Title of Invention

"1-PHENYL ALKYL AMIDE-2-PHENYL-4-(6-OXO-HEXAHYDRO-PYRROLO[1,2-A]-PYRAZIN-2-YL) COMPOUND OF FORMULA (I) AND PROCESS THEREOF"

Abstract

The present invention relates to piperidinc derivatives of formula (I): R represents halogen or C alkyl; ri represents Cn alkyl; R2 or R3 independently represent hydrogen or C1-4 alkyl; R, represents trifluoromethyl, , alky], ClJ( alkoxy, trifluoromethoxy or halogen; R5 represents hydrogen , C1-4 alky] or 03.7 cycloalkyl; R6 is hydrogen and R7 is a radical of formula (W): R6 is a radical of formula (W) and R7 is hy drogen; X represents CH2, NR3 or O; Y represents Nitrogen and Z is CH or Y represents CH and Z is Nitrogen; A represents C(O) or S(O)q, pro vided that when Y is nitrogen and Z is CH, A is not S(O)q; m is zero or an integer from 1 to 3; n is an integer from 1 to 3; p and q are independently an integer from 1 to 2; and pharmaceutically acceptable salts and solvates thereof. The process for their preparation and their use in the treatment of condition mediated by tachykinins.

Full Text

PIPBRIDINB DERIVATIVES The present invention relates to diazabicycle derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their medical use. In particular, the invention relates to novel compounds which are potent and specific antagonists of tachykinins, including substance P and other neurokinins. Thus, the present invention provides compounds of formula (I) (Figure Remove) (R) R represents halogen or C\j( alkyl; r! represents C\^ alkyl; R2 or R3 independently represent hydrogen or C^ alkyl; > R4 represents trifluorometiiyJ, C\j( alky), Cj_4 alkoxy, trifluoromethoxy or halogen; R5 represents hydrogen, C\^ alkyl or €3.7 cycloalkyl; Rg is hydrogen and &7 is a radical of formula (W): (Figure Remove) (W) or Rg is a radical of formula (W) and R; is hydrogen; X represents CH2, NRs or O; Y represents Nitrogen and Z is CH or Y represents CH and Z is Nitrogen; A represents C(O) or S(O)q, provided that when Y is nitrogen and Z is CH, A is not S(O)q; m is zero or an integer from 1 to 3; n is an integer from 1 to 3; p and q are independently an integer from 1 to 2; and pharmaceutically acceptable salts and solvates thereof. A further embodiment of the invention is (Figure Remove) (1) wherein A represents C(O) or S(O)q; X represents CH2, NRs or O; R represents halogen atom or C 1.4 alkyl; r! represents a Cj^ alkyl group; R2 or Rj independently represent hydrogen or C]_4 alkyl; R4 represents trifluoromethyl, Cj_4 alkyl, Ci_4 alkoxy, trifluoromethoxy or a halogen; R5 represents hydrogen, Cm alkyl or €3.7 cycloalkyl; m is zero or an integer from 1 to 3; n is an integer from 1 to 3; p or q are independently an integer from 1 to 2 and pharmaceutically acceptable salts and solvates thereof. Suitable pharmaceutically acceptable salts of the compounds of general formula (I) include acid addition salts formed with pharmaceutically acceptable organic or inorganic acids, for example hydrochlorides, hydrobromides, sulphates, alkyl- or aiylsulphonates (e.g. methanesulphonates or p-toluenesulphonates), phosphates, acetates, citrates, succinates, tartrates, trifluoroacetates, lactates, fumarates, malates and maleates. The solvates may, for example, be hydrates. References hereinafter to a compound according to the invention include both compounds of formula (I) and their pharmaceutically acceptable acid addition salts together with pharmaceutically acceptable solvates. * Suitable pharmaceutical acceptable salts of the compounds of general formula (I) may be obtained in a crystalline form and/or in an amorphous form or as a mixture thereof. It will be appreciated by those skilled in the art that the compounds of formula (I) contain at least three chiral centres (namely the carbon atom shown as * in the formulae from la to 4h). Thus, when Rg is hydrogen, Ry is a radical of formula (W), Z is nitrogen and Y is carbon, the chiral centres may be represented by the formulae (la, Ib, Ic, Id, le, If, Ig and Ih) (Figure Remove) When Ry is hydrogen, Rg is a radical of formula (W), Z is CH and Y is nitrogen, the chiral centres may be represented by the formulae (2a, 2b, 2c, 2d, 2e, 2f, 2g and 2h) (Figure Remove) When R^ is hydrogen, Ry is a radical of fonnula (W), Z is CH and Y is nitrogen, the chiral centres may be represented by the formulae (3a, 3b, 3c, 3d, 3e, 3f, 3g and 3h) When rv is hydrogen, R$ is a radical of formula (W), Z is nitrogen and Y is carbon, the chiral centres may be represented by the formulae (4a, 4b, 4c, 4d, 4e, 4f, 4g and 4h) The wedge shaped bond indicates that the bond is above the plane of the paper and it is referred to as p configuration. The broken bond indicates that the bond is below the plane of the paper and is in the a configuration. In the specific compounds named below when Y is CH and Z is Nitrogen, the 0 configuration at the 2 position of the piperidine ring corresponds to the R configuration and the p configuration at 4 position of the piperidine ring corresponds to the S configuration. The a configuration at the 2 position of the piperidine ring corresponds to die S configuration and the a configuration at 4 position of the piperidine ring corresponds to the R configuration. In the specific compounds named below when Y is Nitrogen and Z is CH , the p configuration at the 2 position of the piperidine ring corresponds to the S configuration and the p configuration at 4 position of the piperidine ring corresponds to the S configuration. The a configuration at the 2 position of the piperidine ring corresponds to the R configuration and the a configuration at 4 position of the piperidine ring corresponds to the R configuration. The assignment of the R or S configuration at the 2 and the 4 positions has been made according to the rules of Cahn, Ingold and Prelog, Experientia 1956,12, 81. x The configuration of the chiral carbons atom of the piperidine ring shown in formulae from Ic to If, from 2o to 2f, from 3c to 3f and from 4c a 4f Is hereinafter referred to as anti configuration and in formulae la, Ib, Ig, In, 2a, 2b, 2g, 2h, 3a, 3b, 3g, 3h, 4a, 4b, 4g and 4h as the syn configuration. Further asymmetric carbon atoms are possible in the compounds of formula (I). Thus, when R2 and R3 are not the same group, the compounds of formula (I) possess at least four asymmetric carbon atoms. It is to be understood that all stereoisomeric forms, including all enantiomers, diastereoisomers and all mixtures thereof, including racemates, are encompassed within the scope of the present invention and the reference to compounds of formula (I) includes all stereoisomeric forms unless otherwise stated. 4 Compounds (I) may be obtained as a crystalline form . Thus for example Compounds of formula(I) may be obtained as an anhydrous crystalline form or as a dihydrate crystalline form or a mixture thereof. It is to be understood that these crystalline forms or a mixture thereof are encompassed within the scope of the invention. Furthermore, some of the crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention. The present invention also includes isotopically-labelled compound. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as 3H, "C, 14C, "F,IMIandlMI. Compounds of the present invention and phannaceuticaUy acceptable salts of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the present invention. Isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H, UC are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon- 14, i.e., UC, isotopes are particularly preferred for then* ease of preparation and detectability. "C and UF isotopes are particularly useful in PET (positron emission tomography) and 125I are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Furthermore, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of formula (I) of this invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below by substituting a readily available isotopicalry lalfelled reagent for a non-isotopically labelled reagent The term C \_4 alkyl as used herein as a group or a part of the group refers to a straight or branched alkyl group containing from 1 to 4 carbon atoms; examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert butyl. The term C^ alkoxy group may be a straight chain or a branched chain alkoxy group, for example methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy or methylprop-2-oxy. The term halogen refers to a fluorine, chlorine, bromine or iodine atom. The term €3.7 cycloalkyt group means a non aromatic monocyclic hydrocarbon ring of 3 to 7 carbon atoms such as, for example, cyclopropyl, cyciobutyl, cyclopentyl, cyclohexyl or cycloheptyl. A group of preferred compounds of the invention is that in which Rg is hydrogen, Ry is a radical of formula (W) and Y is CH and Z is nitrogen or wherein Rg is a radical of formula (W), R-7 is a hydrogen and Y is nitrogen and Z is CH . These compounds are represented by the formulae (1) and (2) respectively, wherein R, Rj, R2, rs, R4, A, X, m, n, and p have the meanings defined for compounds of formula (I). (Figure Remove) A preferred class of compounds of formula(I) is that wherein A is C(O). Another preferred class of compounds of formula(I) is that wherein X is CH2, A further preferred class of compounds of fonnulafl) is that wherein p is 1. When Y is CH and Z is Nitrogen, a preferred group of compounds of formula (I) is that in which the carbon atom at the 2-position of the piperidine ring is in the p configuration. When Y is CH and Z is Nitrogen, a further preferred group of compounds of formula (I) is that in which the carbon atom at the 2-position of the piperidine ring and the carbon atom bearing the group (W) are in the P configuration. A further preferred group of compounds of formula (I) is that hi which the carbon atom at the 2-position of the piperidine ring and the carbon atom bearing the group (W) are in the syn configuration. When R represents halogen, this is suitably chlorine or more preferably fluorine or when R is Cj_4 alkyl, this is suitably methyl or ethyl. R is preferably a halogen (e.g. fluorine) and/or a C]_4 alkyl (e.g. methyl) group and m is preferably zero or an integer from 1 to 2. r! is preferably a methyl group. R2 is preferably a hydrogen atom or a methyl group. R3 is preferably a hydrogen atom or a methyl group. R4 is preferably a trifluoromethyl group or halogen (e.g. chlorine). A preferred class of compounds of formula (I) is that wherein eacn K is independently a halogen (e.g. fluorine) or a Cj_4 alkyl (e.g. methyl) group, wherein m is 0, 1 or 2. More preferably, m is 1 or 2. Within this class, those wherein R is at the 2 and/or 4 position in the phenyi ring are particularly preferred. Compounds of formula (I), wherein each R4 is independently trifluoromethyl group or halogen (e.g. chlorine), n is 2, represent a preferred class of compounds and within this class the groups 64 are preferably at the 3 and 5 position in the phenyi ring. A group of preferred compounds of formula (I) is that wherein Rg is hydrogen, Ry is a radical of formula (W) and Y is CH and Z is nitrogen or wherein Rg is a radical of formula (W), Ry is a hydrogen and Y is nitrogen and Z is CH and A is C(0). A group of further preferred compounds of formula(I) is that in which Rg is hydrogen, Ry is a radical of formula (W) and Y is CH and Z is nitrogen or wherein Rg is a radical of formula (W), Ry is a hydrogen and Y is nitrogen and Z is CH; A is C(O) and X is CH2- A group of further particularly preferred compounds of formula (I) is that in which Rg is hydrogen, Ry is a radical of formula (W) and Y is CH and Z is nitrogen or wherein Rg is a radical of formula (W), Ry is a hydrogen and Y is nitrogen and Z is CH; ^ AisC(O); XisCH2; R is independently a halogen (e.g. fluorine) or a C 1.4 alkyl (e.g. methyl) group; R4 is a trifluoromethyl group; mis lor 2; nis2; pisl. Preferred compounds according to the invention are: 2-(R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-(6-oxo-hex8hydro-pyrrolo[ 1,2-a]-pyrazin-2-yl)- piperidine-1 -carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-memyIamide; 2^H4-Fluoro-2-methyl-phenylH^SH^x«>-hexahydro-pyrrolo[lr2-a]-pyrazin-2-yl)- piperidme-l-carboxylicacid[l-(R)-(3,5-bis-trifluoromethyl-phenyl)-€thyl]-methylainide; 1^4-Fluoro-2-methyl-phenylM^6H3xo-hexahydro-pyrrolo[l,2-a]pyrazin-2-yl)-piperidine-2- carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide; and enantiomers, diastereoisomers pharmaceutically acceptable salts (e.g. hydrochloride, methanesulphonate or maleate) and solvates thereof. Particular preferred compounds of the invention are: 2KRH4-FIuoro-2-memyl-phenylH^SK(*^)^^x^e3^y^^Pyn'ol0[l^-fl]-pyrazin-2- yl)^iperidme-l-carbo]Qrlicacid[l^X3>S-bis-trifluoromethyl-phenyl>ethyl]-inethylamide; 2-(R)-(4-Fluoro-2-memyl-phenyl)-4-(SH(8aR)-6^^ yl)-piperidine-1 -carboxylic acid [ 1 -(RX3»5-bis-*rifluoromeAyl-phenyI)-ethyl]-methylamide; and amorphous and crystalline forms thereof and pharmaceutically acceptable salts (e.g. hydrochloride or maleate ) and solvates thereof. Tachykinins are a family of peptides that share a common carboxyl-terminal sequence (Phe-X-Gly-Leu-Met-NH2). They are actively involved in the physiology of both lower and advanced lifeforms. In mammalian lifefonns, the main tachykinins are substance P (SP), Neurokinin A (NKA) and Neurokinin B (NKB) which act as neurotransmitters and neuromodulators. Mammalian tachykinins may contribute to the pathophysiology of a number of human diseases. Three types of tachykinins receptors have been identified, namely NKl(SP-preferring), NK2 (NKA-preferring) and NK3 (NKB-preferring) which are widely distributed throughout the central nervous (CNS) and peripheral nervous system. Particularly, the compounds of the invention are antagonists of the NK1 receptor. By virtue of their efficacy as tachykinins receptor (expecially NK1 receptor) antagonists, the compounds of the present invention are particularly useful for the treatment of QMS disorders and psychotic disorders, in particular in the treatment or prevention of depressive states and /or in the treatment of anxiety. NKj-receptor binding affinity has been determined in vitro by measuring the compounds' ability to displace [3HJ - substance f (SP) from recombmant human NKj receptor expressed in Chinese Hamster Ovary (CHO) cell membranes and from gerbil and marmoset brain cortex homogenates. Membrane preparation from hNKl-CHO cells were performed essentially as described by Beattie et al. (Br. J. Pharmacol, 116:3149-3157,1995). hNKl-CHO cells were harvested in phosphate buffered saline (PBS) containing SmM EDTA and centrifuged at 913g for 8 min at 4°C. Cells were men re-suspended in 10 volumes of membrane-preparation buffer (HEPES SOmM, pH 7.4, containing O.lmM leupeptin, 40ug/ml bacftracin, ImM EDTA, IraM Pefabloc and 2uM pepstatin A) and homogenised. The suspension was centrifuged at 48,000g for 20 minutes at 4°C. The final pellet was re-suspended in 10 volumes of membrane preparation buffer and re-homogenised. Suspensions of membrane were then frozen at -80°C until required. The assay volume of 200 ul consisted of 2ul of DMSO or increasing concentrations of test compound dissolved in DMSO (IpM-luM final concentration), lOOul of [3HJ-SP (O.SnM final concentration), and lOOul of membrane suspension (8 ug of protein per well) in incubation buffer (containing SOmM HEPES, pH 7.4, 3mM MnC12, and 0.02% BSA). The incubation was carried out at room temperature for 40min. Non-specific binding was defined by the addition of cold SP (luM). The reaction was stopped by rapid filtration. Filters were washed 5 times with 200ul of ice-cold 0.9% w/v NaCl, and radioactivity was counted in a microplate scintillation counter. In each experiment, every concentration of displacer was tested in duplicate. Mongolian gerbil (60g, Charles River) and common marmoset (Callithrix jacchus, 300-400g, GSK colony, Verona, Italy) brain cortex homogenates were prepared as follows: fresh tissues were weighed, crumbled and homogenised in 10 volumes of membrane-preparation buffer. The homogenate was then centrifuged at 48,000g for 20 minutes, and the pellet was washed once more by ^suspension in 10 volumes of membrane preparation buffer and centrifugation at 48,000g for 20 minutes. The final pellet was re-suspended in 7-10 volumes of membrane preparation buffer and subdivided in aliquots frozen at -80°C until use. The assay volume of 400 ul consisted of lOOul of incubation buffer (containing 50mM HEPES, pH 7.4, 3mM MnC12, and 0.02% BSA), 4ul of DMSO or increasing concentrations of test compound dissolved in DMSO (1 pM-luM final concentration), lOOul of [3H]-SP (O.SnM-0.8nM final concentration) in incubation buffer and 200ul of membrane suspension (0.6 mg protein for gerbil, and 0.8 mg protein for marmoset) in incubation buffer containing 2 ug/ml ieupeptin, 20 fig/ml bachracin and O.SuM phosphoramidon. The incubation proceeded at room temperature for 60 min. Non-specific binding was defined by the addition of cold SP (luM). The reaction was stopped by rapid filtration. Filters were washed 3 tunes with 1ml ice cold wash buffer (containing SOmM HEPES, pH 7.4, and 3mM MnC12), and radioactivity was counted in a liquid scintillation counter. > The potency of test compounds to inhibit SP or GR73632-induced increase of [Ca2+]i in KNK1/CHO cells was determined in functional experiments by using FLEPR (fluorimetric imaging plate reader) technology. hNKl/CHO cells were seeded at a density of 60,000 cells