AU2002253361A1 - N-aroyl cyclic amines - Google Patents

Description

N-AROYL CYCLIC AMINES

This invention relates to N-aroyl cyclic amine derivatives and their use as pharmaceuticals.

Many medically significant biological processes are mediated by proteins 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 (HFGA 72), have been identified and are disclosed in EP-A-875565, EP-A-875566 and WO 96/34877. Polypeptides and polynucleotides encoding a second human orexin receptor, orexin-2 (HFGANP), have been identified and are disclosed in EP-A-893498.

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

Orexin receptors are found in the mammalian host and may be responsible for many biological functions, including pathologies including, but not limited to, depression; anxiety; addictions; obsessive compulsive disorder; affective neurosis/disorder; depressive neurosis/disorder; anxiety neurosis; dysthymic disorder; behaviour disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; sexual disorder; schizophrenia; manic depression; delerium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Gilles de la Tourett's syndrome; disturbed biological and circadian rhythms; feeding disorders, such as anorexia, bulimia, cachexia, and obesity; diabetes; appetite/taste disorders; vomiting nausea; asthma; cancer; Parkinson's disease; Cushing's syndrome / disease; basophil adenoma; prolactinoma; hyperprolactinemia; hypopituitarism; hypophysis tumor / adenoma; hypothalamic diseases; Froehlich's syndrome; adrenohypophysis disease; hypophysis disease; hypophysis tumor / adenoma; pituitary growth hormone; adrenohypophysis hypofunction; adrenohypophysis hyperfunction; hypothalamic hypogonadism; Kallman's syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic- adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth hormone deficiency; dwarfism; gigantism; acromegaly; disturbed biological and circadian rhythms; and sleep disturbances associated with such diseases as neurological disorders, neuropathic pain and restless leg syndrome, heart and lung diseases; acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; ischaemic or haemorrhagic stroke; subarachnoid haemorrhage; head injury such as sub-arachnoid haemorrhage associated with traumatic head injury; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired glucose tolerance; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain, such as hyperalgesia, causalgia and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back 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; postoperative pain; neuralgia; nausea and vomiting; conditions associated with visceral pain including irritable bowel syndrome, migraine and angina; urinary bladder incontinence e.g. urge incontinence; tolerance to narcotics or withdrawal from narcotics; sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet-lag syndrome; and neurodegenerative disorders, which includes nosological entities such as disinhibition-dementia-parkinsonism- amyotrophy complex; pallido-ponto-nigral degeneration, epilepsy, and seizure disorders. Experiments have shown that central administration of the ligand orexin-A (described in more detail below) stimulated food intake in freely-feeding rats during a 4 hour time period. This increase was approximately four-fold over control rats receiving vehicle. These data suggest that orexin-A may be an endogenous regulator of appetite. Therefore, antagonists of its receptor may be useful in- the treatment of obesity and diabetes, see Cell, 1998, 92, 573-585.

There is a significant incidence of obesity in westernised societies. According to WHO definitions a mean of 35% of subjects in 39 studies were overweight and a further 22% clinically obese. It has been estimated that 5.7% of all healthcare costs in the USA are a consequence of obesity. About 85% of Type 2 diabetics are obese, and diet and exercise are of value in all diabetics. The incidence of diagnosed diabetes in westernised countries is typically 5% and there are estimated to be an equal number undiagnosed. The incidence of both diseases is rising, demonstrating the inadequacy of current treatments which may be either ineffective or have toxicity risks including cardiovascular effects. Treatment of diabetes with sulfonylureas or insulin can cause hypoglycaemia, whilst metformin causes GI side-effects. No drug treatment for Type 2 diabetes has been shown to reduce the long-term complications of the disease. Insulin sensitisers will be useful for many diabetics, however they do not have an anti-obesity effect.

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

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

International Patent Applications WO99/09024, WO99/58533, WO00/47577 and WO00/47580 disclose phenyl urea derivatives and WO00/47576 discloses quinolinyl cinnamide derivatives as orexin receptor antagonists. WO01/96302 discloses Ν-aroyl cyclic amine derivatives. According to the invention there is provided a compound of formula (I) :

CD wherein:

Y represents a bond, oxygen, or a group (CH₂)„, 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 (C_1-4)alkyl;

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 cont_ώιing 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^^ )alkoxy, halo, cyano, optionally substitated(C_1-6)alkyl, optionally substituted phenyl, or an optionally substituted 5- or 6- membered heterocyclyl group containing up to 4 heteroatoms selected fromN, 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 NH. m is preferably 1. p is preferably 0.

Even more preferably m is 1 when p is 0. Preferably R is hydrogen.

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

(la) wherein:

Y represents a bond, oxygen, or a group (CH₂)„, 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 R and further optional substituents; or Ar represents an optionally substituted bicyclic aromatic or bicyclic heteroaromatic group containing up to 3 heteroatoms selected from N, O and S;

R¹ represents hydrogen, optionally substituted^^ )alkoxy, halo, cyano, optionally substituted(Cι_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 when Y is a bond then At² 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)„ wherein n is 1 or 2. Even more preferably Y is a bond, oxygen or (CH )_n wherein n is 1

Alternatively R¹ represents hydrogen, optionally substituted^^ )alkoxy, halo, optionally substituted^ϊ^alkyl, optionally substituted phenyl or an optionally substituted 5- or 6-membered heterocyclyl group containing up to 3 heteroatoms selected from N, O and S. Alternatively R¹ represents optionally substituted^^ )alkoxy, halo, optionally 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 quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, pyridinyl, pyrimidinyl, or thiazolyl. Additionally Ar¹ can be selected from pyridazinyl, pyrazinyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl, quinolinyl, benzofiiranyl, indolyl, benzothiazolyl, oxazolyl[4,5-b]pyridiyl, pyridopyrimidinyl or isoquinolinyl. Furthermore Ar¹ can be furanyl or thienyl. Preferably Ar¹ is benzoxazolyl, benzimidazolyl, quinoxalinyl, quinazolinyl, pyrimidinyl, pyridinyl, naphthyridinyl, Additionally Ar¹ can be quinolinyl, pyridopyrimidine, thiazolyl, oxazolylpyridinyl, benzothiazolyl, isoquinolinyl or pyrazinyl. More preferably Ar¹ is benzoxazolyl, benzimidazolyl, quinoxalinyl, quinazolinyl, pyrimidinyl, pyridinyl, naphthyridinyl or oxazolyl[4,5-b]pyridinyl. When At² is a 5- or 6-membered heterocyclyl group cont∑uning up to 3 heteroatoms selected from N, O and S, it may be furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl or pyrazolyl. When R¹ is a 5- or 6-membered heterocyclyl group containing up to 4 heteroatoms selected from N, O and S, it may be furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl or pyrazolyl. Additionally it can be tetrazoyl, piperazinyl, piperidinyl, morpholinyl or thiomorpholinyl.

Preferably when R¹ is a 5- or 6-membered heterocyclic ring containing up to 4 heteroatoms selected from N, O and S, it is furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazinyl, pyrimidinyl, isothiazolyl, isoxazolyl, pyrazinyl or pyrazolyl. Preferably R¹ is a 5- or 6-membered heterocyclic ring it contains up to 3 heteroatoms selected from N, O 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 benzothiadiazolyl.

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-triazolyl.

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, (Ci^alkyl, (C^alkoxy, hydroxy(Cι-₄)alkyl, hydroxy(Cι__.)alkoxy, halo(C_1- )alkyl, halo(C_1- )alkoxy, aryl(Cι_-4)alkoxy, (C_1- )alkylthio, hydroxy(C_1- )alkyl, (Cι_ ₄)alkoxy(C_1-4)alkyl, (C₃.₆)cycloalkyl(C_M)alkoxy, (d^alkanoyl, (C_1-4)alkoxycarbonyl, (Ci. ₄)alkylsulfonyl, (C_1- )_ύ1cylsulfonyl(Cι_-4)alkyl, arylsulfonyl, arylsulfonyloxy, arylsulfonyl(Ci )_tlkyl, ₄)alkylsulfonamido(Cι. )a_kyl, (Cι- )_u_yl_ιmido(C_1- )alkyl, arylsulfonamido, arylcarboxamido, arylsulfonamido(Cι- )alkyl, arylcarboxamido(Cι.__t)alkyl, aroyl, aroyl(Cι_ ₄)alkyl, or aryl(C_1-4)alkanoyl group; a group ^-, R^aOCO(CH₂)_r, R^aCON(R^a)(CH₂)_r, independently represents a hydrogen atom or a (C_1- )alkyl group or where appropriate R^aR^b forms part of a (C_3-6)azacyloalkane or (C_3-6)(2-oxo)azacycloalkane ring and r represents zero or an integer from 1 to 4. Additional substituents are (Ci-^acyl, aryl, aryl(Cι_₄)alkyl, (C_M)alkylamino(C_M)alkyl, R^^CH^n-, R⁸R^b (CH₂)nO-, wherein n represents an integer from 1 to 4. Additionally when the substituent is R^^CH^n- or R R^(CH_.»)nO, R^a with at least one CH₂ of the (CH₂)n portion of the group form a (C_3-6)azacycloalkane and R^b represents hydrogen, a group or with the nitrogen to which it is attached forms a second (C₃-6)azacycloalkane fused to the first (C_3-6)azacycloalkane.

Preferred optional substituents for Ar² are halogen, cyano, (C_1- )alkyl. Additional preferred optional substituents are R^^CH^n, R^^ . Further optional substituents for Ar² can also be halogen, cyano, (C_M)alkyl, R^aR^bN(CH₂)nO or (C_M)alkoxy.

. Preferred optional substituents for Ar¹ are halogen, cyano, (C^alkanoyl. Other preferred substituents are hydroxy(Cι_-4)alkyl, (C_1- )alkyl or CF₃.

Preferred optional substituents for R¹ are halogen, (Cι- )aj_koxy(Cι- )alkyl, R^' , R^^CHa^O and R^^CH^n. Other preferred substituents are (C_M)alkoxy or (C^ ₄)alkanoyl.

In the groups Ar¹ and Ar², substituents positioned ortho to one another may be linked to form a ring.

