Title of Invention	AZACYCLIC COMPOUNDS.
Abstract	R is a hydrogen, a cyclic or straight-chained or branched acyclic organyl group, a lower hydroxyalkyl group, a lower aminoalkyl group, or an aralkyl or heteroaralkyl group; nisO, 1, or 2; X1 is methylene, vinylene, or an NH or N(lower alkyl) group; and X2 is methylene , or, when X1 is methylene or vinylene, X2 is methylene or a bond; or when X1 is methylene, X2 is O, S, NH, or N(lower alkyl) or a bond; Y1 is methylene and Y2 is methylene, vinylene, ethylene, propylene, or a bond; or Y1 is a bond and Y2 is vinylene; or Y1 is ethylene and Y2 is O, S, NH, or N(lower alkyl); Ar1 and Ar2 independently are unsubstituted or substituted aryl or heteroaryl groups, provided that Ar1 and Ar2 are not simultaneously phenyl; and W is oxygen or sulfur.

Title of Invention

AZACYCLIC COMPOUNDS.

Abstract

R is a hydrogen, a cyclic or straight-chained or branched acyclic organyl group, a lower hydroxyalkyl group, a lower aminoalkyl group, or an aralkyl or heteroaralkyl group; nisO, 1, or 2; X1 is methylene, vinylene, or an NH or N(lower alkyl) group; and X2 is methylene , or, when X1 is methylene or vinylene, X2 is methylene or a bond; or when X1 is methylene, X2 is O, S, NH, or N(lower alkyl) or a bond; Y1 is methylene and Y2 is methylene, vinylene, ethylene, propylene, or a bond; or Y1 is a bond and Y2 is vinylene; or Y1 is ethylene and Y2 is O, S, NH, or N(lower alkyl); Ar1 and Ar2 independently are unsubstituted or substituted aryl or heteroaryl groups, provided that Ar1 and Ar2 are not simultaneously phenyl; and W is oxygen or sulfur.

Full Text	WO 01/66521 PCT7US01/07187 Field of the Invention AZACYCLIC-COMPOUNDS FOR USE, IN THE TREATMENT OP SEROTONIN RELATED Dlb'KAbES The present invention relates to novel compounds tnat arteci monoamine receptors, including serotonin receptors. The invention specifically provides compounds that are active as inverse agonists, and therefore also as antagonists, at the 5-HT2A subtype of human serotonin receptors. The invention also provides methods, utilizing the compounds of the invention for modulating 5-HT2A receptor-mediated events, that are useful for treating or alleviating disease conditions in which modification of the activity of these receptors is beneficial. Background of the Invention Serotonin or 5-hydroxytryptamine (5-HT) plays a significant role in^he functioning of the mammalian body. In the central nervous system, 5-HT is an important neurotransmitter and neioromodulator that is implicated in such diverse behaviors and responses as sleeping, eating, locomotion, perceiving pain, learning and memory, sexual behavior, controlling body temperature and blood pressure. In the spinal column, serotonin plays an .important role m the control systems of the afferent peripheral nociceptors (Moulignier, Rev. Neurol 150:3-15,(1994)). Peripheral functions in the cardiovascular, hematological and gastrointestinal systems have also been ascribed to 5-HT. 5-HT has been found to mediate a variety of contractile, secretory, and elcctraphysiologic effects including vascular and nonvascular smooth muscle contraction, and platelet aj^regan'on. (Fuller, Biology ofSerotonergic Transmission, 1982; BouHin, Serotonin In Mental Abnormalities 1:316 (197S); Barenas, et al., Serotonin and Behavior, (1973)) The 5-HT2A receptor subtype (also referered to as subclass) is widely yet discretely expressed in the human brain, including many cortical, limbic, and forebram regions postulated to be involved in the modulation of higher cognitive and affective functions. This receptor subtype is also expressed on mature platelets where it mediates, in part, platelet aggregation, one of the initial steps in the process of vascular thrombosis. Given the broad distribution of serotonin within the body, it is understandable that tremendous interest in drugs that affect serotonergic systems exists (Gershon, et 1 WO 01/66521 PCT/US01/07187 al.. The Peripheral Actions of 5-Hydroxytryptamine, 246 (1989); Saxena, et aL, J Cardiovascular Pharmacol 15: Supp. 7 (1990)) Serotonin receptors are members of a large human gene family of membrane-spanning proteins that function as transducers of intercellular communication. They exist on the surface of various cell types, including neurons and platelets, where, upon their activation by either their endogenous Hgand serotonin or exogenously administered drugs, they change their conformational structure and subsequently interact with downstream mediators of cellular signaling. Many of these receptors, including the 5-HT2A subclass, are G-protein coupled receptors (GPCRs) that signal by activating guanine nucleotide binding proteins (G-proteins), resulting in the generation, or inhibition of, second messenger molecules such as cyclic AMP, inositol phosphates, and diacylglyceroL These second messengers then modulate the function of a variety of intracellular enzymes, including kinases and ion channels, -which ultimately affect cellular excitability and function. At least 15 genetically distinct 5-HT receptor subtypes have been identified and assigned to one of seven families (5-HT1-7) Each subtype displays a unique distribution, preference for various Ugands, and functional correlate^). Serotonin may be an important component in various types of pathological conditions such as certain psychiatric disorders (depression, aggressiveness, panic attacks, obsessive compulsive disorders, psychosis, schizophrenia, suicidal tendency), certain neurodegenerarjve disorders (Alzheimer-type dementia, Parkinsonism, Hnntington's chorea), anorexia, bulimia, disorders associated with alcoholism, cerebral vascular accidents, and migraine (Mcltzcr, Netiropsychopharmocology, 21:106S-l I5S (1999); Barnes & Sharp, S&trani'Mrmncoloty, 38:1033-1152 (1999); Gknnon. Neurpsd. BiobekavioraJ Rev^ 14:35 (1990)). Rscert evidence strongh-implicates the 5-HT2 receptor subtype in the etiology of such medical conditions as hypertension, thrombosis, migraine, vasospasm, ischemia, depression, anxiety, psychosis, schizophrenia, sleep disorders and appetite disorders. Schizophrenia is a particularly devastating neuropsychiatric disorder that affects approximately 1% of the human population. It has been estimated that the total financial cost for the diagnosis, treatment, and lost societal productivity of individnals affected by this disease exceeds 2% of the gross national product (GNP) of the United States. Current treatment primarily involves phannacotherapy with a class of drugs known as antipsychotics. Antipsychotics are effective in ameliorating 2 WO 01/66521 PCT/US01/07187 positive symptoms (e.g., hallucinations and delusions), yet tiaey frequently do not improve negative symptoms (e.g., social and emotional withdrawal, apathy, and poverty of speech). Cwrently, nine major classes of antipsychotics are prescribed to treat psychotic symptoms. Use of these compounds is limited, however, by their side effect profiles. Nearly all of the "typical" or older generation compounds have significant adverse effects on human motor function. These "extrapyramidal" side effects, so termed due to their effects on modulatory human motor systems, can be both acute (e.g., dystonic reactions, a potentially life threatening but rare neuroleptic malignant syndrome) and chronic (e.g., akathisias, tremors, and tardive dyskinesia). Drug development efforts have, therefore, focused on newer "atypical" agents free of these adverse effects. Antipsychotic drugs have been shown to interact with a large number of central monoaminergic neurotransmitter receptors, including dopaminergic, serotonergic, adrecergic, muscarinic, and histammergic receptors. It is likely that the therapeutic and adverse effects of these drugs are mediated by distinct receptor subtypes. The high degree of genetic and pharmacological homology between these receptor subtypes has hampered the development of subtype-selective compounds, as well as the determination of the normal physiologic 6i pathophysiologic role of any particular receptor subtype. Thus there is a need to develop drugs that are selective for individual receptor classes and subclasses amongst monoaminergic nemotransiintter receptors. The prevailing theory for the mechanism of action of antipsychotic drugs involves antagonism of dopanrine D2 receptors. UcfaitmiatdY, it is likely that atssgerrism of depamine TO receptors-also mediates the extrapyrainidal^ide effects. Antagonism of 5-HT2A is an alternate molecular mechanism for drugs with antipsychotic efficacy, possibly ihrough antagonism of heightened or exaggerated signal transduction through seroionergic systems. 5-HT2A antagonists are therefore good candidates fox treating psychosis without extrapyramidal side effects. Traditionally, these recejitors have been assumed to exist in a quiescent state unless activated by the binding of an agonist (a drug that activates a receptor). It is now appreciated that many, if not most, of the GPCR rnonoamine receptors, including serotonin receptors, can exist in a partially activated state in the absence of their endogenous agonists. This increased basal activity (constitutive activity) can be 3 WO 01/66521 PCT/US01/07187 inhibited by compounds called inverse agonists. Both agonists and inverse agonists possess intrinsic activity at a receptor, in that they alone can activate or inactivate these molecules, respectively. In contrast, classic or neutral antagonists compete against agonists and inverse agonists for access to the receptor, but do not possess the intrinsic ability to inhibit elevated basal or constitutive receptor responses. We have recently elucidated an important aspect of 5-HT2A receptor function by applying the Receptor Selection and Amplification Technology (U.S. Patent 5,707,798,1998; CkemAbstr. 128:111548 (1998) and citations therein), to the study of the 5-HT2 subclass of serotonin receptors. R-SAT is a phenotypic assay of receptor ftmction that involves the beterologous expression of receptors in mammalian fibroblasts. Using this technology we were able to demonstrate that native 5-HT2A receptors possess significant constitutive, or agonist-independent, receptor activity (U.S. Patent Application Ser. No. 60/103,317, herein incorportated by reference). Furthermore, by directly testing a large number of centrally acting medicinal compounds with known clinical activity in neuropsychiatric disease, we determined that compounds with anlipsychotic efficacy all shared a common molecular property. Nearly all of these compounds, which are used by psychiatrists to treat psychosis, were found to be ]x>tent 5-HT2A inverse agonists. This unique clinico-pharmacologic correlation at a single receptor subtype is compelling evidence that 5-HT2A receptor inverse agonism is a molecular mechanism of antipsychotic efficacy in humans. Detailed pharmacological chiiracterization of a large number of antxDsvchotic compounds revealed that they possess broad activity at multiple related receptor subtypes. Most of tbese compounds display agonist, competitive antagonist, or inverse agonist activity at multiple monoaminergic receptor subtypes, including serotoninergic, dopaminergic, adrcncrgic, muscarinic and fcist&ninergic receptors. Tins broad activity is likely responsible for the sedating, hypotensive, and motor side effects of these compounds. It would therefore be of great advantage to develop compounds that are selective inverse agonists of the 5-HT2A receptor, but which have little or no activity on other monaminie receptors subtypes, especially dopamme D2 receptors. Such compounds may be useful in the treatment of human disease (e.g., as anti-psychotics), and may avoid the adverse side effects associated with non-selective receptor interactions. 4 WO 01/66521 PCTAJS01/07187 Summary of the Invention The present invention provides compounds of the general formula (I) that affect monoamine receptors, especially serotonin receptors, and share as a common property inverse agonist activity at the 5-HT2A subtype of human serotonin receptors: R is hydrogen, a cyclic or straight-chained or branched acyclic organyl group, a low er hydroxyaflcyl group, a lower aminoalkv] group, or an aralkyl or heteroaralkyl group; nisO, I,or2; Xi is methylene, vinylene,or an NH or K(lower alkyl) group;and Xj is methylene, or, when X\ is methylene or vinylene, X2 is methylene or a bond, or whec Xi is methylene, X2 is O, S, NH. or N(lower alkyl) or a bond; Yj is methylene and Y2 is methylene, vinylene, ethylene, propyiene, OT a bond; Yi is a bond and Y2 is vinylene; or Yi is ethylene and Y2 is O, S, NH, or NQower alkyl); Ai] and Ar2 independently are unsubstituted or substituted aryl or heteroaryl groups; W is oxygen or sulibr; or a phannaceuticalry acccpta3>Ie salt, ester, or prodrug thereof. The present invention also provides pharmaceutical compositions comprising an effective amount of a compound of formula (I) or phannaceutically acceptable salts, esters, or prodrugs thereof. 5 WO 01/66521 PCT/US01/07187 Also provided are methods of inhibiting an activity of a monoamine receptor comprising contacting the monoamine receptor or a system containing the monoamine receptor with an effective amount of a compound of formula (I), as well as kits for performing the same. Preferably, the receptor is a serotonin receptor of the 5-HT2A subclass. Tlie receptor may be located in either the central or peripheral nervous system, blood cells or platelets, and may be mutated or modified. In a preferred embodiment, the receptor is constitutively active. Furthermore, the present invention relates to a method of inhibiting an activation of a monoamine receptor comprising contacting the monoamine receptor or a system containing the monoamine receptor with an effective amount of compound of formula (I), as well as kits for performing the same In a preferred embodiment, the compound is selective for the 5-HT2A serotonin receptor. In another preferred embodiment, the compound has little or substantially no anti-dopaminergic activity. The receptor may be constitutively active or may be activated by an endogenous or exogenous agonistic agent. Another aspect of the present invention relates to a method of treating a disease condition associated with a monoamine receptor comprising administering to a mammal in need of such treatment an effective amount of a compound of formula (I), and kits for performing the same. Examples of disease conditions for which such treannent using the compounds of the invention, cr phannaceuticaj compositions comprising them, is useful include, but are not Umited to, neuropsychiatric diseases such as schizophrenia and related idiopathic psychoses, depression, anxiety, sleep disorders, appetite disorders, affective disorders such as major depression, bipolar disorder, and depression with psychotic features, and Tourette's Syndrome. Said compounds may also be beneficial for the tresanem of drug-induced psychoses as well as psychoses secondary to neurodegencrauve disorders such as Alzheimer's or Huntington s Disease. The compounds of the invention may also be useful in treating hypertension, migraine, vasospasm, ischemia and the primary treatment and secondary prevention of various thrombotic conditions including myocardial infarction, thrombotic or ischemic stroke, idiopathic and thrombotic thrombocytopexoc purpma, and peripteral vascular disease. Further provided is a method for identifying a genetic polymorphism predisposing a subject to being responsive to a compound of formula (I), comprising administering to a subject an effective amount of the compound; identifying a 6 WO 01/66521 PCT/US01/07187 responsive subject having an ameliorated disease condition associated with a roonoamine receptor; and identifying a genetic polymorphism in the responsive subject, wherein the genetic polymorphism predisposes a subject to being responsive to the compound. Also provided are kits for performing the same. A method for identifying a subject suitable for treatment with the compound of formula (I) and kits for identifying the same, is also provided. According to the method, the presence of a polymorphism that predisposes the subject to being responsive to the compound is detected, wherein the presence of the polymorphism indicates that the subject is suitable for treatment. Brief Description of the Drawings Figure 1 is a graph showing data obtained from a dose response analysis of 26HCH17 and ritanserin as 5-FfT2A receptor inverse agonists. Figure 2 is a graphic representation of in vivo pharmacology data obtained in mice with 2-(4-methoxyphenyl)-Ar-(4-methylben2yl)-W-(l-methylpiperidin-4-yl)acetamide hydrochloride. Figure 2A shows the effects of this novel antipsychotic agent compound in a head twitch behavioral model; Figure 2B shows the results of locomotor experiments; and in Figure 2C pre-pulse inhibition study results are shown. Detailed Description of the Invention Definitions For the purpose of the current disclosure, the following definitions shall in their entireties be used to define technical terms, and shall also, in their entireties, be used to define the scope of the composition of matter for which protection is sought in the claims. "Constitutive activity" is defined as the elevated basal activity of a receptor which is independent of the presence of an agonist Constitutive activity of a receptor may be measured using a number of different methods, including cellular (e.g., membrane) preparations (see, e.g., Barr &. Manning, J. Biol. Chem. 272:32979-87 (1997)), purified reconstituted receptors with or without the associated G-protein in pbospbofipid vesicles (Cerionc et aL, Biochemistry 23:4519-25 (1984)), and functional cellular assays (U.S. Patent Application Ser. No. 60/103,317)- " Agonist" is defined as a compound that increases the activity of a receptor when it contacts the receptor. 7 WO 01/66521 PCT/US01/07187 An "antagonist" is defined as a compound that competes with an agonist or inverse agonist for binding to a receptor, thereby blocking the action of an agonist or inverse agonist on the receptor. However, an antagonist (also known as a '"neutral" antagonist) has no effect on constitutive receptor activity. An "inverse agonist is defined as a compound that decreases the basal activity of a receptor (i.e., signalling mediated by the receptor). Such compounds are also known as negative antagonists. An inverse agonist is a ligand for a receptor that causes the receptor to adopt an inactive state relative to a basal state occurring in the absence of any ligand. Thus, while an antagonist can inhibit the activity of an agonist, an inverse agonist is a ligand that can alter the conformation of the receptor in the absence of an agonist. The concept of an inverse agonist has been explored by Bond et al. in Nature 374:272 (1995). More specifically, Bond et al. have proposed that unliganded p 2-adrenoceptor exists in an equilibrium between an inactive conformation and a spontaneously active conformation. Agonists are proposed to stabilize the receptor in an active confonnation. Conversely, inverse agonists are believed to stabilize an inactive receptor conformation. Thus, while an antagonist manifests its activity by virtue of inhibiting an agonist, an inverse agonist can additionally manifest its activity in the absence of an agonist by inhibiting the spontaneous conversion of an unliganded receptor to an active confonnation. The "5-HT2A receptor" is defined as a receptor, having an activity corresponding to the activity of the human serotonin receptor subtype, which was characterized through molecular cloning and pharmacology as detailed in Saltzman et al., Biochem. Biophys. Res. Comm. 181:1469-78; and Julius et al., Proc. Natl Acad. Sci. USA 87:928-932. The term "subject refers to sn animal^ preferably a mammal, most preferably a human, who is the object of treafcrsnt, observation or experiment "Selective" is defined as a property of a compound whereby an amount of the compound sufficient to effect a desired response from a particular receptor type, subtype, class or subclass with substantially little or no effect upon the activity other receptor types. "Selectivity or "selective, as an inverse agonist is understood as a property of a compound of the invention whereby an amount of compound that effectively inversely agonises the 5-HT2A receptor, and thereby decreases its activity, causes little or no inverse agonistic or antagonistic activity at other, related or 8 WO 01/66521 PCT/US01/07187 unrelated, receptors. In particular, the compounds of the invention have surprisingly been found not to interact strongly with other serotonin receptors (5-HT 1A, IB, ID, IE, IF, 2B, 2C, 4A, 6, and 7) at concentrations where the signalling of the 5-HT2A receptor is strongly or completely inhibited. Preferably, the compounds of the invention are also selective with respect to other monoamine-binding receptors, such as the dopaminergic, histaminergic, adrenergic and muscarinic receptors. Compounds that are highly selective for 5-HT2A receptors may have a beneficial effect in the treatment of psychosis, schizophrenia or similar neuropsychiatric disorders, while avoiding adverse effects associated with drugs hitherto suggested for this purpose. EC50 for an agonist is intended to denote the concentration of a compound needed to achieve 50% of a maximal response seen in R-SAT. For inverse agonists, EC50 is intended to denote the concentration of a compound needed to achieve 50% inhibition of an R-SAT response from basal, no compound, levels. As used herein, "coadministration" of pharmacologically active compounds refers to the dehvery of two or more separate chemical entities, whether in vitro or in vivo. Coadministration refers to the simultaneous delivery of separate agents; to the simultaneous delivery of a mixture of agents; as well as to the delivery of one agent followed by delivery of a second agent or additional agents. In all cases, agents that are coadministered are intended to work in conjunction with each other. "Cyclic organyl groups' are aliphatic, alicyclic groups in which carbon atoms form a ring. In preferred embodiments containing four, five, six or seven carbon atoms, the ring, as a substituent, is connected either directly via one of the ring atoms or via one or more appended carbon atoms. Particular examples of such groups include cyclopentyl, cyclohexyl, cycioheptyl, cyclopentylmethyl, cyclohexymiemyi, cyclohexylethyl groups, and the like. "Straight-chained acyclic orjjanyl groups" are substituent groups consisting of a linear arrangement of carbon atoms, where accordingly each carbon atom binds a maximum of two other carbon atom ;, connected through single, double, or triple bonds. The straight-chained organy] groups may contain none, one, or several multiple bonds, and are, for example, commonly referred to as alkyl, alkenyl or alkynyl, or alkadieiryl groups, respectively. Examples of straight-chained organyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, propenyl, butenyl, pentadienyl, propargyl, butynyl. 9 WO 01/66521 PCT/US01/07187 "Branched acyclic organyi groups" are substituent groups consisting of a branched arrangement of carbon atoms, where accordingly one or more carbon atoms may bind more than two other carbon atoms, connected through single, double, or triple bonds. The branched organyi groups may contain none, one, or several multiple bonds. Examples of branched organyi groups include iso-propyl, iso-butyl, tor-butyl, methylbutyL methylbatenyl, methylburynyl. "Lower alkoxy groups" are Cm cyclic or acyclic organyi groups connected, as substituents, via an oxygen atom. Examples of lower alkoxy groups include methoxy, ethoxy, iso-propoxy, butoxy, tert-butoxy. "Lower alkyl groups" are Ci_6 cyclic, straight-chained or branched aliphatic substituent groups connected via a carbon atom. Examples include methyl, ethyl, propyl, butyl, methylbutyl, cyclopropyl, cyclohexyl, tro-propvl, tert-butyl. "Lower alkylamino groups" are understood as lower alkyl groups connected, as substituents, via a nitrogen atom, which may cany one or two lower alkyl groups. Particular examples include methylamino, dimethylamino, iso-propylamino. Optionally, lower aminoalkyi groups may consist of 4-6 membered nitrogen-containing rings, such as pytrolidino. "Lower anunoalkyl groups" are lower alkyl groups carrying, as a substituent, an additional amino group. Examples include aminomethyl and arninoethyl. "Lower hydroxyalkyi groups" are understood as lower alkyl groups carrying, as a substituent, an additional hydroxy group. Examples include bydroxymetnyL bydroxyethyL 24rydroxy-2-propyt hydroxypentyL "Acyl groups" are hydrogen or lower alkyl groups connected, as substituents, via a carbonyl group. Example;; include formyi, acetyl, propanoyL "Halo groups" are understood to be fiuoro, chloro, bromo, or iodo substituents, with fluoro and chloro being generally preferred. "Lower alkylene groups" are straight-chained tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples inr.rndrs methylene (-CH2-), etbytene (-CHjCHr), propylene (-CH2CH2CH2-) or butylene (-(CHik-) groups. "Vinylene groups" are ethene-l,2-diyl groups (-CHCH-) having (E) or (Z) configuration. "Aralkyl groups" are aryl groups connected, as substituents, via a lower alkykne group. The aryl groups of aralkyl groups may be substituted or unsubstituted. 10 WO 01/66S21 PCT/US01/07187 Examples include benzyl, substituted benzyl, 2-phcnylethyl, 3-phenylpropyl, naphthylalkyl. 