluorophenyl)-2-methyl-thiazole-4-caii)oxylic acid (0.069g) according to the method of
Example 32. Mass Spectrum (Electrospray LC/MS): Found 471. C24H2iF3N4OS requires
470.
Example 208: 3^-Difluoro-4-I((S)-l-{l-[5-(4-fluoro-phenyI)-2-methyl-thiazol-4-yl]-
methanoyl}-pyrrolidin-2-ylmethy!)-amino]-benzonitrile
The title compound (0.09g) was obtained from the compound of D84 and 5-(4-fluorophenyl)-
2-niethyl-thia2»le-4-carboxylic acid (0.095g) according to the method of Example
32. Mass Spectrum (Electrospray LC/MS): Found 457 (MH4). QoHpF^OS requires
456.
Example 216: !-{(S)-2-[(5-Ethyl-pyriniidm-2-yIaniino>methyl]-pyrTolidin-l-yl}-l-f5-
(4-fluoro-phenyI)-2-methyl-thiazol-4-yI]-methanone
The title compound (0.05g) was obtained from the compound of D86 (0.07g) and 5-{4-
fluoro-phenyl)-2-memyl-thiazole-4-carboxylic acid (0.068g) according to the method of
Example 32. Mass Spectrum (Electrospray LC/MS): Found 426 (MH4). C22H24FN5OS
requires 425.
Example 217: l^(S)-2-{[(5-Bromo-pyrimidin-2-yl>-methyl-amino]-methyl}-pyrrolidinl-
yl)-l-[5-(4-fluoro-phenyI)-2-methyl-thiazol-4-yI]-methanone
The title compound (O.lg) was obtained from the compound of D91 (0.275g) and 5-(4-
fluoro-phenyl)-2-nMJthyl-thiazole-4-carboxylic acid (0.285g) according to the method of
Example 32. Mass Spectrum (Electrospray LC/MS): Found 490 (MH4). C2]H2i79BrFN5OS
requires 489.
Example 218: l^(S)-2-{[(5-Bromo-pyrimidm-2-yl)-methyl-ainino]-methyl}-pyiTolidinl-
y!)-l-[4-{4-fluoro-phenyI)-l-methyI-LEr-pyrazol-3-yIJ-inethaiione
The title compound (0.02g) was obtained from the compound of D91. (0.275g) and 4-(4-
fluoro-phenyl)-lrmethyl-l/frpyrazole-3-carboxyUc acid (0.260g) according to-fhe method of
Example 32. Mass Spectrum (Electrospray LC/MS): Found 473 (MH4). CaiHb^BrFNfiO
requires.472.
Example 225: !-{2-[((S)-l-{l-[5-(4-Chloro-phenyl>-2-methyl-thiazol-4-yI]-methanoyI}-
pyrroUdm-2-ylmethyl)-ammo]-pyrimidin-5-yl}-ethanone
The title product (0.04g) was obtained from me compound of D93 (0.133g) and 5-(4-chlorophenyl)-
2-metbyl-thiazole-4-carboxyh"c acid (0.076g) using a similar procedure to that
described in Example 32. Mass Spectrum (Electrospray LC/MS): Found 456 (MH4).
ONsChS requires 455.
Example 226: l-{(S>2-[(5-Chloro-pyrixnidin-2-ylamino)-methyI]-pyrrolidin-l-yI}-l-[5-
(4-fluoro-phenyl)-2-methyl-thia2ol-4-yl]-methanoBe
The title product (0.095g) was obtained from the amine of D95 (0.064g) and 5-{4-
fluorophenyl)-2-methyl-thiazole-4-carboxylic acid (0.071g) using the method of Example
32. Mass Spectrum (Electrospray LC/MS): Found 432 (MH4). C2oHi935ClFN5OS requires
431.
Example 227: l-{(S>2-[(5^hloro-pyrimidin-2-ylamino)-niethylJ-pyrroHdin-l-yI}-l-[2-
(3-methyI-[l^,4]oxadiazol-5-yI)-phenyl]-memanone
The title compound (0.052g) was obtained from the amine of D95 (0.064g) and 2-(3-
memyi-[l^,4]oxadiazol-5-yl)-benzoic acid (0.061g) according to the method of Example
32. Mass Spectrum (Electrospray LOMS): Found 399 (MH*). CjpHw^ClNfiCb requires
398.
Example 228: l-[5-{4-FIuoro-phenyl)-2-metliyl-thiazol-4-yl]-l-{(S)-2-[(5-methylpyrimidin-
2-ylamino)-methyl]-pyrrolidin-l-yl}-methanone
To the compound of Example 194 (0.36g) in dunethylformarnide was added lithium
chloride (0.096g), tetramethyl tin (0.126 ml) and dicUorobis(triphenyjtphosphine) palladium
(0) (0.035g) and the resulting mixture heated at 100°C under argon for 18h. The reaction
was men evaporated, diluted with dichloromethane, filtered and the filtrate washed with
water, dried and evaporated. Chromatography of the residue on silica gel, eluting with
raethanol-dichloromethane mixtures, afforded the title product (0_2g) as a yellow
amorphous solid. Mass Spectrum (API4): Found 412 (MH4). CaiHzaFNsOS requires 411.
Example 229: 6-f((S)-l-{l-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yIJ-uiethanoyI)-
pyrroUdin-2-ylmethyl)'amino]-nicotuionirrile
A mixture of the amine of D97 (0.134g), 5-(4-fluoro-phenyl)-2-niethyl-tiiiazole-4-
carboxylic acid (0.172g), EDC (0.139g) and 1-hydroxybenzottiazole (O.Olg) in
dichloromethane (8 ml) was stirred at ambient temperature for 7 days. The reaction was
washed with saturated aqueous sodium bicarbonate solution, dried and evaporated.
Chromatography of the residue on silica gel, eluting with ethyl acetate - hexane mixtures
afforded the title product (0.196g), Mass Spectrum (Electrospray LC/MS): Found 422
(MH4). C22H2oFN5OS requires 421.
Example 234: l-[5-{4-Flnoro-phenyl)-2-inethyl-thiazol-4-y]J-l-{(S)-2-[(6-inethyl-2-
methykutfanyl-pyriniidm^ylammo)-merhyl]-pyrTolidin-l-yl}-methanone
The title product (0.095g) was obtained from the amine of D101 (0.15g) and the compound
of D98 (0.14g) using a similar method to mat described in D69. Mass Spectrum
(Electrospray LC/MS): Found 458 (MH4). CzzHMFNsC^ requires 457.
Example 235: l-[5-(4-Fluoro-phenyI)-2-methyI-thiazol-4-yl]-l-{(S>-2-[(2-