Illustrative compounds of formula (I) are selected from:

Example Compound Name

55 1 - {(S)-2-[(6,7-Difluoro-3-me yl-qumoxalm-2-yl__mino)-methyl]-piperidin- 1 - yl}-l-[4-(4-fluoro-phenyl)-l-methyl-lH-pyrazol-3-yl]-methanone

56 l-{(S)-2-[(6_?7-Difluoro-3-methyl-qumoxalin-2-ylamino)-methyl]-piperidin-l- yl} - 1 -f4-(4-fluoro-phenyl)- 1 H-pyrazol-3 -yl]-methanone

57 l-{(S)-2-[(6,7-Difluoro-3-me yl-qumoxalm-2-ylaιιύno)-methyl]-piperidin-l- yl}-l-[2-(4-ιluoro-phen3 )-5-methyl-2H-pyrazol-3-yl]-methanone

58 l-{(S)-2-[(6,7-Difluoro-3-methyl-qumoxalm-2-yla_rr__no)-memyl]-piperidin-l- yl}-l-[4-(4-fluoro-phenyl)-2-methyI-2H-pyrazol-3-yI]-methanone

59 l-{(S)-2-[(6,7-Difluoro-3-memyl-qumoxaliri-2-yIamino)-methyI]-piperidin-l- yl } - 1 -naphthalen- 1 -yl-methanone

60 l-{(S)-2-[(6_?7-Difluoro-quinoxalin-2-ylamino)'-methyl]-piperidin-l-yl}-l- uinoIin-4-yl-methanone

61 l-{(S)-2-[(6,7-Difluoro-qu_noχalm-2-yla_^ fluoro-phenyl)-2-methyl-oxazol-4-yl]-methanone

62 l-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylammo)-methyl]-piperidin-l-yl}-l-[5-(4- fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

63 l-{(S)-2-[(6,7-Difluoro-qιunoxalm-2-ylammo)-me yl]-piρeridin-l-yl}-l-[2-(3- methyl-[l,2,4]oxadiazol-5-yl)-phenyl]-methanone

64 l-{(S)-2-[(6,7-Difluoro-qu_noxal -2-ylammo)-methyl]-piperidin-l-yl}-l-(2- trifluoromethoxy-ρhenyl)-methanone

65 l-BiphenyI-2-yl-l-{(S)-2-[(6,7-difluoro-qτι oxal -2-ylarnino)-methyl]- ρiperidin-1 -yl}-methanone

66 l-(5-Bromo-2-memoxy-phenyl)-l-{(S)-2-[(6,7-difl^ methyl]-piperidin-l -yl}-methanone

67 l-{(S)-2-[(6 -Difluoro-quinoxalin-2-ylammo)-methyl]-piperidin-l-yl}-l-[4-(4- fluoro-phenyl)-l-methyl-lH-pyrazol-3-yl]-methanone

68 l-{(S)-2-[(6,7-Difluoro-quinoxalm-2-ylammo)-memyl]-piperidin-l-yl}-l-[4-(4- fluoro-phenyl)-2-methyl-2H-pyrazol-3-yl]-methanone

69 1 - { (S)-2-[(6,7-Difluoro-q nox-din-2-ylamino)-methyl]-piperidin- 1 -yl} - 1 -[5-(4- fluoro-phenyl)-2-methyl-2H-[l,2,3]triazol-4-yl]-methanone

70 l-{(S)-2-[(6,7-Difluoro-quinoxalm-2-ylammo)-memyl]-piperidin-l-yl}-l- aphthalen- 1 -yl-methanone ^~

71 l-((S)-2-[(6,7-Difluoro-quinoxal -2-ylarruno)-me yl]-piperid -l-yl}-l-[5-(4- fluoro-phenyl)-thiazol-4-yl3-methanone

72 l-[4-(4-Fluoro-phenyl)-l-memyl-lH-pyrazol-3-yl]-l-[(R)-2-(quinazolin-2- laminomethyl)-piperidin-l-yl]-methanone

73 l-[2-(3-Methyl-[l,2,4]oxadiazol-5-yl)-phenyl]-l-[2-(oxazolo[4,5-b]pyridin-2- ylaminomethyl)-piperidin- 1 -yl]-methanone

74 l-[2-(Oxazolo[4,5-b]pyridin-2-ylammomethyl)-ρiρeri trifluoromethoxy-ρhenyl)-methanone

75 l-[5-(4-Fluoro-phenyl)-2-memyl-thiazol-4-yy ylaminomethyl)-piperidin-l -yl] -methanone

and pharmaceutically acceptable salts thereof. Additional compounds of formula (I) are selected from:

Examplej CompundName

109 1 - { (S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin- 1 -yl} - 1 -(4- fluoro-benzofuran-2-yl)-methanone

110 2-[((S)-l-{l-[5-(4-Fluoro-phenyl)-2-memyl-tmazol-4-yl]-memanoyl}-piperidin- 2-ylme yl)-amino]-nicotinonitrile

111 2-[((S)-l-{l-[2-(3-Me l-[l,2,4]oxadiazol-5-yl)-phenyl]-methanoyl}-piperidin- 2-ylmemyl)-am no]-nicotinonitrile

112 2-[((S)-l-{l-[5-(4-Fluoro-phenyl)-2-memyl-thiazol-4-yl]-methanoyl}-piperidin- 2-ylmethyl)-amino]-isonicotinonitrile

113 l-Benzo[TD]tMophen-2-yl-l-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)- methyll-piperidin- 1 -yl } -methanone

114 l-(lH-Benzoimidazol-5-yl)-l-{(S)-2-[(6,7-difluoro-quinoxalin-2-ylamino)- methyl]-piperidin- 1 -yl } -methanone

Example Compound Name

159 1 -{(S)-2-[(5-Bromo-ρyrimidm-2-ylammo)-memyl]-piperidin- 1 -yl}-l -[ 1 -(2- dimethylamino-ethyl)-4-(4-fluoro-phenyl)- 1 H-pyrazol-3 -yl] -methanone

160 l-[4-(4-Fluoro-ρhenyl)-l-(2-methoxy-ethyl)-lH-pyrazol-3-yl]-l-[(S)-2- (pyrido [2,3-b]pyrazm-2-ylaminomethyl)-piperidin- 1 -yl]-methanone

162 l-(lH-Benzoimidazol-5-yl)-l-{(S)-2-[(5-bromo-pyrir dm-2-ylamino)-methyl]- piperidin- 1 -yl} -methanone

163 l-Benzo_nran-2-yl-l-{(S)-2-[(5-bromo-pyrimidin-2-ylamino)-methyl]-piperidin- 1-yl} -methanone

164 1 -{(S)-2-[(5-Bromo-ρyrimidm-2-yl__mmo)-memyl]-piperidin-l -yl}-l -(2- methoxy-phenyl)-methanone ;

165 l-{(S)-2-[(5-Bromo-ρyrimidin-2-ylammo)-memyl]-piperidm-l-yl}-l-qumolin-4- yl-methanone

166 l-{(S)-2-[(6,7-Difluoro-qvmoxalin-2-ylam dimemylamino-propoxy)-phenyl]-methanone

170 {(S)-2-[(5-Bromo-ρvrimidm-2-ylarr___no)-m fluoro-phenyl)-l-methyl-lH-pyrazol-3-yl]-methanone

119 1 - { (S)-2-[(6,7-Difluoro-qumoxdm-2-ylamino)-methyl]-pyrrolidin- 1 -yl } - 1 -[1 - ethyl-4-(4-fluoro-phenyl)- 1 H-pyrazol-3 -yl]-methanone

120 1 - {(S)-2- [(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidin- 1 -yl} - 1 -[5-(4- fluoro-phenyl)-2H-[l,2,3]triazol-4-yl]-methanone

167 l-{(S)-2-[(5-Bromo-ρyrimidm-2-ylammo)-memyl]-pyrrolidin-l-yl}-l-[4-(4- fluoro-phenyl)-l-methyl-lH-pyrazol-3-yl]-methanone

168 l-{(S)-2-[(6,7-Di_fluoro-qumoxalm-2-ylancιino)-memyl]-pyrrolidin-l-yl}-l-[5-(2- fluoro-ρhenyl)-thiazol-4-yl]-methanone

169 l-{(S)-2-[(6,7-Difluoro-qumoxaI-n-2-ylamino)-methyl]-pyrrolidin-l-yl}-l-[4-(4- fluoro-phenyl)- 1 -methyl- 1 H-pyrazol-3 -yl] -methanone

171 l-{2-[((S)-l-{l-[4-(4-Fluoro-phenyl)-l-methyl-lH-pyrazol-3-yl]-methanoyl}- piperidm-2-ylmemyl)-ammo]-pyrimidin-5-yl}-ethanone

172 l-[4-(4-Fluoro-phenyl)-l-methyl-lH-pyrazol-3-yl]-l-((S)-2-{[5-(l-hydroxy- emyl)-pyriπudm-2-ylan-dno]-memyl}-piperidm-l-yl)-methanone

173 2-[((S)-l-{l-[4-(4-Fluoro-phenyl)-l-methyl-lH-pyrazol-3-yl]-methanoyl}- piperidm-2-ylmemyl)-amino]-pyr-midine-5-carbonitrile

174 3-(l-{(S)-2-[(6,7-Difluoro-qumoxalin-2-ylam methanoyl)-N-methyl-benzamide and pharmaceutically acceptable salts thereof.

Further compounds of formula (I) are selected from:

Example Compound Name

175 l-{(S)-2-[(5-Bromo-ρyrimidm-2-yl_unino)-methyl]-piperidin-l-yl}-l-phenyl- methanone Example Compound Name

274 l-((S)-2-{[(5-Bromo-pyrimidin-2-yl)-m memyl-quinolin-5-yl)-methanone

275 l-{(S)-2-[(5-CMoro-ρyrin_idm-2-ylammo)-memyl]-piperidin-l-yl}-l-[5-(4-fluoro- phenyl)-2-methyl-thiazol-4-yl]-methanone

and pharmaceutically acceptable salts thereof.

Preferred compounds of formula (1) are selected from:

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

When the compound of formula (1) contains an alkyl group, whether alone or forming part of a larger group, e.g. alkoxy or alkylthio, the alkyl group may be straight chain, branched or cyclic, or combinations thereof, it is preferably methyl or ethyl. When used herein the term aryl means a 5- to 6- membered 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 (I) may exist as R or S enantiomers. The jpresent invention includes within its scope all such isomers, including mixtures. Where additional chiral centres are present in compounds of formula (I), the present invention includes within its scope all possible diastereoismers, including mixtures thereof. The different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.

It will be understood that the invention includes pharmaceutically acceptable derivatives of compounds of formula (I) and that these are included within the scope of the invention.

Particular compounds according to the invention include those mentioned in the examples and their pharmaceutically acceptable derivatives.

As used herein "pharmaceutically acceptable derivative" includes any pharmaceutically acceptable salt, ester or salt of such ester of a compound of formula (I) which, upon administration to the recipient is capable of providing (directly or indirectly) a compound of formula (T) 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 (1) and are included within the scope of this invention. Also included within the scope of the invention are solvates and hydrates of compounds of formula (I).

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

Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions. According to a further feature of the invention there is provided a process for the preparation of compounds of formula (I) and derivatives thereof. The following schemes detail some synthetic routes to compounds of the invention.

Scheme la

deprotection

(II)

(I) 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, OSO₂Me, OSO₂(4-tolyl). The reaction of (V) with (VI) preferably proceeds in an inert solvent such as N,N-dimethylformamide in the presence of a base such as triemylamine, sodium hydride or potassium t-butoxide.

Scheme lb

deprotection

(ID

(I)

Reaction of (VflT) with (EX) 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 lc.

Scheme lc

Reaction of (XI) with an alkylating agent (C^L¹ 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, 0C(=O)alkyl and OC(=O)O-alkyl. The transformation (U) to (I) may be carried out in an inert solvent such as dichloromethane, in the presence of a base such as trie&ylamine. Alternatively this step may be carried out when L² represents hydroxy, in which case reaction with (II) takes place in an inert solvent such as dichloromethane in the presence of a dii ide reagent such as 1- emyl-3-(3-dimemylan_ιinopropyl)c_ιrbodiimide hydrochloride, and an activator such as 1- hydroxybenzotriazole. Examples of protecting groups P include t-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), (VI) and (TX) are known in the literature or can be prepared by known methods. Compounds (VTfl) 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 in compounds (TV) conversion of protecting group P for another protecting group P, or conversion of one compound of formula (I) to another of formula (T) 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 (VH) 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) .

Scheme 2

(VH) (I)

Wherein Y, Ar², m, p, Ar¹, 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 pharmaceutically acceptable derivatives thereof.