per well and cultured overnight in Ham's F-12 medium supplemented with 10% (v/v) heat-inactivated foetal bovine serum and 2 mM glutamine. The cells were then incubated for the labelling in the culture medium containing the fluorescent calcium indicator Fluo-4 AM (2uM), the organic anions transport blocker probenecid (5mM), and HEPES (20mM) for 30 min hi a humidified atmosphere of 5% CO2. After washing with Hanks' Balanced Salts Solution (HBSS) containing 20mM HEPES and 2.5mM probenecid, the cells were incubated for 60min at 37C in wash buffer containing 0.02%BSA either in the absence (control) or in the presence of test compounds. The plates were men placed into a FLIPR to monitor cell fluorescence (cx-488 nm, em™510-570 nm) before and after the addition of different concentrations of SP or GR73632«in assay buffer. Experiments were carried out by using a laser setting of 1.0 W and a 0.4 sec charge coupled device (CCD) camera shutter speed. Compounds of the invention have also been found to exhibit anxiolytic activity in conventional tests. For example in marmoset human threat test (Costall et al., 1988). The action of the compounds of the invention at the NKj receptor may be determined by using conventional tests. Thus, the ability to penetrate the central nervous system and to bind at the NKj receptor was demonstrated in vivo by their inhibitory effect on the change in the behaviour induced by intracerebroventricular applied substance P in the gerbil, according to the gerbil foot tapping model as described by Rupniak & Williams, Eur. J. of Phannacol., 265,179-183, 1994. Compounds of the invention are useful in the treatment of CNS disorders and psychotic disorders, in particular in the treatment or prevention of depressive states and /or hi the treatment of anxiety as defined in, but not restricted to, Diagnostic Statistical of Mental Disorder (DSM) IV edition edit by American Psychiatric Association and International Classification Diseases 10th revision (ICD10). Thus, for example, depressive states include Major Depressive Disorders (MDD), including bipolar depression, unipolar depression, single or recurrent major depressive episodes , recurrent brief depression, with or without psychotic features, catatonic features, melancholic features including anorexia, weight loss, atypical features, anxious depression, cyclothymic or postpartum onset. Other mood disorders encompassed within the term major depressive disorders include dysthymic disorders with early or late onset and with or without atypical features, neurotic depression, post-traumatic stress disorders and social phobia; dementia of the Alzheimer's type, with early or late onset, with depressed mood; vascular dementia with depressed mood; mood disorders induced by alcohol, amphetamines, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiorytics and other substances; schizoaffective disorder of the depressed type; and adjustment disorder with depressed mood. Major depressive disorders may also result from a general medical condition including, but not limited to, myocardial infarction, diabetes, miscarriage or abortion, etc. The term anxiety includes anxiety disorders, such as panic disorders with or without agoraphobia, agoraphobia, phobias, for example, social phobias or agoraphobia, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorders, generalised anxiety disorders, acute stress disorders and mixed anxiety-depression disorders. Compounds of the invention are useful as analgesics. In particular, they are useful hi the treatment of traumatic pain such as postoperative pain; traumatic avulsion pain such as bracbial plexus; chronic pain such as arthritic pain such as occurring in osteo-, rheumatoid or psoriatic arthritis; neuropathic pain such as post-herpetic neuralgia, trigeminal neuralgia, segmental or intercostal neuralgia, ftbromyalgia, causalgia, peripheral neuropathy, diabetic neuropathy, chemotherapy-induced neuropathy, AIDS related neuropathy, occipital neuralgia, geniculate neuralgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, phantom limb pain; various forms of headache such as migraine, acute or chronic tension headache, temporomandibular pain, maxillary sinus pain, cluster headache; odontalgia; cancer pain; pain of visceral origin; gastrointestinal pain; nerve entrapment pain; sporfs injury pain; dysmennorrhoea; menstrual pain; meningitis; arachnoiditis; musculoskeletal pain; low back pain e.g. spinal stenosis; prolapsed disc; sciatica; angina; ankylosihg spondyolitis; gout; burns; scar pain; itch and thalamic pain such as post stroke thalamtc pain. Compounds of the invention are also useful in the treatment of sleep disorders including dysomnia, insomnia, sleep apnea, narcolepsy, and circadian ritmic disorders. Compounds of the invention are also useful in the treatment or prevention of the cognitive disorders. Cognitive disorders include dementia, amnestic disorders and cognitive disorders not otherwise specified. Furthermore, compounds of the invention are also useful as memory and/or cognition enhancers in healthy humans with no cognitive and/or memory deficit. Compounds of the invention are also useful in the treatment of tolerance to and dependence on a number of substances. For example, they are useful in the treatment of dependence on nicotine, alcohol, caffeine, phencyclidine (phencyclidine like compounds) or in the treatment of tolerance to and dependence on opiates (e.g. cannabis, heroin, morphine) or benzodiazepines; in the treatment of addiction to cocaine, sedative ipnotic, amphetamine or amphetamine-related drugs (e.g. dextroamphetamine, methylamphetamine) or a combination thereof. Compounds of the invention are also useful as anti-inflammatory agents. In particular, they are useful in the treatment of inflammation La asthma, influenza, chronic bronchitis and rheumatoid arthritis; in the treatment of inflammatory diseases of the gastrointestinal tract such as Crohn's disease, ulcerative colitis, inflammatory bowel disease and non-steroidal anti-inflammatory drug induced damage; inflammatory diseases of the skin such as herpes and eczema; inflammatory diseases of the bladder such as cystitis and urge incontinence; and eye and dental inflammation. Compounds of the invention are also useful hi the treatment of allergic disorders, in particular allergic disorders of the skin such as urticaria, and allergic disorders of the airways such as rhinitis. Compounds of the invention are also useful in the treatment or prevention of schizophrenic disorders including paranoid schizophrenia, disorganised schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, residual schizophrenia. Compounds of the invention are also useful in the treatment of emesis, i.e. nausea, retching and vomiting. Emesis includes acute emesis, delayed emesis and anticipatory emesis. The compounds of the invention arc useful hi the treatment of emesis however induced. For example, emesis may be induced by drugs such as cancer chemotherapeutic agents such as aikylating agents, e.g. cyclophosphamide, cannustine, lomustine and chlorambucil; cytotoxic antibiotics, e.g. dactinomycin, doxorubicin, mhomycin-C and bleomycin; anti-metabolites, e.g. cytarabine, methotrexate and 5- fluorouracil; vinca alkaloids, e.g. etoposide, vinblastine and vincristine; and others such as cisplatin, dacarbazine, procarbazine and hydroxyurea; and combinations thereof; radiation sickness; radiation therapy, e.g. irradiation of the thorax or abdomen, such as in the treatment of cancer; poisons; toxins such as toxins caused by metabolic disorders or by infection, e.g. gastritis, or released during bacterial or viral gastrointestinal infection; pregnancy; vestibular disorders, such as motion sickness, vertigo, dizziness and Meniere's disease; post-operative sickness; gastrointestinal obstruction; reduced gastrointestinal motility; visceral pain, e.g. myocardial infarction or peritonitis; migraine; increased intercranial pressure; decreased intercranial pressure (e.g. altitude sickness); opioid analgesics, such as morphine; and gastro-oesophageal reflux disease (GERD) such as erosive GERD and symptomatic GERD or non erosive OERD, acid indigestion, over-indulgence of food or drink, acid stomach, sour stomach, waterbrash/regurgitation, heartburn, such as episodic heartburn, nocturnal heartburn, and meal-induced heartburn, dyspepsia and functional dyspepsia. Compounds of the invention are also useful in the treatment of gastrointestinal disorders such as irritable bowel syndrome, gastro-oesophageal reflux disease (GERD) such as erosive GERD and symptomatic OERD or non erosive GERD, acid indigestion, over-indulgence of food or drink, acid stomach, sour stomach, waterbrash/regurgitation, heartburn, such as episodic heartburn, nocturnal heartburn, and meal-induced heartburn, dyspepsia and functional dyspepsia (such as ulcer-like dyspepsia ,dysmotility-like dyspepsia and unspecified dyspepsia) chronic constipation; skin disorders such as psoriasis, pruritis and sunburn; vasospastic diseases such as angina, vascular headache and Reynaud's disease; cerebral ischeamia such as cerebral vasospasm following subarachnoid haemorrhage; fibrosing and collagen diseases such as scleroderma and eosinophilic rascioliasis; disorders related to immune enhancement or suppression such as systemic lupus erythematosus and rheumatic diseases such as fibrositis; and cough. The compounds of the invention are also useful in premenstrual dysphoric disorder (PMDD), in chronic fatigue syndrome and Multiple sclerosis. Compounds of the invention have been found to exhibit anxiolytic and antidepressant activity in conventional tests. For example, in Guinea pig pups separation-induced vocalisations (Molewijketal., 1996). Compounds of the invention are also useful in the treatment of convulsions and epilepsy. Compounds of the invention may be administered in combination with other active substances such as 5HT3 antagonists, serotonin agonists, selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptake inhibitors (SNRI), tricyclic antidepressanta or dopaminergic antidepressants. Suitable 5HT3 antagonists •which may be used in combination with the compounds of the inventions include for example ondansetron, granisetron and metoclopramide. Suitable serotonin agonists which may be used in combination with the compounds of the invention include sumatriptan, rauwolscine, yohunbine aad metoclopramide. Suitable SSRI which may be used hi combination with the compounds of the invention include fluoxetine, citalopram, femoxetine, fluvoxamine, paroxetine, indalpine, sertraline and zuneldine. Suitable SHRI which may be used in combination with the compounds of the invention include venlafaxine and reboxetine. Suitable tricyclic antidepressants which may be used in combination with a compound of the invention include imipramine, aminiptiline, chlomipramioe andnortriptiline. Suitable dopaminergic antidepressants which may be used in combination with a compound of the invention include bupropion and amineptine. It will be appreciated that the compounds of the combination may be administered simultaneously (either in the same or different pharmaceutical formulations) or sequentially. The invention therefore provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy, in particular in human medicine. There is also provided as a further aspect of the invention the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof hi the preparation of a medicament for use in the treatment of conditions mediated by tachykinins, including substance P and other neuroktnins. In a further aspect of the invention there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof b the treatment of conditions mediated by tachykinins, including substance P and other neurokuuns. * In an alternative or further aspect there is provided a method for the treatment of a mammal, including man, in particular in the treatment of conditions mediated by tachykinins, including substance P and other neurokinins, comprising administration of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. It will be appreciated that reference to treatment is intended to include prophylaxis as well as the alleviation of established symptoms. Compounds of formula (I) may be administered as the raw chemical but the active ingredient is preferably presented as a pharmaceutical formulation. Accordingly, the invention also provides a pharmaceutical composition which comprises at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and formulated for administration by any convenient route. Such compositions are preferably in a form adapted for use in medicine, in particular human medicine, and can conveniently be formulated hi a conventional manner using one or more pharmaceutically acceptable carriers or excipients. Thus, compounds of formula (I) may be formulated for oral, buccal, parenteral, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose). For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with phannaceuticalry acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl-p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate. Preparations for oral administration may be suitably formulated to give controlled release of the active compound. For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner. 4 The compounds of the invention may be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain fbrraulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use. The compounds of the invention may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Ointments for administration to the eye may be manufactured in a sterile manner using sterilised components. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, stabilising agents, solubilising agents or suspending agents. They may also contain a preservative. The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides. The compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, die compounds of the invention may be formulated with suitable polymeric or hydrophobic materia&(for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt For intranasal administration, the compounds of the invention may be formulated as solutions for administration via a suitable metered or unitary dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device. A proposed dose of the compounds of the invention is I to about lOOOmg per day. It will be appreciated that it may be necessary to make routine variations to the dosage, depending on the age and condition of the patient and the precise dosage will be ultimately at the discretion of the attendant physician or veterinarian. The dosage will also depend on the route of administration and the particular compound selected. Compounds of formula (I), and salts and solvates thereof, may be prepared by the general methods outlined hereinafter. In the following description, the groups X, Y, Z, A, R, Rj, R2> R3, R4, Rf, Rfi, R?, m, n and p, have the meaning as previously defined for compounds of formula (I) unless otherwise stated. Compounds of formula (I) may be prepared by reductive N-alkylation of a compound of formula (II), wherein Rg is =O and % is hydrogen or Rg is hydrogen and Rg is «O with diazabicycle derivatives (ffl) or salts thereof. The reaction is conveniently carried out in an aprotic solvent such as dichloroethane and in the presence of a suitable metal reducing agent such as sodium borohydride or sodium triacetoxyborohydride. In a further embodiment of the invention, compounds of formula CD, wherein Y is CH, Z is nitrogen may be prepared by reaction of a compound of formula (IV) R6 (Figure Remove) with triphosgene or S(O)pCl wherein p is an integer from 1 to 2 in an aprotic solvent such as dichloromethane and in the presence of an organic base such triethylamine to form the intermediate compound (V) in which A is C(O) or S(O)p respectively which may be isolated if required, followed by reaction of compound (V) with the amine compound (VI) (Figure Remove) The reaction conveniently takes place in an aprotic solvent such as a hydrocarbon, a halohydrocarbon such as dichloromethane or an ether such as tetrahydrofuran optionally in the presence of a base such as a tertiary amine e.g. diisopropylethylamine. In a further embodiment of the invention, compounds of formula (I) wherein Y is nitrogen and Z is CH may be prepared by reaction of an activated derivative of the carboxylic acid of formula (YD), with amine (VI) or salts thereof, optionally in the presence of a suitable base. (Figure Remove) (R)m (vn) Suitable activated derivatives of the carboxyl group include die corresponding acyl halide, mixed anhydride, activated ester such as a thioester or a derivative formed between the carboxylic acid group and a coupling agent such as that used in peptide chemistry, for example CKbenzotriazol-l-yO-N.N.N'N'-tetramethyluronium tetrafluoroborate^ The reaction is preferably carried out in an aprotic solvent such as an ether, e.g. tetrahydrofuran, a halohydrocarbon, e.g. dichloromethane, N^f-dimethylformamide or acetonitrile. Suitable base for use in this reaction include organic base such as triethylamine or N,N diisopropylethylamine. The activated derivatives of the carboxylic acid (VET) may be prepared by conventional means. A particularly suitable activated derivative for use in this reaction is obtained by reaction of the carboxylic acid (II) with O-(bciizotriazol-l-yl>-N>N,N'N'-tetramethyluroaium