methylsiih^nyl-pyrimidm^ylariimo)-memyl]-pyrroh"diii-l-yl}-methanone
-84-
The title compound (O.OSg) was obtained from the amine of D101 (0.15g) and 4-chloro-2-
methylsulfanyl-pyrimidine (0.076g) using a similar method to that described in D69. Mass
Spectrum (Electrospray LC/MS): Found 444 (MH4). C2iH22FN5OS2 requires 443.
The following compounds were prepared using methods similar to that described in
Examples 234 and 235.
Ar'
Example Amin Ar1 Mass spectrum
(Electrospray
LCMS),APf
236 D101 Bond Found 494 (MH4).
requires 493.
Me
237 D101 Bond Found 426 (MET*)-
requires 425.
Me
238 D101 Bond Found 466 (MET*).
C2,H,9F4N5OS
requires 465.
Example 239: 1^3-{[(5-Bromo-pyrimidin-2-y^methyl-ainino]-methyI}-moi^holin-^
yI)-l-[5-{4-fluoro-phenyI)-2-niethyl-thiazol-4-yl]-methanone The title compound
(0.056g) was obtained from the compound of D105 (0.095g) and 5-(4-fluorophenyl)-2-
methyl-thiazole-4-catbo3(ylic acid (0.1 Og) according to the method of Example 32. Mass
Spectrum (Electrospray LC/MS): Found 506 (MH4). C2iH21
79BrFN5O2S requires 505.
Example 240: 1^3-{[(5-Bromo-pyrimidm-2-yl>-methyl-ammo]-me^yl}-morpholin-4-
yl)-l-[2-(4-fluoro-phenyI)-thiophen-3-yI]-methanone
To the compound of D105 (0.095g) in dichloromethane (8ml) containing triethylamine
(0.06ml>was added 2-(4-fluorophenyl)-thiophene-3-carbonyl chloride (0.084g). After 72h
at ambient temperature the reaction mixture was washed with brine, dried and evaporated;
the residue was chromatographed on silica gel, eluting with ethyl acetate-pentane mixtures
to afford the title product (0.093g). Mass Spectrum (Electrospray LC/MS): Found 491
(MH4). C2iH2o79BrFN402S requires 490.
Example 249: l-[5-(4-Flttoro-phenyl)-2-methyl-thiazol-4-yl]-l-{(S)-2-[(5-
trifluoromethyl-pyrimidm-2-ylamino)-methyl]-pyrrolidin-l-yI}-methanone
Example 249: l-I5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yI]-l-{(S)-2-[(5-
trifluoromethyl-pyrimidm-2-ylammo)-methyl]-pyrroIidin-l-yI}-methanone
To the compound from Example 194 (0.36g) in dimemylformamide (5ml) was added
potassium trifluoroacetate (0.23g), copper iodide (0.3g) and toluene (5ml) and the resulting
mixture heated at reflux under Dean-Stark conditions for 3h, before refluxing for a further
20L The reaction mixture was cooled, poured into water/ether and filtered through
kieselguhr. The aqueous layer from the filtrate was extracted with ether, and the combined
ether extracts washed with water, dried and evaporated. The aqueous was re-extracted with
dichloromethane and the extract evaporated. The combined extracts were chromatographed
on silica gel, eluting with methanol-dichloromethane mixtures, to afford the title product
(O.OOlg). Mass Spectrum (Electrospray LGMS): Found 466 (MH*).
requires 465.
The compounds in the table below -wereprepared using methods described above
Example R Ar2 Mass Spectrum
(Electrospray
267 CH2 H Found 486 (MH^).
requires 485.
268 CH2 H Found 526 (MH*).
requires 525.
269 CH2 H Found 540 (MH*),
requires 539.
270 CH2 Me
(Figure Removed)
It is understood that the present invention covers all combinations of particular and
preferred groups described herein above.
Determination of Orexin-1 Receptor Antagonist Activity
The orexin-1 receptor antagonist activity of the compounds of formula (T) was
determined in accordance with the following experimental method.
Experimental Method
CHO-DG44 cells expressing the human orexin-1 receptor were grown in cell
medium (MEM medium with Earl's salts) containing 2 mM L-Glutamine, 0.4 mg/mL G418
Sulphate from GEBCO BRL and 10% heat inactivated fetal calf serum from Gibco BRL.
The cells were seeded at 20,000 cells/100 /tlAvell into 96-well black clear bottom sterile
plates from Costar which had been pre-coated with 10 /tg/well of poly-L-Iysine from
SIGMA. The seeded plates were incubated overnight at 37C in 5% COa-
Agonists were prepared as 1 mM stocks in watenDMSO (1:1). EC50 values (the
concentration required to produce 50% maximal response) were estimated using 1 Ix half
log unit dilutions (Biomek 2000, Beckman) in Tyrode's buffer containing probenecid (10
mM HEPES with 145mM NaCl, lOmM glucose, 2.5 mM KC1,1.5 mM CaCl2,1.2 mM
MgCl2 and 2.5mM probenecid; pH7.4). Antagonists were prepared as 10 mM stocks in
DMSO (100%). Antagonist IC50 values (the concentration of compound needed to inhibit
50% of the agonist response) were determined against 3.0 nM human orexin-A using 1 Ix
half log unit dilutions in Tyrode's buffer containing 10% DMSO and probenecid.
On the day of assay 50 fd of cell medium containing probenecid (Sigma) and
FluoS AM (Texas Fluorescence Laboratories) was added (Quadra, Tomtec) to each well to
give final concentrations of 25 mM and 4 /iM, respectively. The 96-well plates were
incubated for 60 min at 37C in 5% CO2. The loading solution containing dye was then
aspirated and cells were washed with 4x150 /il Tyrode's buffer containing probenecid and