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

The compounds of formula (I) and their pharmaceutically acceptable derivatives are useful for the treatment of diseases or disorders where an antagonist of a human Orexin 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 (I) 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 in 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; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndromes I and II; _ιrthritic 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 Orexin receptor is required, which comprises administering to a subject in need thereof an effective amount of a compound of formula (I), or a pharmaceutically acceptable derivative thereof. The invention also provides a compound of formula (I), or a pharmaceutically acceptable derivative thereof, for use in the treatment or prophylaxis of diseases or disorders where an antagonist of a human Orexin receptor is required. The invention also provides the use of a compound of formula (I), 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 (I) and their pharmaceutically acceptable derivatives may be administered by any convenient method, e.g. by oral, parenteral, buccal, sublingual, nasal, rectal or transdermal 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 in a suitable liquid carrier(s) 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 carrier(s), 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 adrninistration.

Compositions for nasal adrninistration 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 non- aqueous 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 (T).

No toxicological effects are indicated/expected when a compound of formula (I) is adrriinistered 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 15

Tyr Glu Leu Leu His Gly Ala Gly Asn His Ala Ala Gly He 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. coli. In particular, a polynucleotide encoding the orexin-1 receptor is used to transfect cells to express the receptor. The expressed receptor is then contacted with a test compound and an orexin-1 receptor ligand to observe inhibition of a functional response. One such screening procedure involves the use of melanophores which are transfected to express the orexin-1 receptor, as described in 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 in 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 FLIPR 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.

In the Examples 1H NMR's were measured at 250MHz in CDC1₃ unless otherwise stated.

Description 1: (S) 2-AminomethyI-piperidine-l-carboxylic acid tert butyl ester a) 2,2,2-Trifluoro-N-[(S)-l-((R)-2-hydroxy-l-phenyl-ethyl)-piperidm-2-ylmethyI]- acetamide

(R)-2-[(S)-2-Aminomethyl-ρiperidin-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 triemylamine (13.0ml) were dissolved in dichloromethane (500ml), cooled to 0°C and trifluoroacetic anhydride (12.66ml) added dropwise. The mixture was warmed 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 (API⁴): Found 331 (MH⁴). C₁₆H₂₁F₃N₂O₂ requires 330. [α]_D -55°@ 28° 1% in chloroform b) 2,2,2-Trifluoro-N-(S)-l-piperidin-2-yImethyI-acetaιnide 2,2,2-Trifluoro-N-[(S)-l-((R)-2-hyάVoxy-l-ρhenyl-emyl)-ρiρeridin-2-ylmethyl]-acetam^ (28.0g) was dissolved in ethanol (200ml) containing Pearlmans catalyst (2.0g) and shaken under a hydrogen atmosphere (50psi) 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 methanol/ammonia) in dichloromethane eluant) to give the title compound (14.18g) as a colourless oil. Mass Spectrum (API⁴): Found 211 (MH⁴). C₈Hι₃F₃N₂O requires 210. [α]_D +18°@ 28° 1% in chloroform ^lH NMR δ: (d⁶-DMSO) 1.07 (IH, ), 1.32 (2H, m), 1.35 - 1.60 (2H, m), 1.72 (IH, m), 2.54 (IH, t), 2.70 (IH, m), 3.00 (IH, d), 3.17 (3H, m), 9.30 (IH, br. s.) c) (S)-2-[(2,2,2-Trifluoro-ethanoylamino)-methyI]-piperidine-l -carboxylic acid tert butyl ester

2,2,2-Trifluoro-N-(S)-l-piρeridin-2-ylmethyl-acetamide (14.18g) was dissolved in dichloromethane (250ml) and treated with di-tert-butyl dicarbonate (14.95g). The mixture was stirred for 16h, washed with water, 2N hydrochloric acid and saturated brine, dried and solvent removed at reduced pressure to give the title compound (18.3g) Mass Spectrum (API⁴): Found 311 (MH⁴). C₁₃H₂₁F₃N₂O₃ requires 310. [α]_D -94°@ 28° 1% in chloroform

1H NMR δ: (d⁶-DMSO) 1.27 (IH, m), 1.36, 1.47 (9H, s), 1.49 - 1.58 (5H, m), 2.88 (IH, m), 3.22 (IH, m), 3.49 (IH, m), 3.84 (IH, m), 4.34 (IH, m) and 9.42 (IH, br. s.). d) (S) 2-Aminomethyl-piperidine-l -carboxylic acid tert butyl ester (S)-2-[(2,2,2-Trifluoro-eth_moylamino)-methyl]-piperidirle-l-carboxylic acid tert butyl ester (18.2g) was dissolved in methanol (500ml) and treated with potassium carbonate (16.1g). After stirring for 16h 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 (API⁴): Found 215 (MH⁴). requires 214. [α]_D -32.2°@ 28° 1% in chloroform

1H NMR δ: 1.44 (2H, m), 1.50 (9H, s), 2.64 - 2.80 (2H, m), 2.94 (IH, dd), 3.99 (IH, m) and 4.15 (lH, m).

Description 2: (RS) 2-(Benzoxazol-2-ylammomethyl)-piperidine-l-carboxylic acid tert butyl ester

(RS) 2-Aminomethyl-piperidine-l -carboxylic acid tert butyl ester (0.21 g) and 2- chlorobenzoxazole (0.153g) and triethylamine (O.lg) were combined in tetiahydrofuran (10ml) 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 (0.36g) as an oil that solidified on standing. Mass Spectrum (API⁴): Found 332 (MH⁴). Cι₈H₂₅N₃O₃ requires 331.

Description 3: (RS) Benzoxazol-2-yl-piperidm-2-yImethyI-anιme

The compound of description 2 (0.36g) was stirred in trifluoroacetic acid (10ml) 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 (API⁴): Found 232 (MH⁴). C_]3Hι₇N₃O requires 231.

Description 4: (R)-2-[(S)-2-(BenzooxazoI-2-ylaminomethyI)-piperidin-l-yl]-2-phenyl- ethanol

A mixture of (R)-2-[(S)-2-Ammomethyl-piperidin-l-yl])-2-phenyl-ethanol (l.Og) (Froelich, Olivier; Desos, Patrice; Bonin, 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).

1HNMR δ: 1.59 - 1.71 (4H, m), 1.91 (IH, t), 2.73 (IH, m), 2.95 (IH, m), 3.71 (2H, m), 4.0 (IH, m), 4.10 (IH, m), 4.26 (IH, m), 5.7 (IH, m), 7.03 (IH, m), 7.17 (IH, m), 7.23 - 7.26 (3H, m) and 7.32 - 7.40 (4H, m). Mass Spectrum (API⁴): Found 352 (MH⁴). C₂ιH₂₅N₃O requires 351.

Description 5: Benzoxazol-2-yI-(S)-l-piperidin-2-yIm^!ethyl-amme

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. 1HNMR δ: 1.16 - 1.85 (7H, m), 2.64 (IH, m), 2.85 -2.99 (IH, m), 3.11 (IH, m), 3.31 (IH, m), 3.55 (IH, m), 7.00 (IH, dd), 7.12 (IH, m), 7.20 (IH, d) and 7.30 (IH, m). Mass Spectrum (API⁴): Found 232 (MH⁴). Cι₃H₁₇N₃O requires 231.

Description 6: (RS)-Benzoxazol-2-yl-(4-benzyl-morpholin-3-ylmethyl)-amme

From (4-benzyl-moφhol -3-yl)-me ylamine (lg) (Morie, Toshiya; Kato, Shiro; Harada, Hiroshi; Yoshida, Naoyuki; Fujiwara, Iwao; Matsumoto, Jun-ichi., Chem. Pharm. Bull.

1995, 43, 1137-47) and 2-chlorobenzoxazole (0.78g), the title compound (0.77g) was prepared according to the method of D4.

1H NMR δ: 2.33 (IH, m), 2.73 -2.80 (2H, m), 3.33 (IH, d), 3.51 - 3.90 (6H, m), 4.10 (IH, d), 5.58 (IH, s), 7.04 (IH, m), 7.17 (IH, m) and 7.24 - 7.39 (7H, m). Mass Spectrum (API⁴): Found 324 (MH ). C₁₉H₂₁N₃O₂ requires 323.

Description 7: (RS)-Benzoxazol-2-yl-morphoIi_α-3-ylmethyI-amine

From the compound of D6 (0.77g) the title compound (0.55g) was prepared-according to the method of D5. 1H NMR δ: 2.93 - 3.23 (2H, m), 3.46 - 4.03 (7H, m), 6.95 - 7.23 (4H, m). Mass Spectrum (API⁴): Found 234 (JVΪH⁴). C₁₂Hι₅N₃O₂ requires 233.

Description 8: (RS) 2-(l_fiT-Benzoimidazol-2-yIammomethyl)-piperidine-l-carboxyIic acid tert butyl ester (RS)-2-Aminomethyl-piperidine- 1 -carboxylic 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 - ethyl acetate/pentane 1 : 1 eluant) to give the title compound (0.1 g). 1HNMR δ: 1.47 (9H, m), 1.65 - 1.81 (7H, m), 2.85 (IH, t), 3.47 (2H, m), 3.91 (IH, d), 4.32

(IH, s), 5.78 (IH, s), 7.04 (3H, m) and 7.29 (IH, s).

Mass Spectrum (API⁴): Found 331 (MH*). C₁₈H₂₆N₄O₂ requires 330.

Description 9: (RS)-(iJ?-BenzoimidazoI-2-yl)-piperidin-2-yb_nethyl-amine dihydrochloride.

The compound of D8 (0.39g) was stirred in a mixture of 4M HCl 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 (MH⁴). Cι₃H₁₈N₄ requires 230.

Description 10: (RS) 2-(Quinolin-2-ylaminomethyl)-p'iperidine-l -carboxylic acid tert butyl ester

The title compound (O.lg) was prepared.from (RS) 2-aminomethyl-piperidine-l -carboxylic acid tert butyl ester (0.5ml) and 2-chloroquinoline (0.5g) according to the procedure of D8. Mass Spectrum (API⁴): Found 342 (MH ). C₂₀H₂₇N₃O₂ requires 341.

Description 11: (RS)-Piperidin-2-ylmethyl-quinolin-2-yl-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 dichloromethane, washed with saturated sodium hydrogen carbonate, the organic phase separated, dried and solvent removed at reduced pressure to give the title compound.

1H NMR δ: 1.20 - 1.96 (6H, m), 2.64 (IH, m), 2.85 (IH, m), 3.10 (IH, ), 3.35 (IH, m),

3.60 (IH, m), 5.17 (IH, m), 6.66 (IH, d), 7.19 (IH, dt), 7.48 - 7.58 (2H, m), 7.66 (IH, d) and 7.78 (IH, d).

Mass Spectrum (API⁴): Found 242 (MH*). C₁₅H₁₉N₃ requires 241.

Description 12: (TRS)-2-(BenzothiazoI-2-ylaminomethyI)-piperidme-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-an ιomethyl-piperidine-l -carboxylic acid tert butyl ester (2.0g) and 2-chlorobenzothiazole (1.58g) according to the method of D2. Mass Spectrum (API⁴): Found 348 (MH⁴). C₁₈H₂₅N₃O₂S requires 347.

Description 13: (RS)-Benzothiazol-2-yl-piperidin-2-ylmethyl-amine

The compound of D12 (1.2g) was dissolved in methanol (60ml) and treated with 4N HCl 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 solvent removed at reduced pressure to give the title compound (0.70g). Mass Spectrum (API⁴): Found 348 (MH⁴). C₁₃H₁₇N₃S requires 347.

Description 14: 2-(RS)-(Isoquinolin-l-yIaminomethyI)-piperidine-l-carboxyIic acid tert butyl ester The title compound (0.76g) was prepared from (RS) 2-aminomethyl-piperidine-l -carboxylic 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 (MH ). C₂₀H₂₇N₃O₂ requires 341.

Description 15: Isoquinolin-l-yl-piperidin-2-ylmethyI-amine

The title compound (0.39g) was prepared according to the method of description 13 from the compound of D14 (0.75g).