tetrafluorpborate in a suitable aprotic solvent such as an ether e.g. tetrahydrofuran, a halohydrocarbon e.g. dichloromethane, an amide e.g. N,N-dimethylformamide or acetonitrile. Compounds of formula (II), in which Y is CH , Z is nitrogen may be prepared by treating compounds of formula (VIE), wherein Rg and Rp have the meanings defined for compounds of formula (IT) and Ra is a nitrogen protecting group, (Figure Remove) (R)m (VHI) using, alter removal of Ra, the same procedures described above for the preparation of compounds of formula (I) from compounds of formula (TV). Compounds of formula (IT), wherein Rg and Rp have the meanings defined for compounds of formula (11) and in which Y is nitrogen, Z is CH,. may be prepared by treating compounds of formula (DC) (R)m using the same procedures described above for the preparation of compounds of formula (IT) from compounds of formula (VET). Compounds of formulae (IV) and (VD) may be prepared by reductive N-alkylation of a piperidine of formula (Vffl) and a carboxylic acid (DC) or esters thereof (such as methyl.ethyl and the like) respectively with a diazabicycle derivatives (113) or salts thereof. The reaction is conveniently carried out in an aprotic solvent such as dichloroethane and in the presence of a suitable metal reducing agent such as sodium borohydride or sodium triacetoxyborohydride. « Examples of suitable nitrogen protecting groups Ra include alkoxycarbonyl e.g. t-butoxycarbonyl, benzyloxycarbonyl, arylsulphonyl e.g. phenysulphonyl or 2-triraemylsilyleihoxvmethyl. Protection and deprotection may be effected using conventional techniques such as those described hi "Protective Groups in Organic Synthesis 2* Ed." by T.W. Greene and P. G. M. Wuts (John Wiley and Sons, 1991) and as described in the examples hereinafter Compounds of formula (VET) are either known compounds or may be prepared by analogous methods to those used for known compounds. Thus, for example, compound (VHI) and enantiomers thereof may be prepared using Comins reaction as described in Journal American Chemical Society 1994,116, 4719-4728, followed by reduction of 2,3 dihydro-lH-pyridin-4-one derivative to piperidine-4-one derivative. The reduction may be effected using hydrogen and metal catalyst e.g. palladium on a suitable support e.g. carbon or alumina. The reaction is carried out in a solvent such as ester e.g. ethyl acetate. Compounds of formula (EX) wherein Rg is =O and Ity is hydrogen are known compounds and may may be prepared according to the procedures as described in Bioorganic & Medicinal Chemistry Letters, Vol 2, N°l 1, pp 1357-1360,1992. Compounds of fodbula (IX) wherein Rp is =O and Rg is hydrogen are novel compounds and they may be prepared for example by reaction of an amine (XIV) with ethyl glyoxalate to obtain the intermediates (Xm) which may be converted into 4-oxo-tetrahydropyridine intermediates (XII) which in turn may be reduced to an intermediate of formula (XI), Said intermediate (XI) may be hi turn hydrolysed, thus forming an intermediate of formula(DC). It will be appreciated by those skilled in the art that the compounds of formula (ED) contain one chiral center (namely the carbon atom shown as * in me formulae ma and fflb). (Figure Remove) It is to be understood that the reference to compounds of formula (IK) includes all stereoisomeric forms and all mixtures thereof. Compounds of formula (HI) are known compounds or may be prepared by analogous methods to those used for known compounds. Thus, compounds of formula (HI) wherein X is CH2 and p is 1 may be prepared as described in Bioorganic & Medicinal Chemistry Letters, (1998) pages 3469-3474; or hi Journal of Medicinal Chemistry, 2000 Vol 43 N°10 pages 1969-1974. Thus, in a particular embodiment of the invention, compounds of formula (HI), wherein X is CH2 and p is 1, may be prepared by reacting 2-methylpyrazine (XV) with a tert-butyhaloacetate such as for example ferl-butylbromoacetate hi the presence of a suitable base such as for example lithium diisopropylamine hi an aprotic solvent such as tetrahydrofuran and at a temperature around -78° to obtain compound (XVI) which hi turn may be converted into compound (XVII) > wherein rio is methyl or ethyl, by reaction with sodium ethylate or with hydrochloride hi methanol. Said compound may be subsequently reduced and cyclized to obtain compound (HI). The reduction may be carried out by heating and using hydrogen and a metal catalyst e.g palladium. Where it is desired to isolate a compound formula (I) as a salt, for example a pharmaceutically acceptable salt, mis may be achieved by reacting the compound of formula (I) in the form of the free base with an appropriate amount of suitable acid and in a suitable solvent such as an alcohol (e.g. ethanol or methanol), an ester (e.g. ethyl acetatej or an ether (e.g. diethyl ether or tetrahydrofuran). Pharmaceutically acceptable salts may also be prepared from other salts, including other pharmaceutically acceptable salts, of the compounds of formula (I) using conventional methods. The compounds of formula (I) may readily be isolated in association with solvent molecules by crystallisation from or evaporation of an appropriate solvent to give the corresponding solvates. When a specific enantiomer of a compound of general formula (I) is required, this may be obtained for example by resolution of a corresponding enantiomeric mixture of a compound of formula CD using conventional methods. Thus, for example, specific enantiomers of the compounds of formula (I) may be obtained from the corresponding enantiomeric mixture of a compound of formula (I) usin& chiral HPLC procedure. Alternatively, enantiomers of a compound of general formula (I) may be synthesised from the appropriate optically active intermediates (ffl), (IV), (V),(VD), (VIQ) and (DC) using any of the general processes described herein. Thus, for example, the chiral compounds (US), (IV) and (VHI) may be prepared from the corresponding racemic compounds (HI), (IV) and (VEU) using conventional procedures such as salt formation with a suitable optically active acid. Suitable optically active acid for use in the process is L(+)mandelic acid or SH+)-O- acetylmandelic acid. The chiral compounds (VU) and (IX) may be prepared from the corresponding racemic compounds (VII) and (IX) using conventional procedures such as salt formation with a suitable optically active amine. Said diastereoisomeric salt forms are subsequently separated by conventional means e.g. chromatography and crystallisation and and the enantiomers are subsequently liberated by hydrolysis of the diastereoisomeric salts. The invention is further illustrated by the following Intermediates and Examples which are not intended as a limitation of the invention. In the Intermediates and Examples unless otherwise stated: Melting points (m.p.) were determined on a Buchi m.p. apparatus and are uncorrected. R.T. or r.t. refer to room temperature. Infrared spectra (IR) were measures in chloroform or nujol solutions on a FT-IR instrument Proton Magnetic Resonance (NMR) spectra were recorded on Varian instruments at 400 or 500 MHz, chemical shifts are reported hi ppm (5) using the residual solvent line as internal standard. Splitting patterns are designed as s, singlet; d, double; t, triple; q, quartet; m, multiple!; b, broad. Mass spectra (MS) were taken on a VG Quattro mass spectrometer. Optical rotations were determined at 20°C with a Jasco DIP360 instrument (1=10 cm, cell volume = 1 mL,X - 589 run). Flash silica gel chromatography was carried out over silica gel 230-400 mesh supplied by Merck AG Darmstadt, Germany. T.l.c. refers to thin layer chromatography on 0.25 mm silica gel plates (60F-254 Merck) and visualized with UV light Solutions were dried over anhydrous sodium sulphate. Methylene chloride was redistilled over calcium hydride and tetrahydrofuran was redistilled over sodium. The following abbreviation are used in the text: AcOEt = ethyl acetate, CH = cyclohexane, DCM = methylene chloride, DIPEA = N,N-diisopropylethylamine, DMF = N,N'- dimethylformamide, Et2O - diethyl ether, EtOH = ethanol, MeOH = methanohTEA. = triethylamine, THF •» tetrahydrofuran. The X-ray powder diffraction pattern of a crystalline form of the compound of the invention was obtained by loading the sample into the diffractometer (Siemens D5005 X-ray diffractometer equipped with 6/6 goniometer, scintillation counter and graphite monochromator. The diffractometer was set up with the instrumental parameters given below. Instrumental parameters monochromatic radiation: Cu -1.54056/1.54439 26RANOE: 2°-40° 26 generator voltage/current: 40kV/50mA STEP SEE: 0.04° 26 time per step: 2 sec"1 rotation: off diveroence/antiscatterino slit: variable (fixed area) SAMPLE HOLDER: TTK sample holder (Alan Paar instruments) TEMPERATURE: 25 °C The spectrum obtained was analysed using the data evaluation software EVA3.0. Intermediate 1 l-^enzvloivc«rboiivlV244-fluoro-2-roethYl-pheaYR-213-dUiYdro-4-pyridone A small amount of iodine was added to a suspension of magnesium turnings (13.2 g) in dry THF (300 mL), at r.t, under a nitrogen atmosphere, then the mixture was vigorously refluxed for 20 minutes. To this suspension, a 15% of a solution of 2-bromo-S-fluoro-toluene (52.5 mL) hi anhydrous THF (300 mL) Was added. The suspension was heated under vigorous reflux until the brown colour disappeared. The remaining part of the bromide solution was added drop-wise over 1 hour to the refluxing suspension which was then stirred for a further 1 hour. This solution of Grignard reagent was then added drop-wise to the pyridinium salt obtained from benzyl chlorofonnate (48.7 mL) and 4-methoxypyridine (25 mL>in dry THF (900mL)at-23°C. The obtained solution was stirred 1 hour at -20°C men it was warmed up to 20°C, a 10% hydrochloric acid solution (560 mL) was added and the aqueous layer was extracted with AcOEt(2x750mL). The combined organic extracts were washed with 5% sodium hydrogen carbonate solution (600 mL) and brine (600 mL) then partially concentrated in vacua. CH (400 mL) was added drop-wise over 1 hour at 20°C and the resulting mixture was stirred 30 minutes and then filtered to give the title compound as a white solid (66 g). IR (nujol, cnV1): 1726 and 1655 (CO), 1608 (OC). NMR (d«-DMSO): 5 (ppm) 8.19 (d, 1H); 7,31-7.18 (m, 5H); 7.08 (m, 2H); 6.94 (dt, 1H); 5.77 (d, 1H); 5.36 (d, 1H); 5.16 (2d, 2H); 3.26 (dd, 1H); 2.32 (d, 1H); 226 (s, 3H). MS (ES/f): m/z=340 [MHj*. Intermediate 2' 2-f4-Fluoro-2-metfavi-phenYlVpipcridine-4-one Method A; 4-Fluoro-2-methyl-benzaldehyde (4 g) was added to a solution of 4-aminobutan-2-one ethylene acetal (3.8 g) in dry benzene (SO mL) and the solution was stirred at r.t under a nitrogen atmosphere. After 1 hour the mixture was heated at reflux for 16 hours and men allowed to cool to r.t. This solution was slowly added to a refluxing solution of p-toluenesulphonic acid (10.6 g) in dry benzene (50 mL) previously refluxed for 1 hour with a Dean-Stark apparatus. After 3.5 hours the crude solution was cooled and made basic with a saturated potassium carbonate solution and taken up with AcOEt (50 mL). The aqueous phase was extracted with AcOEt (3 x 50 mL) and Et2O (2 x 50 mL). The organic layer was dried and concentrated in vacua to a yellow thick oil as residue (7.23 g). A portion of the crude mixture (3 g) was dissolved in a 6N hydrochloric acid solution (20 mL) and stirred at 60°C for 16 hours. The solution was basified with solid potassium carbonate and extracted with DCM (5 x 50 mL). The combined organic phases were washed with brine (50 mL), dried and concentrated in vacua to give the tjtle compound (2.5 g) as a thick yellow oil. Method B L-selectride (1M solution in dry THF, 210 mL) was added drop-wise, over 80 minutes, to a solution of intermediate 1 (50 g) in dry THF (1065 mL) previously cooled to -72°C under a nitrogen atmosphere. After 45 minutes, 2% sodium hydrogen carbonate solution (994 mL) was added drop-wise and the solution was extracted with AcOEt (3 x 994 mL). The combined organic phases were washed with water (284 mL) and brine (568 mL). The organic phase was dried and concentrated in vacua to get l-benzyloxycarbonyl-2-(4-fiuoro-2-methyl- phenyl)-pipeiidine-4-one as a pale yellow thick oil (94 g) which was used as a crude. This material (94 g) was dissolved hi AcOEt (710 mL), then 10% Pd/C (30.5 g) was added under a nitrogen atmosphere. The slurry was hydrogenated at 1 atmosphere for 30 minutes. The mixture was filtered through Celite and the organic phase was concentrate J/n vacua to give the crude 2-(4-fluoro-2-methyl-phenyl)-piperidine-4-one as a yellow oil. This material was dissolved hi AcOEt (518 mL) at r.t. and racemic campborsulphonic acid (48.3 g) was added. The mixture was stirred at r.t for 18 hours, then the solid was filtered off, washed with AcOEt (2 x 50 mL) and dried in vacua for 18 hours to give 2-(4-fluoro-2-methyl-phenyl)- piperidine-4-one, 10-camphorsulfonic acid salt as a pale yellow solid (68.5 g). (M.p.: 167- 169°C - NMR (drDMSO): 8 (ppra) 9.43 (bs, 1H); 9.23 (bs, 1H); 7.66 (dd, 1H); 7.19 (m, 2H); 4.97 (bd, 1H); 3.6 (m, 2H); 2.87 (m, 3H); 2.66 (m, 1H); 2.53 (m, 2H); 237 (s + d, 4H); 2.22 (m, 1H); 1.93 (t, 1H); 1.8 (m, 2H); 1.26 (m, 2H); 1.03 (s, 3H); 0.73 (s, 3H). This material (68.5 g) was suspended hi AcOEt (480 mL) and stirred with a saturated sodium hydrogen carbonate (274 mL). The organic layer was separated and washed with further water (274 mL). The organic phase was dried and concentrated in vacua to give the title compound (31 g) as a yellow-orange oil. NMR (dj-DMSO): 8 (ppm) 7.49 (dd, 1H); 7.00 (m, 2H); 3.97 (dd, 1H); 3.27 (m, 1H); 2.82 (dt, 1H); 2.72 (bm, 1H); 2.47 (m, 1H); 2.40 (m, 1H); 2.29 (s, 3H); 2.25 (dt, 1H); 3.18 (m, 1H). MS (ES/+): m/z?=208 [MH]*. Intermediate 3 244-Fiuoro-2-roethvl-DhenvlV^f-9i9-DtDeridine-l-c»rboxvUc acid (3,5-bis- triflnoromethvl-benzvlVmethvlamjde A solution of triphosgene (1.43 g) dissolved in dry DCM (10 mL) was added to a solution of intermediate 2 (2.5 g) and DIPEA (8.4 mL) in dry DCM (20 mL) previously cooled to 0°C under a nitrogen atmosphere. The solution was stirred at 0°C for 2 hours, then (3,5-bis-tnfluoromethyl-benzyO-methylamine hydrochloride (S.63 g) and DIPEA (3.34 mL) were added. The mixture was stirred under nitrogen at r. t. for 14 hours. The mixture was taken up with AcOEt (SO mL), washed with cold IN hydrochloric acid solution (3 x 20 mL) and brine (10 mL). The organic layer was dried and concentrated in vacua to a residue which was purified by flash chromatography (AcOEt/CH 3:7) to give the title compound as a white foam (3.85 g). IR(nujol, cm1): 1721 and 1641 (CO). NMR (d6-DMSO): 8 (ppm) 7.96 (s, 1H); 7.76 (s, 2H); 7.25 (dd, 1H); 6.97 (dd, 1H); 6.90 (dt, 1H); 5.22 (t, 1H); 4.59 (d, 1H); 4.43 (d, 1H); 3.63-3.49 (m, 2H); 2.79 (s, 3H); 2.69 (m, 2H); 2.49 (m, 2H); 2 26 (s, 3H). MS (ES/+): m/z - 491 (MHJ*. Intermediate 4 2-(RW4-Flaoro-2-methYl-phenYD-4-oio-|>lperidine-l-carborylic acid fl-(K)-3.S-bis- rrifluoromethvl-DbenYn-etb.Yll-metliYl«inldef4») and 2-rSW4-Fluoro-2-methvl-beaYl>-4-oio-piperidine-l-carboivlic acid fl-flRV3.S-bis- Method A; A solution of triphosgene (147 mg) dissolved in dry DCM (5 mL) was added drop-wise to a solution of intermediate 2 (250 mg) and DIPEA (860 uL) in dry DCM (IS mL) previously cooled to 0°C under a nitrogen atmosphere. After 2 hours, [l-(R>3J5-bis-trifluoromethyl-phenyl>ethyl]-methylamino hydrochloride (503 mg) and DIPEA (320 uL) in dry acetonitrile (20 mL) were added and the mixture was heated to 70°C for 16 hours. Further [l-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-raethylarauie hydrochloride (170 mg) and DIPEA (100 uL) were added and the mixture was stirred at 70°C for further 4 hours. Next, the mixture was allowed to cool to r.t, taken up with AcOEt (30 mL), washed with a IN hydrochloric acid cold solution (3 x 15 mL) and brine (2 x 10 mL). The organic layer was dried and concentrated in vacua to a residue, which was purified by flash chromatography (CH/AcOEt 8:2) to give: intermediate 4a (230 mg) as a white foam, intermediate 4b (23 1 mg) as a white foam. « Intermediate 4a NMR (dt-DMSO): 8 (ppm) 7.98 (bs, 1H); 7.77 (bs, 2H); 7.24 (dd, 1H); 6.97 (dd, 1H); 6.89 (m, 1H); 5.24 (t, 1H); 5.14 (q, 1H); 3.61 (m, 1H); 3.55 (m, 1H); 2.71 (m, 2H); 2.56 (s, 3H); 2.50 (m, 2H); 2.26 (s, 3H); 1 .57 (d, 3H). Intermediate 4b NMR (d«-DMSO): 8 (ppm) 7.96 (bs, 1H); 7.75 (bs, 2H); 7.24 (dd, 1H); 6.98 (dd, 1H); 6.93 (dt, 1H); 5^9 (q, 1H); 5^4 (t, 1H); 3.56 (m, 1H); 3.48 (m, 1H); 2.70 (s, 3H); 2.50 (m, 4H); 2.26 (s, 3H); 1.54 (d, 3H). Intermediate 4a Method B A saturated sodium hydrogen carbonate solution (324 mL) was added to a solution of intermediate 9 (21.6 g) in AcOEt (324 mL) and the resulting mixture was vigorously stirred for 15 minutes. The aqueous layer was back-extracted with further AcOEt (216 mL) and the combined organic extracts were dried and concentrated in vacua to give intermediate 8 as a yellow oil, which was treated with TEA (19 mL) and AcOEt (114 mL). The solution obtained was added drop-wise over 40 minutes to a solution of triphosgene (8 g) in AcOEt (64 mL) previously cooled to 0°C under a nitrogen atmosphere, maintaining the temperature between 0°C and 8°C. After stirring for 1 hours at 0°C and for 3 hours at 20°C, [l-(RH3>5-bis-trifluoromethylphenyl>ethyl]-methylamine hydrochloride (29.7 g), AcOEt (190 mL) and TEA (38 mL)were added to the reaction mixture which