0.1% gelatin (Denley Cell Wash). The volume of buffer left in each well was 125 jil.
Antagonist or buffer (25 /il) was added (Quadra) the cell plates gently shaken and incubated
at 37C in 5% CQz for 30 minutes. Cell plates were then transferred to the Fluorescent
Imaging Plate Reader (FLIPR, Molecular Devices) instrument Prior to drug addition a
single image of the cell plate was taken (signal test), to evaluate dye loading consistency.
The run protocol used 60 images taken at 1 second intervals followed by a further 24 images
at 5 second intervals. Agonists were added (by the FLIPR) after 20 seconds (during
continuous reading). From each well, peak fluorescence was determined over the whole
assay period and me mean of readings 1-19 inclusive was subtracted from this figure. The
peak increase in fluorescence was plotted against compound concentration and iteranVely
curve fitted using a four parameter logistic fit (as described by Bowen and Jerman, TIPS,
1995,16,413-417) to generate a concentration effect value. Antagonist Kb values were
calculated using the equation:
Kb= IC50/(l+([3/EC50])
where EC50 was the potency of human orexin-A detennined in the assay (in nM
terms) and IC50 is expressed in molar terms.
Compounds of Examples tested according to mis method had pKb values hi the
range 6.7 - 9.7 at the human cloned orexiri-1 receptor.
The orexin-2 receptor antagonist activity of me compounds of formula (I) was detennined in
accordance with the following experimental method.
Experimental Method
CHO-DG44 cells expressing the human orexin-2 receptor were grown hi cell
medium (MEM medium with Earl's salts) containing 2 mM L-Glutamine, 0.4 mg/mL G418
Sulphate from GIBCO BRL and 10% heat inactivated fetal calf serum from Gibco BRL.
The cells were seeded at 20,000 cells/100 /ilAvell into 96-well black clear bottom sterile
plates from Costar which had been pre-coated with 10 /tg/well of poly-I/-lysine from
SIGMA. The seeded plates were incubated overnight at 37C in 5% CC^.
Agonists were prepared as 1 mM stocks in watenDMSO (1:1). EC50 values (the
concentration required to produce 50% maximal response) were estimated using 1 Ix half
log unit dilutions (Biomek 2000, Beckman) hi Tyrode's buffer containing probenecid (10
mM HEPES with 145mM NaCL lOmM glucose, 2.5 mM KCL. 1 -5 mM CaCl2,1.2 mM
MgCl2 and 2.5mM probenecid; pH7.4). Antagonists were prepared as 10 mM stocks in
DMSO (100%). Antagonist IC50 values (the concentration of compound needed to inhibit
50% of the agonist response) were determined against 10.0 nM human orexin-A using 1 Ix
half log unit dilutions in Tyrode's buffer containing 10% DMSO and probenecid.
On the day of assay 50 /il of cell medium containing probenecid (Sigma) and
FluoSAM (Texas Fluorescence Laboratories) was added (Quadra, Tomtec) to each well to
give final concentrations of 2.5 mM and 4 /iM, respectively. The 96-well plates were
incubated for 60 min at 37C hi 5% CQj. The loading solution containing dye was then
aspirated and cells were washed with 4x150 [A Tyrode's buffer containing probenecid and
0.1% gelatin (Denley Cell Wash). The volume of buffer left in each well was 125 fd.
Antagonist or buffer (25 /d) was added (Quadra) the cell plates gently shaken and incubated
at 37C in 5% COa for 30 min. Cell plates were then transferred to the Fluorescent Imaging
Plate Reader (FLIPR, Molecular Devices) instrument Prior to drug addition a single image
of the cell plate was taken (signal test), to evaluate dye loading consistency. The run
protocol used 60 images taken at 1 second intervals followed by a further 24 images at 5
second intervals. Agonists were added (by the FUPR) after 20 sec (during continuous
reading). From each well, peak fluorescence was determined over the whole assay period
and the mean of readings 1-19 inclusive was subtracted from this figure. The peak increase
in fluorescence was plotted against compound concentration and iteratively curve fitted
using a four parameter logistic fit (as described by Bowen and Jerman, TiPS, 1995,16,413-
417) to generate a concentration effect value. Antagonist Kb values were calculated using
the equation:
Kb=IC50/(l+([3/BC50])
where EC50 was the potency of human orexin-A determined in the assay (in nM
terms) and IC50 is expressed in molar terms.
Compounds of Examples tested according to this method had pKb values in the range - 9.1 at the human cloned orexin-2 receptor.
The application of which this description and claims forms part maybe used as a basis for
priority in respect of any subsequent application. The claims of such subsequent application
may be directed to any feature or combination of features described herein. They may take
the form of product, composition, process, or use claims and may include, by way of
example and without limitation the following claims:

We Claims:
1. A N-aroyl cyclic amines compound of formula (I):
(Formula Removed)
wherein:
Y represents a bond, oxygen, or a group (CH2)n, wherein n represents 1, 2
or 3;
R is H or (C1-4)alkyl;
Ar1 is an aryl group selected from phenyl, quinoxalinyl, quinazolinyl,
pyridopyrazinyl, baazoxazolyl, benzothiophenyl, benzimidazolyl,
naphthyridinyl, pyridinyl, pyrimidinyl, thiazolyl, pyridazinyl, pyrazinyl,
oxazolyl, triazolyl, imidazolyl, pyrazolyl, quinolinyl, benzofuranyl, indolyl,
benzothiazolyl, oxazolyl[4,5-b]pyridiyl, pyridopyrimidinyl, isoquinolinyl,
furanyl or thienyl, which aryl is optionally substituted with 1, 2 or 3
optional substituents;
Ar2 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 R1 and further optional
substituents; or Ar2 represents an optionally substituted bicyclic
aromatic or bicyclic heteroaromatic group containing up to 3
heteroatoms selected from N, O and S;
R1 represents hydrogen, optionally substituted(C1-4 jalkoxy, halo, cyano,
optionally substituted(Ci-6)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 the optional substituents for the groups Ar1, Ar2, R and R1 are selected from halogen, hydroxy, oxo, cyano, nitro, (C1-4)alkyl, (C1-4)alkoxy, hydroxy(C1-4)alkyl, hydroxy(C1-4)alkoxy, halo(C1-4)alkyl, halo(C1-4)alkoxy, aryl(C1-4)alkoxy, (C1-4)alkylthio, hydroxy(C1-4)alkyl, (C1-4)alkoxy(C1-4)alkyl, (C3-6)cycloalkyl(C1-4)alkoxy, (C1-4)alkanoyl, (C1-4)alkoxycarbonyl, (C1-4)alkylsulfonyl, (C1-4)alkylsulfonyloxy, (C1-4)alkylsulfonyl(C1-4)alkyl,