'Hcteroaralkyl groups' are understood as heteroaiyl groups connected, as substituents, via a lower alkylene group. The heteroaryl groups of heteroaralkyl groups may be substituted or unsubstituted. Examples include 2-tbienylroethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, imidazolylaltyl, and their substituted as well as benzo-fused analog. "Aryl groups" are aromatic, preferably benzenoid or naphthoid, groups connected via one of the ring-forming carbon atoms, and optionally carrying one or more substituents selected from halo, hydroxy, amino, cyano, nitro, aDcylamido, acyl, lower alkoxy, lower alkyl, lower hydroxyalkyl, lower aminoalkyl, lower alkylamino, alkylsulfenyl, aDcylsulfinyl, alkylsulfonyl, sulfaraoyl, or trifluoromethyl. Preferred aryl groups are phenyl, and, most suitably, substituted phenyl groups, carrying one or two, same or different, of the substituents listed above. The preferred pattern of substitution hpara and/or meta. Representative examples of aryl groups include, but are not limited to, phenyl, 3-balophenyl, 4-halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-anunophenyl, 4-aminophenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphtbyi, hydroxynaphtfayl, hydrox^miethyipbenyl, trifluoroinethylphenyL "Heteroaryl groups" are understood as aromatic, Cj^ cyclic groups containing one O or S atom or up to four N atoms, or a combination of one O or S atom with up to two N atoms, and their substituted as well as benzo- and pyrido-fosed derivatives, preferably connected via one of the ring-forming carbon atoms. Heteroaryi groups may carry one or more substituents, selected from halo, hydroxy, amino, cyano. nitio. alkylamidQ, acyl, lower alkoxy, lower alkyl, lower hydroxyalkyl, lower aminoalkyl, lower alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. Preferred heteroaryl groups are five- and six-membered aromatic heterocyclic systems carrying 0,1, or 2 substituents, which may be the same as OT different from one another, selected from the list above. Representative examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofurac, thiophene, benzotbiopbene, pyrrole, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzotbiazole, isothiazole, imidazole, benziinidazole, pyrazole, mdazole, and tetrazole, which are all preferred as well as furazan, 1,2,3-oxadiaaote, V^3-thiadiazole, l,2,4 tbiadiazole, 11 WO 01/66521 PCT/US01/07187 triazole, benzotriazole, pyndine, quionohne, isoquinohne, pyridazine, pyrimidine, purine, pyrazine, ptcridine, and triazine. The most preferred substituents are halo, hydroxy, cyano, lower alkoxy, lower alkyl, lower hydroxyalkyl, lower alkylamino, and lower aminoalkyl. The present invention provides compounds preferably showing a realtively high selectivity toward serotonin receptors, particularly, 5-HT2A receptors, which may have a beneficial effect in the treatment of neuropsychiatric disorders. According to one embodiment, the present invention provides compounds of the general formula (I): in which R is a hydrogen, a cyclic or straight-chained or branched acyclic organyl group, a lower hydroxyaHcyl group, a lower aminoalkyl group, or an aralkyl or beteroaraBcyl group; nisO, 1,OT2; XI is methylene, vinylene,or an NH or N (lower alkyl) group; and X2 is methylene, or, when Xi is methylene or vinylene, X2 is methylene or a bond; or when Xi is methylene, X2 is O, S, NH, or NGower alkyl) or 2 bond; X Yi is methylene and Y2 is methylene, vinylene, ethylene, propylene, or a bond; or Yi is a bond and Y2 is vinylene; or Y] is ethylene and Y2 is O, S, NH, or N(lower alkyl); 12 WO 01/66521 PCT/US01/07187 Ari and Ar2 independently are unsubstituted or substituted aryl or heteroaryl groups; and W is oxygen or sulfur; or a pharmacologically acceptable salt, ester, or prodrug thereof. In general, compounds of formula (I) are active at monoamine receptors, specifically serotonin receptors. Preferred compounds share the common property of acting as inverse agonists at fee 5-HT2A receptor. Thus, experiments performed on cells transiently expressing the human phenotype of said receptor have shown that the compounds of general formula (I) attenuate the signalling of such receptors in the absence of additional ligands acting upon the Teceptor. The compounds have thus been found to possess intrinsic activity at this receptor and are able to attenuate the basal, non-agonist-stimulated, constitutive signalling responses that the 5-HT2A receptor displays. The observation that the compunds of general formula (I) are inverse agonists also indicates that these compounds have the ability to antagonize the activation of 5-HT2A receptors that is mediated by endogenous agonists or exogenous synthetic agonist ligands. In a preferred embodiment, the present invention provides compounds that preferably show a relatively high degree of selectivity towards the 5-HT2A subtype of serotonin receptors relative to other subtypes of the serotonin (5-HT) family of receptors as well as to other receptors, most particularly the roonoammergic G-protein coupled receptors, such as dopamine receptors. In another preferred embodiment, the compounds of the present invention act as inverse agonists at the 5-HT2A subtype of serotonin receptors. The compoonds of genera] formula (I) znzy therefore be useful for treating or alienating symptoms of disease condraons associated with impaired function, in particular elevated levels of activity, of especially 5-HT2A receptors, whether this impaired function is associated with improper levels of receptor stimulation or phenotypicaJ aberrations. Others have previously hypothesised that certain neuropsychological diseases might be caused by altered levels of constitutive activity of monoamine receptors. Such constitutive activity might be modified via contacting the relevant receptor with a synthetic inverse agonist. By directly testing a large number of centrally acting medicinal compounds with known clinical activity in neuropsychiatric disease, we determined that compounds with antipsychotic efficacy all shared a common 13 WO 01/66521 PCTAJSO1/O7187 molecular property. Nearly all of these compounds that are used by psychiatrists to treat psychosis were found to be potent 5-HT2A inverse agonists. This correlation is compelling evidence that 5-HT2A receptor inverse agonism is a molecular mechanism of antipsychotic efficacy in humans Detailed pharmacological characterization of a large number of antipsychotic compounds in our laboratory revealed that they possess broad activity at multiple related receptor subtypes. Most of these compounds display either agonist, competitive antagonist, or inverse agonist activity at multiple monoarninergic receptor subtypes including serotoninergic, dopaminergic. adrenergic, muscarinic and histaminergic receptors. This broad activity is likely responsible for the sedating, hypotensive, and motor side effects of these compounds. It follows that the compounds disclosed herein will possess efficacy as, for example, novel antipsychotics, but will have fewer or less severe side effects than existing compounds. The present invention also provides pharmaceutical compositions comprising an effective amount of a compound of general formula (I). In a preferred embodiment of the compounds of formula (I), Yj is methylene and Y2 is a bond, methylene, ethylene, or vinylene, or Yj is ethylene and Y2 is O or S, and Xi is methylene and X2 is a bond, methylene, O, or S, or X] is NH or NQower alkyl). In a further preferred embodiment of the compounds of formula (I), Z is aid W is oxygen. In a more preferred embodiment of the compounds of formula (I), n is r, Yi is methylene, Y2 is a bond, methylene, ethylene, or vinylene, Xiis methylene andX2 is a bond, or Xi is NH or N(lower alkyl) and X2 is methylene. In a further preferred embodiment of the compounds of formula (I), W is oxygen and An and Ar2 are different aryl or heteroary] groups, with different mono-substituted phenyl groups being particularly preferred. Preferably, An and A12 are not simultaneousry phenyl Also preferred compounds of formula (I) are those where Z is l-(organyl or araIkyI)-4-piperidinyl. 14 WO 01/66521 PCT/US01/07187 In another embodiment, the invention provides preferred compounds ot the formula (II): in which RN is hydrogen, lower alkyl, aralkyl, or heteroaralkyl; Ai " is selected from lower alkyl, lower alkoxy and halogen ArSs selected from lower alkyl, lower alkoxy and halogen; k is 1 or 2 and A is a suitable anion. According to the invention, a suitable anion may be any anion capable of forming a pharmaceuticaily acceptable salt of the compound, as described in further detail below. The present invention also provides a method of inhibiting an activity of a monoamine receptor. This method comprises contacting a monoamine receptor or a system containg the monamine receptor, wi:b an effective amount of a compound of formula (I). Accoding to one embodiment, the monamine receptor is a serotonin receptor. In a preferred embodiment, tbe compound is selective for the 5-HT2A receptor subclass. In another preferred embodiment, the compound has little or substantially no activity to other types of receptors, incrariing other serotonergic receptors and most particularly, monoaminergic G-protein coupled receptors, such as dopaminergic receptors. The system containing the monoamine receptor may, for example, be a subject such as a mammal, non-human primate or a human. The receptor may be located in the central or peripheral nervous system, blood cells or platelets. The system may also be an in vivo or in vitro experimental model, such as a cell culture model system that expresses a monamine receptor, a cell-free extract thereof that contains a monoamine receptor, or a purified receptor. Non-limiting examples of such systems are tissue culture cells expressing the receptor or extracts or lysates thereof. Cells that may be used in the present method include any cells 15 WO 01/66521 PCTAJS01/07187 capable of mediating signal transaction via monoamine receptors, expecially the 5-HT2A receptor, either via endogenous expression of this receptor (e.g., certain types of neuronal cells lines, for example, natively express the 5-HT2A receptor), or following transfection of cells with plasrnids containing the receptor gene. Such cells are typically mammalian cells (or other eukaryotic cells, such as insect cells or Xenopus oocytes), because cells of lower organisms generally lack the appropriate signal transduction pathways for the present purpose. Examples of suitable cells include: the mouse fibroblast cell line NIH 3T3 (ATCC CRL 1658), which responds to transfected 5-HT2A receptors by stimulating growth; RAT 1 cells (Pace et al., Proc. Natl. Acad Sci. USA 88:7031-35 (1991)); and pituitary cells (Vallar et al, Nature 330:556-58 (1987)). Other useful mammalian cells for the present method include HEK 293 cells, CHO cells and COS cells. The invention specifically provides methods of inhibiting an activity of a native, mutated or modified monoamine receptor. Also provided are kits for performing the same. In a preferred embodiment, the activity of the receptor is a signalling activity. In another preferred embodiment^ the activiny of the receptor is the constitutive basal activity of the receptor. Preferrably, the compound is an inverse agonist selective for the 5-HT2A receptor. Most preferably, the compound has little or substantially no activity toward other serotonergic or other monoaminergic receptors, such as dopamraergic receptors. In one embodiment, the activity of the receptor is a response, such as a signalling response, to an endogenous agonist, such as 5-HT, or an exogenous agonistic agent, such as a drug or other synthetic ligand. The compound of formula (I) preferably acts by inversely agonising or antagonising the receptor. Furthermore, the present invention relates to a method of inhibiting an activation of a monoamine receptor ramprising contacting the monoamine receptor, or a system containing the monoamine receptor, with one or more compounds of the invention. The activation of the receptor may be due to an exogenous or endogenous agonist agent, or may be the constitutive activation associated with a native, mutated or modified receptor. The receptor may purified or present in an in vitro or in vivo system. The receptor may also be present in the central or peripheral nervous system, blood cells or platelets of a nonhuman or human subject. Also provided are kits for performing the same. 16 WO 01/66521 PCT/US01/07187 In a preferred embodiment, the compound is selective for 5-HT class serotonin receptors, more preferably, the 5-HT2A sublass of serotonin receptors. In another preferred embodiment, the compound has little or substantially no anti-dopaminergic activity. The present invention provides methods of treating a disease condition associated with a monoamine receptor comprising administering to a mammal in need of such treatment an effective amount of a compound of formula (I). The invention specifically provides methods for treating or alleviating disease conditions associated with improper function or stimulation of native, as well as mutated or otherwise modified, forms of central serotonin receptors, particularly the 5-HT class of such receptors, comprising administration of an effective amount of a selective inverse agonist of the general formula (I) to a host in need of such treatment. Also provided are kits for performing the same. In a preferred embodiment, ihe receptor is the 5-HT2A subclass. In one embodiment, the disease condition is associated with dysfunction of the serotonin receptor. In another embodiment, the disease condition is associated with activation of the serotonin receptor, preferably inappropriately elevated or constitutive activation, elevated serotonergic tone, as well as disease conditions associated with secondary cellular functions imparicd by such pathologies. Examples of diseases for which such treatment using the compounds of the im eniioo, or pharmaceutical compositions comprising such compounds, is useful include, but arc not limited to, neuropsychiatric diseases such schizophrenia and related idiopathic psychoses, anxiety, sleep disorders, appetite disorders, affective disorders such as major depression, bipolar disorder, and depression with psychotic features, and Tourette's Syndrome, cirug-induced psychoses, psychoses secondary to neurodegenerative disorders such as Alzheimer's or Huntington's Disease. It is anticipated that the compounds of this invention, particularly selective inverse agonists of 5-HT2A that show little or no activity on dopaminergic receptors, may be especially useful for treating schizophrenia. Treament using the compounds of the invention may also be useful in treating migraine, vasospasm, hypertension, various thrombotic conditions including myocardial infarction, thrombotic or ischenric stroke, idiopathic and thrombotic thrombocytopenic purpura, and peripheral vascular disease. In a further embodiment the present invention provides methods for treating or alleviating a disease condition associated with improper function, dysfunction, or 17 WO 01/66521 PCT/US01/07187 stimulation of native, as well as mutated or otherwise modified, forms of central or peripheral monoamine receptors, such methods comprising administration of an effective amount of a compound of the general formula (I) to a host in need of such treatment. Preferably the monaminc receptor is serotonin receptor in the peripheral nervous system, blood or platelets; more preferably a 5-HT2A subclass receptor. In additional embodiments, the disease condition is associated with increased activity or activation of a serotonin receptor. AJso provided are kits for performing the same. The present invention also pertains to the field of predictive medicine in which pharmacogenomics is used for prognostic (predictive) purposes. Pharmacogenomics deals with clinically significant hereditary variations in the response to drugs due to altered drug disposition and abnormal action in affected persons. See e g., Eichelbaum, Clin Exp Pharmacol PhysioL, 23:983-985 (1996), and Under, Clin. Chem. 43:254-66(1997). In general, two types of pharmacogenetic conditions can be differentiated: genetic conditions n-ansmitted as a single factor altering the way drugs act on the body (altered drug action), and genetic conditions transmitted as single factors altering the way the body acts on drugs (altered drug metabolism). These pharmacogenetic conditions can occur as naturally occurring polymorphisms. One pharmacogenomics approach to identifying genes that predict drug response, known as "a genome-wide association," relies primarily on a high-resolution map of the human genome consisting of already known gene-related markers (e.g., a "bi-allelic" gene marker map that consists of 60,000-100,000 polymorphic or variable sites on the human genome, each of which has two variants). Such a high-resolution genetic map can be compared to a map of the genome of each of a statistically significant number of patients taking part in a Phase U/IH drug trial to identify markers associated with a particular observed drug response or side effect. Alternatively, such a high-resolution map can be generated from a combination of some ten-million known single nucleotide polymorphisms (SNPs) in the human genome. As used herein, a "SNP is a common alteration mat occurs in a single nucleotide base in a stretch of DNA. For example, a SNP may occur once per every 1,000 bases of DNA. A SNP may be involved in a disease process; however, the vast majority may not be disease-associated. Given a genetic map based on the occurrence of such SNPs, individuals can be grouped into genetic categories depending on a particular pattern of SNPs in their individual genome. In such a manner, treatment 18 WO 01/66521 PCT/USOI/07187 regimens can be tailored to groups of genetically similar individuals, taking into account traits that maybe common among such genetically similar individuals. Alternatively, a method termed the "candidate gene approach" can be utilized to identify genes that predict drug response. According to this method, if a gene that encodes a drug's target is known (e.g., a protein or a receptor of the present invention), all common variants of that gene can be fairly easily identified in the population and it can be determined if having one version of the gene versus another is associated with a particular drug response. Alternatively, a method termed the "gene expression profiling", can be utilized to identify genes that predict drug response. For example, the gene expression of an animal dosed with a drug (e.g., a molecule or modulator of the present invention) can give an indication whether gene pathways related to toxicity have been turned on. Information generated from more than one of the above phannacogenomics approaches can be used to determine appropriate dosage and treatment regimens for prophylactic or therapeutic treatment of an individual. This knowledge, when applied to dosing or drug selection, can avoid adverse reactions or therapeutic failure and thus enhance therapeutic or prophylactic efficiency when treating a subject with a molecule or modulator of the invention, such as a modulator identified by one of the exemplary screening assays descril>ed herein. As we have described previously, this approach can also be used to identify novel candidate receptor or other genes suitable for further pharmacological characterization in vitro and in vivo. Accordingly, the present invention also provides methods and kits for identifying a genetic polymorphism predisposing a subject to being responsive to a compound described herein. The zrtethcxi comprises administering to & subject an effective amount of a compound^ identiiying a responsive subject having'an ameliorated disease condition associated with a monamine receptor; and identifying a genetic polymorphism in the responsive subject, wherein the genetic polymorphism predisposes a subject to being responsive to the compound. It is anticipated mat this method may be useful both for predicting which individuals are responsive to therapeutic effects of a compound and also for predicting those likely to experience adverse side effect responses. This approach may be useful for identifying, for exampie, polymorphisms in a serotonin receptor that lead to constitutive activation and are thus amenable to inverse agonist therapy. In addition, this method may be useful for identifying polymorphisms that lead to altered drug metabolism whereby 19 WO 01/66521 PCT/US01/07187 toxic byproducts are generated in the body Such a mechanism has been implicated in the rare, but potentially life threatening side effects of the atypical antipsychotic, clozapine. In a related embodiment, a method for identifying a subject suitable for treatment with a compound of the present invention is provided. According to the method, the presence of a polymorphism that predisposes the subject to being responsive to the compound is detected, the presence of the polymorphism indicating that the subject is suitable for treatment. AJso provided are kits for performing the same. The compounds of this invention preferably show selective inverse agonist activity towards the 5-HT2A receptor. Such activity is defined by an ability of the ligand to attenuate or abolish the constitutive signaling activity of this receptor. Selectivity in the present context is understood as a property of a compound of the invention whereby an amount of compound that effectively inversely agonizes the 5-HT2A receptor and thereby decreases its activity causes httle or no inverse agonistic or antagonistic activity at other, related or unrelated, receptors. In particular, the compounds of the invention ha\e surprisingly been found not to interact strongly with otheT serotonin receptors (5-HT 1A, IB, ID. IE, IF, 2B, 2C, 4A, 6, and 7) at concentrations where the signaling of the 5-HT2A receptor is strongly or completely inhibited. Preferably, the compounds of tbe invention are also selective with respect to other monoamine-bicding receptors, such as the dopaminergk, histaminergic, adrencrgic and nrascarinic receptors. A particularly preferred embodimeni of this invention includes: N^l^l-^nethylctny0piperidm-4-yf)-N-((4-methy^icnyi)memyl)-4-methoxyphenylacetamide; N-( 1 --4-methoxyphenylacetamide; N^l-penty^iperidiiH4-yl)-N-^(4-^DethylphenyI^nethyl)-4-methoxyphenyiacetamide; N-(l -hexy!piperidm-4-yi)-N-((4-me&ylphenyl)methy l>-4-methoxyphenylacetamidc; N-(l-cyclohexylpiperidin-4-yi>N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide; 20 WO 01/66521 PCT/US01/07187 N-(l-cyclopentylpiperidiD-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacet amide; N-(l-cyclobutylpiperidm-4-yl)-N-((4-methylphenyl)methy])-4-methoxyphenylacetamide; N-(l-cyclopropylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide; N-(l-(cyclopentylmethyI)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-m ethoxyphenyl acetamide; N-(I-(cycIobutylmethyl)piperidiD-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide; N-(l-(cyclopropylmcthyI)piperidiii-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide; N-{l-(2-hydroxyethyl)piperidin-4-yI)-N-((4-methylphenyl)methyl)-4-methoxyphenylacctamide; N-(H3-hydroxypropyl)piperidin-4-yl)-N-((4-methylphenyl)methyI)-4-methoxyphenylacetamide; K-((4-Methy]phenyl)methy])-N-(pipendin-4-y])-N>-phenyhneihylcarbamide; N-((4-MetfaylphenyI)methyl)-N-(l-(2-methylpropyI)piperidin-4-yI)-N'-phenylmethylcarbamide; K-(H(2-BromopheDyl)me1hyl)pipericTn-4-yJ>N-((4-nietfaylphenyl)methyl)-N' -pheny lmethylcaibainidc; N-(l-((4-Hydroxy-3-methoxypheJiyI)methyl)piperi N NT -phenyhnethylcarbamidc; N^l-(Imida2o]-2-ylmcthy])piperidin^yI>N-((4-methylphCTyl)methyl)-N'-pheDylmethylcarbaraide; N^HCyclohexyhnethyl)piperidin-4-yl>-N-((4-iDethylphenyl)metfayl)-N>- phcnylmetbylcaibazmde; N^H(4-HuoropbcnyI)mcaiyI)pipciidiiHV-yl)-NK(4-mcthyipfacaj^^^ N1 -phenyhnethylcart>amidc; N-((4-Methylphenyl)methyl)-N-(piperidiB-4-yl)-4-methoxypheny]acetamide; N-((4-MctbyIphcnyI)mcthyl)-N-(l-inethyIpipcridiD-4-yI)-4-methoxyphenylacetamide; 21 WO 01/66521 PCTYUSO1/07187 N-(l-Ethylpiperidin-4-y])-N-((4-methylphenyl)methyl)-4-methoxyphcnylacetamide; N-((4-Methy]phenyl)methyl)-N-(l-prapylpipendin-4-y!)-4-methoxypbenylacetamide; N-(l-Butylpiperidui-4-yl)-N-((4-methylphenyl)niethyI>4-rnethoxyphenylacetamide; N-(l-(3)3-Diinethy]butyl)piperidiii-4-yl)-N-((4-inethylphenyl)methyl)-4-methoxypbenylacetamide; N-(l-(Cyclohexylinethy])piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide; N-((4-Methylpheayl)mettiyl)-N-(l-(2-inetliylpropyl)pipendin-4-yl)-4-methoxyphenyl acetam ide; N-((4-Methylphenyl)metbyl)-N-(l-((4-methylphenyl)methyl)piperidin-4-yl)-4-methoxyphenylacetamide; N-(l ((4-Hydroxyphenyl)methyl)piperidiii-4-yl)-N-((4-methyIphenyl)niethyl)-4-methoxyphenylacetamide; N-(l-((2-Hydroxyphenyl)methy!)piperidin-4'yI)-N-((4-tnethylph6nyl)methyl)-4-Di ethoxyphcnylacetamidc; N-(3-Plienylprapyl)-N-(ptp eri din-4-yl)-4-methoxyphenylacetamide; N-(2-Pheny]ethy])-N-(piperidin-4-y])-4-methoxypheiiylac6taiiude; N^(2-Mcthoxyphcnyl)mcthyl)-N-(piperidin-4-yl>4-methoxyphenylacetamide; K-((2-Ch!orophenyl)metiiy])-N-^> iped din -4-yl)-4-methoxypbenylacetami de; N^(3,4-DiHnethoxyphcnyI)mcthyI)-N-(pq)cridin-4-yl)-4-methoxyphenylacetamide; N^(4-Fluorophenyl)methyI>N^iperidjm-4-yl>4-methoxypheiiylacetaiDide; N- NK(3-Metfay^enyl)methyl>-N^p6ridin-4-yl>^-methoxyphCTylacctainide; N^(3-BromophcnyI)mcthyI)-N^ipcridin-4-yI)^mctiioxyphenylacetamide; N-(l -(Phenylmethyl)piperidin-4-yl)-N-(3-plienyl-2-propen-l -yiy4-m ethoxyphcnylacetami de; N-((4-Mcthy Iphcny I)tncthyl)-N-( I -piperidin-4-yI)-phenylacctamidc; N-{(4-MethyIphenyl)inethyl)-N- 22 WO 01/66521 PCT/US01/07187 N-((4-Methylpheny])methyI)-N-{l-pipendin-4-yl)-(phenylthio)acctamide; N-((4-Methylpheny1)methyl)-N-{l-pjperidin-4-yl)-phenoxyacetamide; N-((4-Methylphenyl)metliyl)-N-(l-piperidin-4-yl)-(4-chlorophenoxy)acetamide; N-((4-Methylphenyl)methyl)-N-(l-piperidin-4-yl)-3-methoxyphenylacetamide; N-((4-Methylphenyl)methyl)-N-{l-pipendin-4-yl)-4-fluorophenylacetanude; N-((4-Methy]pheny])methy1)-N-(l-piperidin-4-y])-2,5-di-methoxyphenylacetamide; N-((4-Methylphenyl)methyI)-N-(l-pipcridin-4-yI)-4-chlorophenylacetamide; N-((4-MethylphenyI)methy])-N-(l-(phenylmethyl)pyn-oIidin-3-yI)-N'-phenylmethylcarbamide; N-((4-Methylpheny])inethyl)-N-(l-(phenylmethyl)pyrrolidin-3-yl)-4-methoxyphenylacetamide; 2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(piperidin-4-yl)acetamide; 2-(4-methoxyphenyI>N-(4-methylbenzyl)-N-( 1 -methy lpiperidin-4-yl) acetamide; 2-(4-methoxyphenyI)-N-(4-rnethylbenzyl)-N-(l-ethyIpiperidin-4-yl) acctanide; 2-(4-methoxyphsnyl>N-(4-c.hlorbenzyl)-N-(l -ethylpiperidin-4-yI) acetamide; 2-(4-methoxypheoyl)-N-(4-ch]orbenzy])-N-(l-isopropylpiperidin-4-yl) acetamide; 2-(4-metlioxyphenyI)-N-{4-chlorobeiizyl)-N-(piperidiii-4-yl) acetamide; 2-(4-me1iioxyphenyI>N-(4-chIorben2>'!>N-( 1 -cycI 2-(4-methoxypheny])-N-(4-cliIorben2yl)-N-(l-isopropylpiperidin-4-yI) acetamide; 2-(phenyl>N-{4-trifluoromethyJben2yI)-N-(l-methyIpiperidin-4-yl) acetamide; 2-{4-3uorophenyl)-N-(4-trifluoTX5methyIbeiizyl)-N-(l -methylpiperidm-4-yI) acetamide; 2-(4-Methoxyphenyl)-N-(4-tiifluoromethylbeiizyl)-N-(l-mcthylpiperidin-4-yl) acetamide; 23 WO 01/66521 PCT/US01/07I87 2-(4-TrifluororaethyIphenyi[)-N-(4-triiluoromethyIbenzyl)-N-(l-methylpiperidin-4-yl) acetamide; 2-(4-Fluorophenyl)-N-(4-fluoroben23'l)-N-(l-inethylpiperidin-4-yl)acetanude; 2-(4-Methoxypbenyl)-N-(4 -iluorobenzyl)-N-(l -methylpiperidin-4-yl) acetamide; 2-(phenyl) N-(4-fluorobenzyI)-N-(l -methylpiperidin-4-yl) acetamide; 2-(4-Trifluoromethylphenyl)-N-(4-fluorobenzyI)-N-(l-methylpiperidui-4-yI) acetamide; 2-(4-trifluoromethyIphenyl)-N-[4-(rDethoxycarbonyl)benzyl]-N-(l-methylpiperidin-4-yI) acetamide; 2-Phenyl-N-[4-(methoxycarboiiyl)ben2yl3-N-(l-methylpiperidin-4-yl) acetamide; 2-(4-ChlorophenyI)-N-t4-(methoxycarbonyI)ben2yl]-N-(l-methyIpiperidin-4- yl) acetamide; 2-(4-MethoxyphejiyI)-N-[4-(methoxycarbon\l)ben2yl]-N-(l-n)emylpiperidin- 4-yl) acetamide; 2-(4-trifiuoromethylpheDyl)-N-[4-(methoxycarbonyl)benzyI]-N-(l-methylpiperidin-4-yI) acetamide; 2-PheuyI-N'[4-(inetboxycari>onyl)benz>l]-K-{l-methylpiperidin-4-yl) acetamide; 2^4l)benzyl]-N-(l-methylpiperidin-4- yl) acetamide; 2^4 Me&oxypbenyl)-N-[4-(methoxycajbo^ 4-yI) acetamide; 2-(4methoxypbenyI)-N-(4-methylben2y I>N-[ 1 - 2- 2phenyI)-NK2^(fluoropbenyl)emyI)-N^l-methylpiperidin-4-yl) acetamide; 2-(4-methox>-phenyl}-N-[2-{2,5-dimemoxyphenyl)ethyl]-N-(l-methylpiperidin-4-yI) acetamide; 2-{4-methoxyphenyl)-N-[2-(2s4-dich]orophenyl)ethyl]-N-(l-methylpiperidin- 4-,yl) acetamide; 24 WO 01/66521 PCT/US01/07187 2-(4-methoxyphenyl)-N-[2 -(3-cttorophenyl) ethyl]-N-(l -methylpiperidin-4-y]) acetamide; 2-(4-methoxyphenyI)-N-[2- (4-methoxyphenyl) ethyl]-N-(l -methylpiperidin-4-yl) acetamide; 2-(4-methoxyphenyl)-N-[2-(3-fluoropheny])ethyIJ-N-(l-methyIpiperidin-4-yl) acetamide; 2-(4-ethoxyphenyI)-N-[2-(4-fluorophenethyl]-N-(l-methylpiperidin-4-yl) acetamide; 2-(4-ethoxyphenyl)-N-(4-fluorobenz>i)-N-(l-methylpiperidin-4-yl) acetamide, 2-(4-methoxyphenyI)-N-(4-methylbenzy3)-N- {1 -[2-(2-hydroxyethoxy)ethyl] piperidin-4-yl} acetamide; 2-(4-methoxyphenyl>N-(4-![nethyIbenzyl)-N-[l-((2-ch3oro-5-thienyI)methyl) piperidin-4-yl] acetamide; 2-(4-methoxyphenyl)-N-(4-3iiethy]benzy l)-N-[ 1 -(2-(imidazolidinon-1 -yl)ethyI)piperidm-4-yl] acetamide; 2-(4-methoxyphenyl)-N-(4-methyIbenzyI)-N- {1 -[2-(2,4(lH,3H)quina2olinedion-3-yl)e1hyl] piperidin-4-yl} acetamide; 2-{4-methoxypheny])-N--K-{l-[2-(l^-dioxolan-2-yl)ethyl3piperidin-4-yI} acetamide; 2-(4-methoxyphenyl)-N-(4-inethy]benzyl)-N- {1 -[2-(3"mdoly3)ethyl] piperidin-4-yl} acetamide; 2-{4-metboxyphenyI>-N- 2-(4H0ietboxyphenyI>-N-(4-rnethylbenzyI>-N-[ 1 - 2-{4-methoxyphenyl)-N-(4-methylbeiizyl)-N-[l- 2-(4-methoxypheay]>-N- 2-{4-Chlorophenyl)-N-(4-mc:thy Ibenzy I>N-( 1 -isopropylpiperidin-4-yl)-acetamide; 2-(4-Chlorophenyl)-N-(4-methy lbenzy l)-N-( 1 -ethylpiperidin-4-yl)-acetamide; 2-Phcnyl-N-{4-methylbenzy])-N-(l-methylpiperidin-4-yl)-acctamide^-(4-Chlorophenyl)-N-(4-methyIbeiizyl)-N-{l-methylpipeiidin-4-yl>-^;etainide; 25 WO 01/66521 PCT/US01/07187 2-(4-Chloropheny])-N-(4-methy]benzy])-N-(l-cyc]opentylpipendin-4-yl)-acetamide; 2- 2-(4-Chlorophenyl)-N-(4-methyIbenz>'l)-N-(l-(2-hydroxyethyl)-piperidin-4-yl)-acetamide; 2-(4-Ch]orophenyl)-N-(4-niethyIbenzyl)-N-(l-cyclobutylpipendiji-4-yl)-acetamide; 2-(4-Methox>fphenyI)-N-(4-inethyIben2yI)-N-(l-cyclobutyIpiperidin-4-yl)-acetamide; 2 -(4-Methoxjphenyl>-N-(4-methylben2y 1)-N -(tropin-4-yl)-acetamide; N_(4-Methylbenzyl)-N-(l-methylpiperidin-4-yl)-N'-benzyl-cart) amide; N- N-Phcnethyl-N-(l-mcthylpiperidin-4-yl)-N'-benzyl-cart) amide; 2-Phenyl-N-(4-methoxybenzyI)-N-(l-me(hy]piperidin-4-yI)-acetaraide; 2-(4-TrifluoromethyIphenyl)-N-(4-methoxybenz>'l)-N-(l-mcthylpiperidin-4-yl)-acetamide; 2-(4-FIuorophenyl)-N-(4-methoxyben2yl)-N-(l-raethylpiperidin'4-yl)-acetaznide; 2-(4-Methoxj-phenyl)-N-(4-methoxybciiz>l}-N- 2-(4-MethyIphen3d)-N^4-chlorobenzyI)--N- acetamide; 2-(4-HydroxypbenyI)-N-(4-incihyIbenz>'I>N- acetamide; N-Phenetb}'I-N-(l-methyJpiperidiii-4-yI)-N'-pheDy]-cari) amide; N-(3-Phenylpropy I)-N-( 1 -mcthyIpiperidin-4-yl)-N '-benzyl-carbamide; N-(3-Phenylpiopyl>-N^l-methyIpiperidm-4-yO-N -pheiiyl--carbamide; 2-(4-MethoxyphcnyI)-2^- tbylcne-N^4-methylbenzyI)-N-(l-methylpiperidi3-4-yl) acetamide; 2-{4-Methoxyphenyl)-N-alpha-methyIben2yI-N-{ 1 -methylpiperidin-4-yl) acetamide; 2-(4-MethoxyphenyI)-N-(4-methylben2yI)-N-(3-tropen-4-yl) acetamide; 2-PhenyI-2-elhyl-N-(4-methylbenzyl)-N-( 1 -methylpiperidin-4-yl) acetamide; 26 WO 01/66521 PCT/US01/07187 N-PhenetbyJ-N-(4-methyJbenzy]>N-( 1 -methylpiperidin-4-y])-amine; 2-(4-Methoxyphenyl>N-(l-indanyl)-N-(l -methylpipendin-4-yI) acetamide; N-(4-MethyIbenzyl)-N- 2-(3J4-dimethoxyphenyl)->J-(4-raethylbenzyl)-N- 2-(3,4-MethylenedioxyphenyI>-N-(4 methy]benzy])-N-(l-methy]piperidin-4 y]) acetamide; 2-(4-MethoxyphenyI)-N-(4-methyIbenzyI)-N-(l-t-but>'Ipiperidin-4-yI)-acetamide; N-(4-MethyIbenzyl)-N-(l-inethylpiperidin-4-yl)-N'-phenethyl-carbaiiiide; N-Phenethyl-N-(l-methylpipKidin-4-yl)-N'-phenethyl-carbaraide; N-(4-MethyIbenzyl)-N-(l-l-butylpiperidin-4-yl)-N'-(4-methoxybenzyl)-carbamide; 2-(4-Ethoxyphenyi)-N-(4-niethy!benzyl)-N-(l-metfayIpiperidi3i-4-yl) acetamide; 2-(4-Butoxyphenyl)-N-(4-methylbenzyn-N-( 1 -methylpiperidin-4-yl) acetamide; 2-{4-i-Propoxypheny3)-N-(^methyIbenzyl)-N-(l-methylpiperidm-4-yl) acetamide; 2-(4-t-Butoxyphenyl)-N-{4-methyIbenzyI)-N-( 1 -methylpiperidin-4-yl) acetamide; 2^4-ButoxyphenyI)-N^4-fluorc4>eiizyIVN^l-tnethylpipeiidiD-4-yI) acetamide; 2-(4-Propoxyphenyl)-N-(4- flourobenzyI)-N-(l -methylpiperidin-4-yl) acetamide; 2-{4-i-Propoxyphenyl)-N-(4-fluoroben2y l)-N-{ 1 -methylpiperidin-4-y I) acetamide; and, 2-(4-t-ButoxyphenyI)-N-{4-fluorobenzyl)-N-eridin-4-yl) acetamide. Suitable phannaceutically acceptable salts of the compounds of this invention include acid addition salts that may,, for example, be formed by mixing a solution of the compound according to the invention with a solution of a phannaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, 27 succinic acid, acetic acid, bcnzoic acid, oxalic acid, citric acid, tartanc acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof nay include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts, and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. Examples of pharmaceutically acceptable salts include the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, carbonate, chloride, cla>rulanate, citrate, dihydrochloride, fumarate, gluconate, glutamate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malcate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, phosphate/diphosphate, salicylate, stearate, sulfate, succinate, tannate, tartrate, tosylate, triethiodide and valerate salt. The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs are inactive derivatives of the compounds of this invention that are readily co avertible in vivo into the required compound. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985). Metabolites o^Jjffe n^KrarK3s"in^Iu^e^ctive species mat are produced upon introduction of compounds of this invention into the biological milieu. Where the compounds according to the invention have at least one crural center, they may exist as a raccinate or as enantiomers. It should be noted mat all such isomers and mixtures (hereof are included in the scope of the present invention. Furthermore, some of the crystalline forms for compounds of the present invention may exist as poryraorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates are also included in the scope of this invention. Where the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoi&omers, such isomers may be separated by conventional techniques such as preparative chiral chromatography. The compounds may be prepared in racemic fonn or individual enantiomers may be prepared by stereoselective synthesis or by resolution. The compounds may be resolved into their component cnantiomers by standard techniques, such as the formation of 28 WO 01/66521 PCT/US01/07187 diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-dj-p-toluoyl-I-tartaric acid, followed by fractional crystallization and regeneration of the free base. The compound's may also be resolved by formation of diastereomeric esters or amides followed by chromatographic separation and removal of the chiral auxiliary. Compounds of the present invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever specific pharmacological modification of the activity of monoamine receptors is required. The present invention also provides pharmaceutical compositions comprising one or more compounds of the invention together with a pharmaceutically acceptable diluent or excipient. Preferably such compositions are in unit dosage forms such as tablets, pills, capsules (including sustained-release or delayed-release formulations), powders, granules, elixirs, tinctures, syrups and emulsions, sterile parenteral solutions or suspensions, aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral (e.g., intravenous, intramuscular or subcutaneous), intraiusal, sublingual or rectal administration, or for administration by inhalation or insufflation, and may be formulated in an appropriate manner and in accordance with accepted practices such as those disclosed in Remington's Pharmaceutical Sciences, (Gennaro, ed., Mack Publishing Co., Easton PA, 1990, herein incorportated by reference). Alternatively, the compositions may be in sustained-release form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decaiioate salt, may be adapted to provide a depot preparation for intramuscular injection. The present invention also contemplates providing suitable topical formulations for administration to, e.g., eye or skin or mucusa. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, flavoring agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in 29 WO 01/66521 PCT/US01/07187 these dosage forms include, without limitation, sodium oleate, sodium stearatc, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentomte, xantban gum and the like. For preparing solid compositions such as tablets, the active ingredient is mixed with a suitable pharmaceutical excipient such as the ones described above and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention or a pharmaceutically acceptable salt thereof. By the term "homogeneous" is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdhided into equally effective unit dosage forms such as tablets, pills and capsules. The solid preformulation composition may then be subdivided into unit dosage forms of the type described above containing from O.I to about 50 mg of the active ingredient of the present invention. The tablets or pills of the present composition may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner core containing Ihe active compound and an outer layer as a coating surrounding the core. The outer coating may be an enteric layer that serves to resist disintegration in the stomach and permits the inner core to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings including a number of polymeric acids and mixtures of polymeric acids with conventional :EBaterials such as shellac, cetyl alcohol and cellulose acetate. The liquid forms in which the present compositions may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical carriers. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanm, acacia, algmaie, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose or polyvinylpyrrolidone. Other dispersing agents that may be employed include glycerin and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations that gisnerally contain suitable preservatives are employed when intravenous administration is desired. The compositions can also be 30 WO 01/66521 PCT/US01/07I87 formulated as an ophthalmic solution or suspension formation, i.e., eye drops, for ocular administration Consequently, the present invention also relates to a method of alleviating or treating a disease condition in which modification of monoamine receptor activity, in particular 5-HT2A serotonergic receptor activity, has a beneficial effect by administering a therapeutically effective amount of a compound of the present invention to a subject in need of such treatment. Such diseases or conditions may, for instance arise from inappropriate stimulation or activation of serotonergic receptors. It is anticipated that by using compounds that are selective for a particular serotonin receptor subtype, m particular 5-HT2A, the problems with adverse side effects observed with the known antipsychotic drugs, such as extrapyramidal effects, may be avoided substantially. The term "therapeuhcally effective amount" as used herein means an amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated. Advantageously, compounds of the present invention may be administered in a smgle daily dose, or the total daily dosage may be administered in divided doses, for example, two, three or four times daily. Furthermore, compounds of the present invention may be administered in intranasal form via topical use of suitable intranasal vehicles, via transdermal routes, using those forms of transderxnal skin patches well known to persons skilled in the art, by implantable pumps; or by any other suitable means of administration. To be administered in the form of a transdennal delivery system, for example, the dosage administration wiD,-of course, be continuous rather than intermittent throughout the dosage regimen. The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound employed. A physician or veterinarian of ordmary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the disease or disorder that is being treated. 31 WO 01/66521 PCT/US01/07187 The daily dosage of the products may be varied over a wide range from about 0.01 mg to about 100 mg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01,0.05, 0.1, 0.5, 1.0,2.5, 5.0,10.0,15.0, 25.0 or 50.0 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A unit dose typically contains from about 0.001 mg to about 50 mg of the active ingredient, preferably from about 1 mg to about 10 mg of active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0001 mg/kg to about 25 mg/kg of body weight per day. Preferably, the range is from about 0.001 to 10 mg/kg of body weight per day, and especially from about 0.001 mg/kg to 1 mg/kg of body weight per day. Compounds according to the present invention may be used alone at appropriate dosages defined by routine testing in order to obtain optimal pharmacological effect on a monoaininergic receptor, in particular the 5-HT2A serotonergic receptor subtype, while minimizing any potential toxic or otherwise unwanted effects. In addition, co-administration or sequential administration of other agcnis that improve the effect of the compound may, in some cases, be desirable The pharmacological properties and the selectivity of the compounds of this invention for specific serotonergic receptor subtypes may be demonstrated by a number of different assay methods using recombinant receptor subtypes, preferably of the human receptors if these are available, e.g. conventional second messenger or binding assays. A particularly convenient functional assay system is the receptor selection and amplifJcatioG assay disclosed in U.S. Pat No. 5,707,798, which describes a method of screening for bioactive compounds by utilizing the ability of cells transfected with receptor DNA, e.g., coding for the different serotonergic subtypes, to amplify in the presence of a ligand of the receptor. Cell amplification is detected as increased levels of a marker also expressed by the cells. Methods o/preparation The compounds in accordance with the present invention may be synthesized by methods described below, or by modification of these methods. Ways of modifying the methodology include, among others, temperature, solvent, reagents etc, and will be obvious to those skilled in the art For instance, compounds of the formula C may be synthesized from the corresponding ketone A by reductive aminatjon utilizing any primary amine. The 32 WO 01/66521 PCTAJS01/07187 reaction is conveniently carried out by stirring the reactants in an inert solvent such as methanol or ethanol containing acetic acid. As reducing agent NaBHU, NaCNBH3, BH3 pyridine or any related reagent may be used including solid-supported reagents. The reaction is typically carried out at room temperature. The ketone A, as exemplified by the piperidone, may be chosen from a list of compounds corresponding to the Z-group listed in formula (I). The ketones can either be obtained commercially or synthesized by methodology disclosed in Lowe et al. J. Med. Chem. 37: 2831-40 (1994); Carroll et al J.Med Chem 35:2184-91 (1992); or Rubiralta et al. Pipendine - Structure, Perparation, Reactivity and Synthetic Applications of Piperidine and its Derivatives. (Studies in Organic Chemistry 43, Elsevier, Amsterdam, 1991). The protecting group P includes groups such as those described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry; 3. Ed. John Wiley & Sons, 1999, and they should be chosen in such a way, that they are stable to the reaction conditions applied and readily removed at a convenient stage using methodology known from the art. Typical protecting groups are N-Boc, N-Cbz, N-Bn. Alternatively, the amine C c;an be synthesized from the primary amine B by reductive amination with any aldehyde. The reaction is conveniently carried out by stirring the reactants in an inert solvent such as methanol or ethanol containing acetic acid. As reducing agent NaBH4, NaCNBH3, BH3-pyridine or any related reagent may be used including solid-supported reagents. The reaction is typically carried out at room temperature. The primary amine B, as exemplified by the 4-aminopiperidine, may be chosen from a list of compounds corresponding to the Z-groups listed in formula (I). The amines can either be obtained commercially or synthesized from the corresponding ketones. The protecting group P may be chosen as stated above. Alternatively, the amine C can be synthesized from the primary amine B by alkylation with any alkylating agent (R-Lj)- The leaving group Li is suitably a halogen atom, e.g., bromine or iodine, or a sulfonate, e.g. tosylate or mesylate, or another leaving group favoring the reaction. The reaction is conveniently carried out by stirring the reagents under basic conditions in an inert solvent, e.g., diisopropylethyiamme in acetonitrilc, or K2CO3 in A'.A^-dimethylformamide. The reaction is typically carried out at temperatures between room temperature and 80°C. The primary amine B, as exemplified by the 4-aminopiperidine, may be chosen from a list of compounds corresponding to the Z-groups listed in formula (I). The amines 33 WO 01/66521 PCT/US01/07187 can either be obtained commercially or synthesized from the corresponding ketones. The protecting group P may be chosen as stated above. Wherein R and R are defined in agreement with formula (I), and P represents a suitable protecting group, and Lt represents a suitable leaving group. The secondary amine C may be acylated using any isocyanate or isothiocyanate (Qi-NO=W) to give the cotiesponduig ureas or thioureas D. The reaction is typically carried out by stirring the reactants, using an excess of isocyanate or isothiocyanate in an inert solvent, e.g-, dicfclsroaethane at a temperature,between 0°C and room temperature and under dry conditions. The amine C may also be acylated using any carboxylic acid halide (QsCOX), e.g., chloride, or carboxylic anhydride ((QtfXykO) to give amides of the general structure E. The reaction is typically carried out using an excess of the acylating agent and a suitable base, e.g., triethylamine or diisopropylethylamine in an inert solvent, e.g., dichJoromethane, at a temperature between 0°C and room temperature and under dry conditions. As an alternative to the carboxylic acid halides and carboxylic acid anhydrides, the amine C may be acylated using a carboxylic acid (Q2COOH) and a suitable coupling reagent e.g. DCC or EDCI. The reaction is typically carried out using an excess of the 34 WO 01/66521 PCT/US01/07187 acylating agent and the coupling reagent in an mert solvent, e.g., dichloromethane at a temperature between 0°C and room temperature and under dry conditions. The compounds of the general structure (E) may be converted into the corresponding thioamides using methodology disclosed in Varraa et al, Org. Lett. 1: 697-700 (1999); Cherkasov et al. Tetrahedron 412567 (1985); or Scheibye et al Bull. Soc. Chim. Belg. 87229 (1978). Wherein R^ Qu Q^ and W lire defined m agreement wife formula (I), P represents a suitable protecting group, and X represents a halide. The substituent G on the ring nitrogen can be introduced by g. two step procedure. First, the protecting group on the urea D or the amide E is removed using well-known methods. For example., the N-Boc group is removed by treating the protected compound with 4 M HC1 in dioxane or trifluoroaceu'c acid in dichloromethane. Second, the secondary amines obtained from D and £ can be alkylated by reductive aminan'on wring any aldehyde (T-CHO). The reaction is conveniently carried out by stirring the reactsnts in an inert solvent such as methanol or ethanol. As a reducing agent, solid-supported borohydride, NaBH . NaCNBEb, BHspyridine or any related reagent may be used, including solid-supported reagents. The reaction is typically carried out at room temperature. 35 WO 01/66521 PCT/US01/07187 Alternatively, the compounds F and G can be synthesized from the secondary amine obtained from D or E as described above by alkylation with any aKcylating agent (T- Li). The leaving group Lj is suitably a halogen atom, e.g., bromine or iodine, or a sulfonate, e.g., tosylate or mesylate, or another leaving group favoring the reaction. The reaction is conveniently carried out by stirring the reagents under basic conditions in an inert solvent, for example diisopropylethyl amine in acetonitrile, or K2CO3 in K N-dunethylfonnamidc. The reaction is typically carried out at temperatures between room temperature and 80°C. Alternatively, the T-group can be introduced in the first step of the synthetic sequence leading to the compounds in accordance with the present invention by A-alkylation of compound H with any alkylating agent (T- Li). The leaving group Li is suitably a halogen atom, e.g., bromine or iodine, or a sulfonate, e.g., tosylate or mesylate, or another leaving group favoring the reaction. The reaction is conveniently carried out by stirring the reagent under basic conditions in an inert solvent, e g., diisopropylethylamine in acetonitrile, or K2CO3 in yV.W-dimethylformamide. The reaction is typically carried out at temperatures between room temperature and 80°C. The secondary amine H, as exemplified by 4-piperidone, may be chosen from a list of compounds corresponding to the Z-groups listed in formula (I). The amines can either be obtained commercially or synthesized from methodology disclosed in Lowe et al., J, Med. Chem. 37.2831-40 (1994); and Carroll et al., J. Med. Chem. 35:2184-91 (1992). Alternatively, compounds of the general structure J may be synthesized starting from K using the method disclosed m: Kuehne et aL, J. Org. Chem. 56:2701 (1991); and Kuehne et al, J. Org. Chem. (1991), 56:513. 36 WO 01/66521 PCT/US01/07187 wherein R, Qi, Qi, W, and T are defined in agreement with formula (I), and Li is a suitable leaving group. In general, dining any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of tbe molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J.F.W. McGmie, Plenum Press, 1973); and Greene & Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. 37 WO 01/66521 PCT/US01/07187 Examples The invention is disclosed in further detail in the following examples that are not in any way intended to limit the scope of the invention as claimed. General LC-MS procedure for Examples 1-41: All spectra were obtained using an HP 1100 LC/MSD-instrument A setup with a binary pump, autosampler, column oven, diode array detecter, and electrospray ionization interface was used. A reversed phase column (CIS Luna 3mm particle size, 7.5 cm x 4.6 mm ID) with a guard cartridge system was used. The column was maintained at a temperature of 30°C. The mobile phase was acetonitrile/8 mM aqueous ammonium acetate. A 15 minute gradient program was used, starting at 70% acetonitrile, over 12 minutes to 95 % acetonitrile, over 1 minute back to 70% acetonitrile, where it stayed for 2 minutes. The flow rate was 0.6 ml/min. The tj- values reported in the specific examples below were obtained using this procedure. Example 1 - AH(4-Methylphenyl)methyl)-Ar-(piperidin-4-yI)-Ar'-phenylmethylcarbamide (26HCH65) To a solution of commercially available rer;-butyl 4-oxo-l-piperidine carboxylate (1.75 g, 8.S mmol) and 4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added acetic acid in methanol Q M, 6.7 mj) followed by NaCNBH3 in methanol (0.3 M, 30 ml). The resulting solution was stored at room temperature. After 20 h, water (5 ml) was added, and the mixture was stirred for 1 h before it was concentrated. Flash chromatography in dichloromethanermethanol 10:1 gave tert-butyl 4^4-melhylphetiyI)memyI)amino-piperidme carboxylate. Yield: 2.4 g, 98%. To a solution of tert-butyl 4^4-memy^heo>1)methyl>ainmo-piperidme carboxyiate (800 mg, 2.63 mmol) in dry dichloromethape (20 ml) was added benzylisocyanate (0.65 ml, 5.26 mmol). The solution was stiued at room temperature. After 48 h, an excess of 2-dimethylaminoethylanaine was added. The mixture was stirred for another 24 h, before it was concentrated. The resulting solid was rtdissolved in dichloromcthane (20 ml), sequentially washed with HC1 (0.2 N, 3x30 ml), and water (20 ml), dried (Na2SO4), filtered and concentrated. Flash chromatograpfay in dichloromethanermethanol 10:1 gave A^-((4-methylphenyI)methyI)-Ar-( l-(/err-butyloxycari>onyl)pip eridin-4-y 1)-W -phenylmethylcarbamide (760 mg, 66 %), which was dissolved in diethyl ether (5 ml). HC1 (4 M) in dioxane (3 ml) was added, and the solution was stirred at room 38 WO 01/66521 PCT/USOJ/07187 temperature for 60 min, then concentrated The resulting oil was redissolved in a mixture of dichJoromethanc and diethyl ether (4.1). The organic layer was extracted with HC1 (0.2 M, 3x20 ml). The combined aqueous layers were treated with NaOH (0.2 M) until basic (pH>8), then extracted with dichloromethane (3x20 ml). The combined organic layers were dried (Na2SC>4), filtered, and concentrated to give the title compound Yield: 406 mg, 70%; 13C-NMR (CDCI3): 6 21.3, 31.6, 45.0, 45.9, 46.4, 53.0, 126.3,127.2,127.4, 128.6, 129.8, 135.3, 137.4, 139.7, 158.5. Example 2 - - -MethylpbenyOmetbyl -fl -methylpropyOpiperidin-4-yl)-iV-pheiiy]inethylcarbamide (26HCH66-02) The product from example 1 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 2-MethylpropionaJdehyde (0.08 ml, 0.6 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound IR: 1640, 1185, IIIOCTT ; LC-MS: (M+H)+ 394.2, t,- 5.60 mis. Example 3 - Ar- The product from example 1 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 2-Bromdbenzaldehyde (0.07 ml, 0.6 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (03 mmol/g resin), which was washed with methanol (3x6 ml), and elated with 10% NH3 in methanol, and concentrated to give the title compound. IR: 1635,1180, lllOcm" ; LC-MS: (M+H)+ 506.1, tr 8.37 min. 39 WO 01/66521 PCT/US01/07187 Example 4 - A4l-((4-Hydroxy-3-methox>'pheny])methyl)piperidin-4-yl)-^-((^niethylpbenyOmethyiy-A^-pbenylniethylcarbainide (26HCH66-04) The product from example 1 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 4-Hydroxy-3-methoxybenzaldehyde (91 mg, 0.6 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 4S h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed wife methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. 13C-NMR (CD3OD, selected): 6 19.9,55.4, 126.5,127.0,128.1,129.0, 140.3, 148.0, 148.1, 158.8. Example 5 - N-(l-((5-EthyJthien-2-yi)methyI)piperidin-4-yl)-N-((4-methylpbenyl)methyI)-N'-phenyImethylcarbamide (26HCH66-05) The product from example 1 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 5-Ethyl-2-thiophencarboxaldehyde (84 mg, 0.6 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken al room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed wife methanol (3x6 ml), and eroted with 10% NH3 in methanol, and concentrated to give the title compound. IR: 1640,1185,1110, 805, 700,620 cm"3; LC-MS: (M+H)+462.3, ^ 7.52 min. Example 6 - N-(l-(Inudazo^ylmethyI)piperidiii-4-yI)-N-((4-methy]pheny!)methyl)-N'-pfaenylmethyIcarbamide (2 6H CH 66-06) The product from example 1 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). Imidazole-2-carboxaMehyde (58 rag, 0.6 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was 40 WO 01/66521 PCT/US01/07187 added on to a column carrying strongly acidic cation exchange resin (0 3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. IR: 1620,1190,1100, 805, 700, 620 cm"1; LC-MS: (M+H)+ 418.2, tr 2.05 min. Example 7 - ;V-(l-(QcJohexyJroethy])piperidin -yl)-;V-((4-methylphenyl)methyl)-iV-phenylmethylcarbamide (26HCH66-09) The product from example 1 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). Cyclohexanecarboxaldehyde (67 mg, 0.6 mmol) was added followed by solid-supported borohydridc (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. IR: 1635,1175,1100, 805, 695, 620 cm"3; LC-MS: (M+H)+ 434.4, tr 7.44 min. Example 8 - 7V-(l-((4-F!uorophenyi)methyl)piperidiii-4-yI>A'-((4-roethylphenyI)metbyI)-Aw-pbenylmetbvicarb amide (26HCH66-10) The product from example 1 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 4-Fluorobenzaldehyde (0-08 ml, 0.6 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 02 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissorved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound IR: 1640,1175,1110, 805, 700,620 cm"1; LC-MS: (M+H)+ 4463, t, 5.62 min. Example 9 - N-((4-MetbylphenyI)methyI>N-(l-{pbeiiylniethyI)piperidiii-4-yI)-N'-phenyImethylcarbamide kydrochloride (26HCH16D) To a solution of l-benzyl-4-piperidone (1.74 g, 9.2 mmol) and 4-methylbenzylamine (0.97 g, 8 mmol) in methanol (30 ml) was added sodium 41 WO 01/66521 PCT/US01/07J87 borohydride (525 mg) in small portions over 30 min. The reaction mixture was stirred at room temperature. After 16 h, the mixture was concentrated. Water (30 ml) was added, and the mixture was extracted with dichloromethane (2x20 ml). The combined organic layers were dried O SC ), filtered, and concentrated to give 4-((4- methylphenyl)methyl)ammo-l-phenylmethylpiperidme. The crude product was used without further purification. 4-((4-Methylphenyl)methyl)amino-l-phenylmethylpiperiduie (800 mg, 2.7 rnmol) was dissolved in dry dichloromethane (30 ml). Benzylisocyanate (543 mg, 4.1 mmol) was added. The reaction mixture was stirred at room temperature. After 16 h, water (10 ml) was added followed by NaOH (6 N, 2 ml). After additional 30 minutes of stirring the white crystals were filtered off The organic layer was isolated and dried (Na2SC>4), filtered, and concentrated. Flash chromatography in dichloroniethane/methanol 10/1 leftiV-((4-Methylphenyl)methyl)-A'--(l-(phenylmethyI)piperidin-4-yl)-A -phenylinethylcarbamide Yield: 820 mg, 71%; A sample was concentrated with HC1 (4 M in dioxane) followed by recrystallization from dichloromethane/diethyl ether leaving the title compound. H-NMR (CDCI3): 5 1.87 (br d, 2 H), 2.30 (s, 3 H), 2.59 (dq, 2 H), 2.76 (br q, 2 H), 3.44 (br d, 2 H), 4.09 (d, 2 H), 4.30 (d, 2 H), 4.40 (s, 2 H), 4.64-4.76 (in, 2 H), 6.98-7.64 (Aromatic protons, 14 H); I3C-NMR (CDCI3): 5 21.2, 26.7,45.0, 46.0, 49.7, 52.2, 61.0,126.2, 127.26, 126.31, 128-2, 128.6, 229.6,129.9,130.4, 131.6,134.4, 137.6, 139.3,158.5; (tm)C-NMR (CD3OD, rotamers): 6 19.8,26.4,27.8,40.3, 443, 51.6, 51.9, 54.5, 60.5,110.0, 112-1.114.0,114.2, 117.5, 125.9, 126.2,126.7, 126.8,128.9, 129.1,129.2,129.4, 129.7,130.1,131 , 134.5,137.4,159.1,173.8,175.0; Mp. l09-112oC; Eleinental analysis: Found Q 70.06; H, 7.62; N, 8.60; calcd for monohydrale: C, 69.76; H, 7.53; N,8.7Z Example 10 - N-((4-Methylphcny0metbyl)-N-(l-{phenylmetfayl)piperidiii-4-yl>-N'-pbeDyliDcthylcarbainide oxalatc (34JJ59oxaI) H( Methylphenyl)methyi)-iV l henymiethyI iperi6U&4-yI)-A -pbenybnethylcarbamide was prepared as described in example 9 above. A sample was precipitated as the ox al ate and reciystallizcd from ethyl acetate to give the title compound. 