was then heated to reflux for 16 hours. The solution was washed with 10% sodium hydroxide solution (180 mL), 1% hydrochloric acid solution (4 x 150 mL), water (3 x 180 mL) and brine (180 mL). The organic layer was dried and concentrated in vacua to a residue, which was purified through a silica pad (CH/AcOEt 9:1) to give the title compound (21.5 g) as a brown thick oil. NMR (ds-DMSO): 6 (ppm) 7.97-7.77 (bs + bs, 3H); 7.24 (dd, 1H); 6.97 (dd, 1H); 6.88 (td, 1H); 5.24 (m, 1H); 5.14 (q, 1H); 3.58 (m, 2H); 2.7 (m, 2H); 2.56 (s, 3H); 2.49 (ra, 2H); 2.26 (s,3H);1.57(d,3H). > Intermediate 5 2-fSW4-Flaoro-2-methvI-pfcenYn-4-oio-pii>eridlBe-l-carboTYlic acid fl-(SW3.5-bis- trifluoromethvl-pheBYlVethYll-methYlamidefSa) and 2-fRVf4-Fluoro-2-methYl-pheHYn-4-oxo-piDeridio6-l-curbozYlic add fl-(SW3.S-big- trifluQromethvl-DhenvIVetliYll-metbvlaiaide(Sfr) A solution of triphosgene (147 mg) dissolved in dry DCM (5 mL) was added to a solution of intermediate 2 (250 mg) and DIPEA (860 uL) in dry DCM (15 mL) previously cooled to 0°C under a nitrogen atmosphere. After 2 hours, a solution of [l-(S)-(3>5-bis-trifluoromemyl-phenyl)-ethyl]-methylamine hydrochloride (510 mg) and DIPEA (320 uL) in dry acetonitrile (20 mL) was added and the mixture was heated to 70°C for 16 hours. Next, further [1-(S> (3,5-bis-trifluoromethyl-phenyl>ethyl]-methylamine hydrochloride (170 mg) and DIPEA (105 uL) were added. After further 4 hours at 70°C, the mixture was allowed to cooi to r.t, taken up with AcOEt (30 mL), washed with a IN hydrochloric acid cold solution (3x15 mL) and brine (2x10 mL). The organic layer was dried and concentrated in vacua to a residue, which was purified by flash chromatography (CH/AcOEt 8:2) to give: intermediate 5a ( 234 mg) as a white foam, intermediate 5b (244 mg) as a white foam. Intermediate Sa Intermediate Sb NMR (dj-DMSO): 5 (ppm) 7.98 (bs, 1H); 7-77 (bs, 2H); 7.24 (dd, 1H); 6.97 (dd, 1H); 6.89 (m, 1H); 5.24 (t, 1H); 5.14 (q, 1H); 3.61 (m, 1H); 3.55 (m, 1H); 2.71 (m, 2H); 2.56 (s, 3H); 2.50 (m, 2H); 2.26 (s, 3H); 1.57 (d, 311). Intermediates 6 2^SW4-Fluoro-2-methvl-phen\1V4-oio-3.4-dihYdro-2H-pvridine-l-cartx>xYlic acid (1R, 2S. SRV-2-faopropYl-S-methYt-CYclohervl eater (6al and 2-rRW4-Fluoro-2-methvl-pheaYn-4-oio-3.4-dihYdro-2H-Pvridin&-l-carborvlic acid (1R, 2S. SRV-2-isoDroDvi-S-qiethYt-cYcloheryI eater f6b) A solution of 2-bromo-5-fluoro-toluene (3.68 g) in dry THF (10 mL) was dropped over 30 minutes, into a mixture of magnesium (525 ing) and iodine (1 crystal) in dry THF (5 mL) previously heated to 70°C under a nitrogen atmosphere. The mixture was stirred at 70°C for 1.5 hours, then allowed to cool to r.t.. A solution of (->mentyl chloroformate (3.53 mL) in dry THF (15 mL) was added to a solution of 4-methoxypyridine (1.52 mL) in dry THF (35 mL) previously cooled to -78°C under a nitrogen atmosphere. After 15 minutes, the solution containing the 4-fluoro-2-methyl-phenyl magnesium bromide was added drop-wise, and the mixture was stirred at -78°C for 1 hour. The reaction was quenched by the addition of 1M hydrochloric acid solution (20 mL), warmed to r.t. and stirred at 23°C for 30 minutes. After extraction with AcOEt (2 x 150 mL), the combined organic extracts were washed with brine (50 mL), dried and concentrated in vacua to a residue, which was purified by flash chromatography (CH/THF/tolueno 8:1:1) to give: intermediate 6* (3.44g - yellow oil) intermediate 6b (530 mg- white solid). fotennediate 6» T.I.C.: CH/THF/toluene 7:2:1, Rf=0.59. R(najo|, cm'1): 1718 and 1675 (CO). NMR(oVDMSO): 6 (ppm) 8.14 (d, 1H); 7.08 (dd, 1H); 7.02 (dd, 1H); 6.95 (m, 1H); 5.68 (d, 1H); 5.34 (d, 1H); 4.47 (m, 1H); 3.26 (dd, 1H); 2.30 (m, 4H); 1.7 (m, 4H); 1.33 (m, 2H); 0.8 (m,HH). Intermediate 6b M.p.: U7-120°C. 4 T.U.: CH/THF/toluene 7:2:1, RJH).56. IR (nujol, cm-'): 1718 and 1669 (OO). NMR(d«-DMSO): 6 (ppm) 8.17 (d, 1H); 7.04-6.94 (m, 3H); 5.70 (d, lH)j 5.35 (d, 1H); 4.42 (m, 1H); 3.26 (dd, 1H); 2.30 (m, 4H); 1.58-1.40 (m, 3H); 1.2-0.7 (m, 8H); 0.51-0.34 (bs, 6H): Intermediate 7 2-rRW4-Fluoro-2-meUiYl-phenvn-23-dlhvdro-lH-PYridln-4-ODe Sodium methoxido (100 mg) was added to a solution of intermediate od Intermediate 8 2-(RW4-Flaoro-2-mefliYl-phenYn-piDeridln-4-one Palladium over charcoal (10% - 74 mg) was added to a solution of intermediate 7 (145 mg) in MeOH (8 mL) and THF (2 mL). The mixture was allowed to react with hydrogen in a pressure reactor (2 aim) overnight After flushing with nitrogen, the solution was filtered and the solvent removed in vacua. The crude product was purified by flash chromatography (AcOEt/MeOH 9: 1) to give the tide compomuj (26 mg) as a yellow oil. The enantiomeric excess (90-95%) was detected by chiral HPLC. T.l.c.:AcOEt/MeOH 9: 1, RJH).2. > NMR (dj-DMSO): 8 (ppm) 7.49 (dd, 1H); 7.00 (m, 2H); 3.97 (dd, 1H); 3.27 (m, 1H); 2.82 (dt, 1H); 2,72 (bm, 1H); 2.47 (m, 1H); 2.40 (m, 1H); 2.29 (s, 3H); 2.25 (dt, 1H); 2.18 (m, 1H). MS (ES/+): m/z?=208 [MHJ*. +82.1 (c=1.07, DMSO). Intermediate 9 2-fRW4-Fluoro-2-roethYl-phenYl>-pipcridln-4-oneL-f-fVpnmdelate A solution of L-(+>mandelic acid (22.6 g) in AcOEt (308 mL) was added to a solution of intermediate 2 (31 g) in AcOEt (308 mL). Then isopropanol (616 mL) was added and the solution was concentrated in vacua to 274 mL. The solution was then cooled to 0°C and further cold isopropanol (96 mL) was added. The thick precipitate was stirred under nitrogen for 5 hours at 0°C, then filtered and washed with cold Et2O (250 mL) to give 4he title compound as a pale yellow solid (20.3 g). M.p.: 82-85°C. NMR(d«-DMSO): 6 (ppm) 7.51 (dd, 1H); 7.40 (m, 2H); 7.32 (m, 2H); 7.26 (m, 1H); 7.0 (m, 2H); 4.95 (s, 1H); 4.04 (dd, 1H); 3.31 (m, 1H); 2.88 (m, 1H); 2.49-22 (m, 4H); 2.29 (s, 3H). Chiral HPLC: HP 1100 HPLC system; column Chiralcel OD-H, 25 cm x 4.6 mm; mobile phase: n-hexane/isopropanol 95:5 + 1% diethylamine; flow: 1.3 ral/min; detection: 240/2 15nm; retention time 12.07 minutes. Intermediate 10 2-fRV4-Fl'ioro-2-methvl-pheHYl>-4-i)io-DiDeridine-l-carboivlic acid (3.S-bis- trifluoromethvl-benzvlVniethvlamide ' Method A A solution of triphosgene (17 mg) in dry DCM (2 mL) was added to a solution of intermediate 8 (26 mg) and DEPEA (65 mg) in dry DCM (3 mL) previously cooled to 0°C under a nitrogen atmosphere. After two hours acetonitrile (10 mL) was added, the temperature was allowed to reach r.t and the DCM evaporated under a nitrogen flush. Then, a solution of 3,5-(bis-trifluoroniethyI-benzyl)-methylamine hydrochloride (74 mg) and DIPEA (130 mg) in acetonitrile (3 mL) was added and the mixture was stirred at 23°C overnight The solvent was concentrated in vacua. The residue was dissolved in AcOEt (10 mL) and washed with IN hydrochloric acid solution (3x5 mL), 5% sodium hydrogen carbonate (5 mL) and brine (10 mL). The organic layer was dried and concentrated in vacua to a residue, which was purified by flash chromatography (CH/AcOEt 1:1) to give the title compound (50 mg) as a white solid. Method B A saturated sodium hydrogen carbonate solution (348 mL) was added to absolution of intermediate 9 (23.2 g) hi AcOEt (348 mL) and the resulting mixture was vigorously stirred for 15 minutes. The aqueous layer was back-extracted with further AcOEt (230 mL) and the combined organic extracts were dried and concentrated in vacua to give intermediate 8 (12.31 g) as a yellow oil, which was treated with TEA (20.5 mL) and AcOEt (123 mL). The solution obtained was added drop-wise over 40 minutes to a solution of triphosgene (8 g) in AcOEt (61 mL) previously cooled to 0°C under a nitrogen atmosphere, maintaining the temperature between 0°C and 8°C. After stirring for 2 hours at 20°C, 3,5-(bis-trifluoromemyl-benzyl)-methylamine hydrochloride (28.1 g), AcOEt (184 mL) and TEA (33 mL) were added to the reaction mixture which was then further stirred for 2 hours at 20°C. The solution was washed with 10% sodium hydroxide solution (3 x 185 mL) and 1% hydrochloric acid solution (3 x 185 mL). The organic layer was dried and concentrated in vacua to a crude (38 g), which was purified through a silica pad (CH/AcOEt from 9:1 to 1:1) to give the title compound (24.7 g) as a colourless oil. « NMR (oVDMSO): 6 (ppm) 7.96 (s, 1H); 7.76 (s, 2H); 7.26 (dd, 1H); 6.98 (dd, 1H); 6.90 (td, 1H); 5.23 (t, 1H); 4.61 (d, 1H); 4.41 (d, 1H); 3.60 (m, 2H); 2.69 (m, 2H); 2.79 (s, 3H); 2.50 (m,2H);2.27(s,3H). MS (ES/+): m/2?-491 fMH]+. intermediate 11 1.4-DibenzvI-2-Dii>erazinecarboxaldeiivde A solution of ethyl 2,3-dibromopropionate (6 raL) in anhydrous toluene (SO mL) was added to a solution of N,N'-dibenzylethylenediamine (5 g) and DIPEA (12 mL) in anhydrous toluene (SO mL) under a Nitrogen atmosphere. The resulting mixture was heated to 100°C for 21 hours, then allowed to cool to r.t., diluted with AcOEt (100 mL) and washed with brine (3 x 100 mL). The organic extract was dried and concentrated in vacua to a residue which was purified by flash chromatography (CH/AcOEt 9:1) to give ethyl l,4-dibenzyl-piperazine-2-carboxylate (5.65 g) as a yellow oil, which was used without any purification in the next step. Diisobutylaluminium hydride (1M in toluene - 29 mL) was dropped into a solution of ethyl l,4-dibenzyl-piperazine-2-carboxylate (S.47 g) in anhydrous toluene (110 mL) previously cooled to -78°C under a Nitrogen atmosphere. The solution was stirred at -78°C for 1 hour, then a 20% sodium hydroxide solution (20 mL) was added and the mixture was allowed to warm to r.t. Further 20% sodium hydroxide solution (SO mL) was added and the solution was extracted with Et2O (2 x ISO mL). The combined organic extracts were dried and concentrated in vacua to give the title compound (S.33 g) as a crude, which was used without any further purification hi the next step. T.I.C.: CH/AcOEt 8:2, M-0.36. NMR(d6-DMSO): 8 (ppm) 9.62 (s, 1H); 7.4-7.15 (m, 10H); 3.86 (d, 1H); 3.6 (d, 1H); 3.46 (s, 2H); 3.09 (bt, 1H); 2.82 (t, 1H); 2.55-2.45 (m, 2H); 2.4-2.3 (m, 3H). Intermediate 12 HcxahYdro-DYrrolofU-glPYr«zin-6-one Method A; (Caroemoxymeuylene)triphenylphospb.orane (11.72 g) was added in two portions to a solution of intermediate 11 (4.95 g) in anhydrous toluene (100 mL) under a Nitrogen atmosphere. The mixture was heated to 80°C for 24 hours, then it was allowed to cool to r.t. and washed with water (100 mL). The organic layer was dried and concentrated in vacua to a residue, which was purified by flash chromatography (CH/AcOEt 85:15) to give ethyl 1,4-dibenzyl-2-piperazme-3-acrylate (4.2 g - T.l.c.: CH/AcOEt 8:2, Rf-0.36). A solution of ethyl l,4-dibenzyl-2-piperazuw-3-acrylate (2.84 g) in abs. EtOH (40 mL) was hydrogenated over Pd/C 10% (1.42 g) at 3.5 atm. for 2 days. After filtration, the solution was concentrated to nearly 30 mL and heated to 70°C for 16 hours until complete cyclization occurred. The solution was concentrated in vacua and the residue was purified by flash chromatography (DCM/MeOH 7:3) to give the title compound (820 mg) as a pale yellow oil. MethodB; Diisobutylaluminium hydride (1.2M in toluene - 262 mL) was dropped into a solution of ethyl l,4-dibenzyl-piperazine-2-carboxylate (48.4g) synthesised as previously described in anhydrous toluene (450 mL) previously cooled to -78°C under a Nitrogen atmosphere (addition of DIBAL-H took l.S hours and the internal temperature was always maintained below -70°C). The solution was stirred at -78°C for 2 hour, then a 10% sodium hydroxide solution (500 mL) was added and the mixture was allowed to warm to r.t.. Further 10% sodium hydroxide solution (400 mL) was added and the solution was extracted with toluene (2 x 250 mL). The combined organic extracts were dried and concentrated in vacua until a volume of -100 mL containing l,4-dibenzyl-2-piperazinecarboxaldehyde, which was used without any further purification in the next step. (Carbethoxymethylene)triphenylphosphorane (75 g) was added in two portions to the previous solution of l,4-dibenzyl-2-piperazine carboxaldehyde in toluene (450 mL) under a Nitrogen atmosphere. The mixture was heated to 80°C overnight, then it was allowed to cool to r.t. and washed with water (2 x 400 mL) and brine (250 mL) The organic layer was dried and concentrated in vacua to a residue, which was purified by flash chromatography (CH/AcOBt 85:15) to give ethyl l,4-dibenzyl-2-piperazine-3-acrylate (44.8 g - T.l.c.: CH/AcOEt 8:2, RfH>.36). To a solution of ethyl l,4-dibenzyl-2-piperazine-3-acrylate (44.8 g) hi MeOH (450 mL) under a Nitrogen atmosphere, ammonium formate (23.2 g) and 5% palladium on charcoal (8.96 g) were added. The resulting mixture was heated to reflux temperature for 6h. After filtration over Celite, the solution was concentrated in vacua and the residue was purified by flash chromatography (DCM/MeOH 8:2) to give the title compound (14.15 g) as a pale yellow oil. Method C; >. Intermediate 15 (820 g) and toluene (1680 g) were charged in a 5 L stainless steel autoclave and palladium on charcoal (5 %, dry - 50 g) was added. The autoclave was rendered inert with nitrogen, subsequently filled with 100 bar hydrogen, and then heated to 100 °C. When the internal pressure has fallen to 90 bar, the pressure was increased to 100 bar again. After the hydrogen uptake ceased, the autoclave was cooled below 30 °C and the reaction solution was removed. The catalyst was then filtered off with a buchner funnel and washed with toluene (2 x 200 mL). After concentrating the filtrate with a rotatory evaporator, the product was distilled over a 15 cm Vigreux column (bp: 115 to 125 °C @ 0.07 mbar) giving title compound 12 (574 g) as a slightly yellowish oil. T.I.C.: DCM/MeOH 7:3, RfN).17 (detection with ninhydrin) NMR (CDC13): 5 (ppm) 4.01(m, 1H); 3.54 (m, 1H); 3.16 (m, 1H); 3.01 (m, 1H); 2.81 (m, 1H); 2.6 (dt, 1H); 2.38 (m, 3H); 2.16 (m, 1H); 1.6 (m, 1H). MS (ES/+): ra/z= 141 [M+HT Intermediates 13 (8aSV-Hexabvdro-Dvrrolotl.2-g1Pvrazin-6-one(13a'> and Method A; Intermediate 12 (746 mg) was separated into the enantiomers via preparative HPLC (Column: Chiralpack AD 25 x 2 cm; mobile phase: n-hexane/EtOH 8:2; flux=l mL/min;X=225 nm). Thus, intermediate 13a (330 mg) and intermediate 13b (320 mg) were obtained. Intermediate 13a (enantiomer 1) : HPLC: Column Chiralpack AD 25cm x 4.6mm x 5jt; mobile phase n-hexane/EtOH 8:2; flux=l mL/min; fc=225 nm; retention time 10.7 minutes. Ratio 13a/13b=100:0. Intermediate 13b (enantiomer 2): HPLC: Column Chiralpack AD 25cm x 4.6mm x 5u; mobile phase n-hexane/EtOH 8:2; flux=l mL/min; X=225 nm; retention time 12.8 minutes. Ratio 13a/13b=0:100. Intermediate 13b: Method B; A solution of L-(+>mandelic acid (13.03 g) in isopropanol (60 mL) was dropped over 20 minutes into a solution of intermediate 12 (12 g) in isopropanol (60 mL) under a Nitrogen atmosphere. The suspension was stirred at 23°C for 2 hours, then it was filtered off and washed with further isopropanol (120 mL). The solid obtained (ratio enantiomers 20:80) was recrystallized three times from isopropanol (10 volumes) until a complete HPLC enantioselectivity was detected. In this way, (8aR)-hexahydro-pYrrolo[l,2-a]pyrazin-6-one L- (+>mandelate (5.84 g - enantiomer 2) was obtained. This material (6.469 g) was dissolved in EtOH (40 mL) and water (4 mL) and stirred with a suspension of resin IRA68 (112 g - previously washed with a 0.05N sodiuor hydroxide solution (370 mL) and water (4 L) until neutral pH) in EtOH (200 mL). The mixture was stirred at 23 °C for 1.5 hours, men filtered off. The organic layer was concentrated in vacua to give the tirie compound 13b (3.1 g) as a white solid. Intermediate 13b: HPLC: Column Chiralpack AD 25cm x 4.6mm x 5u; mobile phase n-hexane/EtOH 8:2; flux**l mL/min; X=225 nm; retention time 12.8 minutes. Ratio 13a/13b=0:100. Intermediate 13a; Method B; A part of the mother liquors (3.48 g with ratio 13a:13b=63:37) was treated with a suspension of resin ERA68 (70 g - previously washed with a 0.05N sodium hydroxide solution (150 mL) and water until neutral pH) in EtOH (150 mL) and water (1 mL). The mixture was stirred at 23°C for 2 hours, then filtered off. The organic layer was concentrated in vacua to give the free hexahydro-pyrrolo[l,2-«]pyrazin-6-one (1.6 g) as colourless oil. This material (1.6 g) was dissolved in isopropanol (8 mL) and treated with a solution of D-(-)-mandelic acid (1.74 g) in isopropanol (8 mL). The suspension was stirred at 23°C for 16 hours, men it was filtered off and washed with further isopropanol (120 mL). The solid obtained (ratio enantiomers 86:14) was recrystallized three times from isopropanol (10 volumes) until a complete HPLC enantioselectivity was detected. In this way, (8aS>hexahydro-pyrrolo[l,2-a]pyrazb-6-one D-(-)-mandelate (0.88 g — enantiomer 1) was obtained. This material (0.88 g) was dissolved in BtOH (10 mL) and water (1 mL) and stirred with a suspension of resin IRA68 (15 g - previously washed with a 0.05N sodium hydroxide solution (50 mL) and water until neutral pH in EtOH (30 mL). The mixture was stirred at 23°C for 1 hour, then filtered off. The organic layer was concentrated in vacua to give toe title compound I3a (0.434 g) as a white solid. Intermediate 13a: HPLC: Column Chiralpack AD 25cm x 4.6mm x 5u; mobile phase n-hexane/EtOH 8:2; flux=l mL/min; X=225 tun; retention time 10.7 minutes. Ratio 13a/13b=100:0. Intermediate 14 2WRW4-Fluoro-2-roethYl-phenYlM-oxo-piperidine-l-carborvHc acid (3.5-dichloro- bepzvlVniethYlamide A saturated sodium hydrogen carbonate solution (15 mL) was added to a solution of intermediate 9 (1.0 g) in AcOEt (15 mL) and the resulting mixture was vigorously