arylsulfonyl, arylsulfonyloxy, arylsulfonyl(C1-4)alkyl, (C1-
4)alkylsulfonamido (C1-4)aikylamido, (C1-4)alkylsulfonamido(C1-4)alkyl, (C1-4alkylamido(C1-4)alkyl, arylcarboxamido, arylcarboxamido(C1-4)alkyl, aroyl, aroyl(C1-4)alkyl, or aryl(C1-4)alkanoyl group; a group RaRbN, RaOCO(CH2)r, RaCON(Ra)(CH2)r, RaRbNCO(CH2)r or RaS02NRb(CH2)r where each of Ra and Rb independently represents a hydrogen atom or a (C1-4)alkyi group or where appropriate RaRb forms part of a (C3-6)azacyloalkane or (C3-6)(2-oxo)azacycloalkane ring and r represents zero or an integer from 1 to 4, (C1-4)acyl, aryl, aryl(C1-4)alkyl, (C1-4)alkylamino(C1-4)alkyl, RaRbN(CH2)n-, RaRbN(CH2)nO-, wherein n represents an integer from 1 to 4; wherein when Y is a bond Ar2 can not be 2-naphthyl; or a pharmaceutical^ acceptable salt thereof; with the proviso that the compound is not:
(2S)- l-[[7-(3,4-dichlorophenyl)-4,7-dihydro-5methylpyrazolo[ 1,5-
a]pyrimidin-6 -yl] carbonyl] -2 - [ (phenylamino) methyl] pyrrolidine; or
(2-bromophenyl){[l-(phenylcarbonyl)-2-pyrrolidinyl]methyl} amine.
2. A compound as claimed in claim 1 wherein R is H.
3. A compound as claimed in claim 1 or 2 wherein Y is a bond, oxygen or (CH2)n where n is 1 or 2.
4. A compound as claimed in any preceding claim wherein Ar2 represents an optionally substituted phenyl, pyridyl, thiazolyl, pyrazolyl, benzofuryl, naphthyl, triazolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothienyl, benzotriazolyl, benzothiazolyl, indolyl or thienyl.
5. A compound as claimed in any preceding claim wherein Ar1 represents an optionally substituted benzoxazolyl, benzimidazolyl, quinoxalinyl, quinazolinyl, pyrimidinyl, pyridinyl, naphthyridinyl, quinolinyl, pyridopyrimidine, thiazolyl, oxazolylpyridinyl, benzothiazolyl, isoquinolinyl or pyrazinyl.