13C-NMR (CDCI3): 6 21.2,27.0,45.0, 45.9,49.9, 52.1,60.6,126.1, 127.3,127.4,128.5,128.7,129.6, 130.0,130.4, 131.2,134.3,137.7,1393,158.4, 42 WO 01/66521 PCT/US01/07187 163.4; Mp. 18O-1S2°C; ElementaJ analysis: Found C, 69.54; H, 6.73; N, 7.96; calcd formonooxalate: C, 69.61; H, 6.82; N, 8.12 Example 11 - N-((4-Methyipbenyl)methy])-N-(l-(phenylmetbyI)piperidin-4-yI) 4-metboxyphenylacetamide faydrochloride (26HCH17) To a solution of l-benzyl-4-piperidone (1.74 g, 9.2 mmol) and 4-methylbenzylamine (0.97 g, 8 mmol) in methanol (30 ml) was added sodium borohydride (525 mg) in small poiiions over 30 min. The reaction mixture was stirred at room temperature. After 16 h, the mixture was concentrated. Water (30 ml) was added, and the mixture was extracted with dichloromethane (2x20 ml). The combined organic layers were dried (Na2SC>4), filtered, and concentrated to give 4-((4- methylphenyl)methyl)amino-l-phenylmcthylpiperidine. The crude product was used without further purification. To a solution of 4-((4-Meti"yIphenyl)methyI)amino-l-phenylmethyIpiperidine (800 mg, 2.7 mmol) in dry dichloromethane (30 ml) was added diisopropylethylamine (1.5 ml) followed by 4-methoxyphenylacetyl chloride (997 mg, 5.4 mmol). The reaction mixture was stirred at room temperature. After 16 h, the reaction mixture was concentrated, redissolved in diethyl ether, and extracted with HC1 (0.6 N). The aqueous layer was isolated, treated with NaOH (1 N) until basic, and extracted with dichloromethane (20 ml). The organic layer was isolated and dried (Na2SO4), filtered, and concentrated, and redissolved in diethyl ether. The hydrochloride was formed by addition of HC1 (4 M in dioxane), and recrystallized mam diethyl ether to give the title compound. TieW: 600 mg, 50%; iH-NMR (CDCI3): 6 1.75 (d, 2 H), 232 (s. 3 H), 2.50 (q, 2 H), 2.70 (q, 2 H), 338 (d, 2 H), 3.54 (s, 2 H), 3.78 (s, 3 H), 4.06 (d, 2 H), 4.54 (s, 2 H), 4.82 (m, 1 H), 6.78-7.60 (aromatic protons, 13 K); 13C-NMR (CDCI3): 5 21.0, 26.0,40.3, 46.3,49.0, 51.8, 55.3, 60.8, 114.2,125.6, 126.6, 127.9,129.4,129.60,129.62,130.3,131.4,134.8,137.1,158.7,172.9; Mp. 197- 200C; Elemental analysis: Found C, 71.29; H, 7.25; N, 5.73; calcd for hydrate: C, 7137; H, 7.43; N, 5.74. Example 12 - N- Ar-((4-Methylphenyl)methyl)- -( 2 -(phenyImethyl)piperidin-4-yl)-4-methoxyphenylacetamide was prepiao d as described in example 11 above. A sample 43 WO 01/66521 PCT/US01/07187 was precipitated as the oxalate and recrystallized from tetrahydrofuran to give the title compound. 13C-NMR(CDC13): 821.2, 26.4, 40.6, 52.0, 55.5, 114.4, 125.9, 126.7, 128.4,129.6, 129.8,129.9,130.4,131.2,134.6,137.6, 158.9,163 3,172 9; Mp. 171- 173°C; Elemental analysis: Found C, 69.56; H, 6.74; N, 5.16; calcd for monooxalate: C, 69.48; H, 6.61; N, 5.40. Example 13 - N-((4-MethylpheByI)methyI)-N-(piperidin-4-yl)-4-raethoxypbenylacetaniide (26HCH71B) To a solution of commercially available /erf-butyl 4-oxo-l-piperidine carboxylate (1.75 g, 8.8 mmol) and 4-methylbenzylamine (970 rug, 8.0 mmol) in methanol (7 ml) was added acetic acid in methanol (I M, 6.7 ml) followed by NaCNBEb in methanol (0.3 M, 30 ml). The resulting solution was stirred at room temperature. After 20 h, water (5 ml) was added, and the mixture was stirred for 1 h before it was concentrated. Flash chromatography in dichloromethane:methanol 10:1 gave tert-butyl 4-(4-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 2.4 g, 98%. To a solution of tert-butyl 4-(4-methylphenyl)methyl)amino-piperidine carboxylate (862 mg, 2.83 mmol) in dry dichloromethane (10 ml) was-added diisopropylethylamine (1.1 ml, 6.5 mmol) followed by 4-methoxyphenylacety3 chloride (0.66 mi, 4.3 mmol). The reaction mixture was stirred at room temperature. After 48 h, water (5 ml) was added, and the mixture was stirred for additional 2 h before extracted with NaOH (0.2 N, 2x15 ml), HC1 (0.2 N, 2x15 ml), and water (15 ml). The organic layer was dried (SH2SO4) and concentrated to give -((4-methy enyl)memyl)- l rert4}urykacycarbonyi)piperidm-4-yl>4-methoxypbenylacetamide. The crude product was used without any further purification. -((4-Methylphenyl)mcth3'l>-A'-( 1 -( erf-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetainide was dissolved in ether (2 ml) and HC1 (3 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2 h, water (5 ml) was added, and the mixture was extracted with HC1 (0.1 N, 3x30 ml). Ike combined aqueous layers were treated with NaOH (0.2 N) until basic (pH > 8). The aqueous layer was extracted with diethyl ether (2x20 ml). The combined organic layers were dried (Na2SO4) and concentrated, before dissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated. Additional flash chromatography in 44 WO 01/66521 PCT/US01/07187 dichloromethane/methanol 1/1 - methanol containing 2% NH3 gave the title compound. Yield: 466mg, 47%; i3C-NMR (CD3OD, rotamers): 5 19.9,27.8,29.7, 40.2,40.3, 44.4,44.45, 44.50, 52.4, 54.5, 55.5, 114.0, 114.1, 126.0,126.7, 126.9, 127.3, 12S.7, 129.3,129.6,129.7,135.1,136.1, 136.2, 137.1, 159.0, 159.1, 173.1, 173.7. Example 14 - A -(l-(3"3-Diniethylbutyl)piperidiD-4-yI)-iV-((4-methvlphenyl)mcthyl>-4-methoxyphenylacetamide (26HCH79-5) The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 3,3-DimethylbutyraIdehyde (0.143 ml, 1.1 mmol) was added followed by solid-supported borohydride (150 ing, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temptsrature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0i2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 26 mg; C-NMR (CD3OD, rotamers): 6 19.9,27.4, 2S.4, 2S.8, 29.2, 29.3, 38.3, 38.4,40.2, 40.3, 44.3, 52.0, 52.3, 52.4, 53.9, 54.6,54.9,114.0,114.1, 126.0, 126.8, 127.0,127.3, 128.8, 129.4,129.8,129.9,135.0,136.1,136.3,137.1,158.96,159.05,173.2,173.8. Example IS - -(l-(CycIobexylroetbyI)piperidin-4-yI)-Ar-((4-m thylpbenyr)methyI)-4-methoiyphenylacettmide (26HCH79-6) The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). CydohacanecarfxJxaJdehyde (0.138 ml. 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aidrich'32,864-2). The mixture was shaken at room temperature. After 48 b, the resin was filtered off and acetic anhydride (0.02 ml, 02 mmol) was added to the organic solution. After 24 b, the mixture was concentrated and redissolved in methanol (2 ml). The solution was &lded on to a column carrying strongly acidic cation exchange resin (03 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 17 mg; HRMS (FAB , NBA) (M+H)+ 4493163, C29H41N2O2 requires 4493168; LC-MS: (M+H)+ 449.2, Xj. 7.92 min. 45 WO 01/66521 PCT/IISO1/O7187 Example 16 - A4(4-Methy]phenyI)methyl)-;V-(l-(2-methyJpropyJ)piperidin-4-yl)-4-inethoxj'phenylacelamide (26HCH79-7) The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs, ethanol (2 ml).). 2-Methylpropionaldehyde (0.104 ml, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 19 mg; HRMS (FAB+, NBA) (M+H)+ 409.2858, C2 H37N2O2 requires 409.2855; LC-MS: (M+H)+ 409-2, tr 5.97 min. Example 17 - A -((4-Methylphenyl)methyl)-Ar-(l-((4-metbylpbenyI)methyI)piperidiD-4-yI)-4-methoxyphenylacetainide (26HCH79-8) The product from example 13 above (20 mg3 0.06 mmol) was dissolved in abs. ethanol (2 ml). 4-MetbyIbenzaldehyde (0.134 ml, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2 5 mmoL'g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 45 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 mi). The solution was added on to a column carrying stronjUy acidic cation exchange resin (03 mmol/g resin), which was washed with methanol (3x6 raJ). and eluted wiifa 10% NH3 in methanol, and concentrated to give the title compound- Yield: 22 mg; HRMS (FAB+, NBA) (M+H)+ 457.2853, C30H37N2O2 requires 457.2855; LC-MS: (M+H)+ 457.2, t,- 6.97 min. Example 18 - iV l (4-Hyd )iyphenvI)methyI)piperidin-4-yI>-iV-4-met]ioxypbcBylacctanude (26HCH79-9) The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 4-Hydroxybenzaldehyde (139 mg, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, 46 WO 01/66521 PCT/US01/07187 the mixture was concentrated and redissolved m methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 19 rug; HRMS (FAB+, NBA) (M+H)+ 459.2655, C29H35N2O3 requires 459.2648; LC-MS: (M+H)+ 459.1, tr 2.84 min. Example 19 - AHH(2-Hydroxyphen>DmethyI)piperidin-4-yI)-Ar-((4-methylphenyl)methyI)-4-methox3'phenylacetamide (26HCH79-10) The product from example L3 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 2-Hydroxybenzaldehyde (0.122 ml, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (03 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 16 mg; HRMS (FAB+, NBA) (M+H)+ 459.2633, QpH Oj requires 459.2648; LC-MS: (M-r-HT 459.2, V 5.81 mm Example 20 -AH3-PbenyIpropyl>7V-(piperidin-4-y()-4-metboxyphenyUcetamide (26HCH80-1) To a solution of commercially available tert-butyl 4-oxo-l-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 3-phcnyipropylana3e (0.143 ml, 1 mmol) in methanol (1 ml) was added 'acetic add in methanol (1 M, 1.34" ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HC1 (0.1 N, 1x15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SC>4), filtered, and concentrated to give /erf-butyl 4-(3-pbenylpropyl)arnino-piperidme carboxylate. Yield: 110 mg. To a solution of tert-butyl 4-(3-phenylpropyl)amino- 47 WO 01/66521 PCT/US01/07187 piperidine carboxylate (50 mg, 0.16 mmol) in dichloromethane (6 ml) was added diisopropylethylaminc (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HC1 (0 2 N, 2x15 ml), NaOH (0.2 N, 2x15 ml), and water (10 ml), dried (Na2SC>4), filtered and concentrated to give N-(3- pheny!propyl)-7V-( 1 -(/ert-butyIoxycarbonyl)piperidin-4-yI)-4-methoxyphenylacetamide. The crude product was used without any further purification. W-(3-PhenylpropyI)-#-( 1 -(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HC1 (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichJoromethane (10 mi). The mixture was extracted with water (2x15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 61 mg; l C-NMR (CD3OD, rotamers): 6 27.8,29.4, 30.8, 32.3, 32.7: 33.3, 40.2, 40.5,42.0,44.5, 44.6,44.9, 52.7, 54.56, 54.57, 54.9,114.0, 114.1, 125.7, 126.1, 127.0, 127.4,128.2, 128.3,128.5, 129.47,129.55, 141.2,141.8,158.9, 159.0,172.5,172.7. Example 21 - A'-(2-PhenylethyI)-Ar-(piperidin-4-yI)-4-metboiyphenyimethylacetamide (26HCH80-2) To a solution of commercially available /erf-butyl 4-oxo-l-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 2-phenylsthylamine (0.143 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 m methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in dietfayl ether (20 ml), extracted with HC1 (0.1 N, 1x15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-buty] 4-(2-phenylethyl)amino-piperidine carboxylate. Yield: 221 mg. To a solution of tert-butyl 4-{2-phenylethyl)amino- 48 WO 01/66521 PCT/US01/07187 piperidine carboxylatc (50 mg, 0.16 mmol) in dichloromcthane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HCl (0 2 N, 2x15 ml), NaOH (0.2 N, 2x 15 ml), and water (10 ml), dried (Na2SC>4), filtered and concentrated to give //-(2- phenylethyl)- l-(/er?-butyloxycarbonyI)piperidm y]) -memoxyphenylacetamide. The crude product was used without any further purification. iV-(2-PhenylethyI)-JV-(l -((ert-butyloxycarbonyl)piperidm-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2x15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 52 mg; 3C-NMR (CD3OD, retainers): 6 27.1, 28.5, 34.9, 36.6,40.2, 40.4, 44.1,44.2,44.4, 53.3, 54.2, 54.6,114.0,114.1,126.2,126.6, 127.2, 127.4,128.3, 128.6,128.79, 128.82, 129.7, 138.5, 1393,158.96, 159.0, 172.7, 173.1 Example 22 - A (2-MetfaoxyphenyI)methyI)-AHpiperidiii-4--yl>- -methoxypbenylmethyiacetamide (26HCH80-4) To a solution of commercially available rerf-butyi 4-oxo-l -piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 2-methoxybenzylamine (0.130 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HCl (0.1 N, 1x15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 02 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give /er/-butyl 4-((2-methoxyphenyl)methyl)amino-piperidine carboxylate. Yield: 211 mg. To a solution of fert-butyl 4-((2- 49 WO 01/66521 PCTAJS01/07187 methoxyphenyl)methyl)amino-piperidiiie carboxylate (50 ing, 0.16 rnmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture" was stiired at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HC1 (0.2 N, 2x15 ml), NaOH (0.2 N, 2x15 ml), and water (10 ml), dried (Na2SO4), filtered and concentrated to give 7V-((2-methoxyphenyl)methyl)-77-(l-(terf-butyloxycarbonyl)piperidin-4-yl)-4--methoxyphenylacetamide. The crude product was used without any further purification. N-((2-Meihoxyphenyl)meihyl)-N-(l-(tert-buryloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HC1 (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. AAer 2.5 h, NaOH (I ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2x15 ml), dried (Na2SO4), filtered to give a clear solution. The soluton was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and cluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 40 mg; J3C-NMR (CD3OD, retainers). 6 26.1,27.4, 40.0, 40.1, 43.5, 43.9, 51.5, 53.4, 54.5,54.58, 54.63, 54.78, 54.83, 110.1, 110.5, 113.76, 113.78, 113.84, 114.0,114.1, 120.1, 120.5, 125.4, 126.0, 126.5, 126.7, 127.1, 1273,127.7,128.8,129.8,130.0,130.08,130.14, 156.5,157.0,159.0,159.1,173.2, 173.8. Example 23 - AH(2-Chlon he )i)meth>1KV-4-metboxypbenyiacetamide (26HCH80-5) To a solution of commercially available ferr-butyl 4-oxo-l-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 2-chIorobenzylamine (0.121 ml, 1 mmol) in methanol (I ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCN6H3 in methanol (03 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 b, water (2 ml) was added, and the mixture was stirred for 1 h before it was concentrated. The resulting oil was rcdissolved in dicthyl ether (20 ml), extracted with HC1 (0.1 N, 1 x 15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), 50 WO 01/66521 PCT/US01/O7187 filtered, and concentrated to give tert-butyl 4-((2-chlorophenyl)methyI)amino-piperidine carboxylate. Yield: 137 mg. To a solution of tert-butyl 4-((2-chlorophenyl)methyl)amino-piperi ime carboxylate (50 tng, 0.15 rmnol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HC1 (0.2 N, 2x15 ml), NaOH (0.2 N, 2x 15 ml), and water (10 ml), dned (Na2SO4), filtered and concentrated to give 7V- give the title compound. Yield: 45 rag; I3C-KMR (CD3OD, rotamers): 5 25.8,26.9, 40.0,40.1,42.9,43.4,43.7,46.0,51.1,53.0,54.6, 113.77, 113.84,114.0, 114.1, 126.6,126.8,127.08,127.13,1273,127.4,128.1,129.0,129.2,129.8,130.0,130.2, 131.9,132.2,135.0,1353,159.1,173.4,173.8. Example 24 - N (3 AD"-(tm)BdioiyplieoyI)roethyI)-N pip€ridHi-4-yI>-t-methoxypbenylacetamide (26HCH80-6) To a solution of commercially available tert-butyl 4-oxo-l-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 3,4-di-methoxybenzylamine (0.151 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HC1 (0.1 N, 1 x 15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before 51 WO 01/66521 PCT/US01/07187 extracted with dichioromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-((3,4-di-memoxyphenyl)methyl)aniino-piperidine carboxylate. Yield: 162 mg. To a solution of tert-butyl 4-((3,4-di-methoxyphenyl)methyl)amino-piperidine carboxylate (50 mg, 0.14 ramol) in dichioromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HC1 (0.2 N, 2x15 ml), NaOH (0.2 N, 2 15 ml), and water (10 ml), dried (Na2SO4), filtered and concentrated to give7V-((3,4-di-methoxyphenyl)methyl)-7V-(l-(/er/-butyloxycarbonyl)pipendin-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. iVX(3,4-Di-methoxypheoyI)memyl)-AHH'ert-buty!oxycarbonyl)piperidin-4-yl)-4-meuioxvphenylacetamide was dissolved in diethyl ether (2 ml) and HC1 (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichioromethane (10 ml). The mixture was extracted with water (2x15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and ehited with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 54 mg; 13C-NMR (CD3OD, rotamers): 6 25.9,27.3, 40.0,40.1,43.5,43.8,44.1,51.4,53.5,54.6,55.4, no.2, 111.0,113.9, 112.2, 114.0, 114.2,118.6, 119.4,127.1,127.4,129.9,130.0,130.5,132.1, 148.2,148.7, 149.2, 149.7,158.98,159.05,173.3,173.6. Example 25 - N (4-FlDOropbeny!)iDctfayI>-N-(piperidhi-4-yI>4-methoxyphenylacetamide (26HCH80-7) To a solution of commercially available tert-butyl 4-oxo-l-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 4-fluorobenzylamine(0.114 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for I h, before it was concentrated. The resulting oil was rcdissorved in diethyl ether (20 ml), extracted with HC1 (0.1 N, 1 x 15 ml). The aqueous layer was washed 52 WO 01/66521 PCT/US01/07187 with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-((4-fluorophenyl)methyl)amino-piperidine carboxylate. Yield: 130 mg. To a solution of tert-butyl 4-((4 fluorophenyl)methyl)amino-piperidine carboxylate (50 mg, 0.16 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After IS h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HC1 (0.2 N, 2x15 ml), NaOH (0.2 N, 2x15 ml), and water (10 ml), dried (Na2SO4), filtered and concentrated to give W-((4-fluorophenyl)memyl)-tf- give the title compound Yield: 45 mg; 13C-NMR (CD3OD, rotamers): 5 26.1,27.5, 40.1,43.6,43.8, 44.0, 51.6,53.6,54.6,113.77, 113.84,114.0,114.1,114.7,114.9, 115-3, 115.6,126.8,127.2,128.1,128.6,128.7,129.8, 130.0, 130.1,130.6, 131.0, 133.8, 159.1,173.3, 173.6. Example 26 - N-((2,4-Di-chIorophenyI)methyl)-N-{piperidin-4-yI>-4-methoxyphenylacetamide (2 6H CH 80-8) To a solution of commercially available tert-butyl 4-oxo-l-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 2,4-di-chlorobenzyiamine (0.135 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl 53 WO 01/66521 PCT/USO1/07187 ether (20 ml), extracted witfaHCi (0.1 N, 1x15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treaicd with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give /ert-butyl 4-((2J4-di-chlorophenyl)methyl)amino-piperidine carboxylate. Yield: 97 mg. To a solution of tert-butyl 4-((2,4-di-chJorophenyl)methyl)amino-piperidine carboxylate (50 mg, 0.14 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0 4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HC1 (0.2 N, 2x15 ml), NaOH (0.2 N, 2x15 ml), and water (10 ml), dried (Na2SO4); filtered and concentrated to give Al(G2 abfihlgj toyJ)me butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. //-{ Di-chlorophenytym ethyI)-.7V-(l-(/£7?-butyloxycarbonyl)piperidin-4-yI)-4-methoxyphenyIacetamide was dissolved in diethyl ether (2 ml) and HC1 (1 ml, 4 M in dioxanc) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2x 15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and ehited with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 39 mg I3C-NMR (CD3OD, rotamers): S 25.7,26.8, 40.0,42.6, 43.3,43.7, 51.2, 53.0, 54.-5, 54.6, 113.8, 113.8, 134.0, 114.1-, 127.0, 12S.4, 128.8, 129.8,130.0,130.1,131.0,132.7,132.9,134.5, 159.1,173.4,173.6. Example 27 - N-((3-Methylphcny0methyi)-N-(piperidin-4-yI)-4-methoryphcnylacetamide (26HCH80-9) To a solution of commercially available tert-butyl 4-oxo-l-piperidme carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 3-methylbeczylamine (0.125 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl 54 WO 01/66521 PCT7US01/07I87 ether (20 ml), extracted with HC1 (0.1 N, 1 x 15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SC>4), filtered, and concentrated to give tert-butyl 4 ((3-methyIphenyl)methyI)animo-piperidine carboxylate. Yield: 136 mg. To a solution of tert-butyl 4-((3-methylphenyl)methyl)amino-piperidine carboxylate (50 mg, 0.16 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HC1 (0.2 N, 2x15 ml), NaOH (02 N, 2x15 ml), and water (10 ml), dried (Na2SO4), filtered and concentrated to give A (3-methylphenyl)methyl)-JV-(l-(tert-butyloxycarbonyl)piperidm-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. M((3-Methylphenyl)methyl)-W-(l-(ferr-but>loxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HC1 (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 >3) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2 15 ml), dried (Na SCj), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and ehited with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 48 mg; 13c-NMR (CD3OD, retainers): 8 20.4, 26.8, 2S.3,40.2,43.9, 44.1,44.5,51.8, 54.2, 54.57, 54.61, 114.0, 114.1,123.2.123.7, 126.7,127.0,127.1,127.3,128.0,128.1,128.7,129.8,129.9,137.9,138.6,138.9, 159.0,159.1,173.1,173.7. Example 28 - N-((3-Bromophenyl)raethyI)-N-{piperidin-4-yl>-4-methovypbenylacetamide (26HCH80-10) To a solution of commercially available rerz-butyl 4-oxo-l-pipcridinc carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 3-bromobenzylamioe hydrobromide (222 nag, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was stirred at room temperature. After 24 h, water (2 ml) was 55 WO 01/66521 PCT/USO1/O7187 added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HC1 (0.1 N, 1x15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-((3-bromophenyl)methyl)amino-piperidine carboxylate. Yield: 142 mg. To a solution of tert-butyl 4-((3-bromophenyl)methyl)amino-piperidine carboxylate (50 mg, 0.14 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenyIacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with UCl (0.2 N, 2x15 ml), NaOH (0.2 N, 2x15 ml), and water (10 ml), dried (Na2SO4), filtered and concentrated to give 7/-((3-bromophenyl)methyl)- -(l-(zert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. AH(3-Bromopheny!)methyl)-J\r-(l-(tert-butyloxycarbonyl)piperidin-4-yl>4 methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HC1 (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2x 15 ml), cMed (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 49 rag; 13C-NMR (CD3OD, retainers): 6 26.6,28.2, 40.2,43.9,44.0,51.8,54.1,54.6,113.76,113.84, 114.1,114.2,122.2,125.0,125.5, 126.7,127.1,129.2,129.5,129.7,129.8,129.9,130.0,130.5,130.6,140.8,141.8, 159.1,1733,173.7. Example 29 - N- l-yD-4-methoiypbenyUcetamidc (26HCH76B) To a solution of 4-amino-N-benzylpiperidnie (200 mg, 1.05 mmol) in methanol (2 ml) was added trans-cinnamaldehyde (211 mg, 1.6 mmol), followed by Acetic acid in methanol (1 M, 1.4 ml) and sodiumcyanoborohydridc in methanol (0.3 M, 4.4 ml). The reaction mixture was stirred at room temperature. After 48 h, water (2 56 WO 01/66521 PCT/US01/07187 ml) was added. The mixture was stirred for another 2 h before concentrated and redissolved in diethyl ether (20 ml). The organic layer was extracted with HC1 (0.1 N, 2 l o ml). The combined aqueous layers were treated with NaOH (0.2 N) until basic (pH>8). The mixture was extracted with dichloromethane (2x10 ml). The combined organic layers were dried (NB2SO4) and concentrated. The crude product, which was used without any further purification, was dissolved in dichloromethane (5 ml). Diisopropylethylamine (284 ing, 2.1 eq.) was added, followed by 4-methoxyphenylacetyl chloride (387 ing, 2.0 eq). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. After additional 2 h dichloromethane (10 ml) was added. The mixture was extracted with NaOH (0.2 N, 3x15 ml), and water (15 ml). The organic layer was dried (Na2SO4) and concentrated. The crude product was redissolved in methanol (2 ml) and added on to a column carrying strongly acidic cation excnange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. 13C-NMR (CDCI3): 5 28-5>381" 46-6> 47-4> 50.9, 54.7, 62.9, 113.7, 125.5,126.4, 126.6, 127.4, 127.9, 12S.5, 128.6, 129.6, 130.0, 135.2,135.3,138.0,158.2,173.2. Example 30 - iV--pbenylacetamide (26HCH78-1) To a solution of commercially available tert-butyl 4-oxo-l-piperidine carboxylate (1.75 g, 8.8 mmol) and 4-methyIberizylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH3 in methanol (03 M, 30 ml). The resulting solution was stirred at room temperatme. After 20 h, water (5 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. Flash chromatography in dichloromethane:methanol 10:1 gave i£rr-butyl 4-(4-methylphenyl)methyl)araino-piperidine carboxylate. Yield: 2.4 g, 98%. To a solution of/crt-butyl 4 4-memylphenyI)merayI)amino-piperidine carboxylate (80 mg, 0.26 mmol) in dichloromethane (1.8 ml) was added diisopropylethylamme (0.11 ml, 2.4 eq.) followed by pbenylacetyl chloride (81 mg, 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 h, water (1 ml) was added. The mixture was stirred for another 2 h, before diethyl ether (20 ml) was added. The mixture was sequentially extracted with HC1 (0.2 N, 2x15 ml), 57 WO 01/66521 PCT/US01/07187 NaOH (0.2 N, 2x15 ml), and H2O (10 ml), dried (Na2SC>4), filtered and concentrated. The crude material was dissolved in diethyl ether (2 ml) and HC1 (4 M in dioxane, 1 ml). The reaction mixture was stored at room tempeiature After 2 h, NaOH (6 N, 1 ml) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2x 10 ml), dried (NajSC ), and filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 38 nag; C-NMR (CD3OD, rotamers): 5 19.9,26.9, 2S.4, 41.0, 41.1, 44.0,44.1, 44.4, 51.9, 54.4, 126.1, 126.7, 126.8,126.9, 128.5,128.7, 128.78,128.81,128.9,129.4, 129.5, 134.9, 135.2, 135.6, 136.0, 136.3,137.2, 172.8,173.3. Example 31 - N-((4-MetbyIpbenyl)methyl)-N-(l-piperidin-4-yl)-3-phenylpropiooamide (26HCH78-2) To a solution of commercially available tert-butyl 4-oxo-l-piperidine carboxyiate (1.75 g, 8.8 mmol) and 4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added acetic acid in methanol (1 M. 6.7 ml) followed by N3CNBH3 in methanol (03 M, 30 ml). The resulting solution was stirred at room temperature. After 20 h, water (5 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. Hash cliromatography in dichloromethanermethanol 10:1 gave tert-butyl 4 4-mcthylphenyl)methyI)amino-piperidine carboxyiate. Yield: 2.4 g, 98%. To a solution of tert-butyl 4 4-methylphenyI)methyi)amino-piperidine carboxyiate (80 mg, 0.26 mmol) in dichloromethane (1.8 ml) was added diisopropylethylamine (0.11 niL 2.4 eq.) followed by 3-pbenylpropionyl .chloride (0.07S ml, 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 h, water (1 ml) was added The mixture was stirred for another 2 h, before diethyl ether (20 ml) was added. The mixture was sequentially extracted with HC1 (0.2 N, 2x15 ml), NaOH (0.2 N, 2x15 ml), and H2O (10 ml), dried (Na2SO4), filtered and concentrated. The crude material was dissolved in diethyl ether (2 ml) and HC1 (4 M in dioxane, 1 ml). The reaction mixture was stirred at room temperature. After 2 h, NaOH (6 N, 1 ml) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2x10 ml), dried (Na2SO4), and filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin 58 WO 01/66521 PCT/US01/07187 (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 43 mg; 13C-NMR (CD3OD, rotamers): 5 19.9,27.4,29.0, 31.4,31.7,34.7,35.7,44.2,44.3, 51.6, 54.2, 125.9, 126.07,126.15,126.8, 128.3, 128.4, 128.7, 128.8, 129.3,135.1, 136.1, 136.2, 137.0, 141.1,141.2,173.9,174.4. Example 32 - N-((4-Me(hyIphenyI)methyl>N-(l-piperidin-4-yl> (phenylthio)acetamide (26HCH78-3) To a solution of commercially available tert-butyl 4-oxo-l-piperidine carboxylate (1.75 g, 8.8 mmol) and 4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH3 in methanol (0.3 M, 30 ml). The resulting solution was stirred at room temperature. After 20 h, water (5 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. Flash chromatography in dichloromethanermethanol 10:1 gave tert-butyl 4-(4-methylphenyl)methyI)amino-piperidine carboxylate. Yield: 2.4 g, 98%. To a solution of /erf-butyl 4 4-mcthyiphenyl)methyl)amino-piperidine carboxylate (80 mg, 0.26 mmol) in dichloromethane (1.8 ml) was added diisopropylethylamine (0.11 ml, 2.4 eq.) followed by (phenylthio)acetyl chloride (0.07S ml, 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 h, water (1 ml) was added. The mixture was stirred for another 2 h, before diethyl ether (20 ml) was added. The mixture was sequentially extracted with HC1 (0.2 N, 2x15 ml), NaOH (0.2 N, 2x15 ml), and H2O (10 ml), dried (Na2SC>4), filtered and concentrated. The crude material was dissolved in diethyl ether (2 ml) and HC1 (4 M in dioxane, 1 ml). The reaction mixture was stirred al room temperature. After 2 h, NaOH (6 N, 1 ml) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2x 10 ml), dried (Na2SO4), and filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield; 18 mg; HRMS (FAB , NBA) (M+H)+ 355.1841, C21H27N2OS requires 355.1844; LC-MS: (M+H)+ 355.1, t,. 