Mass Spectrum (API⁴): Found 242 (MH⁴). C₁₅H₁₉N₃ requires 241.

Description 16: (S) 2-(Quinolin-2-ylaminomethyl)-piperidine-l -carboxylic acid tert butyl ester ^!

The title compound (0.1 lg) was prepared from (S) 2-_uninomethyl-piperidine-l -carboxylic acid tert butyl ester (1.23g) and 2-chloro.quinoline (lg) according to the procedure of D8. Mass Spectrum (API⁴): Found 342 (MH⁴). C₂₀H₂₇N₃O₂ requires 341.

Description 17: (S)-Piperidm-2-ylmethyl-quinoIin-2-yl-amine

The compound of D16 (0.1 lg) was dissolved in 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 (API⁴): Found 242 (MH¹). ₅H₁₉N₃ requires 241.

Description 18: (RS) 2-(Quinoxalin-2-yIaminomethyl)-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). C₁₉H₂₆N₄O₂ requires 342

Description 19: (RS)-Piperidin-2-ylmethyI-quinoxalin-2-yI-amine

The title compound (0.36g) was prepared from the compound of D18 (0.71g) according to the method of D17.

Mass Spectrum (API⁴): Found 243 (MH⁴). C₁₄Hι₈N₄ requires 242.

Description 20: (RS) 2-(Pyrimidin-2-ylaminomethyl)-piperidine-l-carboxylic acid tert butyl ester

A mixture of (RS) 2-aminomethyl-piperidine-l -carboxylic acid tert butyl ester (1.28g) and 2-cMoropyrimidine 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). Cι₅H₂₄N₄O₂ requires 292. Description 21: (RS)-Piperidin-2-ylmethyl-pyrimidin-2-yl-amine

The title compound (0.350g) was prepared from the compound of D20 (0.4g) according to the method of D17.

Mass Spectrum (API⁴): Found 193 (MH⁴). C₁₀H₁₆N₄ requires 192.

Description 22: (RS) 2-(Pyrazin-2-yIaminomethyl)-piperidine-l-carboxylic acid tert butyl ester

The title compound (0.18g) was prepared from (RS) 2-aminomethyl-piperidine-l -carboxylic acid tert butyl ester (0.54g) and 2-chloropyrazine according to the method of D20. Mass Spectrum (API⁴): Found 293 (MH⁴). Cι₅H₂₄N₄O₂ requires 292.

Description 23: (RSJ-Piperidin^-ylmethyl-pyrazin^-yl-amine

The title compound (0.18g) was prepared from the compound of D22 (0.08g) according to the method of D 17. Mass Spectrum (API⁴): Found 193 (MH⁴). C₁₀Hi₆N₄ requires 192.

Description 24: (S)-2-(Quinazolin-4-ylaminomethyl)-piperidine-l-carboxylic acid tert butyl ester

(S)-2-Aminomethyl-piperidine-l -carboxylic acid tert-butyl ester (l.Og), 4-chloroquinoxaline (0.768g) and diisopropylethylamine (0.816ml) were dissolved in teti_ ydrofuran (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).

1HNMR δ: 1.40 (3H, s), 2.90 (IH, dt), 3.35-3.50 (IH, br.), 3.9-4.05 (IH, br , 4.15-4.3 (IH, br.), 4.68-4.82 (IH, br.), 6.9-7.2 (IH, br.), 7.40 (IH, t), 7.65-7.85 (3H, m), 8.65(1H, s).

Description 25: (S)-2-(Quinazolin-4-ylaminomethyl)-piperidine (S)-2-(Quinazolin-4-ylaminomethyl)-piperidine-l-carboxylic acid tert butyl ester (1.2g) 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), MH⁴243.

Description 26: (S)-2-[(6,7-Difluoro-3-methylquinoxalin-2-ylamino)methyl]- piperidine-1 -carboxylic acid tert buty ester

(S)-2-Aminomethyl-piperidine-l -carboxylic acid tert-butyl ester (1.14g), and 2-chloro-6,7- difluoro-3-methylquinoxaline Teng et al PCT Int. Appl (2000), WO00/42026A1 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-methyIquinoxahn-2-yIamino)methyI]-piperidine (S)-2-[(6,7-Difluoro-3-methylqumox_din-2-ylamino)methyl]-piperidine- 1 -carboxylic acid tert 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-Difluoroquinoxalin-2-ylaώino)methyl]-piperidme-l- carboxylic acid tert buty ester

(S)-2-Aminomethyl-piperidine-l -carboxylic acid tert-butyl ester (0.607g), and 2-chloro-6,7- difluoroquinoxaline McQuaidet. al. J. Med. Chem. (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-Difluoroquinoxalin-2-ylamino)methyl] -piperidine

(S)-2-[(6,7-Difluoroqumoxalin-2-ylamino)methyl]-piperidine-l-carboxylic 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 (0.286g), MH⁴ 279.

Description 30: (R,S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-pyrrolidme-l- carboxylic acid tert butyl ester

(R,S)-2-Aπ_inomethyl-pyrrolidine-l -carboxylic acid tert-butyl ester (3. Og) and 2-chloro- 6,7-difluoroquinoxaline (3.0g) 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 ether :petroleum ether 1 :1) to give the title compound (3.4g) Mass Spectrum (API⁴): Found 365 (MH⁴). C₁₈H₂₂F₂N₄O₂ requires 364.

Description 31: (TR,S)-2-[(6,7-DifluoroquinoxaIin-2-ylamino)methyl]-pyrrolidine

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 (API⁴): Found 265 (MH⁴). Cι₃H_₄F₂N₄ requires 264. 1H NMR δ: 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), 7.59 lH, dd) and 8.16 (lH, s).

Description 32: (S)-2-(quinazolin-2-ylamino)methyI-piperidine-l -carboxylic acid tert butyl ester The title compound (0.6g) was prepared from (S)-2-aminomethyl-piperidine-l -carboxylic acid tert-butyl ester (0.68g) and 2-chloroquinazoline (0.53g) according to the method of D30. Mass Spectrum (API⁴): Found 343 (MH⁴). Cι₉H₂₆N₄O₂ requires 342.

Description 33: (S)-l-Piperidin-2-yImethyl-quinazoIi_α-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 (API⁴): Found 243 (MH⁴). Cι₄H₁₈N₄ requires 242. 1HNMR δ: 1.18 - 1.65 6H, m), 2.66 (IH, m), 3.08 - 3.23 (2H, m), 3.50 (IH, m), 3.69 (IH, m), 6.16 (lh, br. s), 7.20 (IH, t), 7.54 - 7.69 (3H, m) and 8.91 (IH, s).

Description 34: (S)-2-([l,5]Naphthyridin-2-ylaminomethyl)-piperidine-l-carboxylic acid tert butyl ester

The title compound (0.48g) was prepared from (S)-2-ammomethyl-piperidine-l -carboxylic acid tert-butyl ester (0.59g) and 2-chloro-l,5-naphthyridine Rapoport, etal J. Org. Chem. (1971), 36(3), 450-4 (OAOg) according to the method of D30. Mass Spectrum (API ): Found 343 (MH⁴). d₉H₂₆N₄O₂ requires 342.

Description 35: [1 ,5]Naphthyridin-2-yl-(S)-l-piperidin-2-yImethyI-amine The title compound (0.3 Og) was prepared from the compound of D34 (0.48g) according to the method of D31.

Mass Spectrum (API⁴): Found 243 (MH⁴). Cι₄Hι₈N₄ requires 242. 1HNMRδ: 1.25 - 1.88 (6H, m), 2.68 (IH, m), 2.98 (IH, m), 3.16 (IH, m), 3.37-3.50 (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-(l,8-Naphthyridin-2-ylamino)nιethyl-piperidine-l-carboxylic acid tert butyl ester

The title compound (0.28g) was prepared from (S)-2-aminomethyl-piperidine-l -carboxylic acid tert-butyl ester (0.35g) and 2-chloro-l,8-naphthyridine (0.19g) according to the method of D30.

Mass Spectrum (API⁴): Found 343 (MH⁴). Cι₉H₂₆N₄O₂ requires 342.

Description 37: [l,8]Naphthyridin-2-yl-(S)-l-piperidin-2-ylmethyl-amine The title compound (0.1 lg) was prepared from the compound of D36 (0.28g) according to the method of D31.

Mass Spectrum (API⁴): Found 243 (MH⁴). Cj₄H_₈N₄ requires 242.

Description 38: (RS) 2-(4-AzabenzooxazoI-2-yIaminomethyl)-piperidine-l-carboxyIic 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 (API⁴): Found 333 (MH⁴). C₁₇H₂₄N₄O₃ requires 332.

Description 39: ( S)-Oxazolo[4,5-b]]pyridin-2-yl-pipferidin-2-yhnethyl-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 (MH⁴). C₁₂H₁₆N₄O requires 232.

Description 40: ((S)-l-{l-[2-(3-Methyl-[l^,4]-oxadiazol-5-yl)-phenyl]-methanoyl}- piperidin-2-ylmethyl)-carbamic acid tert butyl ester

A mixture of (S)-l-piperidin-2-ylmethyl-carbamic acid tert butyl ester (2.0g) and 2-(3- methyl-[l ,2,4]oxadiazol-5-yl)-benzoic acid (1.9) in dimethylformaide (10ml cont_iining diisopropylethylamine (2.4ml) was treated with [O-(7-azabenzotriazol-l-yl)-l, 1,3,3- 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 (API⁴): Found 401 (MH⁴). C₂ιH₂₈N₄O₄ requires 400.

Description 41 : l-((S)-2-Aminomethyl-piperidin-l-yl)-l-[2-(3-methyl-[l,2,4]oxadiazol- 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 (MH⁴). C₁₆H₂oN₄O₂ requires 300.

Description 42: Methyl-((S)-l-{l-[2-(3-methyI-[l,2,4]oxadiazol-5'-yl)-phenyl]- methanoyl}-piperidin-2-ylmethyI)-carbamic acid dimethyl-ethyl ester ((S)-l-{l-[2-(3-Me%l-[l,2,4]oxadiazol-5-yl)-ρhenyl]-memanoyl}-ρiperidin-2-ylmethyl)- carbamie acid tert butyl ester (0.4g) in tetrahydrofuran (5ml) was treated with sodium hydride (O.lg). After evolution of hydrogen had ceased iodomethane (0.1ml) was added and the reaction stirred for 16 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 (PJSΫ): Found 415 (MH⁴). C₂₂H₃₀N₄O requires 414. Description 43: l-[(R)-2-Methylaminomethyl-piperidin-l-yl])-l-[2-(3-methyl- [l,2,4]oxadiazol-5-yI)-phenyI]-methanone

The title compound (0.15g) was prepared from the compound of D42 according to the method of Dl 3. Mass Spectrum (API⁴): Found 315 (MH⁴). Ci _Hι₂N₄ requires 314.

Description 44: (S)-2-[(6,7-Difluoro-quinoxaIin-2-yIamino)-methyI]-pyrroIidine-l- carboxylic acid tert butyl ester

The title compound (0.53g) was prepared from (S)-2-aminomethyl-pyrrolidine-l -carboxylic acid tert-butyl ester (0.5g) and 2-chloro-6,7-difluoroqύinoxaline (0.5g) according to the method of D30. Mass Spectrum (API⁴): Found 365 (MH⁴). C₁₈H₂₂F₂N₄O_> requires 364.

Description 45: (S)-2-[(6,7-Difluoroquinoxalin-2-ylamino)methyl]-pyrroIidine The title compound (0.38g) was prepared from the compound of D44 (0.53g) according to the method of D31. Mass Spectrum (API⁴): Found 265 (MH⁴). Cι₃Hι₄F₂N₄ requires 264.