6. A compound as claimed in any preceding claim wherein R1 is selected from trifluoromethoxy, methoxy, ethoxy, halo, cyano or an optionally substituted phenyl, pyridyl, pyrazolyl, pyrimidinyl, or oxadiazolyl group.
7. A compound as claimed in claim 1 selected from:

(Table Removed)

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

Documents:

01796-delnp-2003-abstract.pdf

01796-delnp-2003-claims.pdf

01796-delnp-2003-correspondence-others.pdf

01796-delnp-2003-description (complete).pdf

01796-delnp-2003-form-1.pdf

01796-delnp-2003-form-18.pdf

01796-delnp-2003-form-2.pdf

01796-delnp-2003-form-3.pdf

01796-delnp-2003-form-5.pdf

01796-delnp-2003-gpa.pdf

01796-delnp-2003-pct-101.pdf

01796-delnp-2003-pct-304.pdf

01796-delnp-2003-pct-308.pdf

01796-delnp-2003-pct-409.pdf

01796-delnp-2003-pct-416.pdf

1796-DELNP-2003-Abstract-(15-02-2008).pdf

1796-DELNP-2003-Abstract-(17-09-2008).pdf

1796-DELNP-2003-Claims-(15-02-2008).pdf

1796-DELNP-2003-Claims-(17-09-2008).pdf

1796-DELNP-2003-Claims-24-09-2008.pdf

1796-delnp-2003-complete specification (granded).pdf

1796-DELNP-2003-Correspondence-Others-(15-02-2008).pdf

1796-DELNP-2003-Correspondence-Others-(17-09-2008).pdf

1796-DELNP-2003-Description (Complete)-(15-02-2008).pdf

1796-DELNP-2003-Description (Complete)-(17-09-2008).pdf

1796-DELNP-2003-Description (Complete)24-09-2008.pdf

1796-DELNP-2003-Form-1-(15-02-2008).pdf

1796-DELNP-2003-Form-1-(17-09-2008).pdf

1796-DELNP-2003-Form-2-(15-02-2008).pdf

1796-DELNP-2003-Form-2-(17-09-2008).pdf

1796-DELNP-2003-Form-3-(15-02-2008).pdf

1796-DELNP-2003-GPA-(15-02-2008).pdf

1796-DELNP-2003-Others-(15-02-2008).pdf

1796-DELNP-2003-Petition-137-(15-02-2008).pdf

1796-DELNP-2003-Petition-138-(15-02-2008).pdf

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Patent Number

224402

Indian Patent Application Number

01796/DELNP/2003

PG Journal Number

44/2008

Publication Date

31-Oct-2008

Grant Date

14-Oct-2008

Date of Filing

31-Oct-2003

Name of Patentee

SMITHKLINE BEECHAM PLC

Applicant Address

980 GREAT WEST ROAD, BRENTFORD, MIDDLESES TW8 9GS, ENGLAND.

Inventors:

#	Inventor's Name	Inventor's Address
1	CLIVE LESLIE BRANCH	GLAXOSMITHKLINE, NEW FRONTIERS SCIENCE PARK SOUTH, THIRD AVENUE, HARLOW, ESSEX CM 19 5AW, ENGLAND.
2	STEVEN COULTON	GLAXOSMITHKLINE, NEW FRONTIERS SCIENCE PARK SOUTH, THIRD AVENUE, HARLOW, ESSEX CM 19 5AW, ENGLAND.
3	AMANDA JOHNS	GLAXOSMITHKLINE, NEW FRONTIERS SCIENCE PARK SOUTH, THIRD AVENUE, HARLOW, ESSEX CM 19 5AW, ENGLAND.
4	CHRISTOPHER NORBERT JOHNSON	GLAXOSMITHKLINE, NEW FRONTIERS SCIENCE PARK SOUTH, THIRD AVENUE, HARLOW, ESSEX CM 19 5AW, ENGLAND.
5	RODERICK ALAN PORTER	GLAXOSMITHKLINE, NEW FRONTIERS SCIENCE PARK SOUTH, THIRD AVENUE, HARLOW, ESSEX CM 19 5AW, ENGLAND.
6	GEOFFREY STEMP	GLAXOSMITHKLINE, NEW FRONTIERS SCIENCE PARK SOUTH, THIRD AVENUE, HARLOW, ESSEX CM 19 5AW, ENGLAND.
7	KEVIN THEWLIS	GLAXOSMITHKLINE, NEW FRONTIERS SCIENCE PARK SOUTH, THIRD AVENUE, HARLOW, ESSEX CM 19 5AW, ENGLAND.

PCT International Classification Number

C07D 417/14

PCT International Application Number

PCT/GB02/02042

PCT International Filing date

2002-05-02

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	0130331.2	2001-12-19	U.K.
2	0111189.7	2001-05-05	U.K.
3	0121303.2	2001-09-03	U.K.
4	0130392.4	2001-12-19	U.K.
5	0111184.8	2001-05-05	U.K.