2.62 min. 59 WO 01/66521 PCT/USOI/07187 Example 33 - N (4-MethyIphenyl)methyl)-N-0-piperidin-4-yl)-phenoxyacetarnide (26HCH78-4) To a solution of conmiercially available tert-butyl 4-oxo-l-piperidine carboxylate (1.75 g, 8.8 mmol) and 4-metbylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH3 in methanol (0.3 M, 30 ml). The resulting solution was stirred at room temperature. After 20 h, water (5 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. Flash chromatography in dichloromethanermethanol 10:1 gave tert-butyl 4-(4-methyIphenyJ)metbyl)amino-piperidine carboxylate. Yield: 2.4 g, 98%. To a solution of tert-butyl 4-(4-methylphenyl)methyl)amino-piperidine carboxylate (80 mg, 0.26 mmol) in dichloromethane (1.8 ml) was added diisopropylethylarmne (0.11 ml, 2.4 eq.) followed by phenoxyacetyl chloride (0.073 ml, 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 h, water (1 ml) was added. The mixture was stirred for another 2 h, before diethyl ether (20 ml) was added. The mixture was sequentially extracted with HC1 (0.2 N, 2x15 ml), NaOH (0.2 N, 2x15 ml), and H2O (10 ml), dried (Na2SO4), filtered and concentrated. The crude material was dissoh ed in diethyl ether (2 ml) and HC1 (4 M in dioxane, 1 ml). The reaction mixture was snrred at room temperature. After 2 h, NaOH (6 N, 1 ml) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2x10 ml), dried (Na2SO4), and filtered to give a clear solutioa The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 24 mg; C-NMR (CD3OD, rotamers): 5 19.9,25.8,27.4, 43.5, 43.7,44.4, 51.9, 52.3,66.9, 114.7, 114.8, 116.7, 117.0, 121.4,123.6, 126.3, 126.8, 128.4, 128.9,129.3, 129.5, 129.6, 131.0,134.4,136.1,137.4,1583,169.8,170.1. Example 34 - N-((4-M ethjip ben y1)methy l)-N-(l-pi peri din-4-yI>-ropbeoory) cet3imide (26MCH7&-5) To a solution of commercially available tert-butyl 4-oxo-l-piperidine carboxylate (1.75 g, 8.8 mmol) and 4-methyIbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH3 in methanol (0.3 M, 30 ml). The resulting solution was stirred at room 60 WO 01/66521 PCTYUS01/07J87 temperature. After 20 h, water (5 nil) was added, and ihc mixture was stirred for 1 h, before it was concentrated. Flash chromatography in dichloromethanermethanol 10:1 gave tert-butyl 4-(4-methylphenyl)methyl)ammo-piperidine carboxylate. Yield: 2.4 g, 98%. To a solution of tert-butyl 4-(4-methy]pheny])methyl)amino-piperidine carboxylate (SO mg, 0.26 mmol) in dichloromethane (1.8 ml) was added diisopropylethylamine (0.11 ml, 2.4 eq.) followed by 4-chlorophenoxyacetyl chloride (0.082 ml, 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 h, water (1 ml) was added. The mixture was stirred for another 2 b, before diethyl ether (20 ml) was added. The mixture was sequentially extracted with HC1 (0.2 N, 2x15 ml), NaOH (0.2 N, 2x15 ml), and H2O (10 ml), dried (Na2SO4), filtered and concentrated. The crude material was dissolved in diethyl ether (2 ml) and HC1 (4 M in dioxane, 1 ml). The reaction mixture was stirred at room temperature. After 2 h, NaOH (6 N, 1 ml) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2x 10 ml), dried (Na2SO4), and filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield; 21 mg; C-NMR (CD3OD, rotamers): 5 19.9, 26.2, 27.S, 43.6, 43.9, 44.4, 52.2, 52.5, 67.0, 116.2, 116.4, 126.2, 1263, 126.8, 128.6,128.9, 129.1, 129.3, 129.5,131.0, 134.4, 135.6,136.4,137.5,157.1,169.4,169.7. Example 35 - N-((4-Methylpheny!)inethyl>N-(l-piperidin-4-yI)-3-methoxypbenylacetamide (26HCH78-6) To a solution of commercially available tert-butyl 4-oxo-l-piperidine carboxylate (1.75 g, 8.8 mmol) and 4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH3 in methanol (03 M, 30 ml). The resulting solution was stirred at room temperature. After 20 h, water (5 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. Flash chromatography in dichloromcthanc.mcthanol 10:1 gave K7?-butyl 4 4-memy henyl)naethyi)arnino-piperidiiie carboxylate. Yield: 2.4 g, 98%. To a solution of tert-butyl 4-(4-methyIphenyl)methyI)amino-piperidine carboxylate (80 mg, 0.26 mmol) in dichloromethane (1.8 ml) was added diisopropylethylamine (0.11 ml, 2.4 eq.) followed by 3-methoxyphenylacetyl chloride 61 WO 01/66521 PCT/US01/07187 (97 mg, 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 h, water (1 ml) was added The mixture was stirred for another 2 h, before diethyl ether (20 ml) was added The mixture was sequentially extracted with HC1 (0.2 N} 2x15 ml), NaOH (0.2 N, 2x15 ml), and H2O (10 ml), dried (Na SO , filtered and concentrated. The crude material was dissolved in diethyl ether (2 ml) and HC1 (4 M in dioxane, 1 ml). The reaction mixture was stirred at room temperature. After 2 h, NaOH (6 N, 1 ml) was added followed by dichloromethanc (10 ml). The mixture was extracted with water (2x10 ml), dried (Na2SO4), and filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 26 mg; C-NMR (CD3OD, rotamers): 8 19.9,26.3,27.7, 41.0,43.7,43.9, 44.4, 51.5, 53.8, 54.5, 54.6, 112.2, 112.6, 114.3, 114.5, 121.0, 121.2, 126.1, 126.8, 128.S, 129.4, 129.5, 129.8, 134.8,136.0, 136.3, 136.5, 136.9,137.2, 160.2, 160.3, 172.8, 173.2. Example 36 - N-((4-Metny]pbenyI)methyI)-N-(l-piperidiii-4-yI)-4-flnorophenylacetamide (26HCH78-7) To a solution of commercially available terr-butyl 4-oxo-l-piperidine carboxylate (1.75 g, 8.8 mmol) and 4-mcthylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH3 in methanol (0.3 M, 30 ml). The resulting solution was stirred at room temperature. After 20 h, water (5 ml) was added, and the mixture was stirred for 1 h, before it was concentrated- Flash chromatography in dichlorometbanernietharjol 10:1 gave tert-butyl 4 4-methybphcnyI)mcdryi)arnino-pipcridine carboxylate. Yield: 2.4 g, 98%. To a solution of tert-butyl 4 4-methylphenyI)methyI)ammo-piperidine carboxylate (80 mg, 0.26 mmol) in dichloromethane (1.8 ml) was added diisopropylethylamine (0.12 ml, 2.4 eq.) followed by 4-fluorophenylacetyl chloride (0.072 ml, 0.53 mmol). The reaction mixture was stirred at room temperature. Aiter 20 h, water (1 ml) was added. The mixture was stirred for another 2 h, before diethyl ether (20 ml) was added The mixture was sequentially extracted with HC1 (0.2 N, 2x15 ml), NaOH (0.2 N, 2x15 ml), and H2O (10 ml), dried (Na2SO4), filtered and concentrated. The crude material was dissolved in diethyl ether (2 ml) and HC1 (4 M in dioxane, 1 ml). The reaction mixture was stirred at room temperature. After 2 h. 62 WO 01/66521 PCT/USOI/07187 NaOH (6 N, 1 ml) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2x10 ml), dried (Na2SO4), and filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 26 mg; C-NMR (CD3OD, rotamers): 8 19.9, 26.1,27.4, 39.7,39.9,43.5,43.8,44.4,51.3, 53.4, 114.9,115.1,115.3,126.1, 126.7, 128.5,128 S, 129.4, 130 7,130.8,130.9, 131.0, 131.2,131.6, 134.8,136.0,136.3, 137.2,160.9,163.3,172.7,173.2. Example 37 - N-((4-Methylphenyl)me(hyl>N-(l-piperidin-4-yl)-2 -di-metboxyphenylacetamide (26HCH78-8) To a solution of commercially available tert-butyl 4-oxo-l-piperidine carboxylate (1.75 g, 8.8 mmol) and 4-mcthyIbenzylamine (970 mg, 8.0 niraol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH3 in methanol (0.3 M, 30 ml). The resulting solution was stirred at room temperature. After 20 h, water (5 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. Flash chromatography in dichloromethane:methanol 10:1 gave /£7t-butyl 4-(4-methylphenyl)methyl)amnio-piperidine carboxylate. Yield: 2.4 g, 98%. To a solution of tert-hatyl 4 4-methyIphenyl)methyl)amino-piperidine carboxylate (80 mg, 0.26 mmol) in dicbloromethane (1.8 ml) was added diisopropylethylamine (0.11 ml, 2.4 eq.) followed by 2,5-di-methoxyphenylacetyl chloride (0.092 ml, 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 h, water (1 ml) was added. The mixture was stirred for another 2 h, before di ethyl ether (20 ml) was added. The mixture was sequentially extracted witfcHO (0.2 N, 2x15 ml), NaOH (0.2 N, 2x15 ml), andH2O (10ml),dried (Na2SC>4), filtered and concentrated. The crude material was dissolved in diethyl ether (2 ml) and HC1 (4 M in dioxane, 1 ml). The reaction mixture was stirred at room temperature. After 2 h, NaOH (6 N, 1 ml) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2x10 ml), dried (Na2SO4), and filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. 36 mg; 13C-NMR (CD3OD, rotamers): 6 20.0, 26.5,28.2,35.1, 63 WO 01/66521 PCT/US01/07187 35.7, 44.0, 44.4, 51.6, 53.8,54.99, 55.03, 55.2, 55.5, 111.4, 111.7, 112.4. 112.9, 116.6,116.9,124.98,125.02,126.L, 126.7, 128.8, 129.3, 135.0, 136.1.. 136.3,137.0, 151.3, 151.7,153.9,154.0,173.1, 173.5. Example 38 - N-((4-Methylphenyl)methyl)-N-(l-piperidiii-4-yl)-4- chlorophenylacetamide (26HCH78-9) To a solution of commercially available tert-butyl 4-oxo-l-piperidine carboxylate (1.75 g, 8.8 mmol) and 4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added acetic aicid in methanol (1 M, 6.7 ml) followed by NaCNBH3 in methanol (0.3 M, 30 ml). The resulting solution was stiiTed at room temperature. After 20 h, water (5 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. Flash cliromatography in dichloromethane:methanol 10:1 gave tert-butyl 4-(4-methylphenyI)methyl)amino-piperidine carboxylate. Yield: 2.4 g, 98%. To a solution of tert-butyl 4-(4-methylphenyl)methyl)amino-piperidine carboxylate (80 mg, 0.26 mmol) in dichloromethane (1.8 ml) was added diisopropylethylamine (0.11 ml, 2.4 eq.) followed by 4-chlorophenylacety] chloride (99 mg, 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 h, water (1 ml) was added. The mixture was stirred for another 2 h, before diethyl ether (20 ml) was added. The mixture was sequentially extracted with HC1 (0.2 N, 2x15 ml), NaOH (0.2 N, 2x15 ml), and H2O (10 ml), dried (Na2SO4), filtered and concentrated. The crude material WJIS dissolved in diethyl ether (2 ml) and HC1 (4 M in dioxane, 1 ml). The reaction mixiure was stirred at room temperature. Afier 2 h, NaOH (6 N, 1 ml) was added followed by dichloromethane (10 ml). TTie mixture was extracted with water (2x 10 ml), dried (Na2SO4), and filtered to give a clear solution. The solution was added on to a column carrying "strorigly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 22 mg; 13C-NMR (CD3OD, retainers): 6 19.9,263,27.7,39.9,40.0,43.6,43.9,44.4,51.5, 53.6, 126.1,126.7,128.2,128.4,128.6, 128.9,129.4,129.6,130.7,130.9,131.2,131.6, 132.5,132.7,133.9,134.1,134.4,134.8,135.9,136.3,137.2,172.4,172.9. 64 WO 01/66521 PCT/US01/07I87 Example 39 - A'-((4-MethylphenyI)methyl)-A'-(l-(phenylmethyl)pyrroHdin-3-yl)-7V-pheny]methy]carbainide (26HCH50) To a solution of 3-amino-l-phenylmethylpyrrolidine (353 mg, 2 mmol) and 4-methylbenzaldehyde (361 mg, 3 mmol) in methanol (20 ml) was added acetic acid in methanol (2 M, 6.7 ml) followed by NaCNBH3 in methanol (0.3 M, 3 nil). The mixture was stirred at room temperature. After 24 h, water (5 ml) was added. The mixture was stirred for another hour before concentrated. Flash chromatography in dichloromethane/methanol 10/1 gaveA (4-methylphenyl)methyl)amino-l-phenylmethylpyrrolidine. AK(4-MethylphenyI)methyl)aniino-l-phenylmethylpyn'olidine(35 mg, 0.125 mmol) was dissolved in dichloromethane (1.5 ml), and benzylisocyanate (0.09 ml, 0.3 mmol) was added. The reaction mi:icture was stirred at room temperature. After 48 h, the crude reaction mixture was added on to a column carrying strongly acidic cation exchange resin, which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 48 mg, 92%; 13C-NMR (CD3OD): 5 20.0,29.7, 44.2, 51.3, 53.4, 56.4, 57.8, 58.7, 126.8, 127.1, 127.3, 127.6,128.3, 128.4,128.9,129.1, 135.9, 136.8, 140.3, 158.5. Example 40 - N- To a solution of 3-amino-I-phenybnethylpvrTolidine (353 mg, 2 mmol) and 4-methylbenzaldefayde (361 mg, 3 mmol) in methanol (20 ml) was added acetic acid in methanol (2 M, 6.7 ml) followed by NaCNBH3 in methanol (0.3 M, 3 ml). The mixture was sfcrrec at room temperature. After 24 h, water (5 ml) was added. The mixture .was snrred for another hour before concentrated. Flash chroniatography in dicWcTomethane/methanol 10/1 gave? - To a solution of M{(4-Methylphenyl)methyl)amino-1- phenylmethylpynolidme (35 mg, 0.H25 mmol), diisopropylethylamine (0.14 ml) in dichloromethane (1.5 ml) was added. 4-methoxyphenylacetyl chloride (0.1 ml, 0.5 mmol). The reaction mixture was stirred at room temperature. Aiter 48 h, the crude reaction mixture was concentrated and redissolved in methanol. The solution was added on to a column carrying strongly acidic cation exchange resin, which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and 65 WO 01/6652J PCTAJS01/07I87 concentrated Flash chromatography in dichloromethane/methanol 10/1 gave the title compound. Yield: 20 mg, 38%; 13C-NMR (CD3OD)- S 21.3, 30.2, 40.8, 47.8, 53.6, 53.9, 55.5, 57.5, 60.2, 114.4,125.7,127.0, 127.1, 127.3, 127.4, 128.4, 128.5, 128.7, 128.9,129.2, 129.8,130.0,135.9,137.0,158.6. Example 41 - N-((4-Metby1phenyl)methyl)-N-(l-(phenylmethyl)piperidin-4-yl)-4-inethoxyphenyIthioacetamide (RO) A mixture of 7V-((4-Methylphenyl)methyI)-Ar"(l-(phenylmethyl)pipendin-4-yl)-(4-methoxyphenylmethyl) acetamide (20 mg, 0.045mmol) and Lawesson's reagent (25 mg, 0.062 mmol), was taken in a glass vial and mixed thoroughly with magnetic stirbars. The glass vial was then irradiated in a microwave oven (900 W, Whirlpool M401) for 8 min. Upon completion of the reaction, the yellow-colored material was transferred to an ion-exchange column with the aid of methanol (2 ml). The ion-exchange column was subsequently washed with CH2CI2 (2ml) and methanol (2ml) and the product was thereafter eluted from the ion-exchange column (10% NH3 in methanol, 2 ml) to give 7\/'- Example 42 - Receptor Selection and Amplification (R-SAT) Assays. The functional receptor assay, Receptor Selection and Amplification Technology (R-SAT), was used (with minor modifications from that previously described US 5,707,798) to screen compounds for efficacy at the 5-HT2A receptor. Briefly, NIH3T3 cells were grown in 96 well tissue culture piaies to 70-80% confluence. Cells were trdnsfected for 12-16 hours with piasmid DNAs using superfect (Qiagen Inc.) as per manufacture's protocols. R-SAT's were generally performed with 50 ng/well of receptor and 20 ng/well of Beta-galactosidase piasmid DNA. All receptor and G-protein constructs used were in the pSI mammalian expression vector (Promega lac) as described in U.S. 5,707,798. The 5HT2A receptor gene was amplified by nested PCR from brain cDNA using the oligodeoxynucleoades based on the published sequence (i5ee Saltzman et al Biochem. Biophys. Res. Comm. 181:1469-78 (1991)). Large-scale transfections, cells were transfected for 12-16 hours, then feypsinized and frozen in DMSO. Frozen cells were later thawed, plated at 10,000-40,000 cells per well of a 96 well plate that contained drug. With both 66 WO 01/66521 PCT/US01/07187 methods, cells were then grown in a humidified atmosphere with 5% ambient CO2 for five days. Media was then removed from the plates and marker gene activity was measured by the addition of the beta-galactosidase substrate ONPG (in PBS with 5% NP-40). The resulting colorimetric reaction was measured in a spectrophotometric plate reader (Titertek Inc.) at 420 nM. All data were analyzed using the computer program XLFit (IDBSm). Efficacy is the percent maximal repression compared to repression by a control compound (ritanserin in the case of 5HT2A). pIC50 is the negative of the Iog(IC50), where IC50 is the calculated concentration in Molar that produces 50% maximal repression. The results obtained for six compounds of the invention are presented in the following table. Table I. Efficacy of Compounds at the 5-HT2A Receptor Compound Efficacy (average) Efficacy(s tdev) pICSO (average) pICSO (stdev) 26HCH52 98 5.0 7.31 0.16 26HCH66-03 76 13.3 7.42 0.01 \| 26HCH66-05 109 3.0 7.55 0.15 1 26HCH8O-2 89 46 7 78 0.17 1 26HCHSO-7 87 3.7 7.70 0.26 26HCHSO-10 91 4.9 7.21 0.05 Example 43 - In Vitro Efficacy of 26HCH17 as an Inverse Agonist at the 5-IIT2A Receptor. The graph shown in Figure 11 represents the data obtained from a dose response analysis of 26HCH17 and ritanserin as 5-HT2A receptor inverse agonists. Briefly, the 5-HT2A receptor, and the alpha subucit of the guanine nadeotids binding protein Gq were transiently transfected into NIH3T3 cells and assayed using the functional receptor assay, Receptor Selection and Amplification Technology (R-SAT) essentially as disclosed in U.S. Patent No. 5,707,798. Each compound was screened at seven serially diluted concentrations in triplicate. Data were analyzed using least squares fit analysis with GraphPad Prism (San Diego, CA.), and are reported normalized to percent response. Example 44 - Selectivity Profile of Inverse Agonist 26HCH16D R-SAT assays (as described in Example 42) were carried out with cells transfected with receptors (listed below) to determine the receptor selectivity profile for compound 26HCH16D. 5HT2A inverse agonist data (IC50 nM; % efficacy) were 67 WO 01/66521 PCTAJS01/07187 derived from detailed dose response curves (7 points in triplicate). All other data (initial concentration at which at least 30% efficacy observed; actual efficacy figure) derived from the 4 dose profiling protocol in which compounds were tested at 4 doses in duplicate, nr = activity less than 30% at all doses tested (3, 30, 300, 3000QM), therefore EC50AC50 greater than 3000nM). The results are presented in the following table. Table 2. Profile of 5-HT2A Inverse Agonist 26HCHJ6D Receptor Efficacy 5HT2A (human) Agonist nr Inverse A eonist 0 9nM; 79% 5HT2B (human) Agonist nr Antagonist 3000nM; 60% 5HT2C (human) Agonist nr Inverse Agonist 3000nM; 79% 5HT1A (human) Agonist nr Antagonist nr 5HT1A (rat) Antagonist nr 5HTIE (human) Agonist nr P2 (human) Agonist nr Antagonist 3000nM; 73% HI (bmnwi) Agonist nr Antagonist 3000nM; 33% alpha la/D (rat) Agonist nr Antagonist nr alpha I b/B (hamster) Agonist nr Antagonist > nr i alphalc/A (tmman) Agocst nr Antagonist 3000nM;46% alph 2A (human) Agonist or Antagonist m alpha2B (human) Agonist nr Antagonist a!pha2C (human) Agonist or Antagonist m ml (human) Agonist nr Antagonist nr As indicated above, 26HCH16D is a highly selective 5-HT2A inverse agonist 68 WO 01/66521 PCT/US01/07187 General LC-MS procedure for Working Examples ELH01-46, MBT01-14 and AKU01-38. In the following examples, HPLC/MS analyses were performed using either of two general methods (Method A or Method B). The tr values reported below were obtained using one of these procedures, as indicated in the specific examples. The methods were as follows: Method A: AgUent HP1100 HPLC/MSD. G1312A Binary pump, G1313A Autosampler, G1316A Column compartment, G1315A Diode array detector (190-450 nm), 1946A MSD, electrospray ionization, Chromatography: 8 mM amnaoniumacetate in water/acetonitrile Gradient start at 70% org. up to 100 % org. over 12 min, down to 70 % org. over 0.5 min, held for 3.5 min. Total runtime 16 min. Flowrate 1 ml/min Column, Phenoroenex Lima Cl 8(2) 3um 75x4.6mm. MS parameters: Drying gas, 10 1/min. Nebulizer pressure, 40 psig. Gas temp, 350 C. VCap, 4000. Method B: Waters/Micromass HPLC/MS 600 LC-pump, 2700 Sample manager, 24S7 Dual absorbance detector (channel A-205 nm, channel B-Z35 nm), Micromass ZMD-mass-spectrometer, electrospray ionization. Chromatography: 0.15%TFA in water/acetonitrile. Gradient start at 30 % org. up to 100% org. over 10 min, held for 3 min. down to 30 % org. over 0.5 min, held for 4.5 min. Total nm time 18 min. Flowrate, 1 ml/min. Column, Symmetry Cl8,5fun, 4.6x50 mm. or 10 mM ammoniumacetate in water/acetonitrile. Gradient start at 30% org. for 2.5 min, up to 100 % org. over 10 min, held for 9 mm, down to 30 % org. over 0.5 min, held for 5 min. Total run time 27 min. Flowrate, 1 ml/min. Column: Phenomenex Synergi C12,4um, 4.6x50mm. MS parameters: 69 WO 01/66521 PCT/US01/07187 Derivation gas, 404 I/H. Capillary, 5.3kV. Cone, 36V. Extractor, 3V. Source block temp, 130 C. Desolvation temp, 250 C Example 45 - 2-(4-methoxj'phenyI)-Ar-(4-methylbenz>'J)-7V-(piperidiii-4-y]) acetamide (50ELH87) Reaction step 1: N-trifluoroacetyl-4-piperidone (50ELB84) 4-Piperidone hydrochloridc monohydrate (4.0 g, 26 mmol, 1.0 eq) was dissolved in 130 ml of dichloromethane. After addition of triethylamine (8.66 g, 3.3 eq) the reaction mixture was stirred for 10 min. The mixture was cooled on an ice-bath (0°C). Trifluoroacetic anhydride (12.0 g, 2.2 eq) was added dropwise under stirring. After 2 hours the reaction was quenched by addition of distilled water. The aqueous phase was extracted twice with dichloromethane. The combined organic layers were collected and dried with sodium sulfate. Concentration afforded N-irifl uoroacetyl-4-piperidone. Reaction step 2: 4-(4 Methylbenzylamino)-l-(trifluoroacetyl) piperidin (50ELH85) Methanol (150 ml) was added to an Erlenmeyer flask and acetic acid was added under stirring until pH 5. 4-Methylbenzylamine (3.14 g, 25.9 mmol) and N-trifluoroaceiyl-4-piperidone(from reaction step 1) (5.065 g, 25.9 mmol) were added to a 250 ml round-bottomed flask and dissolved in the methanol/acetic acid (150 ml) solution previously made. The reaction mixture was stirred for 5 min and NaCNBHa (2.46 g,. 3S.9 mmol) was added slowly under stirring. After 20 hours the reaction was concentrated and transferred to a separatory funnel containing dichloromethane and distilled water. The aqueous phase was made basic by addition of NajCOs. The aqueous phase was extracted twice with dichloromethane. The combined organic layers were collected and dried with Na2SO . Concentration afforded. 4-(4-mrthylbemylanimeVHtrifruoroacctyl) piperidme. UV/MS 60/53 (M 301), tr (A, MS) 3.267. Reaction step 3:2-(4-Methoxyphenyl)-N-(4-methyIbenzyl) N-(l-trifluoroacetylpiperidin-4-yI) acetamide (50ELH86) The product from reaction step 2 (7.8 g, 25.9 mmol) was dissolved in 100 ml of dichloromethane and stirred while 4-methoxyphenylacetyl chloride (4.8 g, 25.9 mmol) was added. After 4 hours, heptane was added whereupon the product precipitated as the hydrochloride salt The solvent was removed by evaporation. The crude material was purified by flash chromatography EtOAc/Heptane (1:2) Yield (overall: Reaction steps 1+2+3) 3.912 g (34%), UV/MS 91/58 (M 449), V (A, MS) 70 WO 01/66521 PCT/USOJ/07187 4.319. 'H-NMR (400 MHz, CDC13) 8 6.80-7.15 (Ar, 4H), 4.64 (bit, 1H), 4.4 (s, 2H), 3.95 (d, 2H), 3.72 (s, 3H), 3.50 (s. 2H), 3.09 (t, 2H), 2.7(t, 2H), 2.32 (s, 3H), 1.75 (bit, 2H). "C-NMR 172.5; 158.8; 137 4; 134.9, 129 9; 129.9; 129.8; 127.1; 125.8; 114.3; 55.4; 52.2; 47.3; 45.3; 43.4.40.6; 30,1; 29.2; 21.2. Reaction step 4: 2-(4 Methoxyphenyl)-N-(4-methylbenzyl) N (piperidin-4-yl) acetamide (50ELH87) The product from reaction step 3 (3.9 g, 8.7 mmol) was dissolved in methanol (12 ml). In a 250 ml round bottom flask a saturated solution of potassium carbonate in methanol was prepared. To this solution, the 2-(4-methoxyphenyl)-M{4-methylben2yI)-A (A'-trifluoioacetpiperidin-4-yl) acetamide solution was added under stirring. After 4 hours, the solution was concentrated and the remaining solid taken upin base and dichloromethane. The combined organic layers were dried with sodium sulfate and concentrated. UV/MS 91/72 (M 353), tr (A, MS) 2.210. The corresponding hydrocliloride salt was also prepared, by dissolving the free base in dichlorornethane (1 ml) and HC1 (1 eq. 2 M HC1 in ether) was added with stirring. The salt was precipitated by addition of the dichlorom ethane solution into heptane. Concentration on the rotary evaporator returned the product is white crystals. Example 46 - 2-(4-Methoxyphenyi)-A (4-methylbenzyl)-iV-(l-metbylpiperidin-4-yI) acetamide (50ELH27) Reaction step 1: 4-(4-Methylbenzylamino)-l-methylpiperidine (50ELH25) Methanol (50 ml) was added to an Erlenmeyer flask and acetic acid was added under stirring until pH 5. Methyftxazylamine (1.0 g, 8.8 mmol) and I -Methyl-4-piperidone (1.1 g, 8.8 mmol) were added to a 100 ml round-bottomed flask and dissolved in the methanol/acetic acid (40 ml) solution previously made The reaction mixture was snrred for 5 min and NaCNBHa (0.83 g,, 13.2 mmol) was added slowly under stirring. After 20 hours the reaction was concentrated and transferred to a separatory funnel containing dichloromethane and distilled water. The aqueous phase was made basic by addition of Na2CO3. The aqueous phase was extracted twice with dichloromethane. The combined organic layers were collected and dried with Na2SO<. concentration afforded the title compound. yield uv t ms> Reaction step 2; 2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N (l-methylpiperidm-4-yl) acetamide (50ELH27) 71 WO 01/66521 PCT/US01/07187 The product from reaction step 1 (1.9 g, S.7 mmol) was dissolved in 40 ml of dichloromethane and stirred while 4-methoxyphenylacetylchloride (1.606 g, 8.7 mmol) was added. After 4 hours, heptane was added whereupon the product precipitated as the hydrochloride salt. The solvent was removed by evaporation. The crude material was purified by flash chromatography first eluting with 10% MeOH in CH2C12 and thereafter eluting with 0-20% MeOH in CH2CI2 and 5% NEt3. Yield (overall: Reaction steps 1+2). 77%. UV/MS: 100/100 (M 367), t, (A, MS) 4.359, Rf 0.15 (2% MeOH in CH2C12). 'H-NMR (400 MHz, CDC13) 5 12.6 (s, 1H), 7.16 (d, 7=7.0 Hz, 2H), 7.10 (d, 7=7 0 Hz, 2H), 7.04 (d, 7=8.0 Hz, 2H), 6.82 (d, 7=8.0 Hz, 2H), 4.87 (tt, 7=1 1.0, 4.0 Hz, 1H), 4.53 ppm (s, 2H), 3.78 (s, 3H), 3.55 (s, 2H), 3.42 (brd, 7=1 1.0 Hz, 2H), 2.80 (brq, 7-11.0 Hz, 2H), 2.7 (d, 7=4.0 Hz, 3H), 2.42 (dq, 7=13.0, 3.0 Hz, 2H), 2.34 (s, 3H), 1.78 (brd,7=13.0 Hz, 2H). "C-NMR173.1,158.9; 137.4; 134.8; 129.9; 126.7; 125.8; 114.4; 76.9; 55.5; 54.6, 48.8; 43.7; 40.5; 26.4; 21.2 Example 47 - 2-(4-MethosypheDyI)-Ar-(4-methyIbenzyl)-A (l-cyclohexylmethylpiperidin-4-yl) iicetamide (42ELH45) 50ELH87 (the hydrochloride salt) (0.5 g, 1.29 mmol, 1.0 eq) was dissolved in ethanol (100 ml). Cyclohexanecarboxaldehyde (2.5 g, 20 eq.) was added followed by addition of sodium borohydride (0.084 g, 2.0 eq.). The reaction was stirred for 36 h and acetic acid (3 ml) was added The reaction was stirred for additionally 2 h and extracted with sodium hydrogen carbonate (3 tunes) and dichloromethane. The organic layers were dried with sodium sulfate and concentrated. The product was purified by flash chromatography (5-10% MeOH in CH2CI2). The resulting product was dissolved m ether (20 ml) and MeOH (added dropwise until dissolved) and HC1 (1 eq. 2 M HC1 in ether) was added under stirring. The hydrochloride salt of 2-{4-methoxyphenyl)-A 4-methyIbenzy!)-A'-(l-cyclohexyImethylpiperidin-4-yl) acetamide precipitated and the white crystals were filtered. Yield 80 mg (16%), UV/MS 100/100 (M+ 449), rt (A, MS) 7.105, mp 133-135°C, Rf 0.25 (2% MeOH/CH2Cl2). 'H-NMR (400 MHz, CDC13) 6 11.9 (brs, 1H), 7.12 (q, 4H), 7.02 (d, 2H), 6.80 (d, 2H), 4.87 (m, 1H), 4.58 (s, 2H), 3.77 (s, 3H), 3.55 (s, 2H), 3.48 (m, 2H), 2.70 (m, 4H), 231 (s, 3H), 1.91 (d, :>H), 1.75 (m, 3H), 1.64 (d, 1H), 1.22 ( d, 2H), 1.13 (tt, 2H), 1.02 (brq, 2H). "C-2HMR 173.1; 15S.8; 137.2; 135.1; 129.9; 129.8; 126.8; 125.8; 114.4; 64.1; 55.5; 53.4; 49.2; 46.5; 40.4; 33.9; 25.9; 25.8; 25.7; 21.2. 