Description 46: (RS)-3-[(6,7-Difluoro-quinoxalin-2-yIamino)-methyl]-morpholine-4- carboxylic acid tert butyl ester

The title compound (0.58g) was prepared from 2-aminomethylmorpholine-4-carboxylic acid tert-butyl ester (0.82g) and 2-chloro-6,7-difluoroquinoxaline (0.76g) according to the method of D30.

Mass Spectrum (API⁴): Found 381 (MH⁴). Cι₈H₂₂F₂N₄O₃ requires 380.

Description 47: (6,7-Difluoro-quinoxalin-2-yl)-morphoIin-3-ylnιethyl-aιnine

The compound of D46 (0.58g) was dissolved in trifluoroacetic 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 (MH⁴). Cι₃H₁₄F₂N₄O requires 280.

Description 48: 2-(Pyrido[2 -^]pyrazin-2-ylaminomethyl)-piperidine-l-carboxylic acid tert-butyl ester and 2-(Pyrido[2,3-A]-pyrazin-3-ylaminonιethyl)-piperidine-l- carboxylic acid tert butyl ester

A mixture of (S)-2-aminome_hyl-piperid_ne-l -carboxylic acid tert butyl ester (l.Og) and a 2:1 mixture of 2-chloro-pyrido[2,3-b]pyrazine and 3-chloro-p rido[2,3-b]pyrazine (0.8g) was combined and warmed 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-b]pyrazin-2- ylaminomethyl)-piperidine-l -carboxylic acid tert butyl ester (0.48g). mass spectrum (API⁴); Found 344 (MH⁴). Cι₇H₂₅N₅O2 requires 343 and 2-(pyrido[2,3-b]pyrazin-3- ylaminomethyl)-piperidine-l -carboxylic acid tert butyl ester (0.3g) mass spectrum (API⁴): Found 344 (MH⁴). C₁₇H₂₅N₅O2 requires 343.

Description 49: Piperidin-2-ylmethyl-pyrido [2,3-6] pyrazin-2-yl-amine trifluoroacetate salt

2-(Pyrido[2,3-b]pyrazin-2-yl__mmomethyl)-piperidine-l -carboxylic acid 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-evaporatέd with toluene to give the title compound (0.45g).

Mass spectrum (API⁴): Found 244 (MH⁴). Cι₃Hι₇N₅ requires 243.

Description 50: Piperidin-2-yImethyI-pyrido[2,3-6]pyrazin-3-yl-amine trifluoroacetate salt

The title compound (0.3g) was prepared from 2-(pyrido[2,3-b]pyr_ιzin-3-yl_ιminomethyl)- piperidine-1 -carboxylic acid tert butyl ester (0.3g) according to the method of description 49

Mass spectrum (API⁴): Found 244 (MH⁴). C₁₃H₁₇N₅ 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 15 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 (API⁴): Found 274 (MH⁴). Cι₂H₂₃N₃O₂S requires 273.

Description 52: 2-[(4-Phenyl-thiazol-2-ylamino)-methyl]-piperidine-l-carboxyIic 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 (API⁴): Found 274 (MH⁴). C₂₀H₂₇N₃O₂S requires 273.

Description 53: (4-Phenyl-thiazol-2-yl)-piperidin-2-ylmethyl-amine The title compound (1.55g) was prepared from the compound of D52 (2.42g) according to the method of D47.

Mass spectrum (API⁴): Found 174 (MH⁴). C₁₅Hι₉N₃O₂S requires 173.

Description 54: 2-[(5-Cyano-pyridin-2-ylamino)-methyl]-piperidine-l-carboxyIic acid tert butyl ester.

The title compound (1.54g) was prepared from (S)-2-aminomethyl-piperidine-l -carboxylic acid tert-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 (API⁴): Found 317 (MH⁴). C₁₇H₂₄N₄O₂ requires 316.

Description 55: 6-[(Piperidin-2-yImethyl)-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 (API⁴): Found 217 (MH⁴). Cι₂Hι₆N₄ requires 216.

Description 56: 2-[(4-Trifluoromethyl-pyrimidin-2-yIam__αo)-methyl]-piperidine-l- carboxyϊic acid tert butyl ester

The title compound (0.298g) was prepared from (S)-2-_ιminomethyl-piperidine-l -carboxylic acid tert-butyl ester (1.0g) and 2-cMoro-4-trifluoropvrimidine (0.85g) according to the method of D28. Mass spectrum (API⁴): Found 361 (MH⁴). Cι₆H₂₃F₃N₄O₂ requires 360.

Description 57: Piperidin-2-y_methyl-(4-tri_fluoromethyl-pyrimidin-2-yl)-amine. The title compound (0.25g) was prepared from the compound of D56 (0.29g) and trifluoroacetic acid according to the method of D29. Mass spectrum (API⁴): Found 261 (MH⁴). C_πH₁₅F₃N₄ requires 260.

Description 58: ((S)-l-{l-[4-(4-Fluoro-phenyl)-l-methyI-l_fiT-pyrazoI-3-yl]-methanoyl}- piperidin-2-ylmethyl)-carbamic acid tert butyl ester

The title compound (3.96g) was prepared from (S)-l-piperidin-2-ylmethyl-carbamic acid tert butyl ester (2.14g) and 4-(4-fluoro-phenyl)-l-methyl-lH-pyrazol-3-yl carboxylic acid

(2.20g) according to the method of D40.

Mass spectrum (API⁴): Found 417 (MΗ⁴). C₂₂Η₂₉FN₄O₃ requires 416.

Description 59: ((S)-l-{l-[4-(4-Fluoro-phenyl)-l-methyl-lH-pyrazol-3-yl]-methanoyl}- piperidin-2-ylmethyl)-methyl-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 (API⁴): Found 431 (MH⁴). C₂₃H₃ιFN₄O₃ requires 430

Description 60: l-[4-(4-Fluoro-phenyl)-l-methyl-l_fiT-pyrazol-3-yl]-l-((S)-2- methylaminomethyl-piperidin-l-yl)-methanone The title compound (0.15g) was prepared for the compound of D59 (0.50g) according to the method of D29.

Description 61 : (S)-2-[(3-Cyano-pyridin-2-ylamino)-methyl]-piperidine-l-carboxylic acid tert butyl ester

The title compound (0.66g) was prepared from (S)-2-aminomethyl-piperidine-l -carboxylic acid tert-butyl ester (1.55g) and 2-chloro-3-cyanopyridine (l.Og) according to the method of

D28.

Mass spectrum (APJ⁴): Found 317 (MH⁴). C₁₇H₂ N₄O₂ requires 316

Description 62: 2-[((S)-l-Piperidin-2-ylmethyl)-amino]-nicotinonitriIe

The title compound (0.53g) was prepared from the compound of D61 (0.663g) and trifluoroacetic acid according to the method of D29.

Mass spectrum (API⁴): Found 217 (MH⁴). Cι₂H₁₆N₄ requires 216

Description 63: (S)-2-[(4-Cyano-pyridm-2-yIamino)-methyI]-piperidine-l-carboxylic acid tert butyl ester

The title compound (0.24g) was prepared from (S)-2-aminomethyl-piperidine-l -carboxylic acid tert-butyl ester (1.14g) and 2-chloro-4-cyanopyridine (0.74g) according to the method ofD28.

Mass spectrum (API⁴): Found 317 (MH⁴). C₁₇H₂₄N O₂ requires 316

Description 64: 4-Cyano-2-[((S)-l-Piperidin-2-ylmethyl)-amino]-pyridine

The title compound (0.17g) was prepared from the compound of D63 (0.243g) and trifluoroacetic acid according to the method of D29.

Mass spectrum (API⁴): Found 217 (MH⁴). Cι₂Hι₆N₄ requires 216

Description 65: (S)2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidine-l-carboxyIic acid tert butyl carbonate. (S)-2-Aminomethyl-piperidine- 1 -carboxylic acid tert butyl ester ( 1 g), 5-bromo-2- cWoropyrimidine (0.9g) were combined in xylene (20ml) containing potassium carbonate (1.29g) and dnsopropyle ylamine (2.43g) and warmed to reflux for 48h. 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 (MH'-tert BOC). Cι₀H₁₄N₄Br requires 371

Description 66: (S) (5-Bromo-pyrimidin-2-yl)-piperidin-2-ylmethyl-amiιιe 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). C₁₀H_] N.Br requires 271. Description 67: (S) 2-[(3-Cyano-6,7-difluoro-quinoIin-2-yIamino)-methyI]-piperidine- 1-carboxylic acid tert butyl ester.

(S)-2-Aιr_ omethyl-piperidine-l -carboxylic acid tert-butyl ester (l.lg) and 2-chloro-3- cyano-5,6-difluoroquinoline (1.12g) according to the method of D28 were combined in xylene (15ml) 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 fractions the title compound (1.8g). Mass spectrum (API⁴): Found 403 (MH⁴). C₂ιH₂₄F₂N₄O₂ requires 402

Description 68: (S) 6,7-Difluoro-2-[(piperidin-2-yImethyl)-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 (MH⁴). Cι₆H₁₆F₂N₄ requires 302

Description 69: (S)2-[(5-Bromo-pyrimidin-2-yIamino)-methyl]-pyrrolidin-l -carboxylic acid tert butyl carbonate. (S)-2-Aminomethyl-pyrrolidine- 1 -carboxylic acid tert butyl ester (2g), 5-bromo-2- c oropyrimidine (1.93g) were combined in xylene (40ml) containing potassium carbonate (2.76g) and diisopropylemylcimine (5.23ml) and warmed 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 fractions were collected, solvent removed at reduced pressure to give the title compound (1.78g) as a colourless gum Mass spectrum (API⁴): Found 257 (MH -tert BOC). C₁₄H₂ιBrN₄O₂ requires 357

Description 70: (S) (5-Bromo-pyrimidin-2-yl)-pyrrolidin-2-ylmethyl-amine The title compound (1.40g) was prepared from the compound of D69 (1.78 g) according to the method of D9. Mass spectrum (API⁴): Found 258 (MH⁴). C₉H_J2N₄Br requires 257.

Description 71 : 3-(l-{(S)-2-[(6,7-Difluoro-quinoxalin-2-ylamino)-methyl]-piperidin-l- yl}-methanoyl)-benzoic acid

3-(l-{(S)-2-[(6,7-Difluoro-quinox_din-2-ylam_no)-methyl]-piperidin-l-yl}-methanoyl)- benzoic acid methy ester (0.5g) was dissolved in methanol (15ml) 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 24h. 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 (MgSO₄), fioltered and solvent removed at reduced pressure to give the title compound (0.463g) as a yellow solid. Mass spectrum (API⁴): Found 427 (MH⁴). C₂₂H₂₀F₂N₄O₃ 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) and pyridine (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. 1H NMR δ: 7.10 (IH, d, J = 8 Hz), 8.00 (IH, dd, 2.4 and 8 Hz), 8.46 (lH, d, J = 2.4 Hz).

Description 73: (S)-2-[(5-Bromopyridin-2-yIamino)-methyI]-pyrrolidine-l-carboxyIic acid tert-butyl ester >

The title product (0.22g) was obtained from (S)-2-aminomethyl-pyrrolidine-l -carboxylic acid tert butyl ester (lg) and the compound of D72 (1.7g) according to the method of D69. Mass Spectrum (Electrospray LC/MS), API⁴: Found 356 (MH⁴). Cι₅H₂₂ ⁷⁹BrN₃O₂ requires 355.