stirred for 15 minutes. The aqueous layer was back-extracted with further AcOEt (10 mL) and the collected organic phases were dried and concentrated in vacua to give the free base 2-(R)-(4- fluoro-2-methyl-phenyl)-4-oxo-piperidme (0.550 g) as a yellow oil A solution of 2-(RH4-fluoro-2-methyl-phenyl>4-oxo-piperidine (0.550 g) and TEA (20.5 mL) in AcOEt (5.5 mL) was added drop-wise, over 40 minutes, to a solution of triphosgene (0.385 g) in AcOEt (2.75 mL) previously cooled to 0°C under a nitrogen atmosphere. The solution was allowed to warm to r.t. and stirred at 23°C for 2 hours, then N-(3,5-dichloro)- benzyl-methylamine hydrochloride (3.17 g) and TEA (1.860 mL) in AcOEt (8&5 mL) were added. The reaction mixture was stirred for 2 hours at 20°C, then it was washed with 10% sodium hydroxide solution (3x8 mL) and 1% hydrochloric acid solution (3x8 mL). The organic layer was dried and concentrated in vacua to a residue which was purified through a silica pad (CH/AcOEt from 9/1 to 1/1) to give the title compound (0.870 g) as a colourless oil. T.I.C.: CH/AcOEt 1:1, RfN).40. NMR (d«-DMSO): 8 (ppm) 7.45 (t, IH); 7.29 (m, 1H); 7.07 (d, 2H); 7.0-6.94 (m, 2H); 5.16 (dd, IH); 4.40-4.26 (dd, 2H); 3.55 (m, 2H); 2.76 (s, 3H); 2.75-2.6 (m, 2H); 2.5 (m, 2H); 229 (s,3H). Intermediate 15 3-PvrazJp-2-vl-proplonic acid ethvl ester Butyl lithium (2.5M in hexane - 2560 mL) was added within 2 hours into a 10'L flask charged with THF (3350 mL) and diisoprppylamine (658 g) while the temperature was maintained at 0 - 5°C with an ice bam. The LDA solution was then precooled to -50°C and a mixture of methylpyrazine (606 g) and THF (590 mL) was added within 2 hours under vigorous stirring at -40 to -30°C. The deep red anion solution is then pumped to a cooled (-60°C) mixture of fert-butyl bromoacetate (1255 g) and THF (3360 mL) in a 20 L reactor. During the addition of the anion solution, the temperature in the reaction vessel did not exceed -55 °C. After the addition, the mixture is stirred for further 30 mm at -55 °C and then transferred to a 30 L reactor (the transesterification and removal of solvents can be done for two runs at once). A solution of sodium ethylate (142 g) dissolved in EtOH (2200 mL) was then added to the orange mixture and about 12 L of solvents were distilled off until a temperature of 80°C was reached in the distillation head and 100°C in the boiling liquid. The mixture was cooled to approximately 30°C and then toluene (840 mL), AcOEt (840 mL), and water (1180 mL) were added. After separation of die phases, the organic layer was extracted three times with AcOEt (420 mL) and toluene (170 mL) each. The combined organic phases were then concentrated in vacua and the residue was distilled over a Vigreux column (bp 115 to 130 °C @ 0.07 mbar) giving the title compound (S79 g). T.l.c.:CH/EtOAc= 1:1, RfN).36. 'H-NMR (oVDMSO): 8 (ppm) 8.57 (d, 1H); 8.52 (dd, 1H); 8.45 (d, 1H); 4.01 (q, 2H); 3.04 (t, 2H); 2.76 (t,2H); 1.12 (t,3H). MS (ES/+): m/r= 181 [M+H]* Intermediate 16 f8aSVHeiahYdro-DYrrolofl.2-olpYr»zln-6-oBe S-(+VO-acerylmandelate (enantlomer 1} A solution of (SH+)-O-acetylmandelic acid (2.77 g) in acetone (12 mL) was added drop-wise to a solution of intermediate 12 (4 g) in acetone (28 mL) at 20°C. The resulting mixture was seeded to initiate the precipitation. The obtained precipitate was stirred at 20°C over 4 hours men filtered washing^with acetone (12 mL). The solid was dried in vacua at 40°C for 18 hours to give the title compound (3.44 g) as a white solid. HPLC: Column Chiralpack AD 25 x 4.6 x Sum; mobile phase n-hexane/EtOH-l:l; flow=lml/min; X= 210 nm; retention times title compound 5.42min., (8aR) enantiomer 6.06mu>. E.e.>94%. 'H-NMR (d«-DMSO): 8 (ppm) 9.5 (broad, 1H); 7.42 (m, 2H); 7.32 (m, 3H); 5.62 (s, 1H); 3.79 (dd, 1H); 3.55 (m, 1H); 3.14 -3.02 (2dd, 2H); 2.80 (dt, 1H); 2.52 (dt, 1H); 2.40 (t, 1H); 2.19 (m, 2H); 2.06 (s, 3H); 2.05 (m, 1H); 1.49 (m, 1H). MS (ES/+): m/z= 141 [M+H-PhCH(OAc)COOH]*. Intermediate 17 f4-Fluoro-2-methYl-phenvliroino>-acetic acid ethvl ester A solution of ethyl glyoxalate (50% solution in toluene - 40.8 mL) in toluene (180 imL) was heated to reflux for 1.5 hours under a Nitrogen atmosphere, in a flask equipped with a Dean Stark apparatus. Then, a solution of 4-fluoro-2-methyl-aniliae (10 g) in dry toluene (20 mL) was slowly added. The mixture was heated to reflux for 3 hours, then it was concentrated m vacua. The residue was purified by flash chromatography (toluene/CH/AcOEt 4:4:2) to give the title compound (13.06 g) as a yellow oil. T.I.C.: toluene/CH/AcOEt 4:4:2, Rf=0.67. NMR (CDC13): 8 (ppm) 7.8 (s, 1H); 6.95 (d. 1H); 6.85 (d, 2H); 4.4 (q, 2H); 2.35 (s, 3H); 3.3 (t3H). MS (ES/+): m/z=210 [M+H]*. Intermediate 18 ^-(4-Fluoro-2-methvl-pheaYlV4-oxo-lJt3.4-tetn>hvdro-pvridine-2-carboxvlic acid ethvl eater Boron trifluoride etherate (1.22 mL) was added to a solution of intermediate 17 (2 g) in anhydrous DCM (20 rat) previously cooled to -78°C under a Nitrogen atmosphere. After stirring for IS minutes at -78°C, the l-memoxy-3-trimethylsiioxy-l,3-butadiene (2.67 mL) was dropped over 45 minutes. The resulting solution was stirred at -78°C for 2 hours, then TFA (0.74 mL) was added. The mixture was stirred at 0°C for IS minutes, then a saturated sodium hydrogen carbonate solution was added and the mixture was extracted with AcOEt (3 x 50 mL). The combined organic extracts were dried and concentrated in vacua to give a residue, which was purified by flash chromatography (CH/AcOEt from 8:3 to 7:3) to give the fjt|e compound (1.5 g) as a pale yellow solid. T.I.C.: CH/AcOEt 6:4, Rf=0.2. NMR (CDC13): 8 (ppm) 7.4 (dd, 1H); 7.1 (d, 1H); 7.0-6.8 (m, 2H); 5.15 (d, 1H); 4.4 (m, 1H); 4.1 (m, 2H); 3.1-2.85 (m, 2H); 2.4 (s, 3H); 1.15 (t, 3H). Intermediate 19 W4-Fluoro-2-methvl-DbenY|V4-oio-ptperidtpe-2-carboivlic acid etfavl e»ter> L-sclectride (1M solution in dry THF, 3.96 mL) was added drop-wise, over 1 hour, to a solution of intermediate 18 (1 g) in dry THF (30 mL) previously cooled to -78°C under a Nitrogen atmosphere. After 1 hour, a saturated sodium hydrogen carbonate solution (20 mL) was added drop-wise and the solution was extracted with AcOEt (3 x 50 mL). The combined organic extracts were dried and concentrated in vacua to a residue, which was purified by flash chromatography (CH/AcOEt 8:2) to give the title compound (810 mg) as a white solid. T.I.C.: CH/AcOEt6:4, Rf=0.6. NMR (CDC13): 5 (ppm) 7.4 (dd, 1H); 7.1 (dd, 1H); 6.9 (dd, 1H); 6.8 (dt, 1H); 4.2 (q, 2H); 4.15 (m, 1H); 3.6 (m, 1H); 3.2 (m, 1H); 2.8-2.7 (dd, 2H); 2.6 (m, 2H); 2.4 (s, 3H); 1.2 (t, 3H). Intermediate 20 l-f4-Fluoro-2-methvl-phenvlV4-oxo-Diperidine-2-carborylicacid Lithium hydroxide monohydrate (241 mg) was added to a solution of intermediate (19 (300 mg) in MeOH (15 mL) and water (3 mL) and the resulting solution was stirred at 80°C for 1 hour. The solution was allowed to cool to r.t. and extracted with Et2O. The aqueous layer was acidified until pH=6 with acetic acid and extracted with AcOEt (3x15 mL). The combined organic extractes were dried and concentrated in vacua to give the title compound (230 mg) as yellow solid, which was used without any further purification in the next step. MS (ES/+): m/z=252 [M+H]+. Intermediate 21 l-f4-Fluoro-2-methvl-DhepYlV4-oxo-Diperidine-2-carborvlic acid. (3.5-bis-triOuoromethYl-benzvlV-methY|amide DIPEA (2.6 mL) and O-(benzotria2X>l-l-yl)-N,N^>N)-tetramethyluronium hexafluorophosphate (2.48 g) were added to a solution of intermediate 20 (1.259 g) in anhydrous DMF (25 mL) under a Nitrogen atmosphere. After stirring 30 minutes, (3,5-bis-trifluoromethyl-benzyl)-methylamine hydrochioride (1.62 g) was added and the mixture was stirred at r.t. for 16 hours. The reaction mixture was diluted with AcOEt (50 mL) and washed with a saturated ammonium chloride solution (30 mL), a saturated sodium hydrogen carbonate solution (30 mL) and brine (3 x 50 mL). The organic extracts were dried and concentrated in vacua. The residue was purified by flash chromatography (CH/AcOEt 9:1) to give the tide compound (1 .59 g) as a dark yellow oil. T.U.: CH/AcOEt 1:1, Rf=0.25. NMR(oVDMSO): 8(ppm) 8.03 (bs, 1H); 7.84 (bs, 2H); 7.03 (dd, 1H); 6.79 (dd, 1H); 6.64 (td, 1H); 4.80 (d, 1H); 4.67 (m, 1H); 4.29 (d, 1H); 3.55 (m, 1H); 3.04 (m, 1H); 2.74 (m, 1H); 2.5 (m, 1H); 2.4-2.2 (m, 2H); 2.40 (s, 3H); 2.38 (s, 3H). MS (ES/+): m/z-49l [M+HJ*. Eample Diperidiue-l-carborvllc acid (3,5-bis-trifluoromethYl-benzvlVmethYlamtde fla> and 2-rRW4-Fluora-2-methvl-DhenYlV4-rSW6-ox(>-heTahYdro-DvrroloH^-fll-Dvnuin-2-vlV A solution of intermediate 12 (129 rag) in anhydrous acetonhrile (2 mL) was added to a solution of intermediate 10 (300 mg) in anhydrous acetonitrile (5 mL) under a Nitrogen atmosphere. The solution was stirred at r.t for 15 minutes, then sodium triacetoxyborohydride (233 mg) was added. The mixture was stirred at 23°C for 2 days. The solution was diluted with AcOEt (15 mL) and washed with a 5% sodium hydrogen carbonate solution (15 mL) and brine (10 mL). The organic layer was dried and concentrated in vacua to a residue which was purified by flash chromatography (AcOEt/MeOH 8:2) to give two fractions: 1 . example la (21.9 mg) 2. example Ib (48 mg). Example la; T.l.c.:AoOEt/MeOH 8:2, RfH).38. NMR (dj-DMSO): S (ppm) 7.95 (bs, 1H); 7.71 (bs, 2H); 7.31 (dd, 1H); 6.94 (dd, 1H); 6.85 (dt, 1H); 4.89 (m, 1H); 4.55 (d, 1H); 4.41 (d, 1H); 3.78 (m, 1H); 3.52 (m, 1H); 3.35 (m, 1H); 3.14-3.05 (2m, 1H); 3.12 (m, 1H); 2.96-2.91 (2m. 1H); 2.81 (s, 3H); 2.74 (m, 1H); 2.62 (m, 1H); 2.26 (2s, 3H); 2.24 (m, 1H); 2.16 (m, 1H); 2.07 (m, 1H); 1.9 (m, 2H); 1.82 (m, 1H); 1.75 (m 1H); 1.72 (m, 2H); 1.51 (m, 1H). MS (ES/+) m/z-615 [M+H]*. Examnle Ib: T.I.c.:AcOEt/MeOH 8:2, Rf=0.28. NMR (d«-DMSO): 8 (ppm) 7.94 (s, 1H); 7.59 (s, 2H); 7.23 (dd, 1H); 6.89 (dd, 1H); 6.77 (dt, 1H); 4.62 (d, 1H); 4.36 (d, 1H); 4.14 (d, 1H); 3.73 (dd, 1H); 3.45 (m, 2H); 2.97 (dd, 1H); 2.9 (s, 3H); 2.81 (bt, 1H); 2.66 (m, 3H); 2.34 (s, 3H); 2.17 (m, 2H); 2.03 (m, 2H); 1.84 (m, 2H); 1.75 (bt, 1H); 1.65 (m, 1H); 1.5 (m, 1H); 1.39(m, 1H). MS (FAB/NBA) m/z=615 [M+H]+. Example 2 2-OlW4-Fluoro-2-methvt-phenvlV4-rSW6-oxo-hexahvdro-PYrrolofl^-al-pYrazia-2-Yn- pjperidine-l-carboiYlic acid f3^-bis-trifluoromethvl-benzYl)-methvIamide hvdrt)chloride A solution of example Ib (46 mg) in dry Et2O (2 mL) was treated with hydrochloric acid (IM hi Et2O - 0.083 mL) at 0°C under a Nitrogen atmosphere. The resulting solution was starred at 0°C for 30 minutes, then it was concentrated in vacua and the residue was triturated with pentane (2x3 mL) to give the title compound as a white solid (39.4 mg). NMR(dfi-DMSO): ftppm) 10.34 (bs, 1H); 7.96 (bs, 1H); 7.6 (bs, 2H); 12% (m, IK); 6.85 (m, 1H); 6.83 (m, 1H); 4.63 (d, 1H); 4.37 (bd, 1H); 4.22 (bd, 1H); 4.0 (bd, 1H); 3.88 (m, 1H); 3.7-3.2 (m, 6H); 2.94 (s, 3H); 2.4-2.0 (m, 4H); 2.35 (t, 3H); 2.34 (s, 3H); 1.95 (m, 2H); 1.8- 1.5(m,2H). > MS (ES/+) ra/z=615 [M+H-HClf. Examples 3 2-fltW4-Fluoro-2-roethYl-phenv|V4-(RWf8«S>^-oxi>-hexahYdro-pvrrolofl^-gl-PYrazin-2-vlVpiperidine-^-carboxYUc acid f3.5-bto-trifluoromethvl-b«iiZYft-metfaYlamide C3a) and 2^W4-Fluoro-2-methYl-pbenvlM-(SVff8aS>-6-oxo-hexahYdro-pYrrolofl^-a1-PYrazin-2-Yft-piperidlne-l-carboxvlic acid (35-bto-trifluoromethYl-t Intermediate 13a (259.3 mg) was added to a solution of intermediate 10 (550 mg) in anhydrous acetonmile (10 mL) under a Nitrogen atmosphere. The solution was stirred at r.t for 30 minutes, then sodium triacetoxyborohydride (474.8 mg) was added. The mixture was stirred at 23 °C for 8 hours. The solution was diluted with a 5% sodium hydrogen carbonate solution (15 mL) and extracted with AcOEt (3 x 25 mL). The combined organic extracts were dried and concentrated in vacua to a residue which was purified by flash chromatography (AcOEt/MeOH 8:2) to give two fractions: example 3a (177 mg) example 3b (280 mg). Example 3a: T.l.c.:AcOEt/McOH 8:2, RfH>.38. NMR(d«-DMSO): 5 (ppm) 7.96 (s, 1H); 7.72 (s, 2H); 7.31 (dd, 1H); 6.95 (dd, 1H); 6.86 (dt, 1H); 4.89 (t, 1H); 4.55 (d, 1H); 4.42 (d, 1H); 3.8 (d, 1H); 3.52 (m, 1H); 335 (m, 1H); 3.13 (m, IH); 3.06 (m, IH); 2.96 (m, IH); 2.81 (s, IH); 2.75 (m, IH); 2.64 (m, IH); 226 (s, 3H); 2.23-2.17 (m, 2H); 2.07 (m, 1H); 15 (m, 2H); 1.81-1.71 (m, 4H); 1.52 (m, 1H). MS (ES/+) m/z=615 (M+H|*. Example 3b: T,l.c.:AcOEi/MeOH 8:2, R£=0.28. NMR^-DMSO): 5 (ppm) 7.94 (s, 1H); 7.59 (s, 2H); 7.23 (dd, 1H); 6.89 (dd, 1H); 6.77 (dt, 1H); 4.62 (d, 1H); 4.36 (d, IH); 4.14 (d, IH); 3.73 (dd, 1H); 3.45 (m, 2H); 2.97 (dd, 1H); 2.9 (s, 3H); 2.81 (bt, IH); 2.66 (m, 3H); 234 (s, 3H); 2.17 (m, 2H); 2.03 (m, 2H); 1.84 (m, 2H); 1.75 (bt, IH); 1.65 (m, IH); 1.5 (m, IH); 1.39 (m, IH). MS (ES/+) m/z=615 [M+Hf. acid f35-bta^trifluoromethvl-beazvl>-methTlamide hvdrochloride A solution of example 3a (50 mg) in dry EtZO (2 mL) was treated with hydrochloric acid (1M in Et2O - 0.09 mL) at 0°C under a Nitrogen atmosphere. The resulting solution was stirred at 0°C for 10 minutes, then it was concentrated in vacua and the residue vqs triturated with pentane (2x2 mL) to give the t{tle compound as a white solid (50.8 mg). NMR (dg-DMSO): 5 ppm) 10.96 (bs, IH); 7.99 (bs, 1H); 7.81 (bs, 2H); 7.39 (m, IH); 7.01 (dd, IH); 6.93 (m, IH); 5.26 (t, IH); 4.57 (d, IH); 4.41 (d, IH); 4.1-3.75 (bm, 2H); 3.7-3.5 (m, 4H); 3.2 (m, IH); 3.16 (m, IH); 2.95 (s, IH); 2.86 (m, IH); 2.73 (s, 3H); 2^3 (s, 3H); 2.5-2.1 (m, 5H); 1.71 (m, IH); 1.6 (m, IH); 1.25 (m, IH). MS (ES/+) m/z=61 5 IM+H-HC1]*. Examples 2-vIVpiperidine-l-carfaoivlic add fS.S-bis-trifluoromethYl-hydrochloride A solution of example 3b (275 mg) in dry Et2O (5 mL) was treated with hydrochloric acid (1M in Et2O - 0.5 mL) at 0°C under a Nitrogen atmosphere. The resulting solution was stirred at 0°C for 30 minutes, then it was concentrated in vacua and the residue was triturated with pentane (2x3 mL) to give the fide compound as a white solid (268 mg). NMR(d6-DMSO): 5 (ppm) 11.1 (bs, IH); 7.95 (bs, IH); 7.6 (bs, 2H); 7.26 (dd, IH); 6.94 (dd, IH); 6.82 (m, IH); 4.63 (d, IH); 4.37 (d, IH); 4.21 (dd, IH); 3.97 (m, 2H); 3.55 (m, 4H); 3.21 (m, IH); 2.93 (s, 3H); 2.85 (m, 2H); 2.75 (m, IH); 2.32 (s, 3H); 2.4-2.1 (m, 5H); 1.97 (m, IH); 1.69 (q, IH); 1.57 (m, IH). MS (ES/+) m/z=615 [M+H-HCl]*. HPLC: Column Chiralpack AD 25cm x 4.6mm x 5u; mobile phase n-hexane/EtOH 8:2; flux=l mL/min; A.=225 nm; retention time 8.7 minutes. Examples 6 2-vn-piperidioe-l-carfaoxvUc acid f3.5-bU-trifluoromethvi-benzvt>-methvlamide (6a) and 2-fiRW4-Fluoro-2-niethYl-Dhen\1V4-fSWf8«RV6-oxo-hexahYdro-DYfrolo[U-fl1-Dvrazin-l-vR-piperidine-l-carborvlic add f3.S-bU-trifluoromethYl-benzYR-metbYlamide (6VA solution of intermediate 13 b (3.1 g) in anhydrous acetonitrile (60 + 50 mL) was added to a solution of intermediate 10 (7.2 g) in anhydrous acetonitrile (40 mL) under a Nitrogen atmosphere. The solution was stirred at r.t. for 20 minutes, then sodium triacetoxyborohydride (5.6 g) was added. The mixture was stirred at 23 °C for 13 hours. The solution was diluted with a 5% sodium hydrogen carbonate solution (30 mL) and water (90 mL), stirred at 23°C for 10 minutes, then concentrated in vacua to eliminate the acetonitrile. The residue was extracted with AcOEt (2 x 200 mL). The combined organic extracts were •washed with brine (300 mL), dried and concentrated in vacua to a residue which was purified by flash chromatography (AcOEt/MeOH 8:2) to give two fractions: example 6a (2.0 g) example 6b (3.67 g). > Example 6a: T.l.c.:AcOEt/MeOH 8:2, Rf=0.49. NMR (dVDMSO): 6. (ppm) 7.96 (bs, 1H); 7.72 (bs, 2H); 7.31 (bt, 1H); 6.95 (dd, 1H); 6.86 (dt, 1H); 4.89 (m, 1H); 4.55 (d, 1H); 4.42 (d, 1H); 3.78 (m, 1H); 3.53 (m, 1H); 3.35 (m, 1H); 3.14 (m, 2H); 2.92 (m, 1H); 2.82 (s, 3H); 2.75 (m, 1H); 2.63 (m, 1H); 2.27 (s, 3H); 2.23-2.17 (m, 2H); 2.08 (m, 1H); 1.91-1.7 (m, 6H); 1.52 (m, 1H). MS (ES/+) m/zr=615 [M+H]*. Example 6b: T.l.c.:AcOEt/MeOH 8:2, RtM>.33. NMR(d«-DMSO): 8 (ppm) 7.94 (s, 1H); 7.59 (s, 2H); 7.23 (dd, 1H); 6.89 (dd, 1H); 6.77 (dt, 1H); 4.62 (d, 1H); 4.36 (d, 1H); 4.14 (d, 1H); 3.73 (dd, 1H); 3.45 (m, 2H); 2.97 (dd, 1H); 2.9 (s, 3H); 2.81 (bt, 1H); 2.66 (m, 3H); 2.34 (s, 3H); 2.17 (m, 2H); 2.03 (m, 2H); 1.84 (m, 2H); 1.75 (bt, 1H); 1.65 (m, 1H); 1.5 (m, 1H); 1.39 (m, 1H). MS (ES/+) m/zF615 [M+H]+. Example 7 2-vft-piperidine-l-carboxvUc acid r33-bi«-trifluorometfaYl-benzvf>-roethvlamlde hvdrochloride A solution of example 6a (50 mg) hi dry Et2O (2 mL) was treated with hydrochloric acid (1M in Et2O - 0.09 mL) at 0°C under a Nitrogen atmosphere. The resulting solution was stirred at 0°C for 10 minutes, then it was concentrated in vacuo and the residue was triturated with pentane (2x2 mL) to give the title compound as a white solid (50.67 rag). NMR (d«-DMSO): g(ppm) 10.96 (bs, 1H); 7.98 (bs, 1H); 7.81 (bs, 2H); 7.38 (m, 1H); 7.01 (dd, 1H); 6.93 (m, 1H); 5.26 (bt, 1H); 4.56 (d, 1H); 4.41 (d, 1H); 4.1-3.8 (bm, 2H); 3.67 (m, 2H); 3.49 (bd, 2H); 3.21 (m, 2H); 3.13 (m, 1H); 2.91 (m, 1H); 2.73 (s, 3H); 2.24 (s, 3H); 2.5- 2.1 (m, 5H); 1.73 (m, 1H); 1.59 (m, 1H); 1.25 (m, 1H). MS (ES/+) m/z=615 [M+H-HCi]+. Example 8 2-vf>-pip€ridine-}-carborylic acid (3.5-bis-trifluoromethvl-beiizvn-methvlainide hydrochloride A solution of example 6b (3.0 g) in dry Et2O (30 mL) was treated with hydrochloric acid (1M in Et2O - 5.37 mL) at 0°C under a Nitrogen atmosphere. The resulting mixture was stirred at 0°C for 1.5 hours, men pentane (5 mL) and the solid was filtered off. The precipitate was washed with pentane (20 mL), Et2O (5 mL) and further pentane (1 5 + 30 mL) to give the titje compound as a white solid (3.1 g). NMR (d«-DMSO): 6 (ppm) 11.06 (bs, 1H); 7.95 (bs, 1H); 7.6 (bs, 2H); 7.27 (dd, 1H); 6.94 (dd, 1H); 6.82 (m, 1H); 4.63 (d, 1H); 4.37 (d, 1H); 4.22 (dd, 1H); 3.97 (m, 2H); &56 (m, 4H); 3.21 (m, 1H); 2.93 (s, 3H); 2.89 (m, 2H); 2.75 (m, 1H); 2.36 (s, 3H); 2.4-2.1 (m, 5H); 1.91 (m,lH); 1.72 (q, 1H); 1.57 (m, 1H). MS (ES/+) m/z?