72 WO 01/66521 PCT/US01/07187 Example 48 - 2-(4-Methoxyphenyl)-AH4-methylbenzyl)-Ar-(l-ethylpiperidin-4-yI) acetamide (42ELH80) 50ELH87 (0.25 g, 0.71 mmol, 1.0 eq) was dissolved in acetorutrile (15 ml) and ethyl bromide (0.232 g, 3.0 eq.) was added under stirring. After 2 min Hfinings base (0.084 g, 10.0 eq.) was added. After 36 hours, the solution was extracted with sodium hydrogen carbonate solution and dichloromethane (3 times). The organic layers were dried with sodium sulfate and concentratedyielding a yellow oiL The product was purified by flash chromatography (2% MeOH in CH2CI2). The resulting product was dissolved in dichloromethane (1 ml) and HCI (1 eq. 2 M HC1 in ether) was added under stirring. The salt was precipitated by addition of the dichloromethane solution into heptane. Concentrationon the rotary evaporator gave the product as white crystals.Yield 170 mg (63%), UV/MS 98/95 (M 381), mp 153-155°C, rt (A, MS) 3.033, Rf 0.35 (3% MeOH/CH2Cl2). 'H-NMK (400 MHz, CDC13) 8 12.2 (s, 1H), 7.15 (d, 2H), 7.12 (d\ 2H), 7.08 (d, 2H), 6.82 (d, 2H), 4.89 (m, 1H), 4.58 (s, 2H), 3.79 (s, 3H), 3.58 (s, 2H), 3.50 (d, 2H), 2.90 (m, 1H), 2.7 (brq, 2H), 2.45 (m, 2H), 2.34 (s, 3H), 1.80 (d, 2H), 1.44 (t, 3H). 13C-NMR 173.1; 158.9; 137.3; 134.9; 129.9; 125.8; 114.4; 55.5; 52.3; 52.0; 492; 46.5; 40.5; 26.2; 21.2; 9.5. Example 49 - 2 4-MethoxyphenylHV-(4-chlorbenzyl)-A-(l-etfaylpiperidin-4-yl) acetamide (42ELH85). This compound was prepared similarly to 50ELH27 Reaction-step 1: (42ELH84) Starting materials: l-Methyl-4-piperidone (0.5 g, 4.4 mnaol, 1.0 eq.), 4-chJorobenzylamine (0.626 g, 1.0 eq.), sodinm cyanoborohydride (0 79 g, 1.5 eq.). Reaction-step 2: (42ELHB5) Starting materials: 42ELHS4,4-rcethoxyphenylacetylchloride (0.774 g, 1.0 eq.)- The procedure was analogous to 50ELH27, but the product was purified by ion-exchange chromatography followed by HPLC. The hydrochloride salt was made by dissolving the free base in dichloromethane (1 ml) and HCI (1 eq. 2 M HCI in ether) was added under stirring. The salt was precipitated by addition of the dichloromethane solution into heptane followed by concentration on the rotary evaporator. 73 WO 01/66521 PCT/USO1/O7187 Product: White crystals. UV/MS 98/97 (M 387), rt (A, MS) 2.953. 'H NMR (400 MHz, CDC13) 5 12.6 (s, 1H), 7.35 (d, 2H), 7.18 (d, 2H), 7.05 (d, 2H), 6.82 (d, 2H), 4.89 (m, 1H), 4.55 (s, 2H), 3.80 (s, 3H), 3.55 (s, 2H), 3.45 (brs, 2H), 2 80 (bis, 2H)} 2.72 (s, 3H), 2.25 (brs, 3H), 1.80 (bis, 2H). UC-NMR 173.0; 158.9; 136.5; 133.6; 129.8; 129.4; 127.3; 126.3; 114.5; 55.5; 54.6; 48.7; 46.3; 43.7; 40.5; 26.3. 50-2-(4-Methoxyphenyl)-?V-(4-chlorbenzyl)-A'-(l-isopropyIpiperidin-4-yl) acetamide(42ELH79). Procedure as 42ELH80 Starting materials: 50ELHS7 (0.25 g, 0.71 ramol, 1.0 eq.), isopropylbromide (0.262 g, 3.0 eq.,). Product: Yield 130 mg (46%), UV/MS 100/100 (M 395), r, (A, MS) 3.360. 'H-NMR (400 MHz, CDC13) 6 12.0 (s, 1H), 7.15 (d, 2H), 7.10 (d, 2H), 7.05 (d, 2H), 6.82 (d, 2H), 4.87 (m, 1H), 4.60 (s, 2H), 3.79 (s, 3H), 3.57 (s, 2H), 3.38 (brd, 3H), 2.79 (q, 2H), 2.63 (q, 2H), 2.34 (st 3H), 1.80 (d, 2H), 1.39 (d, 6H). i3C-NMR 173.1; 158.9; 137.3; 135.1; 129.8; 126.8; 125.8; 114.4; 57.9; 49.4; 48.2; 46.5; 40.5; 25.9; 21.2; 16.9. Example 51 - 2-(4-Metho phenyI)-A'-(4-chJorobenzyI)-A-(piperidiii-4-yI) acetamide (42ELH89) (As starting material in other reactions, used unpurified) Procedure as 50ELH27. Reaction step 1.- M-Trifluoroacetyl-4-piperidone (42ELH86) Starting materials: 4-Piperidone hydrochloride monohydrate (2.0 g, 13 mmol, 1.0 eq), trifluoroacetic anhydride (6.0, U2 eq.). TLC showed full conversion. Product: RrO.9 (10% MeOH/CHTCb). Reaction step 2:4 4-Chloroben Iamino)-l-(Erifluoroacetyl) piperidin (42ELH87) Starting materials: 42ELH86 (2.5 g, 12.8 mmol, 1.0 eq.), 4-Chloroben2ylamine (1.8 g, 1.0 eq.) Reaction step 3:2 4-Meiho3cyphenyl)-7VL(4-chlorobeiizyl)-iVL Starting materials: 42ELH87 (4.0 g, 12.5 mmol, 1.0 eq.), 4-methoxyphenylaceti cWoride(2Jl g, 1.0 eq.) Reaction step 4:2-(4-Metho3cyphenyI)-7 4-K oroben2yl)-W-(pipcridin-4-yl) acetamide (42ELH89) 74 WO 01/66521 PCTAJS01/07187 Product. Yield: 2 g (57%), UV/MS 80/82 (M 373), Rf 0.2 (50% EtOAc/Heptane). Example 52 - 2-(4-Methoyypheny!)-AK4-chlorbenzyl)- -(l-cycJopenty!piperidin-4-yI) acetamide (42ELH91). Procedure as 42ELH80, but the product was purified by HPLC. The acidic cluent was made basic with sodium carbonate and extracted with dichloromethane (3 times). The combined organic layers were collected and dried with sodium sulfate and concentrated. The remaining product was dissolved in 1 ml of dichloromethane and HC1 (1 eq. 2 M HC1 in ether) was added under stirring. This solution was added dropwise to a large excess of n-heptane to make the hydrochloride precipitate. The solvent was evaporated off to form white crystals of 2-(4-methoxyphenyl)-#-(4-chlorbenzyI)-iV-(l-cyclopentylpiperidin-4-yl) acetamide, hydrochloride. Starting materials: 42ELH89 (025 g, 0.67 mmol, 1.0 eq.), cyclopentylbromide (0.3, 3.0 eq.) Product: Yield: 211.2 mg (76%). Purification by ion-exchange: UWMS 90/98. Purification by HPLC UV7MS 100/J 00 (M 441), Rf 0.2 (3% MeOH/CH2Cl2), r, (A, MS) 4.067. JH-NMR (400 MHz, CDCI3) 5 12.2 (brs, 1H), 7.32 (d, 2H), 7.17 (d, 2H), 7.04 (d, 2H), 6.82 (d, 2H), 4.90 (brt, 1H), 4.58 (s, 2H), 3.79 (s, 3H), 3.58 (brd, 2H), 334 (s, 2H), 3.14 (brq, 2H), 2.58 (brq, 2H), 2.04 (m, 4H), 1.89 (m, 4H), 1.75 (brd, 2H). "C-NMR 173.0; 158.9; 133.5; 129.8; 129.3; 127.3; 126.4; 114.5; 68.4; 55.5; 51.9; 49.1; 462; 40.5; 28.5; 26.0; 23.8. Example S3 - 2--Ar-(l-feopropylpiperidiD-4-yI) acetamide (42ELH90). 42ELH89(0.25 g, 0.67 mmol, 1.0 eq) was transferred to a 4 ml vial and dissolved in acetonitrile (2 ml). Isopropyl bromide (0.25 g, 3.0 eq.) was added along with Hiinigs base (0.87 g, 10.0 eq.). The vial was sealed and shaken for 4 days at 60°C. The reaction mixture was transferred to a separatory funnel with distilled water and CH2Cl2- The aqueous phase was made basic with sodium hydrogen carbonate and extracted with dichloromethane (3 times). The organic layers were collected and dried with sodium sulfate and concentrated, mis resulted in a yellow oil. The product was purified by flash chromatography (3% MeOH in CH2CI2). The resulting product was dissolved in dichloromethane (1 ml) and HC1 (1 eq. 2 M HC1 in ether) was added under stirring. The salt precipitated by addition of the dichloromethane solution into 75 WO 01/66521 PCT/US01/07187 heptane. Concentration on the rotary evaporator returned the product as white crystals.Yield 101.2 mg (63%), UV/MS 94/96 (M 415), Rf 0.25 (3% MeOH/CH2a2). 'H-NMR (400 MHz, CDC13) 8 12.05 (brs, 1H), 7.36 (d, 2H), 7.18 (d, 2H), 7.04 (d, 2H), 6.82 (d, 2H), 4.88(m, 1H), 4.60 (s, 2H), 3.79 (s, 3H), 3.55 (d, 2H), 3.36 (d, 3H), 2.80 (brq, 2H), 2.65 (brq, 2H), 1.76 (brd, 2H), 1.39 (d, 6H). I3C-NMR 173.0; 159.0; 137.0; 136.0; 129.7; 129.3; 127.4; 126.4; 114.5; 57.9; 55.5; 49.2; 48.2; 46.2; 40.5; 25.8; 16.9. Example 54 - 2-(PhenylHV-(4-trinuoromethylbenzylHV-(l-methylpiperidin-4-y!) acetamidc (50ELH14b) Procedure as for 50ELH27. Purification was done by HPLC. The hydrochloride salt was made by dissolving the free-base in dichloromethane (1 ml) and HC1 (1 eq. 2 M HC1 in ether) was added under stirring. The salt was precipitated by addition of the dichloromethane solution into heptanefollowed by concentration. Reaction-step 1: 4-(4-Triflouromethylben2ylamino)-l-methylpiperidin (50ELH2). Starting materials: 1-Methyl-4-piperidone (1.13 g, 10.0 mmol, 1.0 eq.),4-trifluoromethylbenzylamine (1.75 g, 1.0 eq.). Product: UV/MS 80/92 (M 273). Reaction-step 2: 2-(Phenyl)-AT-(4-trifluoromethylbenzyl>7 -(l-methylpiperidin-4-yD acetamide (50ELH14b). Starting materials: 50ELH2 (0.12 g, 0.44 mmol, 1.0 eq.), phenyiacetyichioride (0.068 g, 1.0 cq.). Product: UV/MS 100/97 a 390), rt (A, MS) 3.797, Rf 0.3 . (5%MeOH/CH2Cl2). 'H-NMR (400 MHz, CDC13, rotamers 54/46) 8 7.52 (d, 2H), 7.42 (d, 2H), 7.12-7.30 (m, 4H,), 4.63 and 3.74 (2m, 1H), 4.38 (brs, 2H), 3.80 and 3.50 (2s, 3H), 3.31 and 2.78 (2d, 2H), 233 and 2.18 (2s, 2H), 2.24 and 1.65-1.90 (t andm,4H), 1.60 and 1.22 (2d,2H), I. "C-NMR 172.3; 171.8; 143.9; 135.1; 134.8; 129.1; 129.0; 128>, 128.7; 127.4; 1273; 127.2; 126.3; 126.1; 126.0; 56.0; 55.2; 54.9; 50.9; 46.8; 45.2; 44 , 42 ; 41.7; 30.6; 28.4. Example 55 - 2-(4-Fluorophenyl)-7V-(4-trifluoromethylbenzyl)-M 76 WO 01/66521 PCT/US01/07187 Reaction-step 2: 2-(4-Fluoro-pbenyl)-N-(4-trifluoroiDCthylbcnzyl)-N-(l-methylpiperidin-4-yl) acetamide (50ELH14c). Starting materials: 50ELH2 (0.12 g, 0.44 mmol, 1.0 eq.), 4-fluorophenylacetylchloride (0.076 g, 1.0 eq.). Product: Yield 69.7 mg (36%), UV/MS 100/98 (M 409), rt (A, MS) 3.839, Rf 0.3 (5%MeOH/CH2Cl2). 'H-NMR (400 MHZ, DMSO, retainers 65/35) 5 10.80 and 10.60 (2s, 1H), 7.71 and 7.62 (2d, 2H), 7.47 and 7.38 (2d, 2H), 7.00-7.36 (t and m, 4H), 4.70 and 4.50 (2s, 2H), 430 (m, 1H), 3.93 and 3.56 (2s, 2H), 3.34 (s, 2H), 3.00 (brq, 2H), 2.64 (s, 3H), 2.08 (m, 2H), 1.68 and 1.58 (2d, 2H). 13C-NMR 176.8; 176.4; 167.6; 165.3; 150.0; 149.0; 136.6; 132.5; 131.0; 130.5; 120.6; 120.5; 120.5; 120.4; 58.1; 58.0; 57.0; 54.5; 52.0; 49.3; 47.6; 45.0; 32.4; 31.4. Example 56 - 2-(4-McthoxyphcnyI)-Ar-(4-tri(lnoromethyIbenzyI)-Ar-(l-mcthyIpiperidin-4-yl) acetamide (S0ELH14d) Procedure as 50ELH14B. Reaction-step 2: 2-(4-Metho?yphenyl)-JV-(4-trifluoromethyIbenzyl)-JV-(l-meih>Ipiperidin-4-yl) acetamide (5035LH14d). Starting materials: 50ELH2 (0.15 g, 0.55 mmol, 1.0 eq.), 4-mcthencyphcnylacctylchloride (0.1 g, 1.0 eq.). Product: Yield 57.5 mg (29%), UV/MS 99/100 (M 421), rt (B, MS) 6.30, Rf 0.25 (3%MeOH/CH2CI2). JH-NMR (400 MHz, CDC13) 6 12.4 (brs, 1H), 7.55 (d, 2H), 7.2S (d, 2H), 6.96 (d, 2H), 4.84 (bit, 1H), 4.59 (s, 2H), 3.72 (s, 3H), 3.46 (s, 2H), 3.38 (d, 2HU 2-78 (q, 2H), 2.64 (s, 3H), 2.38 (q, 2H), 1.70 (d, 2H). I3C-NMR 173.0; 159.0; \AZ3; 130.0; 129.8; 1263; 126.2; 114.7; 114 ; 55.5; 54.4; 48.7; 46 ; 43.6; 40.6; 263. Example 57 - 2-(4-TriflHoromethy1phenyI)-7V-(4-trifluoroinethylbeii2yI)-Ar-(l-metby]piperidin-4-yl) acetamide (50ELH14a) Procedure as 50ELH14B. Reaction-step 2:244-TriiluoromethvtohcnylVAM 4-trifluoromethylbeDzyl)- -(l-methylpiperidin-4-yl) acetamide (f>0ELH14a). " Starting materials: 5OELH2 (0.12 g, 0.44 mmol, 1.0 eq.), 4-trifiuoromethylphenylacetylchloride (0.1 g, L0 eq.). Product: Yield 92.6 mg (42%), UV/MS 89/93 (M 458), rt (A, MS) 4.211, Rf 0.3 (5%MeOH/CH2a2). JH-NMR (400 MHz, CDCI3) 5 12.7 (bis, 1H), 7.56 (d, 2H), 77 WO 01/66521 PCT/US01/07187 7.48 (d, 2H), 7.17 (d, 2H), 4.86 (m, 1H), 4.63 (s, 2H), 3.58 (s, 3H), 3.40 (d, 2H), 2.75 (q, 2H), 2.65 (d, 3H), 2.46 (dq, 2H), 1.73 (brs, 2H). "C-NMR 171.8; 141.9; 138.4; 129.4; 127.9; 126.3; 126.3; 126.2; 125.9; 125.8; 54.4; 48.8; 46.6; 43.6; 40.9; 26.2, Example 58 - Z -HuorophenyO-A -flnorobenzyO-AHl-nietbylpiperidin-4-yJ) acetamide (50ELH6) Procedure as 50ELH14B. Reaction-step 1:4-(4-HBorobenzylaminoH-niethylpiperidme (50ELH4). Starting materials: l-Methyl-4-piperidone(1.13 g, 10.0 mmol, 1.0 eq.), 4-fiuorobenzylamine (1.25 g, 1.0 eq.). Product: Yield 2.154 g (97%), UV/MS 79/89 (M 223). Reaction-step 2: 2-(4-Flaoropheqyl)-.AK4-fluorobenzyl)-7/-(l-methvlpiperidin-4-yl) acetamide (50E]LH14a). Starting materials: 50ELH4 (0.12 g, 0.54 mmol, 1.0 eq.), 4-fluoropbenylacetylchloride (0.096 g, 1.0 eq.). Product: Yield 57 mg (29%), UV/MS 100/100 (M 359), rt (A, MS) 3.763, Rf 0.25 (3% MeOH/CH2CI2). JH-NMR (400 MHz, CDCI3) 5 12.6 (brs, 1H), 7.2 (dd, 2H), 7.06 (m, 4H), 6.98 (t, 2H), 4.88 (tt, 1H), 4.58 (s, 4H), 3.45 (d, 2H), 2.81 (q, 2H), 2.72 (d, 3H), 2.4S (brq, 2H), 1.78 (brs, 2H). 13C-NMR 172.5; 163.4; 160.8; 133.4; 130.6; 130.2; 127.5; 127.4; 116.3; 116.1; 115.9; 115.7; 54.5; 48.8; 46.2; 43.6; 40.3; 26.3. Example 59 - 2 4-MctlioxypheDyl>-Ar-(4-fluorobeDzyrHV-{l- metbylpiperidin-4-yJ) acetamide (50ELH8). Procednre as 50ELH14B Reaction-step 2: Starting materials: 50ELH4 (0.12 g, 0.54 mmol, 1.0 eq.), 4-roethoxyphenylacetylchloride (0.1 g, 1.0 eq.). Product: Yield 54 g (26%), UV/MS 100/100 (M 371), rt (A, MS) 3.257, Rf 0 5 (3%MeOH/CH292). !H-NMR (400 MHz, CDC13) S 12.2 (brs, 1H), 7.12 (m, 2H), 6.97 (m, 4H), 6.75 (d, 2H), 4.80 (brt, 1H), 4.49 (s, 2H), 3.71 (s, 3H), 3.47 (s, 2H), 337 (d, 2H), 2.8 (q, 2H), 2.64 (s, 3H), 235 (q, 2H), 1.69 (d, 2H). "C-NMR 173.0; 163J; 161.1; 158 ; 133.7; 133.6; 129.8; 127.6; 127.5; 126.5; 116.2; 116.0; 114.6; 1143; 55.5; 54.4; 48.8; 46.2; 43.6; 40 ; 26.4. 78 WO 01/66521 PCT/US01/07187 Example 60 -2-(Phenyl)-7V-(4-nuorobenz>'])-7V-(l-methylpiperidin-4-yI) acetamide (50ELH1O) Procedure as 50ELH14B. Reaction-step 2: 2-(Phenyl)-iV-(4-fluorobenzyl)-7V-(l -methylpiperidin-4-yl) acetamide (50ELH10). Starting materials: 50ELH4 (0.13 g, 0.59 mmol, 1.0 eq.), phenylacetylchloride (0.091 g, 1.0 eq.). Product: UV/MS 100/94 (M 341), r, (A, MS) 3.127, Rr0.25 (3%MeOH/CH2CI2). 'H-NMR (400 MHz, DMSO, rotamers 54/56) 5 12.38 (brs, lH), 7.35-7.00 (m, 9H), 4.55 and 4.40 (2s,, 2H), 4.50 and 4.25 (brt, 1H), 3.91 and 3.56 (2s, 2H), 3.30 (Hidden under water signal)(2H), 2.98 (d, 2H), 2.64 (s, 3H), 2.09 (brt, 2H), 1.66 and 1.45 (2brd, 2H). "C-NMR 171.9; 171.6; 162.8; 160.4; 136.5; 136.2; 135.4; 129.9; 129.7; 129.5; 129.2; 129.0; 128.9; 128.7; 127.2; 127.1; 116.2; 116.0; 115.6; 53.2; 52.5; 49.8; 46.9; 44.0; 42.8; 40.9; 40.6; 40.4; 40.2; 40.0; 39.8; 39.6; 27.7; 26.6. Example 61 - 2-(4-Trifloorometbylpbeny])-Ar-(4-fluorobenzy))-iV-(l-methylpiperidin-4-yI) acetamide (50ELH122) Procedure as 50ELH14B. Reaction step 0: 4-TrifluoromethylphenylacetyI chloride (50ELH121) 4-Trifluorophenylacetic acid (1.0 g) and thionyl chloride (15 ml) were refluxed for 1 h. The excess thionyl chloride was evaporated off. NMR showed complete conversion. Reaction-step 2: 2 4-TrifluoTomethylpbenyl)-7V-(4-floorobqizyI)-Jtf'-(l-methylprperidin-4-yD acetamide (50ELH122). Starting materials: 50ELH4 (0.12 g. 0.55 mmol, 1.0 eq.), 4-trifluoromethyrphenylacetylchloride (SOELHU1) .] 1 g, 0,5 mmol, 1.0 eq.). Product: Yield 47.1 mg (24%), UV/MS 96/96 (M 409), rt (A, MS) 4.566, R/ 0.25 (3%MeOH/CH2a2). 'H-NMR (400 MHz, CDC13) 6 7.52 (d, 2H), 7.22 (d, 2H), 7.17 (dd, 2H), 7.04 (t, 2H), 4.86 (bit, 1H), 4.58 (s, 2H), 3.64 (s, 2H), 3.45 (brd, 2H), 2.84 (brq, 2H), 2.71 (d, 3H), 2.45 (brq, 2H). 1.77 (brd, 2H). UC-NMR 171.8; 163.6; 161.2; 138.7; 133J; 129.8; 129.5; 127.5; 127.4; 125.8; 125.7; 116.4; 116.2; 54.4; 48.9; 46.3; 43.6; 40.8; 263. Example 62 - 4-(4-MetboxybenzylamiDo)-l-metbyIpiperidine (50ELH18). Procedure as 50ELH27. 79 WO 01/66521 PCT/US01/07187 Starting materials; l-MethyI-4-piperidone (1.13 g, 10.0 ramol, 1 0 eq.). 4-methoxybenzylaniine (1.37 g, 1.0 eq.). Product: UV/MS 95/95 (M 235),rt (A,MS) 3.509.'H-NMR (400MHz, CDCh) o 7.3-O.8 (in, 4H), 3.77 (s, 3H), 3.73 (s, 2H), 2.86 (m, 2H), 2.55 (m, 1H), 2.30 (s, 3H), 2.1 (t, 2H), 1.96 (dd, 2H), 1.50 (m, 2H). Example 63 - 2-(4-TrifluoromethyIphenyl)-iV-[4- (metboxycarbonyl)benzyl]-iV-(l-niethylpiperidin-4-yl)acetaiiiide(S0ELH20A) Procedure as 50ELH14B. Reaction-step 1: Methyl 4-(W-ri-methylpiperiding-4-yn aminomcthyl) benzoate (50ELH19). Starting materials: l-MethyI-4-piperidone (1.13 g, lO.Oinmol, 1.0eq.)> methyl 4-(aminomethyl) benzoate hydrochloride (2.0 g, 1.0 eq.). Product: UV/MS 81/88 (M 263), rt (A, MS) 3 060. H-NMR (400 MHz, CDCb) 5 S.OO (d, 2H), 7.20 (d, 2H), 3i"0 (s, 3H), 3-85 (s, 2H)( 2.96 (dt, 2H), 2.7 (brs, IH), 2.62 (m, 1H), 2.40 (s, 3H), 2.28 (t, 2H), 1.96 (m, 2H), 1.56 (m, 2H). Reaction-step 2: 2-(4-Trifluoromethylphenyl)-A f4-(mclhoxycarbonyl)benzyn-N-(l-methylpiperidin-4-yl) acetamide (50EIJH20A). Starting materials: 50ELH19 (0.20 g, 0.76 mmol, 1.0 eq.), 50ELH121 (0 169 g, 1.0 eq.). Product: Yield 108.9 mg (32%), UV/MS 100/100 (bt 448), rt (A, MS) 3.327S Rf 0.3 (5% MeOH/CH2Cl2). H-NMR (400 MHzJ>MSO, retainers 56/44) 8 10.7 and 10.4 (2bis, IH), 7.96-72& (m, 8H)f 4.70 and 4.51 (2s, 2H), 430 (brt, IH), 4.06 and 3.69 (2s, 2H), 3.83 and 3.81 (2s, 3H), 3.00 (m, 2H), 2.63 (m, 3H), Z05 (bit, =12 Hz, 2H), 1 9 (brt,>=l2 Hz, 2H). "C-NMR (CrX33) 171.9; 166.7; 142.9; 138.5; 130.7; 130.1; 129.7; 126J2; 1255; 55 ; 52 ; 49.2; 47.4; 4U; 3Z1; 26.6; 222; 14.3. Kxample 64 - 2-PbenyI-A'-[4-(iDethoxycarbonyObenzyI]-7V-(l-metfaylpiperidin-4-yI) acetamide (50ELH20B) Procedure as 50ELH14B Reaction-step 2: 2-Phenyl- -f4-(methoyycarbopy3)benzyl]- -(l-methylpipcridin-4-yI) acetamide (50ELH20B) Starting materials: 50ELH19 (0.2 g, 0.76 mmol, 1.0 eq.), phenylacetyichloride (0.117 g, 1.0 eq.). 80 WO 01/66521 PCTAJS01/07187 Product: Yield 82.5 g (29%), UV/MS 100/100 (M 381), r, (A, MS) 2.652, Rf 0.25 (3%MeOH/CH2CI2). 'H-NMR (400 MHz, CDC13) 6 12.2 (brs, 1H), 8.00 (d, J=7A, 2H), 7.4-7.2 (m, 4H), 7.08 (d, J 7.4,2H), 4 89 (bit, 1H), 4.62 (s, 2H), 3.90 (s, 3H), 3.56 (s, 2H), 3.42 (d, >11.0, 2H), 2.84 (q, =11.0, 2H), 2.68 (d, J=3.6, 3H), 2.40 (q,J ll.Of 2H), 1.77 (bid, >11.0, 2H). 13C-NMR 173.0; 168.0; 143.3; 136.7; 130.6; 129.0; 127.4; 125.9; 54.5; 52.4; 48.8; 43.6; 41.4; 26.3. Example 65 - 2-(4-Chlorophenyl)-A [4-(methoxycarbonyI)benzylI-iV-(l-metbylpiperidiD-4-yl) acetamide (50ELH20C). Procedure as 50ELH14B. Reaction-step 2: 2-(4-ChJoropheiiyl)- '-[4-(inethoxycarfaonyl)benzyl1-A -(l-methylpiperidin-4-yl) acetamide (50ELH20C). Starting materials: 50ELH19 (0.2 g, 0.76 mmol, 1.0 eq.), 4-cfalorophenylacetylchloride(0.131 g, 1.0 eq.). Product: Yield 79.2 % (26%), UV/MS 100/96 (M 399), rt (A, MS) 2.333. JH-NMR (400 MHz, DMSO, rotamers 62/38) 5 10.8 and 10.60 (2brs, 1H), 7.95 and 7.85 (2d, =8.6s 2H), 7.4 and 7.28 (2d, 2M), 7.35 and 7.14 (2m, 4H), 4.67 and 4.50 (2s, 2H), 4.29 (m, 1H), 3 93 and 3.84 (2s, 2H), 3.81 (s, 3H), 3 1 (d, >=11.9, 2H), 3.00 (d, J 11.9t 2H), 2.63 (s, 3H), 2.06 (m, :2H), 1.68 and 1.56 (d; J±U.9r 2H). 13C-NMR (CDO3) 172.6; 166.7; 163.4; 161.0; 143.0; 130.7; 130.6; 130.5; 126.0; 115.9; 115.7;; 54.7; 52.4; 48.9; 46.9; 44.0; 40.4; 26.4. Example 66 - 2-{4-Methox;j henyi}-7V-[4-(inethoxycarbonyI)ben2yI]-JV-(l-metfaylpiperidin-4-y]) acetamide (50ELH20D). Procedure as 50HLH146. Reaction-step 2:2 4-Metbaxypbeiiyr)-Ar-f4 metboxycaib Starting materials: 50ELH19 (0.2 g, 0.76 mmol, 1.0 eq.), 4-metboxyphenylacetylchloride (0.140 g, 1.0 eq.). Product: Yield 108.6 g (26%), UV/MS 100/99 (M 410), rt (A, MS) 2 80. 'H-NMR (400 MHz, CDQj) 8 1238 (bis, 1H), 8.00 (d =7 , 2H), 7 8 (d, J=HX 2H), 7.00 (d, J=n2,2H), 6.79 (d, J=72t 2H), 4.88 (bit, 1H), 4.61 (s, 2H), 3.90 (s, 3H), 3.75 (5, 3H), 3.42 (brf, >10.7, 2H), 2.84 (q, J=\0.7,2H), 2.68 (d, >=3.6, 3H), 2.40 (brq, =10.7, 2H), 1.75 (d. 10.7, 2H). I3C NMR 173.0; 166.8; 159.0; 143.3; 81 WO 01/66521 PCT/US01/07187 130.5; 129.9; 129.8; 126.3; 125.9; 114.5; 55.5; 54.7; 52.4; 48.7; 46.7; 43 6; 40.6; 32.1; 26.3; 22.9; 14.3. Example 67 - 2-(4-TMctbyIpbenyJ)-Ar-I4-(methox>'carbonyl)benzyl]-Ar-(l-metbyIpiperidin-4-yl) acetamide (50ELH23) Procedure as 50ELH14B. Reaction-step 2:1 -Phenyl-.V-f'2-(4-nictbylphenyI)etbyl3-A'-(l -methylpiperidm-4-yI) amide (50ELH23). Starting materials: 4-(2-Phenylethyl)amino-l-methylpiperidine (0.20 g, 0.86 mmol, 1.0 eq.), benzoylchloridc (0.158 g, 1.0 eq.). Product; Yield 159 rag (50%), UV/MS 100/100 (M 337), r, (A, MS) 3.289, Rr 0.55 (10% MeOH/CH2Cl2). 'B-NJUR (400 MHz, DMSO (S0°C)) S 10.9 (brs, 1H), 7.44 (s, 2H), 7.34 (d, >=3.0 Hz, 2H), 7.04 (d, 7.0 Hz, 2H), 6.95 (brs, 2H), 4.00 (brs, 1H), 3.40 (d, JM.2 Hz, 2H), 3.35 (d, .£=4.2 Hz, 2H), 2.95 (brs, 2H), 2.77 (t, J==3.2 Hz, 2H), 2.40 (q, J=6A Hz, 2H), 2.24 (s, 3H) 1.83 (d, J=6.4 Hz, 2H). 13C-NMR (CDC13) 171.6; 138.1; 136.3; 136.0; 129.8; 129.6; 129.1; 129.1; 126.7; 53.6; 52.4; 46.1; 42.9; 35.9; 27.3; 21.1. Example 68 - 2-(4-Metho3ryi"henyl)-Ar-(3-pbenyl-l-propyl)-AKl-methylpiperidin-4-yI) acetamide (5QELH65) Procedure as 50ELH14B. Reaction-step 1: 4-f3-Pbenylaininopropyl)piperidine (50ELH59) Starting materials: l-Methyl-4-piperidone(l.l ml, 7.4 mmol, 1.0 eq.), 3-pbenylpropylamiDe (1.35 g, 1.0 eq.). Product: UV/MS 100/94 (M 1133), r, (A, MS) 3.534.). ]H-NMR (400 MHz, CDCI3) 6 7J28-7.12 (m, 5H), 3.40 (tas, 1H), 2.84 (dt, =12J and 3 Hz, 2H), 2.64 (q, J=7.0 Hz ,4H), Z51 (m, 1H), Z27 (s, 3H), 2.05 (brt, =12J Hz, 2H), 1.82 (m, 2H), 1.44 (m, 2H). Reaction-step 2:2-(4-Methoxyphenyl>//-(3-phenyl--l-propyl)-.Af-(l-methylpiperidin-4-yl) acetamide (50ELH65) Starting materials: 50ELH59 (0.50 g, 2.2 mmol, 1.0 eq.), 4-methoxypbenylflcetylcbJoride (0398 g, 1.0 eq.). Product: Yield 153 mg (43%)", UV/MS 100/100 (M 381), rt (A, MS) 2.938. 'H-NMR (400 MHz, DMSO, retainers 55/45) 6 11.0 and 10.90 (2brs, IH), 7.30-7.10 (m, >7.9 Hz, 6H), 6.97 (d, =7.9 Hz, tH), 4.22 and 4.06 (2dt, dH), 3.70 (s, 3H), 3.35 82 WO 01/66S21 PCT7US01/07187 (t, =10.4 Hz, 2H), 3.15 (m, 2H), 3.00 (q, .M0.4 Hz, 2H), 2.66 (d, 3H), 2.52 (q, J=7.9 Hz, 2H), 2.17 (brq, 12 Hz, 2H) 1.73 (m, 2H), 1.70 and 1.52 (2d, 12 Hz, 2H). 13C-NMR(DMSO) 171.3; 171.0; 158.6; 142.2; 141.7; 130.0; 129.0; 128.0; 128.5; 128.2, 126.6; 114.5; 55.7; 55.7; 53.5; 53.3; 50.1; 44.5; 42.9; 41.9; 33.7; 33.1; 32.9; 31.4; 27.8; 26.8. Example 69 - 2-(4-Methoryphenyl>A'-[2-(4-methylphenyS)ethyl)-N- Reaction-step 1:4-f2-(4-Mcthylphenyl)ethylamino1-piperidm (50ELH58) Starling materials: l-Methyl-4-piperidone (1.1 ml, 7.4 mmol, 1.0 eq.), 2-(4-methylphenyl)ethylamine (1.0 g, 1.0 eq.). Product: UV/MS 100/91 (M4 233), n (A, MS) 3.933.). 'H-NMR (400 MHz, CDC13) 5 7.4 (s, 5H), 3.27 (bre, 1H), 2.84 (d, J=7.0 Hz, 4H), 2.75 (m, 2H), 2.54 (m, 1H), 2.29 (2xs, 6H), 2.10 (brt, >12.3 Hz, 2H), 1.86 (brd, 2H), 1.45 (m, 2H). Reaction-step 2: 2-(4-MethoxypheDyl)-..V-[2-(4-methylpheDyI)ethyl)-? -(l-methylpiperidJD-4-yl) acetamide (50ELH68) Starting materials: 5OELH58 (0.30 g, 1.3 mmol, 1.0 eq.), 4-methoxypheny!acetylchloride (0 38 g, 1.0 eq.). Product: Yield 125 mg (26%), UV/MS 100/99 (M 381), r, (A, MS) 3.156. ]B-NMR (400 MHz, DMSO, rotaracre 50/50) 5 11.0 and 10.90 (2brs, IH), 7.25-7.04 (m, 8.7 Hz, 6H), 6.87 and 6.84 (2d, =8.7 Hz, 2H), 4.30 and 4.09 (2dt, Ml 1.5 Hz, dH), 3.73 and 3.58 (2s, 2H), 3.71 and 3.70 (2s, 3H), 3.35 (m, (Underneath waterpeak) 3H), 3 4 (m, IH), 3.02 (m,J=US Hz, 2H), 2.80-2.62 (m, 5H), 2.32 and2.20(2q, >1U Hz, 2H), 2 6 and 2 4 (2s, 3H) 1.78 and 1.49 (2d, >=11.5 Hz, 2H). "C-NMR (DMSO) 171.5; 171.2; 158.6; 136.8; 136.2; 136.0; 135.8; 130.7; 130.5; 129.7; 129.6; 129.4; 129.2; 128.4; 128 J; 114.5; 55.8; 55.7; 53.3; 53.3; 52.2; 50.2; 46.8; 43.9; 42.9; 36.8; 35.2; 27.6; 26.8; 213. Example 70- 2- Procedure as 50ELH14B Reaction-step 1:4-f2-(2-Thieir )etfaylamino]piperidin (50ELH67A) Starting materials: l-Methyl-4-piperidone (0.5 g, 4.4 mmol, 1.0 eq.), thiophene-2-ethylamine (0.563 g, 1.0 eq.). 83 WO 01/66521 PCT/US01/07187 Product: UV/MS 94/93 (M4 225). Reaction-step 2:2-(4-Meth'oxvphenyI>7V-f2-(2-tliieDylethyn-//-(l-methylpiperidip-4-yl) acetamide (50ELH71 A) Starting materials: 50ELH67A (0.243 g, 1.08 mmol, 1 0 eq.), 4-methoxyphenylacetylch]oride(0.2 g, 1.0 eq.). Product: Yield 80.7 mg (33fl/o), UV/MS 100/100 (M 373), r, (A, MS) 2.613. 'H-NMR (400 MHz, DMSO, rotamcre 50/50) 5 10.8 and 10.6 (2brs, IH), 7.36 and 7.31 (2d, >=4.7 Hz, 1H), 7.20 and 7.06 (2d, >8.3 Hz, 2H), 7.00-6.92 (m, J=4J and 2.8 Hz, 2H), 6.87 and 6.40 (2d, J=&3 Hz, 2H), 4.22 and 4.08 (2dt, J=12.2 Hz, 1H), 3.71 (s, 3H), 3.70 (s, 2H), 3.46-3.30 (m, 4H), 3.10-2.90 (m, 4H), 2.67 (m, 2H), 2.28 and 2.12 (2q, =12 Hz, 2H), 1.80 and 1.50 (2d, J=32 Hz, 2H). I3C-NMR (DMSO) 172.5; 158.9; 139.6; 130.0; 129.6; 126.8; 124.5; 114.5; 55.5; 54.7; 49.3; 45.8; 43.8; 41.3; 31.9; 29.9 Example 71 -2-(4-Methox>-phenyl)-A'-[2-(4-Ditropbeiiyl)ethy]J-AKl-metbyIpiperidin-4-yI) acetamide (50ELH71C) Procedure as 50EIJil4B Reaction-step 1: 4-f2-f4-nitrophepyl) ethylaminoi-piperidin (50ELH67C) Starting materials: l-Mcthyl-4-pipendone (0.5 g, 4.4 mmol, 1.0 eq.), 4-nitrophenyI-2-ethyIamine (0.897 g, 1.0 eq.). Product: UV/MS 96/89 (M 264), r, (A, MS) 3.264. Reaction-step 2:2-{4"Methoxifphenyl>Ar-r2-(4-nitrophenyl)e&yl1- -{l-methylpipgridin-4-yI) acetamide (50ELH71A) Starting materials: 50ELH67C (0 185 g, 1.08 mmol, 1.0 eq.), 4-methoxyphenylacetylchloride (0 g, 1.0 eq.). Product: Yield 130.9 mg (30%), UV/MS 100/100 (M 412), r, (A, MS) 2.219. 'H-NMR (400 MHz, DMSO, retainers 50/50) 8 10.8 and 10.6 (2bxs, 1H), 8.17 and 8.12 (2d, =8.6 Hz, 2H), 7.58 and 7.48 (2d, >=8.6 Hx, 2H), 12 and 7.1 (2d, =8.6 Hz, 2H), 6.87 and 6.40 (2d, =8.6 Hz, 2H), 4.25 and 4.10 (2dt, J=X2 Hz, 1H), 3.72 (s, 3H). 3.70 (s, 2H)f 3.48-3 JO (m, 4H), 3.10-2.84 (m, 4HX 2.69 and 2.67 (2d, >4.7 Hz, 3H), 234 and 2.15 (2q, =13 Hz, 2H), 1.79 and 1.47 (2d, J=\Z2 Hz, 2H). Example 72 - MethoxyphenyO-AK -thieayliDethylVAKl-methylpipendin-4-yI) acetamide (50ELH73A) Procedure as 50ELH14B. 84 WO 01/66521 PCT/US01/07I87 Reaction-step 1: 4-f(2-Thienyhnetfayl)aniino1-l-niethylpiperidine (50ELH66A) Starting materials: I-MethyI-4-pipcridone (0.5 g, 4.4 mmol, 1.0 eq.), 2-thienylmethylamine(0.52 g, 1.0 eq.). Product: UV/MS 77/86 (M 211), rt (AMS) 2.739. Reaction-step 2: 2-{4-McthoxypbenylV-A '2-thienylmcthyl)-./V: Starting materials- 50ELH65A (0.228 g, 1.08 mmol, 1.0 eq.), 4-methoxyptaenylacetylchloride (0.2 g, 1.0 eq.). Product: Yield 178.4 mg (50%), UV/MS 100/9S (M 359), rt (A, MS) 3.117. 'H-NMR (400 MHz, DMSO) 6 10.9 and 10.6 (2brs, 1H), 7.47 and 7.32 (2d, J=4.S Hz, 1H), 7.20 and 7.03 (2d, >=8.4 Hz, 2H), 7.03 and 6.9S (2m, 1H), 6.87 (m, 3H), 4.70 and 4.57 (2s, 2H), 4.42 and 4.16 (2t, =l 1.9 Hz, IH), 3.77 and 3.60 (2s, 2H), 3.51 (s, 3H), 3-15 (m, 2H), 2.98 (m. 11.9 Hz, 2H), 2.65 (2d, >4.5 Hz, 3H), 2.25 and2.17 (2q, =11.9Hz, 2H), 1.69 and 1.44 (2d, J±\\.9 Hz, 2H). I3C-NMR (DMSO) 171.4; 158.6; 143.2; 130.7; 128.1; 126.6; 126.3; 125.9; 114.5; 55.7; 53.3; 52.6; 50.0; 42.8; 27.7; 26-8. Example 73 - 2-(4-Methoi3/phenyI)-JV-(furfur>'I)-Ar-{I-metbylpiperidiii-4-yl) acetamide (50ELH73B). Procedure as 50ELH14B. Reaction-step 1: 4- Product: UV/MS 77/92 (M 195), rt (A, MS) 2.812. \ Reaction-step 2:2-(4-Memo> henylVA -(figmryl)-.?y-(l-metiiylpiperidm--4-yl) acetamide (50ELH73B). Starting materials: 50ELH66B (0.21 g, 1.08 mmol, 1.0 eq.), 4-metboxyphenylacetyichJoridc (0 g, 1.0 eq.). Product: Yield 134 mg (36%), UV/MS 100/99 (M 343), rt (A, MS) 2.401. 'H-NMR (400 MHz, DMSO, rotamers 57/43) 5 10 5 and 10.75 (2brs, 1H), 7.63 and 7.48 (s, 1H)S 7.18 and 7.06 (2d, =7.7 Hz, 2H), 6.85 (t, >7.7 Hz, 2H), 6.44 and 633 (2d,. =7.7 Hz, 1H), 6.37 and 6.11 (2K, 1H) 4.5 and 434 (2s, 2H), 4.42 and 4.18 (2dt, J=ll and 2 Hz, 1H), 3.75 and 3.65 (2s, 2H) 3.70 (s, 3H), 3.33 (hidden, 2H), 3.0 (q, 50133758v3 85 WO 01/66521 PCT/US01/07187 2H), 2.64 (d,, J=4.1 Hz, 3H), 2.15 (dq, >=11 and 2 Hz, 2H), 1.65 and 1.50 (2d, =11 Hz,2H). Example 74 - 2(2-thienylmethyI)-Ar-(4-methy]phenylmethyl)-Ar-(l-methylpiperidin-4-yI) acetamide (50ELH82) Procedure as 50ELH14B Reaction-step 2: 2-(2-lhicnylmctliyl)-//-(4-niethylphenylinethyl)-7V-(l -methylpiperidin-4-yl) acetamide (50ELH82) Starting materials; 50ELH25 (0.30 g, 1.38 mmol, 1.0 eq.), thiophene-2-acetylchlorid (0.22 g, 1.0 eq.). Product: Yield 235 mg (62%), UV/MS 97/93 (M 343), rt (A, MS) 2.795. ]H-NMR (400 MHz, DMSO, rotamers 54/46) 5 10.8 and 10.60 (2brs, IH), 7.4 and 7.35 (2d, 1H), 7.2-6.76 (m, 6H), 4.55 and 4.4 (2s, 2H), 4.49 and 4.26 (2dt, J=\ 1 and 2 Hz, 2H), 4.15 and 3.79 (2s, 2H), 3.32 (d, J=\1 Hz, 2H), 2.99 (q, 2H), 2.63 (s, 3H), 2.27 and 2.23 (2s, 3H), 2.09 (q, 11 Hz, 2H), 1.66 and 1.55 (2d, M\ 1 Hz, 2H). Example 75 - 2-(4-MethoxypbeDyI)"Ar-(4-inethyIbenzyl)-iV-(l-cyclopentylpipcridin-4-yl) acetamide (42ELH75) Procedxire as for 42ELH80, except that the reaction was run at 60°C for 3 days. Starting materials: 50ELH87 (0 5 g, 0.71 mmol, 1.0 eq.), Cyclopcntylbromide (0.288 g, 3.0 eq.). Product: Yield 91.2mg(34%),UV/MS S8/93 (M l), (A,MS) 4.450. Example 76 - 2-(4-MetboxyphenylHV-JV-(l-(3-(l -dibydro-2H-benziniida2ol-2-one-l-yDpropyr)piperidine-4-yi) acetamide (50ELHS9). 5OFJf\K7 (0.05 g, 0.14 mmol, L eq.) was transferred xo a 4 ml vial and dissolved in 1 mJ of acetonitrile. Then, l-(3-chioropropyl)-l,3-dinydro-2H-benzimidazol-2-one (0.032 g, I.I eq.), sodium carbonate (0.022 g, 1.1 eq.) and K3 (one crystal) were added and the vial was sealed and shaken for 20 h at 82°C. The mixture was extracted with distilled water (pH 10, sodium carbonate) and dichloromethane (3 times) the organic layers were dried with sodium sulfate and concentrated. The title compound was purified by HPLC and evaporated to dryness, forming a trifluoroacetic acid salt Yield 8.8 mg (12%). UV/MS 100/100 (M 527), rt (A, MS) 2.851. 86 WO 01/66521 PCmJSOl/07187 Example 77 - 2-(4-Melhoxyphenyl>-JV-(4-methylbenzyl)-A'-[l-(2-methyltbiazoM-ylroethyl) piperidin-4-yI) acetamide (63ELH1A). 