Description 74: (5-Bromo-pyridin-2-yl)-(S)-l-pyrrolidin-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. ^!H NMR δ: 1.44 - 1.48 (IH, m), 1.71 - 1.81 (3H, m), 2.05 (IH, br s), 2.93 (2H, m), 3.09 - 3.13 (IH, m), 3.35 - 3.41 (2H, m), 4.99 (IH, br s), 6.32 (IH, d, J = 9 Hz), 7.43 (IH, dd, J = 3 and 9 Hz), 8.08 (IH, d, J = 3 Hz).

Description 75 : N-(4-Benzyl-morpholin-3-yhnethyI)-2^_',2-trifluoroacetamide

To (4-benzyl-morρholin-3-yl)-me1hylamine (7.34g) in dichloromethane (240ml) was added triemylarnine (5.83ml), followed by dropwise addition of trifluoroacetic anhydride (8.23g) over 25 min at 0°C under argon. The reaction mixture was allowed to reach ambient temperature and after stirring for 18h, 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 acetate- pentane mixtures to afford the title product (5.17g) as an orange gum. Mass Spectrum (API⁴): Found 303 (MH⁴). C₁₄Hι₇F₃N₂O₂ requires 302.

Description 76: 2,2,2-Tri__luoro-7V-morphoIin-3-ylmethyl acetamide

To the compound from D75 (1.62g) in methanol (40ml) was added palladium black (0.45g) and formic acid (10 drops) and the mixture stirred at ambient temperature for 16h. Further palladium black (0.225g) and formic acid (10 drops) were added and after lh, 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 (API⁴): Found 213 (MH⁴). C₇H_nF₃N₂O₂ requires 212.

Description 77: 3-[(2,2,2-Trifluoro-ethanoylamino)-methyl]-morpholine-4-carboxylic acid tert-butyl ester

A mixture of the compound from D76 (1.75g), triethylamine (2.25ml) 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 a pale yellow solid. Mass Spectrum (API⁴): Found 213 (MH-'Boc)⁴. C₁₂H₁₉F₃N₂O₄ requires 312. ι

Description 78: 3-Aminomethyl-morpholine-4-carboxylic acid ferf-butyl 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 (API⁴): Found 116 (MH-'Boc) . C₁₀H₂₀N₂O₃ requires 216.

Description 79: 3-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-morpholine-4-carboxylic acid tert-butyl ester

The title compound (1.19g) was obtained from the compound of D78 (0.97g) and 5-bromo- 2-cMoropyrimidine (0.87g) according to the method of D30. Mass spectrum (API⁴): Found 273 (MH^-'Boc). C₁₄H₂₁ ⁷⁹BrN₄O₃ requires 372.

Description 80: (5-Bromo-pyrimidin-2-yl)-morphoIin-3-yImethyl 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 (API⁴): Found 273 (MH⁴). C₉H₁₃ ⁷⁹BrN₄O requires 272.

Description 81 : (S)-2-[(4-Cyano-2,6-difluoro-phenylamino)-methyl]-piperidine-l- carboxylic acid tert-butyl ester

(S)-2-Aminomethyl-piperidine-l -carboxylic acid tert-butyl ester (l-36g) and 3,4,5- trifluorobenzonitrile (1.00g) were heated under argon in xylene (10 ml) containing diisopropylethylamine (3.3 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 (API⁴): Found 252 (MHVBOC). C₁₈H₂₃F₂N₃O₂ requires 351.

Description 82: 3,5-DifIuoro-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 (API⁴): Found 252 (MH⁴). C₁₃Hι₅F₂N₃ requires 251.

Description 83: (S)-2-[(4-Cyano-2,6-difluoro-phenylamino)-methyl]-pyrroHdine-l- carboxylic acid tert-butyl ester

The title compound (0.295g) was obtained from (S)-2-aminomethyl-pyrrolidine-l- carboxylic acid tert-butyl ester (0.402g) and 3,4,5-trifluorobenzonitrile (0.314g) using a similar procedure to that described in Description 81. Mass Spectrum (API⁴): Found 238 (MOr -'Boc) C₁₇H₂ιF₂N₃O₂ requires 337.

Description 84: 3,5-Difluoro-4-[((S)-l-pyrroIidin-2-ylmethyI)-amino]-benzonitriIe The title compound (0.19g) was obtained from the compound of D83 (0.28g) using a similar procedure to that described in Description 82.

Description 85: (S)-2-[(5-Ethyl-pyrimidin-2-ylamino)-methyI]-pyrrolidine-l-carboxyIic 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 (MH⁴). Cι₆H₂₆N₄O₂ requires 306.

Description 86: (5-Ethyl-pyrimidin-2-yl)-(S)-l-pyrro_idin-2-ylmethylamine

The title compound (0.07g) was obtained from the compound of D85 (0.10g) using the method of D9. Mass Spectrum (Electrospray LC/MS): Found 207 (MH⁴). C_nH₁₈N₄ requires 206.

Description 87: (S)-2-[(2^^-Trifluoro-ethanoylamino)-methyl]-pyrrolidine-l- carboxylic acid tert-butyl ester

To a solution of (S)-2-aminomethyl pyrrolidine-1 -carboxylic acid tert-butyl ester (1.3g) in dichloromethane (50 ml) containing triethylamine (1.4 ml) was added trifluoroacetic anhydride (1.6g) dropwise under argon. After 16h 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-ethyl acetate mixtures afforded the title compound (1.43g) as an orange oil. 1H NMR δ: 1.30 - 1.50 (IH, m), 1.47 (9H, s), 1.60 - 1.75 (IH, m), 1.80 - 1.95 (2H, m), 2.00 - 2.10 (IH, m), 3.22 - 3.30 (IH, m), 3.30 - 3.55 (3H, m), 9.03 (IH, br s).

Description 88: (S)-2-{[Methyl-(2,2,2-trifluoro-ethanoyl)-amino]-methyl}-pyrrolidine- 1-carboxylic 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 lh, iodomethane (0.32 ml) was added and the reaction mixture stirred for a further 16h 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 (API⁴): Found 311 (MH⁴): Ci₃H₂ιF₃N₂O₃ requires 310. i

Description 89: (S)-2-MethyIaminomethyl-pyrrolidine-l -carboxylic acid tert-butyl 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 chloroform and water. The aqueous layer was extracted with chloroform 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-yl)-methyl-amino]-methyl}-pyrroIidine- 1-carboxylic acid tert-butyl 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 (API⁴): Found 371 (MH⁴). C₁₅H₂₃ ⁷⁹BrN₄O₂ requires 370.

Description 91 : (5-Bromo-pyrimidin-2-yl)-methyl-(S)-l-pyrroIidin-2-yl)methylamine

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 title product as an orange oil (0.54g). Mass Spectrum (API⁴): Found 271 (MH⁴). C₁₀H₁₅ ⁷⁹BrN₄ requires 270.

Description 92: (S)-2-[(5-Acetyl-pyrimidin-2-ylamino)-methyI]-pyrrolidine-l- carboxylic acid ter/-butyl ester

The title compound (0.57g) was prepared from the compound of D69 (1.06g) (1- emoxyvinyl)tributyl tin (1.2 ml) and tetrakis (txiphenylphosphine)palladium (0) (0.172g) according to the method of Example 171. Mass Spectrum (API⁴): Found 321 (MH⁴). Cι₆H₂₄N₄O₃ requires 320.

Description 93: l-{2-[((S)-l-Pyrrolidin-2-ylmethyl)-amino]-pyrimidin-5-yI}-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 (MH⁴). C_nH₁₆N₄O requires 220.

Description 94 : (S)-2-[(5-ChIoro-py rhnidin-2-ylamino)-methyl] -pyrrolidine-1 - carboxylic acid tert-butyl ester

(S)-2-Aminomethyl pyrrolidine-1 -carboxylic acid tert-butyl ester (3.38g), 2,5- dictøoropyrimidine (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 (API⁴): Found 213 Cι₄H₂₁ ^3sCΪN₄O₂ requires 312.

Description 95: (5-ChIoro-pyrimidin-2-yl)-(S)-l-pyrrolidin-2-ylmethyIamine 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 (MH⁴). C₉H₁₃ ³⁵C1N₄ requires 212.

Description 96: (S)-2-[(5-Cyano-pyridin-2-ylamino)-methyI]-pyrrolidine-l-carboxyIic acid tert-butyl ester

(S)-2-Aminomethyl pyrrolidine-1 -carboxylic acid tert-butyl ester (0.3g), 6- chloronicotinonitrile (0.21g), 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 (API⁴): Found 303 (MH⁴). Ci₆H₂₂N₄O₂ requires 302. .

Description 97: 6-[((S)-l-Pyrrolidin-2-yImethyl)-amino]-nicotinonitrile

A solution of the compound of D96 (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 (MH⁴). CJIH_I4N requires 202. Description 98: 1,1,1-Trifluoromethanesulfonic acid 6-methyl-2-methylsuIfanyl- pyrimidin-4-yl ester

To a solution of 6-methyl-2-methylsulfanyl-pyrirnidin-4-ol (lg) 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 chromatographed on silica gel, eluting with ethyl acetate-pentane mixtures, to afford the title compound (0.8g). "H NMR δ: 2.53 (3H, s), 2.55 (3H, s), 6.63 (IH, s).

Description 99: 2^^-Trifluoro-iV-(S)-l-pyrroIidin-2-yImethyI-acetamide

The title compound (2.31g) was obtained from the compound of D87 (5.5g) using the method of D97. 1HNMR δ: 1.30 - 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, br s).

Description 100: 2,2,2-Trifluoro-N-((S)-l-{l-[5-(4-fluorophenyl)-2-methyl-thiazol-4- yI]-methanoyI}-pyrrolidin-2-yImethyl)-acetamide The title compound (3.84g) was obtained from the compound of D99 (2.3 lg) and 5-(4- fluorophenyl)-2-methyl-tbiazole-4-carboxylic acid (3.08g) using the method of Example 229. Mass Spectrum (Electrospray LC MS): Found 416 (MH⁴). C₁₈H₁₇F N₃0₂S requires 415.

Description 101: l-((S)-2-AminomethyI-pyrroIidin-l-yl)-l-[5-(4-fluoro-phenyI)-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 that described in D78. Mass Spectrum (Electrospray LC/MS): Found

320 (MH ). C₁₆H₁₈FN₃OS requires 319.

Description 102: 3-[(2^ 2-Trifluoro-ethanoylamino)-methyI]-morphoIine-4-carboxyMc acid tert-butyl ester

The title compound (0.56g) was obtained from the compound of D77 (0.55g) and iodomethane (0.12 ml) using a method similar to that of Description 88. Mass Spectrum (API⁴): Found 227 (MH⁴-^tBoc). C_BH₂ιF₃N₂O₄ requires 326.

Description 103: 3-MethyIaminomethyl-morpholine-4-carboxylic acid tert-butyl ester The title compound (0.29g) was obtained from the compound of D 102 (0.56g) using the method of Description 89.

Description 104: 3-{[(5-Bromo-pyrimidin-2-yI)-methyI-amino]-methyl}-morphoIine-4- carboxylic acid tert-butyl ester

The title compound (0.3g) was obtained from the compound of D103 (0.29g) and 5-bromo- 2-cUoropyrimidine (0.26g) using the method of Description 81. Mass Spectrum (Electrospray LC/MS): Found 287 (MH -^tBoc). C₁₅H₂₃ ⁷⁹BrN₄O₃ requires 386.

Description 105; (5-Bromo-pyrimidin-2-yl)-methyI-morphoIin-3-ylmethyl-amine

The title compound (0.19g) was obtained from the compound of D 104 (0.3g) according to the method of Description 91. Mass Spectrum (API⁴): Found 287 (MH⁴). Cι₀H_]5 ⁷⁹BrN₄O requires 286.