=615 [M+H-HClf. HPLC: Column Chiralpack AD 25cm x 4.6mm x 5u; mobile phase n-hexane/EtOH 8:2; flux=l mL/min; X=225 nm; retention time 9.5 minutes. Example 9 2-rRV(4^Fluoro-2-methYt-phenYtV4-(RW(8aS>-6-oxo-hciahYdro-PYrrolofia-a1-pYrazia-2-yl)-pip«ridine-l-carboiYUc acid fl-(RW3^-bis-triflnoromethvl-phenvn-et^vl]-methvlamide f9«) and 2-vtVpiperidine-l-carborylic acid H-rRW3.S-bb-trifluoromethYl-phenvlV-etbvU-roethvlamide Method A; Intermediate 4a (168 mg) and sodium triacetoxyborohydride (127 mg) were added to a solution of intermediate 13a (80 mg) in anhydrous acetomtrile (4 mL) under a Nitrogen atmosphere. The mixture was stirred at 23°C for 14 hours. The solution was diluted with a 5% sodium hydrogen carbonate solution (5 mL) and extracted with AcOEt (2x10 mL). The combined organic extracts were dried and concentrated in vacuo to a residue which was purified by flash chromatography (AcOEt/MeOH 9:1) to give three fractions: 1. example 9a (18 mg) a a white solid mixture of example 9a and 9b (160 rag) example 9b (8 mg) as a white solid. Method B; A solution of intermediate 13a (2.4 g) in anhydrous acetonitrile (80 mL) was added to a solution of intermediate 4a (S.7 g) in anhydrous acetonitrile (30 mL) under a Nitrogen atmosphere. Sodium triacetoxyborohydride (4.36 g) was added in three portions every IS minutes and the mixture was stirred at 23°C for 22 hours. The solution was diluted with water (75 mL) and a saturated sodium hydrogen carbonate solution (25 mL) and extracted with AcOEt (2 x 200 mL). The combined organic extracts were dried and concentrated in vacua to a residue which was purified by flash chroraatography (CH/AcOEt/MeOH 50:50:8) to give four tractions: mixture example 9a and example 9b (1.27 g) in ratio 1:1 example 9b (1.66 g) (ratio 9a:9b=13:87) example 9b (420 mg) (ratio 9a:9b=5:95) example 9b (800 mg) (ratio 9a:9b=2:98) Example 9a: T.l.c.:AcOEt/MeOH 8:2, Rf=0.55. MS (ES/+) m/z?=629 [M+H]*. HPLC: Column Supelcosil ABZ Plus 25cm x 4.6mm x 5ft; mobile phase NH^OAc 10 mmol/CHaCN from 60:40 to 10:90 in 5 min. then NIfcOAc 10 mmol/CH3CNMbr 10 min.; flux=0.8 mL/min; X-220 nm; retention time 9.27 minutes. Example 9b: T.l.c.:AcOEbMeOH 8:2, Rf=0.48. MS (ES/+) m/zr=629 fM+HJ*. HPLC: Column Supelcosil ABZ Plus 25cm x 4.6mm x 5m mobile phase NHiOAc 10 mmol/CHsCN from 60:40 to 10:90 in 5 rain, men NH flux=0.8 mL/min; X-220 nm; retention time 8.84 minutes. Example 10 2-(RW4-Fluoro-2^methYl-pfaenYi>-4-fRW(8aS>-6-oio-he«ihYd ra-pYirotoFl .2-al-pvrazin-?-vn-pipendine-l-carborvllc add H-(RW3^-bi5-triflBorometfavl-phenYn-ethvll-metfavlamldy hydrocfaloride A solution of example 9a (18 mg) in dry Et2O (1.3 mL) was treated with hydrochloric acid (1M hi Et2O - 32 nL) at 0°C under a Nitrogen atmosphere. The resulting mixture was stirred at 0°C for 30 minutes, then the mixture was concentrated in vacua. The precipitate was washed with pentane (2 mL) to give the tfrl? goinpflBlrt M a whHe solid (17.6 mg). NMR (d6-DMSO): 8 (ppm) 10.65 (bin, 1H); 7.99 (s, IH); 7.76 (s, 2H); 7.37 (dd, IH); 7.01 (dd, IH); 6.93 (dd, IH); 5.24 (bm, IH); 5.04 (q, IH); 4.0-3.95 (bm, 2H); 3.68 (m, IH); 3.58 (m, 2H); 3.51 (m, IH); 3.24-3.15 (m, 2H); 2.96 (m, IH); 2.85 (m, IH); 2.54 (s, 3H); 236-2.13 (m, 6H); 2.21 HPLC: Column SupeJcosil ABZ Plus 25cm x 4.6mm x 5/i; mobile phase NfyOAc 10 mmol/CHjCN from 60:40 to 10:90 in 5 min. then NH»OAc 10 mmoyCHjCN 10:90 for 10 min.; flux=0.8 mL/min; X=220 nm; retention time 9.26 minutes. Example 11 2-vR-ptperidiae-l-carboryilc acid fl-flR)-Q^-bto-trifluoromethvl-pheaYD-ethyfl-methYlamide rrydrochloride A solution of example 9b (8 mg) in dry Et2O (1 mL) was treated with hydrochloric acid (1M in Et2O - 14 \tL) at 0°C under a Nitrogen atmosphere. The resulting mixture was stirred at 0°C for 20 minutes, then me mixture was concentrated in vacua. The precipitate was washed with pentane (2 mL) to give me title compound as a white solid (7.6 mg). NMRCds-DMSO): 5 (ppm) 10.22 (bs, 1H); 7.99 (s, 1H); 7.67 (s, 2H); 7.22 (dd, 1H); 6.94 (dd, 1H); 6.81 (t, 1H); 5.31 (q, 1H); 4.2 (dd, 1H); 4.0-3.86 (bin, 2H); 3.6-3.4 (m, 2H); 3.1-2.7 (m, 4H); 2.73 (s, 3H); 2.4-2.0 (m, 5H); 2.35 (s, 3H); 1.94 (m, 1H); 1.74 (q, 1H); 1.57 (d, 3H); 1.46(d,3H). MS (ES/+) m/z=629 [M+H-HC1]*. HPLC: Column Supeloosil ABZ Plus 25cm x 4.6mm x Sp, mobile phase NH mrnoi/CHjCN from 60:40 to 10:90 in 5 min. then NHiOAc 10 mmol/CHjCN frdtn 10:90 for 10 min.; flux=0.8 mL/min; X=220 nm; retention time 8.86 minutes. Column X-Terra 4.6 x 100mm, RF18 3.5fim; mobile phase: eluant A: NKUHCOj 5mM (pH=8yCH3CN 90/10 - eluant B: NH^COj 5mM (pH=8y CH3C!N 10/90 - Gradient: from 50% B to 100% B in 7.5min; 100% B for O.Smin then 50% B for 3 min.; column temp.: 40°C; flow= Imiymtn; X- 210 nm; retention time 4.15 minutes. 2-vn-Dineridine-l-carbo»Ylic acid H-fRVf33-b A 2% sodium hydroxide solution (100 mL) was added to a suspension of example llc(10 g) in AcOEt (150 mL). Then the two phases mixture were stirred for 10 minutes and the layers were separated. The organic phase was washed with water (100 mL) and men concentrated in vacua up to 40 mL. AcOEt (100 mL) was added to the organic phase, which was then concentrated in vacua a second time up to 40 mL. The solution was further diluted with AcOEt (60 mL) and 5-6N hydrochloric acid in tsopropanol (3 mL) was added. After 5 minutes the clear solution was seeded. Precipitation occurred hi a few minutes and after norther 20 minutes stirring, n-heptane (100 mL) was added in 10-15 minutes. The obtained mixture was stirred 2 hours at 20°C.The solid was then filtered, washed with AOEt/n-heptane 1/1 (60 mL) and dried in vacua at 40°C for 16 hours to give the title compound (8.08 g) as a white solid. X ray podwer diffraction data are reported in table 1 Table 1 The X-ray podwer diffraction pattern of the product of the Example lla in terms of d spacing is as follows Examle lib 2-YlV-plperidme-l-carboxYllc adj fl-flRW3«S-bU-triflBoromethy|-DhiiiiYlW^iYJl]-metfavlamide hvdrochloride as dlhvdratc crvstalUae form To a 265 mg of example lla , 3 ml of water was added. The suspension was stirred overnight at 25°C and then centrifuged for 5 min at 10000 rpm. The solid was filtered using a centrifugal filter device (MiHipore Ultrafree-MC 0.45um) to obtain the title compound. ( 250mg) ' X ray podwer diffraction data are reported in table 2 Table 2 The X-ray podwer diffraction pattern of the product of the Example lib in terms of d spacing is as follows Table 2 24RW4-Fluoro-2-metbYl-phettYl>-4^SW(8aSV6-oxo-heiahYdro-pYrrolQfl4-aT-PYrarin-2-vlVpiDeridiae-l-carfaoivlic add methvlamide maleate Method At Intermediate 16 (25 g) was suspended in acetonitrile (300 mL), then TEA (10.4 mL) was quickly added in order to obtain the free base: the aspect of the slurry did not change as a new precipitate of TEA-acetylmandelate salt was formed. The mixture was kept under stirring for 15-20 minutes. Meanwhile intermediate 4a (25 g) was dissolved in acetonitrile (125 mL) and the so-obtained solution was quickly added to die slurry. Then Sodium triacetoxyborohydride (15 g) was added all at once and the mixture was kept under stirring conditions for 22 hours. The white precipitate was filtered off and the mother liquors were evaporated to 100 mL. A.cOEt (250 roL) was added to the so-obtained mixture and the resulting solution was washed with aqueous 4% sodium hydrogen carbonate solution (2 x 125 mL) and then with 5% sodium chloride solution (125 mL). The organic layer dried and evaporated to 100 mL. [sopropyl alcohol (I SO ml) was added and the mixture was evaporated again to 100 mL. This operation was repeated. The final volume of the mixture was adjusted to 200 mL adding further isopropyl alcohol (100 mL). A solution of maleic acid (5.8 g) in isopropyi alcohol (50 mL) was dropped in ca. 10 minutes. The mixture was seeded and precipitation occurred in few minutes. The slurry was stirred 1 hour at 20°C and isoctane (250 mL) was added in 10 minutes. The resulting suspension was stirred at room temperature for 22 hours. The solid was filtered and washed with isopropanol/isoctane 1/1 (ISO mL) and dried in vacua at 40°C for 18 hours giving the title compound (13.75g) as a white solid. Method B; Intennediate 16 (1 g) was suspended in acetooibile (12 mL), then TEA (0.415 mL) was quickly added in order to obtain the free base: the aspect of the slurry did not change as a new precipitate of TEA-acetykuandelate salt was formed. After 30minutes of stirring, the mixture was treated with sodium triacetoxyborohydride (0.6 g) plus formic acid (0.224 mL). Meanwhile intennediate 4a (1 g) was dissolved in acetonitrile (6 mL) and the so-obtained solution was quickly added to the slurry and the resulting mixture was kept under stirring conditions for 18 hours. The slurry was evaporated to small volume. AcOEt (10 mL) was added to the so-obtained mixture and the resulting solution was washed with aqueous 4% sodium hydrogen carbonate (2 x 5 oiL) and then with 5% sodium chloride solution (5 mL). The organic layer was dried and evaporated to a white foam. Isopropyl alcohol (10 mL) was added and the mixture was evaporated again to dryness. The resulting foam was, once again, dissolved in isopropyl alcohol (8 mL) and treated drop-wise with a solution of maleic acid (0232 g) in isopropyi alcohol (2 mL). After 30 minutes the mixture was seeded and precipitation occurred in a few minutes. The slurry was stirred 1 hour at 20°C and then isoctane (10 mL) was added dropwise over 5-10 minutes. The resulting suspension was stirred at room temperature for 19 hours. The solid was filtered and washed with isopropanol/isoctane 1/1 (5 mL) and dried in vacua at 40°C for 18 hours giving the tide compound (0.639 g) as a white solid. HPLC: Column X-Terra 4.6 x 100mm, RP18 3.5um; mobile phase: eluant A: NJL^ICOj SraM (pH-8yCH3CN 90/10 - eluant B: NfyHCOj 5raM (pH=8)/CH3CN 10/90 - Gradient from 50°/o B to 100% B in 7.5 minutes; 100% B for 0.5 minutes men 50% B for 3 minutes; column temp. 40°C; flow* ImL/mia; X« 210 am; retention times 4.15 minutes, >99%a/a. 'H-NMR (de-DMSO): 5 (ppm) 7.98 (bs, IH); 7.68 (bs, 2H); 7.21 (dd, 1H); 6.93 (dd, IH); 6.81 (dt, IH); 6.09 (s, 2H); 5.31 (q, IH); 4,19 (dd, 1H>; 3.93 (m, 1H); 3.74 (bra, IH); 3.46 (m, IH); 3.45 (bm, IH); 3,30 (bm, 2H); 2.93 (bt, IH); 2.79 (t, IH); 2.73 (s, 3H); 2,73 (bm, IH); 2.60 (bm, IH); 2.35 (s, 3H); 2.23 (m, 2H); 2.12 (m, IH); 2.04 (bd, IH); 1.98 (bd, IH); 1.84 (m, IH); 1.64 (q, IH); 1.56 (m, IH); 1.46 (d, 3H). MS (ES/+): m/z?= 629 [MH-HOOCCHCHCOOH]* Example 12 2-yn-piperiditte-l-carboivlic acid H-fRW3,S-big-trifluororoethvl-phepYlVetfaYl|- methvlamide (12a> and 2-ylVpiperidiae-l-carboivlic add H-fftW33-bis-trifluororoethvl-phePYl>-ethYl1-methvlamide (lib) Method A; Intermediate 13b (220 mg) was added to a solution of intermediate 4a (504 mg) in anhydrous acetonhtile (10 mL) under a Nitrogen atmosphere, The solution was stirred at r.t for 15 minutes, then sodium triacetoxyborohydride (422 mg) was added. The mixture was stirred at 23°C for 18 hours. The solution was diluted with a 5% sodium hydrogen carbonate solution (5 mL) and extracted with AcOEt (3 x 30 mL). The combined organic extracts were dried and concentrated in vacua to a residue which was purified by flash chromatography (AcOEt/MeOH 9:1) to give three fractions: example 12a (125 mg) as a white solid. mixture of example 12a and 12b (9SO mg) ^ 3 . example 12b (280 mg) as a white solid. Method B; Intermediate 4a (10.45 g) and sodium triacetoxyborohydride (6.32 g) were added to a solution of intermediate 13b (4.35 g) in anhydrous acetonitrile (200 mL) under a Nitrogen atmosphere. The mixture was stirred at 23°C for 14 hours. The solution was diluted with water (50 mL) and with a saturated solution of sodium hydrogen carbonate (30 mL) and extracted with AcOEt (3 x 100 mL). The combined organic extracts were dried and concentrated in vacua to a residue which was purified by flash chromatography (CH/AcOEt/MeOH 50:50:8) to give these fractions as white foams: mixture 12a and lib (1 g) (ratio 12a:12b=75:25) mixture 12a and 12b (2.65 g) (ratio 12a:12b=50:50) example lib (2.13 g) - (ratio 12a:12b=16:84) example 12b (1.4 g) (ratio 12a:12b=6:94) mixture of 12a and 12b (0.5 g) (ratio 12a:12b=30:70) example 12a (1.6 g) (ratio 12a:12b=95.5) ' Example 12a: T.l.c.:AcOEt/MeOH 9:1, Rf=0.24. MS (ES/+) m/2f=629 [M+H]+. HPLC: Column Supelcosil ABZ Plus 25cm x 4.6mm x 5m mobile phase Nf^OAc 10 mmoVCHjCN from 60:40 to 10:90 in 5 min. then NKUOAc 10 mmol/CHjCN 10:90 for 10 nun.; flux=*0.8 mL/min.; X 220 nm; retention time 9.28 minutes. Example 12b: T.l.c.:AcOEt/MeOH 9:1, RN).2. MS (ES/+) m/z=629 [M+HT. HPLC: Column Supelcosil ABZ Plus 25cm x 4.6mm x 5fi; mobile phase NH^OAc 10 mmol/CHjCN from 60:40 to 10:90 in 5 min. then NH^OAc 10 mmol/CHjCN 10:90 for 10 min.; flux=0.8 mL/min; X=220 nm; retention time 8.86 minutes. Example 13 2-fRVf4-Flaoro-2-roethYl-DhenYl>-4-(RW(8aRV^-oa:o-beiahYdro-pvtToloflJ-a1-pvnudn-2-vn-Diperidiae-l-carfaoxylic acid fl-TRW3.S-bi8-trifluoroniethvI-phenYR-ethvU-methvJainide hvdrochloride A solution of example 12a (125 mg) in dry Et2O (3 mL) was treated with hydrochloric acid (1M in Et2O - 201 \iL) at 0°C under a Nitrogen atmosphere. The resulting mixture was stirred at 0°C for 15 minutes, men the mixture was concentrated in vacua. The precipitate was triturated twice with Et2O/pentane 2: 1 (2 mL) to give the title compound as a white solid (115mg). NMR (d«-DMSO): 8 (ppm) 10.9-10.6 (bm, 1H); 7.99 (s, 1H); 7.76 (s, 2H); 7.36 (dt, 1H); 7.0 (dd, 1H); 6.92 (dt, 1H); 5.25 (bt, 1H); 5.05 (q, 1H); 3.98 (m, 2H); 3.67 (m, 2H); 3.58 (m, 1H); 3.44 (m, 1H); 3.2 (m, 2H); 2.9 (m, 2H); 2.53 (s, 3H); 2.22 (s, 3H); 2.4-2.1 (m, 6H); 1.73 (m, lH);1.56(m,lH);1.56(d,3H). MS(ES/+)m/2^29[M+H-HCl]+. >• ^Example 14 2-YJV-plperidlne-l-carboxYik acid fl-raW3^bi»-trifluoroniethYl-phenYr>-etfayn-metfavliunidfl hydrochloride A solution of example lib (280 mg) in dry Et2O (5 mL) was treated with hydrochloric acid (1M in Et2O - 473 uL) at 0°C under a Nitrogen atmosphere. The resulting mixture was stirred at 0°C for 15 minutes, men the mixture was concentrated in vacua. The precipitate was triturated twice with Et2O/pentane 2: 1 (2 mL) to give the title compound as a white solid (245 rag). NMR (d«-DMSO): 8 (ppm) 11.05 (bs, 1H); 7.95 (s, 1H); 7.64 (s, 2H); 7.19 (dt, 1H); 6.9 (dd, 1H); 6.78 (dt, 1H); 5.28 (q, 1H); 4.16 (dd, 1H); 3.53 (m, 2H); 3.41 (m, 2H); 3.17 (t, 1H); 2.94 (m, 2H); 2.96-2.8 (m, 2H); 2.75 (t, 1H); 2.69 (s, 3H); 2.31 (s, 3H); 2.3-2.0 (m, 1H); 4.9 (m, 1H); 1.75 (q, 1H); 1.5 (m, 1H); 1.43 (d, 3H). MS (ES/+) m/z=629 [M4-H-HC1]+. Example IS 2-vl>-Ptperidine-l-carboxvlic acid methvlamide (15») and 2-fRV-f4-Fluoro-2-inethYl-phenvlV4-(SW-f3^-bla-triflaoromethvl-pheqYl>-e^yll-methvlamide (ISb) Intermediate 13a (250 mg) was added to a solution of intermediate Sb (449 mg) hi anhydrous acetonitrile (9 mL) under a Nitrogen atmosphere. The solution was stirred at r.t for 1 hour, then sodium triacetoxyborohydride (282 mg) was added. The mixture was stirred at 23°C for 16 hours. The solution was diluted with a 5% sodium hydrogen carbonate solution (10 mL) and extracted with AcOEt (3 x 30 mL). The combined organic extracts were washed with brine (10 mL), dried and concentrated in va&io to a residue which was purified by flash chromatography (AcOBt/MeOH 8:2) to give three fractions: example 15a (181 mg) as a white solid. mixture of example ISa and 15b (40 mg) 3 . example 15b (2 1 8 mg) as a white solid. Example 15a: T.l.c.:AcOBt/MeOH 8:2, RHK46. MS (ES/+) m/z=629 [M+Hf. Example ISb: T.l.c.:AcOEtfMeOH 8:2, Rf=0.24. NMR (ds-DMSO): 5 (ppm) 1.45 (m, 1H); 1.47 (d, 3H); 1.65 (m, IH); 1.70 (m, 1H); 1.85 (m, IH); 1.9 (m, IH); 1.95 (m, IH); 2.00 (m, 1H); 2.05 (m, IH); 2.25 (m, 2H); 2.34 (s, 3H); 2.65 (m, 1H); 2.77 (m, 1H); 2.80 (m, IH); 2.81 (s, 3H); 3.40 (m, 1H); 3.41 (ra, 1H); 3.46 (dd, 1H); 3,74 (m, 2H); 4.13 (dd, 1H); 5.33 (q, 1H); 6.74 (m, 1H); 6.88 (dd, 1H); 7.54 (s, 2H); 7.20 (dd, lH);7.93(s,2H). MS (ES/+) m/2?