5OELH87 (0.3 g, 0.852 mmol, 1.0 cq) and 4-(chloromethyl)-2-methylthiazole hydrochloride (0.235 g, 1.5 eq) were added to a 7 ml vial and dissolved in acetonitrile (3ml). Potassium carbonate (141.3 g, 1.2 eq) and a crystal of potassium iodide were added and the vial was sealed and shaken for 20 h at 82°C. The reaction mixture was extracted with distilled water (made basic by potassium carbonate, pH 10) and dichloromethane. The crude product was dried with sodium sulfate and concentrated. After purification by HPLC the product was converted into the hydrochloride salt by dissolving the free base in 1 ml dichloromethane and adding 1 eq. HC1 in ether (2M). This mixture was added drop-wise to an excess of heptane where the product precipitated. The solvent was removed by evaporation leaving a white powder as the product, yield 83.8 mg (21%), UV/MS 100/90 (M 463), r, (B, MS) 11.82. Example 78-2 4-Methoxyphenyl)-JV-(2-HfliiorophenyI) ethyI)-M Reaction-step 1: 4-f2-4-(Fluorophenyl)ethylaminoJ-l-methylpiperidine (50ELH92A) Starting materials: 1-Methyl-4-piperidone (0.3 g, 2.65 mmol, 1.0 eq.), 4-(fluorophenyl)eaiylamine (0369 g, 1.0 eq.). Product: UV/MS 60/92 (M 237), r, (A>tS) 3.422. Reaction-step 2:244-MemoxyphgpylVM(2-4KiliK>rophenyl)ethyl>Jvv-(l-mcthYh)iperidm-4-yI) acetamide (50ELH93 A) Starting materials: 50ELH92A (0.625 g, 2.65 mmoU 1.0 eq.), 4-methoxyphenylacetylchloride (0.488 g, app. 1.0 eq.). Product: Yield 181 mg (18%), UV/MS 87/97 (M 385), rt (A, MS) 2.783. Rf 0.8 (10% MCOH/CH2CI2). 'H-NMR (400 MHz, DMSO, rotamers 50/50) 6 10 (brs, 1H), 7.56 6.8 (m, 8H), 4 6 and 4.02 (2brt, 2H), 3.70 and 3.95 (2s, 3H), 3.59 and 3.57 (2s, 2H), 3.4-3.15 (m, 5H), 2J96-2.66> (m, 5H), 2.62 and 236 (2s, 3H), 2J 9 and 2.10 (2q,2H), 1.73 ad 1.41 (2d,2H). UC-NMR (DMSO) 172.5; 171.4; 1713; 162.9; 162,7; 1605; 1603; 158.9; 158.6; 136.1; 136.1; 1353; 131.4; 1313; 131.1; 131.0; 131.0; 130.6; 130.5; 128.4; 128.4; 126.9; 115.9; 115.8; 115.7; 115.6; 114.5; 55.7; 53.7; 53.5; 52.7; 523; 50.7; 46.7; 43.8; 43.2; 43.0; 363; 34.7; 27.9; 26.9. 87 WO 01/66521 PCT/US01/07187 Example 79 - 2-(4-MethoxyphenyI>7V-[2-(2,5-dimetboxypheDy])ethyI]-Ar-(l-metbylpiperidin-4-yl) acetamide (50ELH93C) Procedure as 50ELH14B. A small amount was purified by HPLC and evaporated to dryness, fonning the trifluoroacetic acid salt. Reaction-step 1: 4-[2-(2,5-dimethoxvphenyl)ethylammo] J-methylpiperidine (50ELH92A) Startiftg materials: Metbyl-4-piperidone (0.3 g, 2.65 mmol, 1.0 eq.), 2,5-(dimethoxvphenyl)ethylamine (0.481 g, 1.0 eq.). Product: UV/MS 81/90 (M 279), rt (AJrfS) 2.868. Reaction-step 2:2-(4-Methoyyphenyl)-A -f2-(2,.5-dimethoxyphenyl)ethyll-A (l-methylpiperidin-4-yl) acetamide (5OELH93Q Starting materials: 5OELH93C (0.737 g, 2.65 mmol, 1.0 eq.). 4-methoxyphenylacetylchJoride (0.488 g, app. 1.0 eq.). Product: UV/MS 82/100 (M 427), r, (B, MS) 8.44. R,0.8 (10% MeOH/CH2Cl2). Example 80- 2-(4-Methox>']phenyl)-Ar-[2-(2,4-dich]orophenyl) etfayl]-7V-{l-mcthylpiperidin-4-yl) acetamide (50ELH93D) Procedure as 50ELH14B, but purified by HPLC and evaporated to dryness forming the trifluoroacetic acid salt Reaction-step 1:4-[2 2ADic orophenv0emylainmoVl-methylpiperidi2e (50ELH92D) Starting materials: 1-Metbyl-4-piperidone (03 g, 2.65 mmol, 1.0 eq.), 2 -(dSchlorophenyl) ethylamine (0 0 g, 1.0 eq.). Product. UV/MS 82/92 (M 287), r, (AMS) 4.875. Reaction-step 2:2-N-[2-(2T4-dichlorophec>fi emyIl-N-(l-methyIpiperidin-4-yI) acetamide (50ELH93P) Starting materials: 50ELH93D (0.76 g, 2.65 mmol, 1.0 eq.), 4-metboxyphenylacetylcblohde (0.488 j app. 1.0 eq.)- Product: UV/MS 100/96 (M 435), rt (A, MS) 4.415. R, 0.8 (10% McOH/CHjCla). Example 81 - 2-Ar-[2- Procedure as 50ELH14B, but purified on HPLC and evaporated to dryness fonning the trifluoroacetic acid salt. 88 WO 01/66521 PCT/US01/07187 Reaction-step 1:4-K3-Ch]orophenyl)ethyI)ainiiiol-l-methylpiperidine (50ELH92E) Starting materials: 1-Methyl-4-piperidone (0.3 g, 2.65 mmol, 1.0 eq.), 3-(chlorophenyl) ethylaminc (0.413 g, 1.0 eq.). Product: UV/MS 86/88 (M 253), r, (A IS) 3.175. Reaction-step 2: 2-(4-MethoxyphenyI)-N-r2-(3-chIorophenvO ethyl1-N-(l-methylpiperidin-4-yl) acetamide (5OELH93E) Starting materials: 50ELH93E (0.67 g, 2.65 mmol, 1.0 eq.), 4-methoxyphenylacetylchloride (0.488 g, app. 1.0 eq.). Product: UV/MS 100/100 (M 401), r, (A, MS) 3.464. Rf 0.8 (10% MeOH/CH2Cl2). Example 82 - 2-(4-MethoxypheDyD-W-I2 (4-metboxyphenyI) ettayl]-iV-(l-jnetby)piperidiD-4-yJ) acetamide (50ELH95B) Procedure as 50ELH14B. Purified by HPLC and evaporated to dryness forming the trifhioroacetic acid salt. Reaction-step 1: 4-[(4-Mcthoxyphenyl)ethyl)amino]-l-tnethylpiperidine (50ELH94B) Starting materials: 1 -Methyl-4-piperidone (0.3 g, 2.65 mmol, 1.0 eq.), 4-methoxyphenylethylamine (0.40 g, 1.0 eq.). Product: UV/MS 74/87 (M 249), rt (A>1S) 2.935. Reaction-step 2: 2-(4-MethoxyphenyD-A f2-(4-methoxyphenyl) hy\\-N-{\ methy3piperidin-4-yl) acetamide (50ELH95B) Starting materials: 50ELH94B (0.657 g, 2-65 rnrnol, 1.0 eq.), 4-metlioxyphenylacetylchloride (0.488 %> app. 1.0 eq.). Product: UV/MS 100/100 (M 397), r, (A, MS) 2389. Rf 0.8 (10% MeOH/CH2a2). Example 83 - 2-(4-MetfaoxypfaenylHV-[2-(3-nnorophenyI) ethyl]-7V-(l-metbylpiperidin-4-yI) acetamide (50ELH95D) Procedure as 50ELH14B- Purified on HPLC and evaporated to dryness, forming the trifhioroacetic acid salt. Reaction-step 1:4-r2 (3-FluoTophcnyI)emyOammo1-l-metbyIpiperidme (5QELH94D) Starting materials: 1-Methyl-4-piperidone (0.3 g, 2.65 mmol, 1.0 eq.), 3-fluorophenylethylamine (0.369 g, 1.0 eq.). 89 WO 01/66521 PCT/US01/07187 Product: UV/MS 74/89 (M4 237), r, (AJtfS) 2.946. Reaction-step 2: 2-(4-methoixypheDyI)-Af-r2-(3-fluorophenyI) ethyl]-Ar-Q-methylpiperidin-4-yl) acetamide (50ELH95D) Starting materials: 50ELH94D (0.625 g, 2.65 mmol, 1.0 eq.), 4-methoxyphenylacetylchloride (0.488 g, app. 1.0 eq.). Product: UV/MS 100/95 (hf 3S5), rt (A, MS) 2.946. R, 0.8 (10% MeOH/CH2a2). Example 84 - 2-(4-etboxvphenyl)- 12 4-fluoropbenyl)ethylJ-VV-(l-methylpiperidin-4-yI) acetamide (63ELH20) Reaction step 1:4-EthoxyphenyJacetic acid chloride(63ELHI9) 4-Ethoxyphenylacetic acid (0.5 g, 2.8 mmol) was transferred to a 7 ml vial and dissolved in thionylchloride (3 ml). The reaction mixture was shaken at 70°C for 2V2 hours. Thionylchloride was evaporated off and the resulting product was used unpurified. Reaction step 2:2-(4-Ethoxy]phenyl)-Ar-[2-(4-fluoropherjyl)ethyl]-Ar-(l-methylpiperidin-4 yl) acetamide (63ELH20) 63ELH17 (0.11 g, 0.47 mmol) was transferred to a 4 ml vial and dissolved in dichlorometbane. 63ELH19 (0.084 mg, 1 eq.) was added and the vial was sealed and the reaction shaken for 20 h. The product was extracted in distilled water (made basic with potassium carbonate, pH 10) and dichloromethane. Dried with sodium sulfate and concentrated. Purified by HPLC. The extraction, drying and concentration was repeatedand the product re-dissolved in dichloromethane (1 ml) and HC1 (1 eq-, 2 M in ether) was added. The mixture was added drop-wise to an excess of heptane whereupon the salt precipitated. Yield 33.4 mg (18%), UV/MS: 92/100 (M 399% t, (B, MS) 10.38- Example 85- 2--AKl-methylpiperidin-4-yI) acetamide (63ELH21) 50ELH4 (O.llg, 0.49 mmol, 1.0 eq.) was transferred to a 4 ml vial and dissolved in dichloromethane. 63ELH19 (0.089 mg, 1.0 eq.) was added and me vial was sealed and the reaction shaken for 20 h. The product was extracted in distilled water (made basic with potassium carbonate, pH 10) and dichlorometharje. Dried with sodium sulfate and concentrated. Purified by HPLC. The extraction, drying and concentration was repeated and the product dissolved in dichloromethane (1 ml) and HC1 (1 eq., 2 M in ether) is added.This mixture was added drop-wise to an excess of 90 WO 01/66521 PCTAJS01/07187 heptane whereupon the salt precipitated. Yield 31 1 mg (16%), UV/MS: 94/100 (M 385), tr (A, MS) 2.573. Example 86 - 7V-((4-methylpbeny])methyI)-Ar-(l-methylpiperidiii-4-yl)-2-(3-hydroxy-4-methoxypbenyl)acetamide (57MBT12B) AK(4-methylphenyI)methyl)-4-amino-l-methylpiperidine (50ELH25) (105 mg, 0.48 mmol) and 3-hydroxy-4-methoxyphenylacetic acid (88 mg, 0.48 mmol) were dissolved in DMF (10 ml). Diisopropylethylamine (DIEA, 250 uL, 1.44 mmol) was added followed by brorno-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP, 336 mg, 0.72 mmol), and the mixture was stirred at r.t for 1 h. Water (50 mL) was added, and the reaction mixture was extracted with EtOAc (2x50 mL). Drying by NajSO4 and concentration yielded 514 mg crude material, which was purified by flash chromatography (0-30% MeOH in CH2CI2). This gave 105 mg (57%) of the title compound as a white solid. Rf=0.20 (10% MeOH in CH2CI2). HPLC-MS (method A) showed MH+=383. UV/MS(%)=100/92. 'H-NMR (400 MHz, CD3OD, Rotamers 52:48): 8 7.18-6.58 (m, 7H), 4.53 (s, 2H), 4.31 and 3.97 (2m, 1H), 3.82 and 3.81 (2s, 3H), 3.80 and 3.55 (2s, 2H), 3.04 and 2.85 (2m, 2H), 2.41 and 2.32 (2s, 3H), 2.35 and 2.12 (2m, 2H), 2.29 and 2.27 (2s, 3H), 1.83 and 1.74 (2m, 2H), 1.72 and 133 (2m, 2H) Example 87- (4-metbyIphenyI)mcth>1>-Ar-(3-in€thylpiperidin-4-yI>-2-(3,4-dibydroxypbenyI)acetomide (57MBT24B) AK(4-memylphen>1)irietnyI> 12 Hz, 2H), 3.02 and 2.95 (2far t, M\2 Hz, 2H), 2.79 (s, 3H), 233 and Z2S (2s, 3H), 2.17 and 1.84 (2dq, >4,12 Hz, 2H), 1.87 and 1.48 (2br d, J=12 Hz, 2H) 91 WO 01/66521 PCT/US01/07187 Example 88 - 7V-((3-hydro3[y-4-inetby]pbenyI)methy])-AHl-metbylpiperidui-4-y])-2 4-methoxyphenyl)aceUmide(57MBT54B) AK(4-melhoxypheoyl)meaij'l)-4-arruno-l -methylpiperidine (lg, 4.27 mmol) was dissolved in 4% formic acid in methanol (60 mL). 10% Pd/C (lg) was added under argon and the reaction mixture was heated to reflux for 24 h. The mixture was filtered through celite and the filtrate was acidified with cone. HC1 to pH 1. Concentration yielded a yellow oil which was purified by flash chromatography (MeOH/CH2Cl2 3:7 + 3.5% NH4OH) to give 249 mg (51%) of 4-amino-l-methylpiperidine (57-MBT36B) as a white solid. RHX13 (10% MeOH in CH2C12 + 3.5% NRtOH). HPLC-MS (method B) showed MH =115. UV/MS(%)=-/100. 4-Amino-l-methylpiperidine (57MBT36B) (26 mg, 0.231 mmol) was dissolved in methanol (1 mL) and 3-hydroxy-4 methylbenzaldehyde (32 mg, 0.231 mmol) and acetic acid (33 jxL) were added. The mixture was cooled to 0 CC. NaBHjCN (29 mg, 0.462 mmol) was; added and the cooling bath was removed. After 3 h the reaction mixture was evaporated and flash chromatography (0-30% MeOH in CH7CI2) gave 27 mg (50%) of tf (3-hydroxy-4-metoyIphenyl)memyl) ainino-l-meihylpiperidine (57MBT44Q as a white solid. R(=0.27 (10% MeOH in CH2C12 + 3.5% NKiOH). HPLC-MS (method A) showed MH =235. UV/MS(%)=99/99. AH(3-hydroxy-4-methylpheny])methyI)-4-ammo-1 -methylpiperidine (57MBT44Q (27 mg, 0.115 mmol) ivas dissolved in CH2C12 (2 mL). 4-Mcthoxyphenylacetyl chloride (17 ptl-, 0.115 mmol) was added dropwise under argon. After 3 h, n-heptane (3 mL) was added and the mixture was evaporated. Flash chromatography (0-20% MeOH in CH2CI2) B&ve 14 m8 (32%) of the title compound as a white solid. 1 =032 (10% MeOH in OfeCb + 3.5% NH4OH). HPLC-MS (method A) showed MH"=383. UV/MS(%)=99/96. !H-NMR (400 MHz, CD3OD, Rotamers 63:37): 5 7.28-6.55 (m, 7H), 4.48 (s, 2H)S 4.37 and 3.95 (2m, 1H), 3.78 and 3.77 (2s, 3H), 3.06 and 2.89 (2brd, >12 Hz, 2H), 2.42 and 232 (2s, 3H), 2.40 and 2.12 (2m, 2H), 2.18 and 2.12 (2s, 3H), 1.86 and 1.83 (2m, 2H), 1-75 and 135 (2br d, >12Hz,2H) Example 89 - -.V-(l-mcthy1piperidm-4-yI>2-(4-bromopbenyl)acetamidebydroch)oridc(57MBT70-lD) 4-Bromophenylacetic acid (54 mg, 0.252 mmol) was dissolved in CH2C12 (2 mL), and -((4-metbylphenyl)methyl]h4-ammo-l-methylpiperidine (292 mg/mL 92 WO 01/66521 PCT/USO1/O7187 stock solution in CH2C12) 171 uL, 0.229 mmol) and polystyrene supported diisopropylethylamine (PS-DIEA with a loading of 3.57 mmol/g, 192 rag, 0.687 mmol) was added followed bybromo-tris-pyrrolidirio-phosphonium hexafluorophosphate (PyBrOP, 160 mg/mL stock solution , 1 mL, 0.334 nunol). The reaction mixture was shaken for 1 h at r.t. and filtered onto a prewashed (methanol) ion exchange column (0.88 ramol/g, Ig). The column was washed with methanol (8 4 mL) and the remaining product was eluted off the column with 10% NH4OH in methanol (2 4 mL) and evaporated. The resulting oil was filtered through silica (H=4 cm, P=l cm) with metbanol/CH2Cl;i 1:9 (20 mL), evaporated and subjected to a second ion exchange column (0.8S mmol/g, lg). The column was washed with methanol (8 4 mL) and the remaining product was eluted off the column with 10% NH4OH in methanol (2 4 mL) and evaporated on rotavap and oil pump. The product was dissolved in CH2CI2 (0.5 mL) and HCI in diethylether (1.0 M, 0.1 mL, 0.1 mmol) was added. The solution was added to n-heptanc (3 mL) and evaporation afforded 29 mg (25%) of the title compound as a white solid. Rr=0.31 (10%MeOH in CH2C12). HPLC-MS (method B) showed MH =416. UV/MS(%)= 100/99. Example 90 - Ar-((4-methylpheDyI)methyl)-Ar-(l -methyl pipe rid in-4-yl)-2- (4-iodophcnyI)acetamidehydrochaoride(57MBT70-2D) The title compound was prepared according to example MBT04. Yield: 33 mg (26%). RrOJl (10% MeOH in CH2C12). HPLC-MS (method B) showed MH =463. UV/MS(%)=100/98. Example 91 -7V (4-inethy]lpbeny0inetfay])-7V -(l-n]etfaylpiperidia-4-yl>-2- (4-(2-propyf)pheiiyi)acetamide bydrochloride(57MBT70-3D) The title compound was prepared according to example MBT04. Yield: 36 mg (34%). R =0.31 (10% MeOH in CR2Ch). HPLC-MS (method B) showed MH =379. UV/MS(%)-10(V97. Example 92 -7V-((4-iDethylphenyI)methyl)-JV-(l-methylpiperidiii-4-yI)-2- (4-tnflaoromethoxypheDy])acetamidebydrDcliloride(57MBT7(MD) The title compound was prepared according to example MBT04. Yield: 35 mg (30%). 1 4=0.27 (10% MeOH in CH2O2). HPLC-MS (method B) showed MH 421. UV/MS(%)=10(V99. 93 WO 01/66521 PCT/US01/07187 Example 93 - Ar-((4-nietliy]pheDyI)inetby])-AHl-methylpiperidin-4-yI>-2-(4-methy]tbiopbenyl)acetamidefaydrochIoride(57MBT70-5D) The title compound was prepared according to example MBT04. Yield: 35 mg (33%). Rf=0.30 (10% MeOH in CH2C12). HPLC-MS (method B) showed MH+=3S3. UV/MS(%)=100/99. Example 94 -7V-((4-methylphenyI)methyl)-7V-(l-niethyIpiperidin-4-yI)-2-(4-(i\VV-diniethylaiiiiDo)pheDyI)acetamidebydrochloride(57MBT70-6D) The title compound was prepared according to example MBT04. Yield: 16 mg (15%). Rf=0-25 (10% MeOH in CH2C12). HPLC-MS (method A) showed MH+=380. UV/MS(%)=100/100. Example 95 - AH(4 metbylphenyI)metbyl)-AHl-niethylpiperidin-4-yI)-2-(4-nUropbenyI)acetamidehydrochioride(57MBT70-7I)) The title compound was prep;ared according to example MBT04. Yield: 28 mg (27%). Rj=0.27 (10% MeOH in CH2C12). HPLC-MS (method B) showed MH+=382. UV/MS(%)=100/100. Example 96-AH(4-metnylpbenyJ)metbyI)rAHl-metbyIpiperidiD-4-yI)-2-(4-metboxy-3-methyIphenyI)acetamidebydrochloride(57MBT70-8D) The title compound was prepjired according to example MBT04. Yield: 34 mg (32%). R Example 97 - A-{(4-methylphenyI)methyI)-A'-(l-niethyIpiperidiii-4-yf)-2-(4-p>Tidyl)acetamidebydrc)cblorid The title compound was prepared according to example MBT04. Yield: 18 mg (17%). RH>.09 (10% MeOH in CH2C12). HPLC-MS (method A) showed MH -338. UV/MS(%)=100/100. Example 98-AK(4-metbylpheDyi)inethyI)-AHl-nietbylpiperidin--4-y!>-2-(4-methylphenyl)acetamidehydrocliloride(57MBT62B) The title compound was prepared according to example MBT04. Yield: 10 mg (35%). R = (10% MeOH in CH2CI2). 13PLC-MS (method A) showed MH =351. UVyMS(%>=100/100. 94 WO 01/66521 PCT/USOI/07187 Example 99 - A4(4-(hydroxymemy1)pbedy0methyl)-AHl-nietbylpiperiduM-yI>2 4 methoxyphcny])flcetamide hydrochJoride(S7MBT72D) To a stirred suspension of LiAIH (285 mg, 7.52 mmol) in diethyiether(10 mL) at 0 °C was added a solution of 4-cyanobenzyl alcohol (0.5 g, 3.76 mmol) in diethylether (5 mL) over 15 min. The grey reaction mixture was heated to reflux for 3 h. After cooling to r.t., the mixture was treated successively with water (1 mL), 2M NaOH (2 mL) and water (2 mL) under vigorous stirring. The resulting white slurry was filtered and washed with CH2C12 (20 mL). Extraction with additional CH2C12 (20 mL) and n-butanol (20 mL) and evaporation yielded an oil, which upon flash chromatography (0-15% MeOH in CH2CI2) gave 152 mg (29%) of 4-(aminomethyl)benzylalcohol (57MBT52B) as a white solid. Rf=O.5I (30% MeOH in CH2CI2 + 3.5% NH4OH). l-Methyl-4-piperidone (84 JJ! 0.73 mmol) was dissolved in methanol (5 mL) and 4-(aniinornethyl)ben2yIalcobol (57MBT52B) (100 mg, 0.73 mmol) was added followed by acetic acid (125 uL). NaBH3CN (92 mg, 1.46 mmol) was added and the mixture was stirred for 3 h. The reaction mixture was evaporated and 2M NaOH (5 mL) was added. Extraction with CH2CI2 (4 5 mL), drying with Na2SO and evaporation gave 152 mg (87%) of A'-((4-{hycToxyiriethyl)phenyl)niethyl>4-amirjo-l-methylpiperidine (57MBT56D) as a white solid. HPLC-MS (method B) showed MH =235. UV/MS(%)=10aa00. (4- ydroxymethyI)phenyI)methyl) aniino-1 -methylpiperidine (57MBTS6D) (20 mg, 0.0853 mmol) was dissolved in CH2C12 (2 mL) and 4-mcthoxypbcnylacetyi chJoridc (26 pL. 0.171 mmol) was added dropwise- The reaction mixture was stirred for 1 h and water (500 \xL) was added followed by evaporation. A solution of sodium (5 mg, 0.179 mmol) in methanol (2 mL) was added. After stirring for 4 h, the solution was transferred to a prewashed (methanol) ion exchange column (0.88 mmol/g, Ig) and washed with methanol (4 4 mL). The remaining product was ehrted off the column with 10% NH4OH in methanol (2 4 mL) and evaporated. The resulting oil was filtered through silica (H=4 cm, D=l cm) with methanol/CH2d2 2:8 (20 mL), evaporated and subjected to a second ion exchange column (0.88 mmol/g, Ig). The column was washed with methanol (8 4 mL) and the remaining product was eluted off the column with 10% NH OH in 95 WO 01/66S21 PCT/US01/07187 methanol (2 4 mL) and evaporated on rotavap and oilpurap. The product was dissolved in CH2Q2 (0.5 mL)and HQ in diethylether (1.0 M, 0.1 mL, 0.1 mmol)was added. The solution was added to n-heptane (3 mL) and evaporation afforded 14 mg (39%) of the title compound as a white solid. Rf=O.l6 (10% MeOH in CH2C12). HPLC-MS (method B) showed MHf=383.UV/MS(%)=100/96. Example 100 - 2-(4-O lor op h enyl>A -(4 -methyl ben zyI)-iV-(l-isopropylpiperidin-4-yl)acetamide(47AJaJ-7) l-Trifluoroacetyl-4-piperidone (47AKU-2) 4-Piperidone hydrochloride monohydrate (3.85 g, 25 mmol) and Triethylamine (10.5 ml, 75 mmol) were partly dissolved in 100 ml of dichloromethane and stirred for 10 min. Reaction mixture was then cooled on ice-bath and trifluoroaceb'c anhydride (7.2 ml, 50 mmol) was slowly added over 10 min. Ice-bath was removed and mixture was stirred overnight. Additional trifhioroacetic anhydride (2 ml) was added and the mixture was stirred for 1 hr. Water (200ml) was added. Phases were separated and aq. phase was re-extracted with dichloromethane. Combined organic phases were washed with brine, dried over MgSC>4 and concentrated (40°C) giving 4.97 g (100%) 47AKU-2 as yellow crystals. TLC (5% methanol in dichloromethane): Rf = 0.8. 'H-NMR (400MHZ, CDCb): &= 3.87-3.99 (4H,m); 2.54-2.61 (4H,m). l3C-NMR(Ct>Cl3): 8-204.7, 118.0, 115.1,44.2,42.8, 41.2,40.5. 4-(4-Methylbenzy!amino)-1 -trifluoroacetyl-piperidine (47 AKU-3) 47AKU-2 (4.97 g, 25 mmol) was dissolved in 100 ml methanol and 4-methylbeozyl-amine (3.2 ml, 25 mmol) was added. Mixture was stirred and acetic acid (-2 ml) was added until pH 5. NaCNBH3 (3.15 g, 50 mmol) was slowly added. After magnetic stirring for 20 hrs the methanol was partly removed on me rotary evaporator (40°C). Dichloromethane, 2M NaOH and water were added until pH 10. Phases were separated and aq. phase was then re-extracted twice with dichloromethane. Combined organic phases were washed with brine and dried over MgSO4. Conccntration(40oC) yielded 6.94 g (92%) 47AKU-3. TLC (10% methanol in dichloromethane): Rf=0.6. HPLC-MS (Method A): M = 301.0 (UV7MS(%)=94/100). 2-(4-Chloit)phenyI)-JV-(4-memyfl>en2yI)- -(l-triiluoroacctylpiperidin-4-yl)acetamide (47AKU-4) 96 WO 01/66521 PCT/US01/07187 47AKU-3 (3.01 g, 10 mmol) in 25 ml of dichlorometbane was placed in a 100 ml flask. Triethylamine (1.4 ml, 10 mmol) was added and the mixture was cooled on an ice-bath and stirred for lOmin. 4-Chlorophenyiacetyl chloride (1.90 g, 10 mmol) was dissolved in 10 ml dichlorometliane and added slowly to the ice-cold mixture. After 15 min. the ice-bath was removed and the mixture was left for 1 br. Precipitation was observed. The reaction mixture was then concentrated at aspirator pressure(40°C). TTie crude product was purified by flash chromatography (0-50% ethylacetate in heptane) yielding 2.38 g (53%) 47AKU-4. TLC (100% dichloromethane): Rf= 0.6. HPLC-MS (Method A): Nf=453.0 (UV/MS(%)=89/84). 2-(4-C3ilorophenyI)-7 4-methyIbenzyI)-7 (piperidin-4-yl)acetamide (47AKU-6) 47AKU-4 (2.38 g; 5 mmol) was dissolved in 50 ml of methanol. K2CO3 (3.5 g; 25 mmol) was added in one portion. After magnetic stirring for 20 hrs, additional K2CO3 (1 g) was added. After 4 hrs magnetic stirring methanol was partly removed by evaporation(40°C). Ethyl acetate (100 ml) and water (100 ml) were added. The phases were separated and the aq. phase was then re-extracted with ethylacetate. The combined organic phases were dried over MgSO 2 4-OUorophenyl)-N-(4-methylbeiizyl)-N-(l-isopropylpiperidin-4-yi)-acetamide (47AKU-7) 47AKU-6 (358 ing, 1,0 mmol) was dissolved in 20 ml of acetonitriie, Triethylamine (1.4 ml, 10 mmol) was added and mixture was stirred for 10 mm. Isopropyl bromide (370 mg, 3.0 mmol) was dissolved in 5 ml of acetonitriie and added to the reaction mixturewhich was stirred at room temp, for 20 hrs and then heated to 60°C for 4 hrs. After cooling, ethylacetate (25 ml) and water (25 ml) were added The phases were separated and die aq. phase was then re-extracted with etbylacetate. The combined organic phases were washed with brine, dried over MgSO4 and concentrated(40°C) giving 362 mg of crude product Purification by flash chromatograpby (0-10% methanol in dichloromethane) and HCl-precipitan'on from 2M HCl/diethyl ether in dichloromethane/heptane gave 76 mg (18%) 47AKU-7. TLC (10% methanol in dichloromcthane): Rf •= 0.4. Mp = 223-224°C. HPLC-MS (Method A): M = 399.1 (UV/MS(%)= 100/99). 'H-NMR (400 MHz, CDCI3): 6= 7.03-7.29 97 WO 01/66521 PCT/US01/07187 (8H, m); AM (1H, m); 4.61 (2H, m); 3.58 (2H, m); 3.37 (3H, m); 2.82 (2H, m); 2.64 (2H, m); 2.34 (3H, s); 1.80 (2H,m); 1.39 (6H, d). l3C-NMR (CDC13): 5= 172.4, 137.4, 134.8,133.3, 133.1, 130.4,129.9,129.0, 125.8, 58.0, 49.5, 48.2, 46.6,40.4, 26.0,21.2,17.0. Example 101 - 2-(4-Chloropheny!)- V-(4-methylbenzyl)-Af- 47AKU-6 (358 mg, l.Ommol) was dissolved in 20 ml of acetonitrile. Triethylamine (1.4 ml, 10 mrnol) was added and the mixture was stirred for 10 min. Ethyl bromide (370 ul, 5.0 mnwl) was added. The mixture was then heated to 50°C and stirred overnight. After cooling, water (25 ml) and ethylacetate (25 ml) were added. The phases were separated and the aq. phase was re-extracted with ethylacetate. The combined organic phases were washed with brine and dried over MgSC>4. Evaporation(40°C) yielded 406 mg of crude product. Purification by ion exchange chromatography (washout with 10% aq. NHjOH (25%) in methanol) gave 166 mg (43%) 47AKU-12. The HCl-!>alt was prepared from 2M HO/diethylether in dicbloromethane/heptane. TLC (10% methanol in dichloromethane): Rf = 0.5. HPLC-MS (Method A): M = 385.1 (UV/MS(%)=100/99). lH-NMR (400 MHz, CDC13, rotamers): 5= 7.02-7.34 (8H, m); 4.62 (1H, m); 4.46 and 4.53 (2H, 2s); 3.81 (1H, s); 3.55 (2H, s); 2.92 (2H, m); 2.34 (3H, s); 2 9 (1H, s); 1.98 (2H, m); 1.52-1.84 (4H, m); 1.03 (3H, t). I3C-NMR(CDa3):2i= 171.7,137.2, 135.4,133.9, 132.8,130.4, 129.7, 128.9,125.8, 52.8, 52.4,46.5, 40.8, 31.2,29.8, 21 , 12.4. Example 102 - 2-Pbe&yK7V 4-metfayIbenzyl)- - 47AKU-5 (218mg, 1.0 mmol) was dissolved in 2 ml of dichlorometiiaDe in a 50-ml flask.l'baryiacetyl chloride (13-4 pi, 1.0mmol) was added:1 After3"nts stnring at room temp, mixture was concentrated on Rotavapor (40°Q. Crude product was purified by ion exchange chromatography (washout with 10% aq. NHiOH (25%) in methanol) and flash chromatography ('3-10% methanol in dichloromethane) giving 48 mg (14%) 47AKU-13. HCl-salt was prepared from 2M HCl/diethylether in dichtorome&ane/heptaiie. TLC (10% methanol in dichloromethane): Rf 0.4. HPLC-MS (Memod A): M = 337.1 (UV/MS(%>=98/98). !H-NMR (400 MHz, CDCI3, rotamers): 5= 7.01-7.40 (9H, m); 4.63 (1H, m); 4.53 and 4.45 (2H, 2s); 3.85 and 3.61 (2H, 2s); 2.86 and 2.77 (2H, 2m); 2.35 and 2.29 (3H, 2s); 2.25 and 2.20 (3H, 2s); 2.09 98 WO 01/66521 PCT/US01/07I87 (2H,m); 1.61-1.86 (4H, m). 13C-N]vtR (CDC13): 5= 172.2, 137.1, 135.5,129.7,128.9, 128.8,127.2,126.9,125.8,55.3,51.6,46.6,46.1,41.6,29.5,21.2. Example 103 - 2-(4-Chlorophenyl)-AH4-niethylbenzyI)-Ar-(l-methylpiperidin-4-yl)-acetamide(47AiaJ-8) 4-(4-MethyIbenzylamino)-1 -methyl-piperidine (47AKU-5) l-Methyl-4-piperidone (1.13 g, 10 mmol) was dissolved in 20 ml of methanol and added to a 100 ml flask. 4-MemylbenzyIamine (1.21 g, 10 mmol) in 10 ml of methanol was added. Acetic acid (-1.5 ml) was added until pH 5. NaCNBH3 (1.26 g, 20 mmol) was slowly added. After 20 hrs magnetic stirring methanol was partly removed on Rotavapor (40°C). Dicliloromethane, water and 2M NaOH were added until pH l 0. The phases were separated and aq. phase was extracted twice with dichloromethane. The combined organic phases were washed with brine and dried over MgSO4. Concentration on Rotavapor (40cC) yielded 2.06 g crude (93%) 47AKU-5. TLC (20% methanol in dichloromethane): Rr = 0.3. HPLC-MS (Method A):M =219.1 (UV/MS(%)=89/98). 2-(4-ChlorophenyI)-N-(4-methyIbenzyI)-N-(l-methylpiperidin-4-yl)-acetamide (47AKU-8) 47AKU-5 (437 ing, 2.0 mmol) was dissolved in 10 ml of dichloromethane in a 50 ml flask. Triethylamine (280 JJJ, 2.0 mmol) was added and the mixture was cooled to 0°C on an ice bath and stirred for 10 min. 4-Chlorophcnylacetyl chloride (380 mg, 2.0 mmol) was dissolved in 10 ml of dichforomethaoe and added to the cooled mixture. After 2 hrs stirring al room temp, additional dichJoromethane (10 ml) and water (20 ml) were added. The phases were separated and the aq. phase was re-extracted with dichloromethane. The combined organic phases were dried over MgSO4 and concentrated on the Rotavapor (40°C) giving 755 mg of crude product Purification by flash chromatography (0-10% methanol in dichloromethane) gave 485 mg (65%) product Further purification by ion exchange chromatography (washout with 10% aq. NH4OH (25%) in mettianol) gave 239 mg (32%) 47AKU-8. The HC1-salt was prepared from 2M HCI/diethyiether in dichlorometfaane/heptane. TLC (10% methanol in dichloromethane): Rf = 0.4. Mp = 217-219°C. HPLC-MS (Method A): M = 371.1 (UV/MS(%)=99/99). 'H-NMR (400 MHz, CD3OD): 5= 7.05-7.39 (8H, m); 4.80 (3H, s); 4.62 + 4.56 (2H, 2s); 4.35 (1H, m); 4.00 (1H, s); 3.71 (1H, s); 3.46 99 WO 01/66521 PCT/US01/07187 (2H, m); 3.06 (2H, m); 2.80 (3H, s); 2.32 + 2.27 (3H, 2s); 2.19 (lH n) 13C-NMR (CD3OD): 5= 173.0,137.5,134.5,133.9,132.6,130.6,129.5,128.5,126.2, 54.0, 51.4, 42.6, 40.2, 31.8, 26.6,19.9. Example 104 - 2-(4-Ch]orophenyI>- -(4-methyIbenzyI)-iV-{l-cyc1opent>'1piperidin-4-yI)-acetamiide(47AKU-ll) 47AKU-6 (358 mg, 1,0 mmol) was dissolved in 20 ml of acetonitrile. Trietbylamine (1.4 ml, 10 mmol) was added and mixture was stirred for 10 min. Cyclopentylbromide (540 pi, 5.0 mmol) was added and the mixture was stirred at room temp. After 20 hrs the mixture was heated to 50°C for an additional 24 hrs. The reaction mixture was then cooled and water (25 ml) and ethylacetate (25 ml) were added. The phases were separated and the aq. phase was re-extracted with ethylacetate. The combined organic jihases were washed with brine and dried over MgSO<. concentration on rotavapor yielded mg of crude product. purification by ion exchange chromatography with aq. nh4oh in methanol and flash dichlorometfaane gave the hcl-salt was prepared from hcl dichloromethane tlc rf hplc-ms a m="425.1" mhz cdci3 rotamers s> Example 105 - 2H4-Rouropfaeny9-AK4-raethyn>enzyI)-A-(l-metfcyipiperidm-4-yI)-acetamide (47AKU-14) 47AKU-S (218mg, 1.0 mmol) was dissolved in 3 ml of dichloromethane in a 50 ml flask. 4-FIuorophenyIacetyl chloride (150 pi, 1.1 mmol) was added. After 4 hrs stirring at room temp, the mixture was concentrated on Rotavapor (40°C). The crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 243 mg (68%) 47AKU-14. The HCI-salt was prepared from 2M HCl/diethyletber in dichlorornethane/lieptane. TLC (10% methanol in dichloromethane): Rf = 0.5. HPLC-MS (Method A): M = 355.1 (UV/MS(%)=100/100). 