Example 1: l-[2-(BenzoxazoI-2-ylaminomethyl)-piperidin-l-yl]-l-(2-methyl-5-phenyI- thiazol-4-yl)-methanone

The amine of D3 (0.1 lg), trie ylamine (0.05g) and 2-methyl-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 (API⁴): Found 433 (MH⁴). C₂ H₂₄N₄O₂S 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.

Example 32: l-[(S)-2-0Benzoxazol-2-ylaminomethyl)-piperidin-l-yl]-l-[5-(4-fluoro- phenyl)-2-methyl-thiazol-4-yl]-methanone

A mixture of amine D5 (0.05g), 2-methyl-5-phenyl-thiazole-4-carboxylic acid (0.026g) and diisopropylemylamine (0.06ml) in dimethylformamide (5ml) was treated with [O-(7- azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium 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 (0.05g). Mass Spectrum (API⁴): Found 451 (MH⁴). C₂₄H₂₃FN₄O₂S requires 450.

The compounds of the Examples below were prepared from the appropriate .unine and acid using similar procedures to that described in Example 32.

Example 93: l-{2-[(6,7-Difluoro-quinoxaIin-2-ylamino)-methylI-pyrroHdm-l-yI}-l-[4- (4-fluoro-phenyl)-2-H-pyrazol-3-yl]-methanone

The .unine of D31 (0.085g) in dimethylformamide (3ml) was treated with 4-(4-fluoro- phenyl)-2H-pyrazole-3-carboxylic acid (0.125g), diisopropylethylamine (0.07ml) and [O- (7-azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate] (O.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 (0.1 g). Mass Spectrum (API⁴): Found 453 (MΗ⁴). C₂₃Η₁₉F3 ₆O requires 452.

residue column chromatographed (silica gel, 3% methanol/diethyl ether) to give the title compound (O.lg).

Mass Spectrum (API⁴): Found 453 (MH⁴). C₂₃H₁₉F₃N₆O requires 452.

Example 105: l-[2-(3-Methyl-[l,2,4]oxadiazol-5-yI)-phenyl]-l-[(S)-2-(oxazolo[4,5- b]]pyridin-2-ylaminomethyl)-piperidin-l-yI]-methanone

The compound of D41 (0.51g) and 2-methylsulfanyl-oxazolo[4,5-b]pyridine (0.25g) were combined and heated under argon at 90°C for 18 hours The mixture was column chromatographed (5% methanol, diethyl ether eluant) to give the title compound (0.26g) Mass Spectrum (API⁴): Found 419 (MH⁴). C₂2H₂₂N₆O₃ requires 418.

Example 106: l-[2-(3-Methyl-[l,2,4]oxadiazoϊ-5-yl)-phenyI]-l-{( )-2-[(methyI- oxazolo[4,5-b]pyridin-2-yl-aιnino)-methyl]piperidm-l-yl}-methanone

The title compound (0.015g) was prepared from the compoimd of D43 (0.15g) according to the method of Example 105.

Mass Spectrum (API⁴). Found 433 (MH⁴). C₂₃H N₆θ₃ requires 432.

Example 107: 6-[((S>l-{l-[4-(4-Fluoro-phenyl)-l-methyl-lH-pyrazoI-3-yl]- methanoyI}-piperidin-2-ylmethyl)-methyl-amino]-nicotinonitrile

The title compound (0.078g) was prepared from the compound of D60 (0.45g) and 2- chloro-5-cyanopyridine (0.189g) according to the method of D26 Mass Spectrum (API⁴): Found 433 (MH⁴). C₂₄H2₅FN₆O requires 432.

Example 108: l-((S)-2-{[(6,7-Difluoro-quinoxaIin-2-yl)-methyl-amino]-methyl}- piperidin-l-yl)-l-{4-(4-fluoro-phenyl)-l-methyl-lH-pyrazol-3-yl]-methanone The title compound (0.031g) was prepared from the compound of D60 (0.15g) and 2- chloro-6,7-difluoroquinoxaline (0.091g) according to the method of D26 Mass Spectrum (API⁴): Found 495 (MH⁴). C₂₆H2₅F₃N₆O requires 494. Example 171: l-{2-[((S)-l-{l-[4-(4-Fluoro-phenyl)-l-methyl-lH-pyrazol-3-yl]- methanoyI}-piperidin-2-ylmethyI)-amino]-pyrimidin-5-yl}-ethanone

A mixture of l-{(S)-2-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-piperidin-l-yl}-l-[4-(4- fluoro-phenyl)-l-methyl-lH-pyrazol-3-yl]-methanone (0.5g) and l-ethoxyv_nyl)tributyltin (0.42ml) tetrakis(triphenylphosphine)palladium[0} (0.06g) was boiled in dioxane (8ml) for 16h. 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 (API⁴): Found 437 (MH⁴). C₂₃H₂₅FN₆O₂ requires 436.

»

Example 172: l-[4-(4-FIuoro-phenyl)-l-methyI-lH-pyrazoI-3-yI]-l-((S)-2-{[5-(l- hydroxy-ethyl)-pyrimidin-2-ylamino]-methyl}-piperidin-l-yl)-methanone l-{2-[((S)-l-{l-[4-(4-Fluoro-phenyl)-l-methyl-lH-pyrazol-3-yl]-methanoyl}-piperidin-2- ylmethyl)-amino]-pyrimidin-5-yI}-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 (MgSO₄) and solvent removed at reduced pressure to give the title compound as a colourless foam.

Mass Spectrum (API⁴): Found 439 (MH⁴). C₂₃H₂₇FN₆O2 requires 438.

Example 173: 2-[((S)-l-{l-[4-(4-Fluoro-phenyl)-l-methyI-lH-pyrazol-3-yl]- methanoyl}-piperidin-2-ylmethyl)-amino]-pyrimidine-5-carbonitrile l-{(S)-2-[(5-Bromo-pyrimidin-2-ylammo)-memyl]-piperidin-l-yl}-l-[4-(4-flu^ l-methyl-lH-pyrazol-3-yl]-methanone (0.35g) in N-methylpvrrolidinone (10ml) containing copper(I)cyanide (0.13g) 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 acetate.pentane 1:1 → ethyl acetate eluant), the appropriate fractions combined and solvent removed at reduced pressure to give the title compound (0.019g). Mass Spectrum (API⁴): Found 420 (MΗ⁴). C₂₂Η₂₂FN₇O requires 419.

Example 174: 3-(l-{(S)-2-[(6,7-Difluoro-quinoxaIin-2-ylamino)-methyI]-piperidin-l- yI}-methanoyl)-N--methyl-benzamide

The compound of description 71 (0.10g) was dissolved in dimethylformamide (5ml) containing HATU (0.095g) and diisopropylemylamine (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 - 10% methanol :ethyl acetate to give the title compound (0.018g). Mass Spectrum (API⁴): Found 440 (MH⁴). C₂₃H₂₃F₂N₅O₂ requires 439.

Example 194: l-{(S)-2-[(5-Bromo-pyrimidin-2-yIamino)-methyl]-pyrrolidin-l-yl}-l-[5- (4-fluoro-phenyI)-2-methyl-thiazol-4-yI]-methanone A mixture of the aniine of D70 (0.070g), 5-(4-fluoro-phenyl)-2-methyl-thiazole-4- carboxylic acid (0.065g), l-(3-dimemyl_-mmopropyl)-3-ethylc__rbodiimide hydrochloride (EDC) (0.042g) and 1-hydroxybenzotriazole hydrate (0.037g) in dimethylformamide (2ml) was stirred at ambient temperature for 18h, evaporated in vacuo 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 LC/MS), API⁴: Found 476 (MH⁴). C₂₀H₁₉ ⁷⁹BrFN₅OS requires 475.

Example 195: l-{(S)-[(5-Bromo-pyrimidin-2-ylammo)-methyI]-pyrroIidin-l-yl}-l-[2- (3-methyϊ-[l,2,4]oxadiazol-5-yl)-phenyl]-methanone The title compound (0.053g) was obtained from the amine of D70 (0.070g) and 2-(3-methyl-[l,2,4]oxadiazol-5-yl)-benzoic acid (0.056g) using the method of Example 194. Mass Spectrum (Electrospray LC/MS) : Found 443 (MH⁴). Cι₉H₁₉ ⁷⁹BrN₆O₂ requires 442.

Example 196: l-{(S)-2-[5-Bromo-pyrimidin-2-ylamino)-methyl]-pyrroIidin-l-yl}-l-[5- (4-chloro-phenyl)-2-methyI-thiazol-4-yl]-methanone

The title compound (0.078g) was obtained from the amine of D70 (0.077g) and 5-(4-chloro- phenyl)-2-methyl-thiazole-4-carboxylic acid (0.076g) according to the method of Example 32. Mass spectrum (Electrospray LC/MS), API⁴: Found 492 (MH⁴). C₂oH₁₉ ⁷⁹Br³⁵ClN₅OS requires 491.

Example 197: l-{(S)-2-[(5-Bromo-pyridin-2-ylamino)-methyl]-pyrrolidin-l-yl}-l-[5-(4- fluoro-phenyl)-2-methyl-thiazol-4-yI]-methanone

The title compound (0.135g) was obtained from the amine of D74 (0.1 lg) and 5-(4-fluoro- phenyl)-2-methyl-thiazole-4-carboxylic acid (0.12g) according to the method of Example 32. Mass Spectrum API⁴: Found 475 (MH⁴). C₂ιH o⁷⁹BrFN₄OS requires 474.

Example 198: l-{(S)-2-[(5-Bromo-pyridin-2-yIamino)-methyl]-pyrroIidm-l-yl}-l-[4-(4- fluoro-phenyl)-l-methyl-lij -pyrazol-3-yl]-methanone The title compound (0.1 Og) was obtained from the amine of D74 (0.11 g) and 4-(4-fluoro- phenyl)-l-methyl-lH-pyrazole-3-carboxylic acid (0.12g) according to the method of Example 32. Mass Spectrum API : Found 458 (MΗ⁴). C₂ιΗ₂₁ ⁷⁹BrFN₅O requires 457.

Example 200: l-{3-[(5-Bromo-pyrimidin-2-ylamino)-methyl]-morpholm-4-yl}-l-[4-(4- fluoro-phenyl)-l-methyl-lfl-pyrazol-3-yϊ]-methanone

The title compound (0.393g) was obtained from the compound of D80 (0.3g) and 4-(4- fluorophenyl)-l-methyHH-pyrazole-3-carboxylic acid (0.242g) according to the method of Example 32. Mass Spectrum (API⁴): Found 475 (MΗ⁴). C₂oΗ₂o⁷⁹BrFN₆O₂ requires 474. Example 203: 3,5-Difluoro-4-[((S)-l-{l-[5-(4-fluorophenyl)-2-methyI-thiazoI-4-yl]- 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-carboxylic acid (0.069g) according to the method of Example 32. Mass Spectrum (Electrospray LC/MS): Found 471. C₂₄H₂₁F₃N₄OS requires 470.

Example 208: 3,5-Difluoro-4-[((S)-l-{l-[5-(4-fluoro-phenyl)-2-methyI-thiazol-4-yl]- methanoyl}-pyrrolidin-2-ylmethyl)-amino]-benzonitrile

The title compound (0.09g) was obtained from the compound of D84 and 5-(4-fluoro- phenyl)-2-methyl-thiazole-4-carboxylic acid (0.095g) according to the method of Example 32. Mass Spectrum (Electrospray LC/MS): Found 457 (MH⁴). C ₃H₁₉F₃N₄OS requires 456.