=629 [M-HI]*. Example 16 2-vn-piperidine-l-carboivUc acid methvlamide (ISbl A solution of example ISb (218 mg) in dry Et2O (1 mL) was treated whh hydrochloric acid (1M in Et2O — 380 uL) at 0°C under a Nitrogen atmosphere. The resulting mixture was stirred at 0°C for 1 hour, men the mixture was concentrated in vacua. The precipitate was triturated twice with pentane to give the titjg compound as a white solid (1 95 mg). NMR (d«-DMSO): 8 (ppm) 10.60 (sb, 1H); 7.94 (s, 1H); 7,54 (s,2H); 7.22 (dd, IH); 6.93 (dd, 1H); 6.80 (td, 1H); 5.33 (q, 1H); 4.20 (bd, IH); 3.98 (bd, 1H); 3.92 (m, 1H); 3.60 (m, 1H); 3.46 (m, IH); 3,53 (m, IH); 3.43 (m, IH); 3.14 (bt, IH); 2.96 (m, IH); 2.86 (m, IH); 2.85 (s, 3H); 2.6 (s, 3H); 2.73 (m, IH); 2.2-2.35 (m, 2H); 2.19 (m, IH); 2.15 (m, IH); 2.16 (m, IH); 1.95 (dd, IH); 1.64 (dd, IH); 1.58 (m, IH); 1.50 (d, 3H). Example 17 2-fRVf4-Fluoro-2-methYl-phenvn-4-rR>-(f8aRV6-oio-hexahvdro-pvrToloflJ-al-Dvrazin-2-vlVpiperidine-l-carboxvlic actd H-(SW3^-bLs-trifluorometfaYl-DhenvlVethvll-methvlamide (17al and 2^Vf4-FJuoro-2-metbvl-pbettvlV4-fSWf8aRV6-ox(>-heMhvdro-PYrTolotl.2-a1-Dvrazin-2-vn-piperidine-l-orboxvlic acid H-fSW33-bjs-trifluoromethvt-phenvn-ethvn-methvlamlde (lib) Intermediate 13b {220 mg) was added to a solution of intermediate 5b (500 mg) in anhydrous acetonitrile (10 mL) wider a Nitrogen atmosphere, The solution was stirred at r.t for 30 minutes, then sodium triacetoxybcrohydnds (422 rag) was added. The mixture was stirred at 23°C for 18 hours. The solution was diluted with a 5% sodium hydrogen carbonate solution (5 mL) and extracted with AcOEt (3x30 mL). The combined organic extracts were washed with brine (10 mL), dried and concentrated in vacua to a residue which was purified by flash chromatography (AcOEt/MeOH 8:2) to give two fractions: example 17a (160 mg) as a white solid. example 17b (243 mg) as a white solid. Example 17a: T,l.c.:AcOEt/MeOH8:2,Rf=0.21. NMR(d«-DMSO): 8 (ppm) 1.50 (d, 3H); 1.53 (m, 1H); 1.71 (m, IH); 1.72 (m,^; 1.75 (m, 1H); 1.81 (m, 1H); 1.88 (m, 1H); 1.94 (m, 1H); 2.09 (m, IH); 2.19 (m, 2H); 226 (s, 3H); 2.64 (m, IH); 2.71 (s, 3H); 2.76 (m, 1H); 2.93 (m, 1H); 3.08 (m, 1H); 3.15 (m, 1H); 3.27 (m, 1H); 3.53 (m, 1H); 3.74 (m, 2H); 3.88 (bm, 1H); 4.85 (dd, IH); 5.27 (q, 1H); 6.84 (td, 1H); 6.94 (dd, 1H); 7.30 (dd, IH); 7.69 (s, 2H); 7.95 (s, 1H). Example 17b: T.l.c.:AcOEtfMeOH8:2,Itf=O.J3. NMR (ds-DMSO): 5 (ppm) L45 (d, 3H); 1.6-2.27 (bm, 10H); 2.3 (s, 3H); 2.61-2.97 (bm, 4H); 2.78 (s, 3H); 2.9 (bd, 1H); 3.4 (d, 2H); 3.7-3.9 (bm, 1H); 4.1 (dd, 1H); 5.27 (q, 1H); 6.72 (td, 1H); 6.84 (dd, 1H); 7.15-7.19 (dd, 1H); 7.5 (s, 2H); 7.89 (s, 1H). Example 18 2-fRVf4-FluorQ-2-me^hYl-pheHYlV4-(SWf8aRV6-oxo-hexahYdro-pvrrolotl^-al-pvrazltt- 2-Yn-piperidtne-l-carborvlic acid H-(SVf3.S-bU-trifluoromethvI-pheavn~ethvl|- methvlamide' A solution of example 17b (235 mg) in dry Et2O (4.2 mL) was treated with hydrochloric acid (1M in Et2O - 411 |iL) at 0°C under a Nitrogen atmosphere. The resulting mixture was stirred at 0°C for IS minutes, then the mixture was concentrated in vacua. The precipitate was triturated three times with pentane to give the title compound as a white solid (243 mg). NMR (d«-DMSO): 5 (ppm) 10.88 (bs, 1H); 7.94 (s, 111); 7.54 (s, IH); 7.23 (dd, 1H); 6.93 (dd, 1H); 6.79 (td, IH); 533 (q, IH); 4.21 (dd, IH); 3.99 (bs, IH); 3.97 (m, IH); 3.55 (m, IH); 3.54-2.7 (m, IH); 3,57 (m, IH); 3,44 (ro, IH); 3.18 (t, IH); 2.95 (m, IH); 2.84 (s, 3H); 2.7 (t, 1H); 236 (s, 3H); 2.3 (m, 1H); 2.17 (m, 1H); 2.15 (q, 1H); 2.1 (m, 1H); 1.69 (q, 1H); 1.56 (m, lH);1.50(d,3H). Examples 19 2-rRW4-FluortH2-methvl-pfaenYn-4-(R>-(fflaS>-6-oio-heiahYdro-pYrroloflJ-fl1-nvrazin-2-vlVniperidine-l-carfaoiYHc add f3.5-dlcbloro-benzvlVinethvlamide flfrp and 2-rRW4-Fluoro-2-methvl-phepvlV4-(SWr8aSV6-oio-hexahYdro-DYrroloH3-a1-pvraain-2-vlVpiperidiae-l-carboxYUc acid (33-dicMoro-beitzvlVinethYlainide fl9b1 Intermediate 13a (40 mg) was added to a solution of intermediate 14 (100 mg) in anhydrous acetooitrile (5 mL) under a Nitrogen atmosphere. The solution was stirred at r.t. for 15 minutes, then sodium triacotoxyborohydridc (90 mg) was added. The mixture was stirred at 23°C for 20 hours. The solution was diluted with a saturated sodium hydrogen carbonate solution (10 mL) and extracted with AcOEt (3 x 50 mL). The combined organic extracts were dried and concentrated in vacua to a residue which was purified by flash chromatography (AcOEt/MeOH 8:2) to give two fractions: example 19a (25 mg) example 19b (40 mg). Example 19a:> T.l.c.:AcOEt/MeOH 8:2, MS (ES/+) m/z=547 {M+Hf. Example 19b: T.l.c.:AcOEl/MeOH 8:2, MS (ES/+) m/z=547 |JM+H]+. Example 20 2-vtVpiperidtnfc-l-carborvlic acid QiS-dichloro-bfflTvlVnicthvliunide hvdrochiortde A solution of example 19a (25 mg) in dry EGO (1 mL) was treated with hydrochloric acid (1M in Et2O - 54 jiL) at 0°C under a Nitrogen atmosphere. The resulting mixture was stirred at 0°C for 15 minutes, then the mixture was concentrated in vacua. The precipitate was triturated with Et2O/pentane 1:1 and men pentane to give the title compound as a white solid (20 mg). NMR (ds-DMSO): 5 (ppm) 10.95 (bs, 1H); 7.44 (s, 2H); 7.35 (m, 2H); 7.00 (s, 1H); 6.85 (m, 1H); 5.2- 4.8 (m, 1H); 4.4-4.2 (dd, 2H); 4.05-3.5 (m, 10H); 3.2-1.5 (m, 8H); 2.7 (s, 3H); 2.27 (s,3H). MS (ES/+) m/z=547 [M+H-HC1]*. Example 21 2-mW4-Fluoi^2-methvl-pheavlV4-fSWr8aS>-€-oxo-heiahYdro-pYrrolofl.2-al-pvrazin-2-vR-Piperidine-l-carboxvllc add f3^-dichloro-benzYlVmethvlamldehvdrochioride A solution of example 19b (40 mg) in dry Et2O (1 mL) was treated with hydrochloric acid (1M in Et2O - 87 fiL) at 0°C under a Nitrogen atmosphere. The resulting mixture was stirred at 0°C for IS minutes, men the mixture was concentrated in yacuo. The precipitate was triturated with Et2O/pentane 1:1 and then pentanc to give the title compound as a white solid (35 mg). NMR (d«-DMSO): 6 (ppm) 10.95 (bs, 1H); 7.44 (t, 1H); 7.28 (dd, 1H); 6.96 (dd, 1H); 6.93 (td, 1H); 6.89 (s, 2H); 4.49 (d, 1H); 4.19 (d, 1H); 4.16 (d, 1H); 3.97 (m, 2H); 3.6 (dd, 1H); 3.54 (m, 1H); 3.51 (dd, 1H); 3.46 (m, 1H); 3.19 (dd, 1H); 2.94 (m, 1H); 2.90 (s, 3H); 2.86 (dd, 1H); 2.37 (S, 3H); 2.26 (m, 1H); 2.24 (dd, 1H); 2.23 (dd, 1H); 2.17 (m, 1H); 1.96 (dd, 1H); 1.69 (dd, 1H); 1.58 (m, 1H). MS (ES/+) m/z=547 [M+H-HClf . Example* 22 2-vlVplperldine-l-cgrbo*ylic add (3.5-dichloro-bepZYlVpieth.Ylainide (22aV aiuj 24RW4-Fluoro-2-metfaYt-phenvfM-fS>-(r8aR>-6-ozo-l|9^«hYdro-PvrroloflJ-al-PYrazln-l-vfl-pjperidine-l-carboivlic acid (3^-dichioro-bemylV-nKthvlamide (12V\ Intermediate 13b (40 mg) was added to a solution of intermediate 14 (100 mg) in anhydrous acctonitrile (5 mL) under a Nitrogen atmosphere. The solution was stirred at r.t. for IS minutes, men sodium triacetoxyborohydride (90 mg) was added. The mixture was stirred at 23°C for 20 hours. The solution was diluted with a saturated sodium hydrogen carbonate solution (10 mL) and extracted with AcOEt (3 x 50 mL). The combined organic extracts were dried and concentrated in vacua to a residue which was purified by flash chromatography (AcOEt/MeOH 8:2) to give two fractions: 1. example 22a (23 mg) 2. example 22b (43 mg). Example 22a: T.l.c.:AcOEt/MeOH 8:2, RfN).36. MS (ES/+) m/z=547 [M+HJ\ Example 22b: T.l.c.:AcOEt/MeOH 8:2, Rf=0.2. MS (ES/+) m/zf547 [M+Hf. 23 2-(RV-r4-Fluoro-2-methvl-pheoYn-4-2-a1-pYrazin-2-YlV-piperidine-l-cnrboxYHc acid f3.S-dichloro-bepgylVmethYlamide hvdrochloride (1M in Et2O - 46 nL) at 0°C under a Nitrogen atmosphere. The resulting mixture was stirred at 0°C for 1 hour, men the mixture was concentrated m vocuq. The precipitate was triturated with pentane to give the title comp^u^ »s a white solid (25 mg). NMR (d«-DMSO): 8 (ppm) 10.77 (bs, IH); 7.48 (t, IH); 7.37 (dd, IH); 7.14 (m, 2H); 7.03 (dd, IH); 6.96 (td, IK); 5.23 (m, IH); 4.33 (d, IH); 4.28 (d, 1H); 3.99 (m, IH); 3.98 (m, 1H); 3.7 (dd, IH); 3.63 (m, IH); 3.6 (dd, IH); 3.49 (m, IH); 3.19 (t, IH); 3.14 (dd, IH); 2.93 (m, IH); 2.71 (s, 3H); 2.4-2.2 (m, 2H); 2.35 (m, IH); 2.27 (s, 3H); 2.22 (m, IH); 2.18 (m, IH); 2.17 (m, IH); 1.75 (m, IH); 1.6 (m, IH). MS (ES/+) m/r=547 [M+H-HC1]*. Example 24 2-vl)-piperidine-l-carboiYlic acid C35-dichloro-bcnzviVinethYl»mide hvdrochloride A solution of example 22b (41 mg) in dry Et2O (1 mL) was treated with hydrochloric acid (1M in Et2O - 46 fiL) at 0°C under a Nitrogen atmosphere. The resulting mixture was stirred at 0°C for 15 minutes, then the mixture was concentrated in vacua. The precipitate was triturated with Et2O/pentane 1:1 and men pentane to give the title compound as a white solid (21 mg). NMR (dtf-DMSO): d (ppm) 10.72 (bs, IH); 7.44 (t, IH); 7.30 (dd, IH); 6.96 (dd, IH); 6.91 (m, IH); 6.89 (s, 2H); 4.49 (d, IH); 4.21 (m, IH); 4.16 (d, IH); 3.98 (m, IH); 3.94 (m, IH); 3.58 (dd, IH); 3.56 (m, IH); 3.5 (dd, IH); 3.44 (m, IH); 3.17 (t, IH); 2.95 (m, IH); 2.90 (s, 3H); 2.88 (dd, IH); 2.74 (dd, IH); 237 (s, 3H); 2.26 (m, 2H); 2.18 (m, IH); 2.17 (m, IH); 2.16 (m, IH); 1.94 (m, IH); 1.72 (m, IH); 1.58 (m, IH). > MS (ES/+) m/^547 fM+H-HClf. Examples 25 piperidine-2-carborrlic acid (3^-bU-rriflaoromethYJ-bemvlVmethvl-amide (25a-auti) and !-/'4-Fluoro-2-methvl-nhenvlV-4--hexahvdro-Dvrrolori^2-fllDvra2lii-2-vlV- Intermediate 13b (10 mg) was added to a solution of intermediate 21 (150 mg) hi dry acetonitrile (1 mL) under a nitrogen atmosphere. The mixture was stirred at 23"C for 30 minutes, then sodium triacetoxyborohydride (24 mg) was added. The solution was stirred at 23°C for 16 hours, then washed with a 5% sodium hydrogen carbonate solution (5 mL) and brine (5 mL). The organic layer was dried and concentrated in vacua to a residue which was purified by flash chromatography (AcOEt/MeOH 8:2) to give three fractions: example 25a (C-2 and C-4 anti configuration - 6.5 mg). example 25a + example 25b (5.5 mg). example 25b (C-2 and C-4 syn configuration - 7.3 mg). Example 25a: T.I.C.: AcOEt/MeOH 8:2, Rf=O.S2. MS (ES/+) m/z?-615 [M+H]+. Example 25a: T.I.C.: AcOEt/MeOH 8:2, Rf=0.39. MS (ES/+) m/z»=615 [M+HT. Example 26 piperidine-2-carborvUc _ acid _ f3^-bis-trifluoromethvl-benzvr>-metfaYl-ftmide hvdrochloride Example 25b (S.4 mg) in dry Et20 (0.5 mL) was treated with hydrochloric acid (1M in EGO - 0.1 mL) and the resulting solution was stirred at 0°C for 30 minutes. The solution was concentrated in vacua. The residue was triturated with Et2O (1 mL) and pentane (1 mL) to give me title compound as a white solid (4 mg). NMR(oVDMSO): 6 (ppm) 1.63 (m,lrl); 1-88 (mb, IH); 2.09 (mb, 1H); 2.19 (m,lH); 2.27 (s, 3H), 2.1-3.8 (13H); 3.11 (s, 3H); 3.95 (mb 1H), 4.02 (bd, 1H); 4.35 (sb, 1H); 4.94 (mb, 1H); 6.91 (dd, IH); 6.73 (td, IH); 7.55 (s, 2H); 7.93 (s, 1H); 7,10 (dd, 1H); 10.51 (bs, 1H). Example 27 144-Fluoro-2-roethvl-phenvl>-4-f(8«S>-$-oxo-he3[ahYdro-PYiToloflt2-oTDYraziii-2-Yl>-piperidine-2-carboxvlic acid O^-bis-trifluoromethvl-beBizviV-methYl-amlde (ZSb-ava) A solution of intermediate 21 (63 mg) in anhydrous acetonitrile (2 mL) wa> added to a solution of intermediate 13a (27 mg) in anhydrous acetonitrile (2 mL) under a nitrogen atmosphere. The mixture was stirred at 23°C for 1 hour, then sodium triacetoxyborohydride (49 mg) was added. The solution was stirred at 23 °C for 24 hours, then further sodium triacetoxyborohydride (13.6 mg) was added and stirring was continued for 7 days. The mixture was diluted with DCM and washed with a saturated sodium hydrogen carbonate solution. The organic layer was dried and concentrated in vacua to a residue which was purified by flash chromatography (AcOEt/MeOH 9:1) to give the title compound (14 mg) as a white foam. T.I.C.: AcOEt/MeOH 8:2, Rf=0.28. NMR (oVDMSO): 8 (ppm) 1.52 (m, IH); 1.65 (m, 2H); 1.75 (m, IH); 1.95 (m, IH); 2.0-2.2 (m, 2H); 2.06 (m, IH); 2.1 (m, IH); 223 (s, 3H); 2.46 (m, IH); 2.69 (m, IH); 2.82 (m, IH); 2.9 (m, IH); 2.92 (m, IH); 2.96 (m, IH); 3.07 (s, 3H); 3.2 (m, IH); 3.48 (m, IH); 3.78 (m, IH); 4.14 (bd, IH); 4.35 (bd, IH); 4.54 (bd, IH); 6.69 (td, IH); 6.81 (dd, IH); 7.04 (dd, IH); 7.54 (s,2H); 7.8 (s,lH). • mmple 28 frvdrochloride (rm) Hydrochloric acid ( 1M in Et2O - 21 .5 uL) was added to a solution of example 27 (12 mg) in dry Et2O (1 mL) previously cooled to 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 0°C for 30 minutes. The solution was concentrated in vacua. The residue was triturated with pentane (2 x 1 mL) to give the title compound as a white solid (12 ing). NMR(d«-DMSO): 6 (ppm) 1.62 (m, 1H); 1.87 (m, 1H); 1.91 (b, 1H); 2.06 (b, 1H); 2.1-2.4 (m, 2H); 2.16 (m, 1H); 2.25 (s, 3H); 2.5 (m, 1H); 2.56 (ra, 1H); 2.6 (m, 1H); 2.7-3.8 (m, 5H); 2.95 (m, 1H); 3.1 (ra, 1H); 3.9 (bd, 1H); 3.96 (bd, 1H); 4.24 (bra, 1H); 4.67 (bd, 1H); 6.81 (td, 1H); 6.82 (dd, 1H); 7.05 (dd, 1H); 7.54 (s, 2H); 7.81 (s, 1H); MS (ES/+) m/r=615 [M+H-HC1]*. Pharmacy examples A. Tablets The active ingredient is blended with the other excipients. The blend can be compressed to form tablets using appropriate punches. The tablets can be coated using conventional techniques and coatings. B. Capsules Active ingredient Microcrystalline Cellulose 25.0 mg (1-100 mg) qs The active ingredient is blended with microcrystalline cellulose and then filled into suitable capsules. Ct Injection Active ingredient , 2-20mg/mL Buffer solution pH 3.5 (3.0 - 4.0) suitable for injection qs to 10 mL (e.g. citrate buffer in sterile water for injection or NaCl 0.9%) The formulation may be packaged in glass or plastic vials or ampules. The formulation may be administered by bolus injection or infusion, e.g. after dilution with D5W or 0.9% NaCl. The affinity of the compound of the invention for NK] receptor was determined using the NKj receptor binding affinity method measuring in vitro by the compounds' ability to displace [3H] - substance P (SP) from recorabinant human NKj receptors expressed in Chinese Hamster Ovary (CHO) cell membranes. The affinity values are expressed as negative logarithm of the inhibition constant (Ki) of displacer ligands (pKi). The pKi values obtained as the average of at least two determinations with representative compounds of the invention are within the range of 9.40 to 11.00. 1. A compound of formula (I) R6 R represents halogen or C^alkyl; r! represents Cj_4 alkyl; R2 or R3 independently represent hydrogen or C\_4 alkyl; R4 represents trifluoromethyl, Cj_4 alkyl, C\^ alkoxy, trifluoromethoxy or halogen; R5 represents hydrogen, Cj_4 alkyl or €3.7 cycloalkyl; Rg is hydrogen and Ry is a radical of formula (W): (Figure Remove) or Rg is a radical of formula (W) and Ry is hydrogen; X represents CH2» N&5 w °5 Y represents Nitrogen and Z is CH or Y represents CH and Z is Nitrogen; A represents C(O) or S(O)q, provided mat when Y is nitrogen and Z is CH, A is not S(0)q; m is zero or an integer from 1 to 3; n is an integer from 1 to 3; p and q are independently an integer from 1 to 2; and pharmaceuticaUy acceptable salts and solvates thereof. A compound as claimed hi claim 1 in which Rg is hydrogen, Ry is a radical of formula (W) and Y is CH and Z is nitrogen or wherein Rg is a radical of formula (W), Ry is a hydrogen and Y is nitrogen and Z is CH . A compound as claimed hi claim 1 or claim 2 wherein A is C(O). A compound as claimed in any claims from 1 to 3 wherein X is CB^. A compound as claimed hi any claims from 1 to 3 wherein p is 1. A compound as claimed in any claims from 1 to 3 wherein each R4 is independently trifluoromethyl group or halogen (e.g. chlorine) and n is 2. A compound as claimed in any claims from 1 to 4 wherein each R is independently a halogen (e.g. fluorine) or a Cj_4 alkyl (e.g. methyl) group, wherein m is 0, 1 or 2. A compound as claimed in any claims from 1 to 5 in which Rg is hydrogen, Ry is a radical of formula (W) and Y is CH and Z is nitrogen or wherein Rg is a radical of formula (W), Ry is a hydrogen and Y is nitrogen and Z is CH; A is C(O) and X is CH2- A compound as claimed in any claims from 1 to 6 in which Rg is hydrogen, JL-j is a radical of formula (W) and Y is CH and Z is nitrogen or wherein Rg is a radical of formuk (W), Ry is a hydrogen and Y is nitrogen and Z is CH , A is C(O), X is CH2, R is independently a halogen (e.g. fluorine) or a C}_4 alkyl (e.g. methyl) group; R4 is a trifluoromethyl group; m is 1 or 2; n is 2 and p is 1 . A compound selected from : piperidine-1-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methylamide; 2^)^4-Fluoro-2-mcmyl-phenylMKSH6-oxo-hexahydro^yjTolo[l,2-a]-pyrazin-2-yl)- piperidine-l-carboxyUcacid[l l-(4-Fluoro-2-mcthyl-phenyl)^^6-oxo-hexahydro-pyn-olo[l>2-a]pyrazin-2-yl)-piperidine-2- carboxylic acid (3,5-bis-trifluoroinethyl-bcnzyl)-methyt-amide; and enantiomers, diastereoisomcrs pharmaceutically acceptable salts (e.g. hydrochloride, methanesulphonate or maleate) and solvates thereof. 11. A compound selected from: 2^R)K4-Fluoro-2-nwmyl-phenylM^SH(8aS)^^xo-hexahydro-pyrrolo[l,2-a]-pyra2an-2-yl)-piperitoe-l-carboxylicacid [l^)-^3,5-bis-trifluoromcthyl-phenyl)-ethyl]-methylamide; 2-OR.)K4-nuoro-2-memyl-phenyl)^^S)K(8aR)^K)xo-hex8hydro-pyrrolo[l,2-fl]-pyrazin-2-yl)-piperidine-l-carboxylicacid[l-(R)-(3J5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide; and amorphous and crystalline forms thereof and pharmaceutically acceptable salts (e.g. hydrochloride or maleate ) and solvates thereof. A compound as claimed in any claims from Ito9 for use in therapy. The use of a compound as claimed in any claims from 1 to 9 in the preparation of a medicament for use in the treatment of conditions mediated by tachykinins, including substance P and other neurokinins. The use of a compound as claimed in any claims from 1 to 9 in the treatment of conditions mediated by tachykinins, including substance P and other neurokinins. A pharmaceutical composition comprising a compound as claimed in any claims from 1 to 9 in admixture with one or more pharmaceutically acceptable carriers or excipients. A method for the treatment of a mammal, including man, in particular in the treatment of conditions mediated by tachykinins, including substance P and other neuroltintns, comprising administration of an effective amount of a compound as claimed in any claims from 1 to 9. A process for the preparation of a compound as claimed in any claims from 1 to 9, which comprises reacting a compound of formula (II), ), wherein Rg is =O and Rg is hydrogen or Rg is hydrogen and Ro is =O (Figure Remove) (HI) with compound of formula (ID) or a salt thereof in the presence of a suitable metal reducing agent, followed where necessary or desired by one or more of the following steps: i) removal of any protecting group; ii) isolation of the compound as a salt or a solvate thereof; iii) separation of a compound of formula (I) or derivative thereof into the enantiomers thereof.