Example 216: l-{(S)-2-[(5-EthyI-pyrimidin-2-yIamino)-methyl]-pyrroUdin-l-yl}-l-[5-

(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone

The title compound (0.05g) was obtained from the compound of D86 (0.07g) and 5-(4- fluoro-phenyl)-2-methyl-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}-pyrroIidin- l-yl)-l-[5-(4-fluoro-phenyl)-2-methyI-thiazol-4-yl]-methanone The title compound (0. lg) was obtained from the compound of D91 (0.275g) and 5-(4- fluoro-phenyl)-2-methyl-tbiazole-4-carboxylic acid (0.285g) according to the method of Example 32. Mass Spectrum (Electrospray LC/MS): Found 490 (MH⁴). C₂₁H₂ι⁷⁹BrFN₅OS requires 489.

Example 218: l-((S)-2-{[(5-Bromo-pyrimidin-2-yl)-methyl-amino]-methyl}-pyrro in- l-yl)-l-[4-(4-fluoro-phenyl)-l-methyl-LH-pyrazol-3-yl]-methanone

The title compound (0.02g) was obtained from the compound of D91 (0.275g) and 4-(4- fluoro-phenyl)-l-methyl-lH-pyrazole-3-carboxylic acid (0.260g) according to-the method of Example 32. Mass Spectrum (Electrospray LC/MS): Found 473 (MΗ⁴). C₂ιΗ2₂ ⁷⁹BrFN₆O requires.472.

Example 225: l-{2-[((S)-l-{l-[5-(4-Chloro-phenyl)-2-methyϊ-thiazol-4-yl]-methanoyl}- pyrrolidin-2-ylmethyl)-amino]-pyrimidin-5-yl}-ethanone

The title product (0.04g) was obtained from the compound of D93 (0.133g) and 5-(4-chloro- phenyl)-2-methyl-thiazole-4-carboxylic acid (0.076g) using a similar procedure to that described in Example 32. Mass Spectrum (Electrospray LC/MS): Found 456 (MH⁴). C₂₂H₂₂ ³⁵ClN₅O₂S requires 455. Example 226: l-{(S)-2-[(5-ChIoro-pyrimidin-2-ylamino)-methyl]-pyrroIidin-l-yl}-l-[5- (4-fluoro-phenyl)-2-methyl-thiazol-4-yI]-methanone

The title product (0.095g) was obtained from the arnine of D95 (0.064g) and 5-(4- fluorophenyl)-2-methyl-thiazole-4-carboxylic acid (0.071 g) using the method of Example 32. Mass Spectrum (Electrospray LC/MS): Found 432 (MH⁴). C₂oH₁₉ ³⁵ClFN₅OS requires 431.

Example 227: l-{(S)-2-[(5-Chloro-pyrimidin-2-yIamino)-methyI]-pyrroIidin-l-yI}-l-[2- (3-methyl- [1 ,2,4] oxadiazol-5-yl)-phenyl]-methanone The title compound (0.052g) was obtained from the .unine of D95 (0.064g) and 2-(3- methyl-[l,2,4]oxadiazol-5-yl)-benzoic acid (0.06 lg) according to the method of Example 32. Mass Spectrum (Electrospray LC/MS): Found 399 (MH⁴). C₁₉Hι₉ ³⁵ClN₆O₂ requires 398.

Example 228: l-[5-(4-Fluoro-phenyl)-2-methyI-thiazol-4-yI]-l-{(S)-2-[(5-methyl- pyrimidin-2-ylamino)-methyI]-pyrroIidin-l-yl}-methanone

To the compound of Example 194 (0.36g) in dimethylformamide was added Uthium chloride (0.096g), tetramethyl tin (0.126 ml) and dichlorobis(triphenylphosphine) palladium (0) (0.035g) and the resulting mixture heated at 100°C under argon for 18h. The reaction was then evaporated, diluted with dichloromethane, filtered and the filtrate washed with water, dried and evaporated. Chromatography of the residue on silica gel, eluting with methanol-dichloromethane mixtures, afforded the title product (0.2g) as a yellow amorphous solid. Mass Spectrum (API⁴): Found 412 (MH⁴). C₂₁H₂₂FN₅OS requires 411.

Example 229: 6-[((S)-l-{l-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yI]-methanoyI}- pyrrolidin-2-ylmethyl)-amino]-nicotinonitrile

A mixture of the amine of D97 (0.134g), 5-(4-fluoro-phenyl)-2-methyl-thiazole-4- carboxyϋc acid (0.172g), EDC (0.139g) and 1-hydroxybenzotriazole (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). C₂₂H2₀FN₅OS requires 421.

Example 234: l-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-l-{(S)-2-[(6-methyI-2- methykulfanyl-pyrimidin-4-ylamino)-methyI]-pyrrolidin-l-yI}-methanone

The title product (0.095 g) was obtained from the amine of D 101 (0.15g) and the compound of D98 (0.14g) using a similar method to that described in D69. Mass Spectrum (Electrospray LC/MS): Found 458 (MH⁴). C2₂H₂ FN₅OS2 requires 457.

Example 235: l-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-l-{(S)-2-[(2- methylsulfanyl-pyrimidin-4-ylamino)-methyl]-pyrrolidin-l-yl}-methanone The title compound (0.05g) 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.

Example 239: l-(3-{[(5-Bromo-pyrimidin-2-yl)-methyI-amino]-methyI}-morpholin-4- yl)-l-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone The title compound (0.056g) was obtained from the compound of D 105 (0.095g) and 5-(4-fluorophenyl)-2- methyl-thiazole-4-carboxylic acid (0.1 Og) according to the method of Example 32. Mass Spectrum (Electrospray LC/MS): Found 506 (MH⁴). C₂ιH₂₁ ⁷⁹BrFN₅O₂S requires 505.

Example 240: l-(3-{[(5-Bromo-pyrimidin-2-yl)-methyI-amino]-methyl}-morpholin-4- yI)-l-[2-(4-fluoro-phenyI)-thiophen-3-yl]-methanone

To the compound of D 105 (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). C₂ιH2o⁷⁹BrFN O₂S requires 490.

Example 249: l-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-l-{(S)-2-[(5- trifluoromethyl-pyrimidin-2-ylamino)-methyl]-pyrrolidin-l-yl}-methanone Example 249: l-[5-(4-Fluoro-phenyl)-2-methyI-thiazoI-4-yI]-l-{(S)-2-[(5- trifluoromethyl-pyrinudin-2-ylannno)-methyl]-pyrrolidin-l-yl}-methanone

To the compound from Example 194 (0.36g) in dimefliylfoimamide (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 20h. 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 sihca gel, eluting with methanol-dichloromethane mixtures, to afford the title product (O.OOlg). Mass Spectrum (Electrospray LC MS): Found 466 (MH⁴). C₂₁Hι₉F₄N₅OS requires 465.

The compounds in the table below were prepared using methods described above

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 ll Glutamine, 0.4 mgmL G418 Sulphate from GIBCO BRL and 10% heat inactivated fetal calf serum from Gibco BRL. The cells were seeded at 20,000 cells/100 μl/well into 96-well black clear bottom sterile plates from Costar which had been pre-coated with 10 μg well of poly-L-lysine from SIGMA. The seeded plates were incubated overnight at 37C in 5% CO₂.

Agonists were prepared as 1 mM stocks in water:DMSO (1:1). EC50 values (the concentration required to produce 50% maximal response) were estimated using 1 lx half log unit dilutions (Biomek 2000, Beckman) in Tyrode's buffer containing probenecid (10 mM HEPES with 145mM NaCl, lOmM glucose, 2.5 mM KCl, 1.5 mM CaCl₂, 1.2 mM MgCb and 2.5mM probenecid; ρH7.4). 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 lx half log unit dilutions in Tyrode's buffer containing 10% DMSO and probenecid.

On the day of assay 50 μl of cell medium containing probenecid (Sigma) and Fluo3 AM Texas Fluorescence Laboratories) was added (Quadra, Tomtec) to each well to give final concentrations of 2.5 mM and 4 μM, 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 μl Tyrode's buffer containing probenecid and 0.1% gelatin (Denley Cell Wash). The volume of buffer left in each well was 125 μl. Antagonist or buffer (25 μl) was added (Quadra) the cell plates gently shaken and incubated at 37C in 5% CO₂ 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 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/EC50]) 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 6.7 - 9.7 at the human cloned orexin-1 receptor.

The orexin-2 receptor antagonist activity of the compounds of formula (I) was determined in accordance with the following experimental method.

Experimental Method

CHO-DG44 cells expressing the human orexin-2 receptor were grown in cell medium (MEM medium with Earl's salts) containing 2 mM I_-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 μl/well into 96-well black clear bottom sterile plates from Costar which had been pre-coated with 10 μg/well of poly-L-lysine from SIGMA. The seeded plates were incubated overnight at 37C in 5% CO₂.

Agonists were prepared as 1 mM stocks in wateπDMSO (1:1). EC50 values (the concentration required to produce 50% maximal response) were estimated using 1 lx half log unit dilutions (Bio ek 2000, Beckman) in Tyrode's buffer containing probenecid (10 mM HEPES with 145mM NaCl, lOmM glucose, 2.5 mM KCl, 1.5 mM CaCl₂, 1.2 mM MgC_₂ 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 lx half log unit dilutions in Tyrode's buffer cont∑iining 10% DMSO and probenecid. On the day of assay 50 μl of cell medium containing probenecid (Sigma) and

Fluo3AM (Texas Fluorescence Laboratories) was added (Quadra, Tomtec) to each well to give final concentrations of 2.5 mM and 4 μM, respectively. The 96-well plates were incubated _»r 60 min at 37C in 5% CO₂. The loading solution containing dye was then aspirated and cells were washed with 4x150 μl Tyrode's buffer containing probenecid and 0.1 % gelatin (Denley Cell Wash). The volume of buffer left in each well was 125 μl.

Antagonist or buffer (25 μl) was added (Quadra) the cell plates gently shaken and incubated at 37C in 5% CO₂ 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 FLIPR) 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/EC50]) 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 <6.3 - 9.1 at the human cloned orexin-2 receptor.

The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent appUcation 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, byway of example and without limitation the following claims:

Claims (9)

1. A compound of formula (J) :

0) wherein:

Y represents a bond, oxygen, or a group (CH₂)_n, 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 (C_1-4)alkyl;

Ar¹ is aryl, or a mono or bicyclic heteroaryl group containing up to 3 heteroatoms selected from N, O and S; any of which maybe 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(C_1-4 )alkoxy, halo, cyano, optionally substituted(C₁_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 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.

A compound of formula (la);

(la) wherein:

Y represents a bond, oxygen, or a group (CH₂)_n, 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(C_1- )alkoxy, halo, cyano, optionally 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 a pharmaceutically acceptable salt thereof.

3. A compoimd according to claim 1 or 2 wherein Y is a bond, oxygen or (CH₂)_n where n is 1 or 2.

4. A compound according to 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 according to any preceding claim wherein Ar¹ represents an optionally substituted is benzoxazolyl, benzimidazolyl, quinoxalinyl, quinazolinyl, pyrimidinyl, pyridinyl, naphthyridinyl, quinolinyl, pyridopyrimidine, thiazolyl, oxazolylpyridinyl, benzothiazolyl, isoquinolinyl or pyrazinyl.

6. A compound according to 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 of formula (I) as defined in any one of Examples 1 to 275, or a pharmaceutically acceptable salt of any one thereof.

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

9. A method of treating or preventing diseases or disorders where an antagonist of a human orexin receptor is required, which comprises a(iministering to a subject in need thereof an effective amount of a compound of formula (I) as defined in any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.