Documents:

1738-DELNP-2004-Abstract-01-04-2008.pdf

1738-delnp-2004-abstract-09-04-2008.pdf

1738-delnp-2004-abstract.pdf

1738-DELNP-2004-Claims-01-04-2008.pdf

1738-delnp-2004-claims-09-04-2008.pdf

1738-delnp-2004-claims.pdf

1738-DELNP-2004-Correspondence-Others-01-04-2008.pdf

1738-DELNP-2004-Correspondence-Others-03-04-2008.pdf

1738-delnp-2004-correspondence-others-09-04-2008.pdf

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1738-delnp-2004-description (complete)-09-04-2008.pdf

1738-delnp-2004-description (complete).pdf

1738-DELNP-2004-Description (Complete)01-04-2008.pdf

1738-DELNP-2004-Form-1-01-04-2008.pdf

1738-delnp-2004-form-1-09-04-2008.pdf

1738-delnp-2004-form-1.pdf

1738-delnp-2004-form-13-03-04-2008.pdf

1738-delnp-2004-form-13.pdf

1738-delnp-2004-form-18.pdf

1738-DELNP-2004-Form-2-01-04-2008.pdf

1738-delnp-2004-form-2-09-04-2008.pdf

1738-delnp-2004-form-2.pdf

1738-DELNP-2004-Form-3-01-04-2008.pdf

1738-DELNP-2004-Form-3-03-04-2008.pdf

1738-delnp-2004-form-3.pdf

1738-delnp-2004-form-5.pdf

1738-DELNP-2004-GPA-01-04-2008.pdf

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1738-DELNP-2004-Other Docoment-01-04-2008.pdf

1738-DELNP-2004-PCT-210-01-04-2008.pdf

1738-delnp-2004-pct-308.pdf

1738-DELNP-2004-PCT-409-01-04-2008.pdf

1738-delnp-2004-pct-409.pdf

1738-DELNP-2004-PCT-416-01-04-2008.pdf

1738-delnp-2004-pct-416.pdf

1738-delnp-2004-pct-demand form.pdf

1738-delnp-2004-pct-notification.pdf

1738-delnp-2004-pct-request form.pdf

1738-delnp-2004-pct-search report.pdf

1738-DELNP-2004-Petition-137-01-04-2008.pdf

1738-DELNP-2004-Petition-138-01-04-2008.pdf