'H-NMR (400 MHz, CDC13): 5= 6.92-7.33 (8H, m); 4.73 100 WO 01/66521 PCT/US01/07187 (IH, m); 4.52 (2H, s); 3.56 (2H, 2s); 3.44 (5H, m); 3.25 (2H, m); 2.52-2.67 (4H, m); 2.33 (3H, s). 13C-NMR (CDC13): 5= 172.5,163.3, 160.9, 139.5, 134.8,130.6, 129.8, 125.8, 115.8, 54.6, 50.8,49.9,46.7,40.4,27.2, 21.2. Example 106 - 2 4-A44-methylbenzyI>-;V-{l-(2-bydroxyetbyl>piperidin-4-yl)-acetaiiude(47AKlM8) 47AKU-6-2 (358 mg, 1,0 mmol) was dissolved in 10 ml ofacctonitrilcin 50 ml flask. Tri ethyl amine (1.4 ml, 10 mmol) was added and mixture was stirred for 10 min. 2-Bromoethanol (215 ui, 3.0 mmol) was added Reaction mixture was then heated to 60°C and stirred overnight. After cooling ethylacetate (25 ml) and water (25 ml) were added. Phases were separated and aq. phase was re-extracted with ethylacetate. Combined organic phases were washed with brine, dried over MgSC>4 and concentrated on Rotavapor (40°C) giving 406 mg crude product. Purification by flash chromatography (0-10% methanol in dichloromethane) afforded 253 mg (63%) 47AKU-18. HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC (10% methanol in dichJoromethane): R = 0.4. HPLC-MS (Method A): M = 401.1 (UV/MS(%)=100/100). 'H-NMR (400 MHz, CDC13, rotamers): 5- 7.04-7.34 (8H, m); 4.60 (IH, m); 4.52 and 4.45 (2H, 2s); 3.55 (4H, m); 3.03 (IH, bs); 2.92 (2H, m); 2.52 (2H, m); 2.36 and 231 (3H, 2s); 2.19 (2H, m); 1.66 (4H, m).). 13C-KMR (CDClj): 5= 171.7,1373,135J2, 133.8,132.9,130.4,129.8, 128.9,125.8, 59.4,58.1, 53.1,52.3,46.8, 40.8,29.7,21.2. Example 107 - 2-(4-Ch Jorophcny I>A'--acctainide (47AKU-19) l-Cyclobrtyi-4 npcridone (47AKU-1S) Partly dissolved quartenary salt (1.23 g, 3.7 mmol) (prepared according to the procedure outlined in the synthesis of 47AKU-47) was slowly added to a rcfluxing solution of Cyclobutylamine (178 nig, 2.5 mmol) and Potassium carbonate (48 mg, 0.34 mmol) in ethanol. The mixture was refhixed for 1.5 hrs. After cooling to room temp, water (10 ml) and dicMoromethane (25 ml) were added. Phases were separated and aq. phase was re-extracted with dichloromethane- Combined organic phases were dried over MgSO4 and concentrated on Rotavapor (40°Q giving 419 mg crude 47AKU-1S. TLC (10% methanol in dichloromethane): Rf = 0.4. HPLC-MS (Method A): M = 154.1 (MS(%)=75). 101 WO 01/66521 PCT/US01/07187 4-(4-MethyIbenzylamino)-]-cyclobutyl-pipCTidiiie(47AKU-16) 4-Methylbenzylamine (215 ing, 1.8 mmol) was dissolved in 5 ml methanol and placed in 50 ml flask. 47AKU-15 (270 mg, 1.8 mmol) in 5 ml methanol was added. Acetic acid (0.3 ml) was addisd until pH 5. NaCNBH3 (226 mg, 3.6 mmol) was slowly added. Gas evolution observed. After 24 hrs magnetic stilling dichloromethane, 2M NaOH and water were added until pH 10. Phases were separated and aq. phase was then re-extracted with dichloromethane. Combined organic phases were dried over MgSO4 and concentrated on Rotavapor (40°C) yielding 419 mg crude 47AKU-16. TLC (10% methanol in dichloromethane): Rf = 0.3. HPLC-MS (Method A): M = 259.1 (UV/MS(%) 44/87). 2-(4-Chlorophenyl)-N-(4-melhylbenzyl)-N-(l-cyclobutylpiperidm-4-yl)-acetamidc (47AKU-19) 47AKU-16 (209 mg, 0.8 mraol) was placed in 50 ml flask and 5 ml dichloromethane was added. 4-Chlorophenylacetyl chlonde (171 mg, 0.9 mmol) in 5 ml dichloromethane was added. After 5 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 101 mg (31%) product. Further purification by ion exchange chromatography (washout with 10% aq. NH4OH (25%) in methanol) gave 55 mg (17%) 47AKU-19. Oxalate-salt was prepared from Oxalic acid (1.1 cq) in dichloromethame/ heptane. TLC (10% methanol in dichloromethane): R, = 0.6. HPLC-MS (Method B): M = 411.2 (UV/MS(%)==91/86). 'H-NMR (400 MHz, CDCU, retainers): S= 7.33-7.01 (8H, m); 4.62 (1H, m); 4.52 and 4.46 (2H, 2s); 3.80 (1H, s); 3.45 and 3.54 (2H, 2s); 2.86 (2H, m); 2.66 (2H, m); 2.28 and 234 (3H, 2s); 13$ (2H, m); 1.80 (2H, m); 1.70-1.52 (6H n). "C-NMR (CDa3): 5= 171.7,137.2,135.4,133.9,1323,130.4,129.7,128.9,125.7,60.4; 523. 49.4, 46.5,40.7,29.4,27.6,21.2, 14.2. Example 108 - 2-p hen yI>.V-(4-methyl ben zyl)-AKl cydobatylpiperidiB-4-yI)acetamide (47AKU-20) 47AKU-16 (209 mg, 0.8 mmol) was placed in 50 ml flask and 5 ml dichloromethane was added. 4-Methoxyphcnylacetyl chloride (167 mg, 0.9 mmol) in 5 ml dictJorometbane was added. After 5 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°Q. Crude product was purified by flash chromatograpby (0-10% methanol in dichloromethane) giving 72 mg (22%) product 102 WO 01/66521 PCTAJS01/07187 Further purification by ion exchange chromatography (washout with 10% aq. NH4OH (25%) in methanol) gave 67 mg (20%) 47AKU-20. Oxalate-salt was prepared from Oxalic acid (1.1 eq) in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf = 0.6. HPLC-MS (Method B): M = 407.3 (UV/MS(%)=93/77). 'H-NMR (400 MHz, CDCI3, rotamers): 6= 7.26-6.79 (SH, m); 4.62 (1H, m); 4.52 and 4.45 (2H, 2s); 3.79 (1H, m); 3.77 (3H, s); 3.52 and 3.45 (2H, 2s); 2.84 (2H, m); 2.66 (2H, m); 2.34 and 2.28 (3H, 2s); 1.98 (2H, m); 1.81 (2H, m); 1.72-1.51 (6H,m). 13C-NMR(CDa3): 5= 172.5,158.7,137.0,135.7, 130.4, 129.8, 127.4, 125.8,114.3, 60.4, 55.5, 52.1,49.4, 46.4, 40.6,29.4, 27.6,21.2,14.2. Example 109 - (47AKU-21) 2-(4-Metboxypbeoyl)-;V-(4-methylbenzyJ)-Ar-(tropin-4-yI)acetamide (47AKU-21) 4-(4-Methylbenzylamino)-tropane (47AKU-17) 4-MethyIbenzylamine (607 mg, 5.0 mmol) was dissolved in 10 ml methanol and placed in 100 ml flask. Tropinone (697 mg, 5.0 mmol) in 10 ml methanol was added. Acetic acid (0.75 ml) was added until pH 5. NaCNBH3 (628 mg, 10 mmol) was slowly added. Gas evolution observed. After 20 hrs magnetic stirring dichloromethane, 2M NaOH and waier were added until pH-10. Phases were separated and aq. phase was then re-extracted with dichloromethane. Combined organic phases were dried over MgSO . Concentration on Rotavapor (40°Q yielded 1.14 g crude 47AKU-17. TLC (10% methanol in dichloromethane): R = 0.4. HPLC-MS (Method A): M = 245.2 {UV/MJH%>=65/96). 2 4-Methoxyphenyl)-N-(4-memyIbenzyI)-NKtropm-4-yl)-acetamidc (47AKU-21) 47AKU-17 (244 mg, 1.0 mmol) was placed in 50 ml flask and 5 ml dichloromethane was added. 4-Methoxyphenylacetyl chloride (203 mg, 1.1 mmol) in 10 ml dichloromethane was added. After 3 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°Q. Crude product was purified by ion exchange chromatography (washout with 10% aq. NH OH (25%) in methanol) and flash chromatography (0-10% methanol in dichloromethane) giving 202 mg (51 %) 47AKU-21. Oxalate-salt was prepared from Oxalic acid (1.1 eq) in dichloromethane/heptane. TLC (10% methanol in dichloromethane): R = 0.4. HPLC-MS (Method B): M% 393.3 (UV/MS(%)=94/92). !H-NMR (400 MHz, CDCb, isomers): 5= 7.02-7.17 (6H, m); 6.78-6.87 (2H, m); 4.74 (1H, s); 4.44 (1H, s); 3.78 103 WO 01/66521 PCT/US01/07I87 and 3.77 (3H, 2s); 3.68 (1H, m); 3.66 and 3.55 (3H, 2s); 2.65 (2H, m); 2.56 (2H, m); 2.32 (3H, s); 2.12-2.26 (6H, m); 2.05 (2H, m). 13C-NMR (CDC13): S= 173.2,171.4, 158.8,137.1, 129.7,127.6,126.9,126.0,114.4, 63.4, 60.9, 55.5, 54 6, 47.5, 41.5, 40.4, 32.8, 31.1, 27.5, 24.9, 21.2. Example 110 - A-(4-MethyIbenzyI)-A'-(l-mcthyIpiperidin-4-yl)-Ar'-beii2yI-carbamide (47AKU-22) 47AKU-5 (219 mg, l.OmmoI) was dissolved in 5 ml dichloromethane and placed in 50 ml flask. Benzylisocyanate (160 mg, 1.2 mmol) in 5 ml dichloromethane was added. After 16 his magnetic stiining the reaction mixture was concentrated on Rotavapor (40°Q. Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 236 mg (67%) 47AKU-22. Oxalate-salt was prepared from Oxalic acid (1.1 eq) in dichlorom ethane/heptane. TLC (10% methanol in dichloromethane): R/= 0.5. HPLC-MS (Method B): M = 352.3 (UV/MS(%)=100/100). 'H-NMR (400 MHz, CDCI3): 6= 7.26-7.02 (9H, m); 4.61 (1H, m); 4.41 (1H, m); 4.33 (4H, m); 2.87 (2H, m); 2.32 (3H, s); 2.25 (3H, s); 2.09 (2H,m); 1.79-1.62 (4H,m). I3C-NMR(CDC13) 5= 158.6,139.7,137.3,135.4,129.8, 128.6, 127.4, 127.2, 126.2, 55.5, 52.2, 46.2,45.8, 45.0, 30.2, 21.2. Example 111 - Ar-(4-MethylbenzyI)-AL(l-niethylpiperidin-4-yl)-7Vr-pbenyl carbamide (47AKU-24) 47AKU-5 (219 mg, 1.0 mmol) was dissolved in 5 ml dichloromethane and placed in 50 ml flask. Phenylisocyanale (143 mg, 1.2 mmol) in 5 ml dichloromethane was added. After 4 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was. purified by flash chromatograpby (0-10% methanol in dichloromethane) giving 181 mg (54%) 47AKU-24. HCI-saxt was prepared from 2M HCl/dietbyJethex in dichloroxnethane/heptane 3XC (10% methanol in dichloromethane): Rf •= 0.4. HPLC-MS (Method A): M = 338.3 (UV/MS(%)=100/100). 'H-NMR (400 MHz, CDC13): 5= 7.12-7.24 (8H, m); 6.93-6.98 (1H, m); 6.26 (1H, s); 4.45 (3H, s); 2.90 (2H, d); 2.36 (3H, s); 2.28 (3H, s); 2.12 (2H,m); 1.69-1.85 (4H,m). I3C-NMP.(CDQ3): 6= 156.1,139.3,137.8,134.9,130.1, 128.9, 1263, 123.1,119.9, 55.5, 52.3, 46.3, 46.2, 30.3, 213. 104 WO 01/66521 PCTAJS01/07187 Example 112 - Ar-l henetbyl-Ar--Ar'-ben2yl-carbamide (47AKU-25) 4-(2-Phenyletoyl)amiiH>-l-methylpiperidine (110 mg, 0.5 mmol) was dissolved in 5 ml dichloromethane and placed in 50 ml flask. Benzylisocyanatc (80 mg, 0.6 mmol) in 5 ml dichloromethane was added. After 20 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatograpby (0-10% methanol in dichloromethane) giving 164 mg (84%) 47AKU-25. HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/beptane. TLC (10% methanol in dichloromethane): Rf 0.4. HPLC-MS (Method A): M = 3523 (UV/MS(%)= 100/100). 'H-NMR (400 MHz, CDC13): 5= 7.34-7.09 (10H, m); 4.52 (1H, m); 4.35 (2H, d); 4.08 (1H, m); 3.33 (2H, t); 2.92 (2H, m); 2.82 (2H, t); 2.28 (3H, s); 2.07 (2H, m); 1 84-1.66 (4H, m). I3C-NMR (CDC13): 5= 157.9, 139.8,139.1, 129.0,128.9,128.8, 127.8,127.4, 126.9, 55.7, 52.8, 46.2, 45.3,44.8,37.5,30.6. Example 113 - 2-PhenyI-7Nr-(4-metho>r>benzyI)-7V-(l-methylpiperidin-4-yI)-acctamide (47AKU-26a) 50ELH-18 (118 mg, 0.5 mmol) was dissolved in 5 ml dichloromethane in 50 ml flask. 4-Fmoropbenylacctyl chloride (104 mg, 0.6 mmol) was added. After 20 hrs stirring at room temp, mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 87 mg (49%) 47AKU-26 . HCl-saH was prepared from 2M HCl/dicthylethcr in dichloromethane/ heptane. HPLC-MS (Method A): M = 353.1 (UV/MS(%)=96V88). Example 114 - 2-(4-Trintioroincthylphenyl)-iV-(4-raetho3r)'benzyI)-iV-(l-metbylpiperidiB-4-y])-acetamidf! (47AKU-26b) 50ELH-18 (118 mg, 0.5 mmol) was dissolved in 5 ml dichloromethane in 50 ml flask. 4-TriihiOTDmethyiphenylacetyl chloride (134 mg, 0.6 mmol) was added After 20 hrs stirring at room temp, mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 81 mg (39%) 47AKU-26b. HCl-salt was prepared from 2M HCl/diethylether 105 WO 01/66521 PCTAJS01/07187 in dichloromethane/heptane. HPLC-MS (Method A): M = 421.1 (UV/MS(%)=90/100). Example 115 - 2-(4-Flooropbenyl)-JV-(4-niethoxybeiizyl)-7V-(l-metbylpiperidin-4-yl)-acetamide(47AKU-26c) 50ELH-18 (118 mg, 0.5 mmol) was dissolved in 5 ml dichloromethane in 50 ml flask. 4-FIuorophenylacetyl chloride (104 nig, 0.6 mmol) was added. After 20 hrs stirring at room temp, mixture was concentrated on Rotavapor (40°Q. Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 68 mg (37%) 47AKU-26c. HQ-salt was prepared from 2M HCl/diethylether in dichloromethane/heptane. HPLC-MS (Method A): M = 371.1 (UV/MS(%) 100/97). Example 116 - 2-(4-MethoxyphenyI)-Ar-(4-methoxybenzyl)-A'-(l-me(bylpiperidiD-4-yl)-acetaniide(47AKU-26d) 50ELH-18 (118 mg, 0.5 mmol) was dissolved in 5 ml dichloromethane in 50 ml flask. 4-Methoxyphenylacetylchloride (111 mg, 0.6 mmol) was added. Aiter 20 hrs stirring at room temp, mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-10% methanol in dichJoromethane) giving 77 mg (40%) 47AKU-26d. HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/heptane. HPLC-MS (Method A): M = 383.1 (UV/MS(%)=100/100). Example 117 - 2-(4-Metbylpbenyl>7V-{4-ch]orobenzyl)-7V-{l-metbyipiperidin-4-yI)-acetainide (4 7AKU-28) 4-(4-CbJorobenzylaiiiino)-l-me&yl-piperidme (47AKU-27) 1 -Methyl-4-piperidone (566 nig, 5.0 mmol) was dissolved in 10 ml methanol and placed in 200 ml flask. 4-Chlorobenzylamine (708 mg, 5.0 mmol) was added. Mixture was stirred and Acetic acid (-0.75 ml) was added until pH 5. NaCNBH3 (628 mg, 10 mmol) was slowly added. Gas evolution observed. After magnetic stirring for 16 hrs methanol was partly removed on Rotavapor (40°C). Dichloromethane, 2M NaOH and water were added until pH 10. Phases were separated and aq. phase was then re-extracted with dichloromethane. Combined organic phases were dried over MgSCU. Concentration on Rotavapor (40°C) yielded 1.14 g crude 47AKU-27. TLC (10% methanol in dichloromethane): Rf = 0.3. HPLC-MS (Method A): M = 239.1 (MS(%)-96). 106 WO 01/66521 PCT/US01/07187 2-(4-Methylphenyl)-N-(4-c1ilorobenzyl)-N-(]-methylpiperidin-4-yl)-acetamidc (47AKU-28) p-Tolylacetic acid (1.50 g) was dissolved in 10 ml thionylchloride and placed in 50 ml flask. Mixture was heated to reflux for 2 hrs and then concentrated on Rotavapor (40°C). p-Tolylacetic chloride (202 mg, 1.2 mmol) in 5 ml dichloromethane was added to 47AKU-27 (239 mg, 1.0 nunol) in 5 ml dichloromethane. After 4 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 104 mg (28%) 47AKU-28. HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/ heptane. TLC (10% methanol in dichloromethane): Rf= 0.5. HPLC-MS (Method A): M = 371.1 (UV/MS(%)=100/90). 'H-NMR (400 MHz; CDC13, rotamers): 6= 7.34-6.99 (SH, m); 4.57 (1H, m); 4.50 and 4.44 (2H, 2s); 3.80 (1H, s); 3.55 (1H, s); 2.96 and 2.82 (2H, 2m); 2.34 (1H, m); 2.32 (3H, s); 2.24 and 2.15 (3H, 2s); 1.91 (lH,m); l.Sl-1.59(4H,m). 13C-NMR(CDC13):S= 172.5,138.2, 136.8, 133.4,131.8,129.7,129.2,128.6,127.4,54.9, 51.3,46.7, 41.3, 30.6,28.6, 21.2. Example 118 - 2- 42ELH-77 (41 mg, 0.1 mmol) was dissolved in 1 ml dry dichloromethane and placed in oven-dried 10 ml flask. Mixture was cooled to -78°C on a dry-ice/isupropanol bath. Borontribromide (1.0 M in dkhloromcfliane, 150 nU 0.15 mmol) was slowry added at -78°C. Ice-bath was removed and mixture was left at room temp, for 2 hrs. Water (3 ml) and saturated NaCI (aq.) were added and aq. phase was extracted with dichloromethane, ethylacetate and n-butanol. Combined organic phases were dried over MgSO4 and concentrated on Rotavapor (40°Q. Crude product was purified by flash chrotnatography (0-20% methanol in dichloromethane) giving 22 mg (63%) 47AKD-29. HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf = 0.3. HPLC-MS (Method A): M = 353.2 (UV/MS(%)=100/100). -NMR (400 MHz, CDCI3, rotamers): 5= 7.07-6.60 (8H, m); 4.48 (1H, m); 4.39 (2H, s); 3.76 and 3.66 (4H, 2bs); 107 WO 01/66521 PCT/US01/07187 3.41 (2H, s); 3.08 (2H, m); 2.49 (1H, m); 2.42 (2H, bs); 2.22 and 2.16 (3HT 2s); 1.96-1.82 (2H, m); 1.66-1.56 (lH,m). 13C-NMR (CDCb): 5= 173.7, 156.0,137.3,134.6, 129.7, 129.6, 125.7,125.4,115.7, 54.4,50.4, 46.8,44.0,40.5, 27.3,20.9. Example 119 - JV-Phenethyl-JV--JV'-phenyl-carbamide (47AKU-30) 4-{2-Phenylethyl)ammo-l-methylpiperidine (110 it"g, 0.5 mmol) was dissolved in 5 ml dichloromethane mi placed in 50 ml flask. Phetiylisocyanate (71 mg, 0.6 mmol) in 5 ml dichloromethane was added. After 16 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified twice by ilash chrpmatography (0-10% methanol in dichloromethane) giving 131 mg (78%) 47AKU-30. HCl-salt was prq)ared fit>m 2M HCl/diethyJether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf= 0.4. HPLC-MS (Method A): M = 338.1 (UV/MS(%)=99/100). H-NMR (400 MHz, CDC13): 6= 7.36-6.93 (10H, m); 6.24 (1H, s); 4J1 (1H, m); 3.50 (2H, t); 3.20 (2H, d); 2.89 (2H, t); 2.57 (2H, m); 2.50 (3H, s); 2-26 (2Rt m); 1.79 (2H, m). 13C-NMR (CDC13): 5= 155.8,139.2,139.0,129.4,129.3, 12S.9,127.3,123.2,120.4, 54.9, 51.3,45.5,44.3, 37.6,28.3. Example 120 - A'- 4 3-Phenylpropy])atniiK)-l-memylpiperidine(l 60 mg. 0.7 mmol) was dissolved in 5 ml dichloromethane and placed m 50 nil flask. Benzylisocyanate (107 mg, 0.8 mmol) in 5 ml dichloromethane was added. After 2 his magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified twice by flash cbxomatography (0-10% methanol m dichlaromethane) giving 156 mg (61%) 47AKU-31. Hd-salt was preparaJ fiom 2M HO/diemyfctha in dicbloromethane/heptane. TLC (10% methanol in dichloromethane): Rf = 0.3. HPLC-MS (Method A): M = 366.1 (UV/MS(%)=100/100). 'H-KMR (400 MHz, CDClj): 6= 734-7.07 (10H, m); 4.33 (3H, m); 4.14 (1H, m); 3.04 (2H, m); 2.89 (2H, d); 2.57 (2H, t); 2.28 (3H, s); 2.06 (2H, m); 1.87 (2H, m); 1.75-1.62 (4H, m). 13C-NMR (CDCU): 5= 157.5,141.0,140.0,129.0, 128.6,1283,128.0, 127.6,126.6, 55.6,52.1,463, 45.1.41.6,33.4,32.2,30.6. 108 WO 01/66521 PCTAJS01/O7J87 Example 121 - Ar-(3-PbenylpropyI)-7V-(l-methyJpiperidin-4-y])-JV'-phenyI-carbamide (47AKU-32) 4-(3-Phenylpropyl)amino-l-methylpipcridine (160 mg, 0.7 mmol) was dissolved in 5 ml dichlaronaethane and placed in 50 ml flask. Phenyhsocyanate (95 mg, 0.8 mmol) in 5 ml dichlorometbane was added. After 20 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 106 mg (43%) 47AKU-32. HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC (10% methanol in dichJoromethane): Rf = 0.3. HPLC-MS (Method A): M = 352.1 (UV/MS(%)=100/100). ]H-NMR (400 MHz, CDC13): &= 7.35-6.95 (10H, tn); 5.99 (1H, s); 4.18 (1H, m); 3.17 (2H, t); 2.91 (2H, d); 2.65 (2H, t); 2.28 (3H, s); 2.07 (2H, m); 1.97 (2H, m); 1.81-1.66 (4H, m). I3C-NMR(CDC13): 5= 154.9,141.0,139.3,129.2,129.0,129A 126.8,123.1, 120.0,55.6,52.2, 46.2, 41.8,33.4,32.3,30.6. Example 122 - 2-(4-Methoiyphenyl)-2,2-etbyIene-AK4-niethylbeDzy!)-A'-(l-metbylpiperidin-4-yI) acetamide (47AKU-33) l-(4-Methoxyphenyl)-l-cyclopropane carboxylic acid (230 mg, 1.2 mmol) was dissolved in 2 ml thionylchloride and placed in 50 ml flask. Mixture was heated to reflux for 2 hrs and then concentrated on Rotavapor (40°Q. Tee acid chloride (250 mg, 12 mmol) in 5 ml dichloromethane was added to 47AKU-5 (220 mg, 1.0 mmol) in 5 ml dichloromethane. After 2 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°Q. Crude product was purified twice by flash chromatography (0-10% methanol in dichloromethane) giving 201 mg (51%) 47AKD-33. HCl-salt was prepared from 2M HO/'diethYiether in dichlotomethane/heptane. TLC (10% methanol in dichloromethane): Rf = 0.6. HPLC-MS (Method A): M = 3932 (UV/MS(%)-95/88). lH-NMR (400 MHz, CDCI3, retainers): 8= 7J22-6.70 (8H, m); 4.44 (2H, s); 4 6 (1H, m); 3.74 (3H, s); 3.12 and 2-89 (2H, 2m); 2 1 (1H, m); 2.32 (3H. m); 226 (3H, s); 2.08-1.52 (4H, m); 1.36 (2H, bs); 1.15-0.95 (3H, m). "C-NMR 109 WO 01/66521 PCTAJS01/07187 Example 123 - 2-(4-MethoxyphenyI>- -(I-phenylethy))-Ar-(i-metbylpiperidin-4-yI) acetamide (47AKU-37) 4-Alpha-mcthylbcnzylamin(>-l-mcthy]-piperidine(47AKU-36) DL-Phenylethylamine (606 mg, 5.0 mmol) was dissolved in 10 ml methanol and l-MethyI-4-piperidone (566 mg, 5.0 mmol) in 10 ml methanol was added Mixture was stirred and Acetic acid (-0.75 ml) was added until pH 5. NaCNBH3 (628 g, 10 mmol) was slowly added. Gas evolution observed. After magnetic stirring for 20 hrs methanol was partly removed on Rotavapor (40°C). Ethylacetate, 2M NaOH and water were added until pH 10. Phases were separated and aq. phase was then re-extracted with ethylacetate and dichloromethane. Combined organic phases were dried overMgSCV Concentration on Rotavapor (40°C) yielded 838 mg crude 47AKU-36. TLC (10% methanol in dichloromethane): Rf = 0.3. HPLC-MS (Method A): M " 219.1 (UWMS(%)=100/94). 2-(4-Methoxyphenyl)-N-alpha-methylbenzyl-N-(l-methylpiperidin-4-yl) acetamide (47AKU-37) 47AKU-36(218mg, 1.0 mmol) was dissolved in 10 ml dichlorometbane and placed in 50 ml flask. 4-Methoxyphenylacetyl chloride (185 mg, 1.2 mmol) in 10 ml dichloromethane was added. After 16 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 256 mg (70%) 47AKU-37. HCl-salt was prepared from 2M HCl/diethylether in dichloTomcthane/beptanc TLC (10% methanol in dichloromethane): Rf= 0.5. HPLC-MS (Method A): M = 3673 (\JV/MS(%y=l(W99)- 'H-NMR (400 MHz, CDCI3, retainers): 5= 734-7.06 (7H, m); 6.84 (2H, d); 5.10 (1H, m); 3.77 (3H, s); 3.67 (2H, m); 3.17 (IH, m); 3.03-2.75 (3H, m); 2.64 (3H, s); 2.38 (2H, m); 1.77-1.05 (6H, m). I3C-NMR (CDC13): 5= 172.0,158.9,139.9, 130.0, 129-0, 128.2,127.1, 114.5, 55.5,53.1, 51.4,42.4, 41.3, 31.1,29.5, 24.9, 18.1. Example 124 - 2 MethbxypbenyI)- -(4-methylbeDzyl)-AK3-tn>P -4-ji) acetamide (47AKU-39) 4-MethyIbenzjdimmo-tiopane (47AKU-38) 4-Methylbenzylamine(1.21 g, lOmmoI) andTropinone(139g, lOmmol) were placed in 100 ml flask and dissolved in 50 ml toluene. Mixture was heated to reflux for 3 hrs and water was removed using a Dean/Stark water-separator. Crude 110 WO 01/66521 PCIYUS01/07187 product was concentrated onRotavapor (40°C) giving 47AKU-38. TLC (10% methanol in dichloromethanc): Rf- 0.3. lH-NMR (400 MHz, CDC13, isomers): 7.20-7.09 (4H, m); 4.47 (1H, m); 3.81 (1H, s); 3.42 (1H, m); 3.31 (1H, m); 2.77- 2.56 (2H, m); 2.47 and 2.41 (3H, 2s); 2.33 and 231 (3H, 2s); 2.27-1.97 (4H, m); 1.69-1.54 (2H, m). 2-(4-Methoxyphenyl>N-(4-methylbeiizyl>N-(3-tropen-4-yl)acetamide (47AKU-39) 47AKU-38 (242 ing, 1.0 mmol) was dissolved in 5 ml dichloromethanc and placed in 50 ml flask. 4-Methoxyphenylacetyl chloride (185 mg, 1.2 mmol) in 10 ml dichloromethane was added. After 16 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-10% methanol ira dichloromethane) giving 69 mg (18%) 47AKU-39. HCl-salt was prepared from 2M HCl/diethylcther in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf = 0.4. HPLC-MS (Method A): M = 391.2 (UV/MS(%>91/86). 'H-NMR (400 MHz, CDCI3, rotamers)- &= 7.22-6.82 (8H, m); 5.41 (1H, bs); 4.71-4.52 (2H, m); 3.78 (3H, s); 3.68 (2H, m); 3.44-3.24 (2H, m); 2.72-2.36 (5Ht m); 232 (3H, s); 2.25-2.00 (2H, m); 1.80-1.54 (2H, m). 13C-NMR (CDCI3): 6= 170.8, 158.7,137.4, 134.9,130.1, 1293,128.9,126.9, 114 , 59.0, 58.0, 55.5, 49.5, 463, 39.7,35.9,33.8,29.7,213. Example 125 - 2-PfaeDyi-2-ctfayWV 4-metbyIbenzyI)-A-(l-metbylprperidnM-ji) acetamide (47AKU-40) 2-PhenyIbmyric acid (197 mg, 1 mmol) was dissolved in 2 ml thionyfchloridcand placed in 50 ml flask. Mixture was heated to reflux for-2 hrs and then concentrated on Rotavapor (50oQ. The acid chloride (1.2 mmol) in 5 ml dichloromethane was added to 47AKU-5 (158 mg, 0.72 mmol) in 5 ml dichloromethane. After 20 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 196 mg (74%) 47AKU-40. HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/ heptane. TLC (10% methanol in dichloromethane): Rf = 0.5. HPLC-MS (Method A): M = 365.4 (UV/MS(%)=99/100). 'H-NMR (400 MHz, CDC13, rotamers): 6= 732-6.98 (8H, m); 4.77 (1H, bs); 4.50 (1H, d); 4.29 (1H, d); 3.43 and 111 WO 01/66521 PCT/US01/07187 3.21 (3H, 2m); 2.72 (2H, m); 2.62 (3H, s); 2.43 (1H, m); 2.32 Example 126- 2-(4-Methoxyphenyl)- -(l-indanyl)-Ar-(l-methylpipcridin-4-yl) acetamide (47AKU-43) 4-0 -lndanamino)-l -methyl-piperidine (47AKU-42) 1 -Aminoindane (666 mg, 5.0 mmol) was dissolved in 10 ml methanol and placed in 100 ml flask. l-Methyl-4-piperidone (566 mg, 5.0 mmol) in 10 ml methanol was added. Mixture was stirred and Acetic acid (-0.75 ml) was added until pH 5. NaCNBHs (628 g, 10 mmol) was slowly added. Gas evolution observed. After magnetic stiiring for 16 hrs methanol was partly removed on Rotavapor (40°C). Dichloromethane, 2M NaOH and water were added until pH l 0. Phases were separated and aq. phase was then re-extracted with ethylacetate and dichloromethane. Combined organic phases were dried over MgSO4. Concentration on Rotavapor (40°C) yielded 1.06 g 47AKU-42. TLC (10% methanol in dichloromethane): Rf = 0.3. HPLC-MS (Method A): M "= 231.1 (UVYMS(%)=72/91). 2-(4-Methoxyphenyl)-N-(l-mdanyl)-N-(l-methylpiperidin-4-yl) acetamide (47AKU-43) 47AKU-42 (230 mg, 1.0 mmol) was dissolved in 10 ml dichloromethane and placed in 50 ml flask. 4-Methoxyphenylacetyl chloride (185 mg, 12 mmol) in 10 ml dichloromethane was added. After 16 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°Q. Ciude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 194 mg (51%) 47AKU-43. HCi-saK was prepared from 2M HCI/diemylether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf = 0.5. HPLC-MS (Method A): M = 379.2 (UV/MS(%>=$4/90). Example 127 - (47AKU-44VV -carbamide (47AKU-44) 47AKU-5 (219 mg, 1.0 mmol) was dissolved in 5 ml dichloromethane and placed in 50 ml flask. 4-MethoxybenzyKsocyanate (196 mg, 1.2 mmol) in 10 ml dichloromethane was added. After 16 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash 112 WO 01/66521 PCT/US01/07187 chromatography (0-10% methanol in dichloromethane) giving 192 mg (50%) 47AKU-44. HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf 0.3. HPLC-MS (Method A): M 382.3 (UV/MS(%>=100/94). 'H-NMR (400 MHz, CDC13): 5= 7.10 (4H, m); 6.98 (2H, m); 6.76 (2H, m); 4.58 (1H, t); 4.45 (1H, m); 4.33 (2H, s); 4.25 (2H, d); 3.76 (3H, s); 2.97 (2H, m); 2.34 (3H, s); 2.32 (3H, s); 2.24 (2H, m); 1.78 (4H, m). 13C-NMR (CDCI3): 6= 158.9,158.5,137.3, 135.2,131.8,129.8,128.8, 126.2, 114.1, 55.5, 55.4, 51.7,45.8,45.7, 44.5,29.7, 21.2. Example 128 - 2-(3,4-dimetboxypbeEyl>A44-methyIbenzyl)-JV-(l-metbylpiperidin-4-yI) a c et amide (47AKU-45) 3,4-DimethoxyphenyIbutyric acid (235 mg, 1.2 mmol) was dissolved in 2 mi thionylchloride and placed in 50 ml flask. Mixture was heated to reflux for 2 hrs and then concentrated on Rotavapor (50°C). The acid chloride (1.2 mmoi) in 5 ml dichloromethane was added to 47AKU-S (219 mg, 1.0 mmol) in 10ml dichloromethane. After 16 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°Q. Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 129 mg (33%) 47AKU-4S. HCl-saK was prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf= 0.4. HPLC-MS (Method A): M = 397.4 (UV/MS(%)=98/89). 'H-NMR (400 MHz, CDCI3, rotamers): 5= 7.17-6.60 (7H, m); 4.75 (1H, m); 4.51 (2H, s); 3.83 (3H, s); 3.79 (3H, s); 3.53 (2H, s); 3.27 (2H, d); 2.65 (2H, t); 2L58 (3H, s); 2.32 (3H, s); 2J24 (2H, m); 1.72 (2H, d). UC-NMR (Cr>Cb): 6= 172 , 1493, 1483,137.4,135.0,129.8, 127.4,125.8,121.0,112.2,111.6, 56.2,36.1, 54.6,49.6,46.7,44.0, 40 , 27.0,212. Example 129 - 2-'phenyI>Ar-Ar-(3-methylpfperidin-4-yI) acetamlde (47AKU-46) 3,4-Methylenedioxyphenylacetic acid (216 mg, 1.2 mmol) was dissolved in 2 ml thionylchloride and placed in 50 ;ml flask. Mixture was heated to reflux for 2 hrs and mol concentrated on Rotavapor (50°C). The acid chloride (1.2 mmol) in 5 ml dicbloromethane was added to 47AKU-5 (219 rug, 1.0 mmol) in 10 ml dichloromethane. After 2 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 188 mg (49%) product. Further purification by 113 WO 01/66521 PCT/US01/07187 ion exchange cbromatography (washout with 10% aq. NH4OH (25%) in methanol) yielded 149 mg (39%) 47AKU-46. HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/ heptane. TLC (10% methanol in dichloromethane): Rf = 0.4. HPLC-MS (Method A): M = 381.2 (UV/MS(%)=96/95). 'H-NMR (400 MHz, CDC13, rotamers): 5- 7.17-7.02 (4H, m); 6.77-6.51 (3H, m); 5.91 and 5.93 (2H, 2s); 4.70 (1H, m); 4.52 and 4.49 (2H, 2s); 3.51 (2H, s); 3.26 (2H, d); 2.49 (3H, s); 2.33 (3H, s); 2.14-1.66 (6H, m) 13C-NMR(CDC13):5= 172.5,148.1,146.8, 137.3,135.1,129.8, 128.6,125.8, 121.9, 109.4, 108.5, 101.2,54.8,50.2,46.7,44.6,41.1,27.7,21.2. Example 130 - 2-(4-Methoxypheny])-A 4-methylbenzyl)-A'- l-BenzyI-4-piperidone(I.89g, 10 mmol) was dissolved in 15 ml acetone. Metbyliodide (0.90 ml, 15 mmol) was slowly added over 5 min. After 2 hrs magnetic stirring additional Methyliodide (1.8 ml, 30 mmo!) was added. After 1 hr magnetic stirring 20 ml diethyl-ether was added. Crude product was collected by filtration and washed with acetone/diethylether. White crystals were dried under vacuum giving 806 mg quartenary salt TLC (10% methanol in dichloromethane): Rf = 0.7. Partly dissolved salt in 5 ml water was added to 50°C hot mixture of t-Butylamine (120 mg, 1.6 mmol) and Potassiumcarbonate (32 mg, 0.22 mmol) in 3 ml ethanol. The resulting mixture was stirred and heated to reflux ( 80°C) for 1 hr. After cooling water (20 ml) and dichloromethane (20 ml) were added. Phases were separated and aq. phase was re-extracted with dichloromethane and ethylaceiate. Combined organic phases were dried ovcx MgSO4 and concentrated cm Roiavapor (40°Q giving 496 mg 47AKU-47. TLC (lOftmeOunol in dicfaloromeftiane): Rf = 0.3; 'H-NMR (400MHz,-CDCi ): 5= 2.82 (4H, t); 2.41 (4H, t); 1.12 (9H, s). 13C-NMR (CDC13): 6= 210SL, 54.3, 46.4, 42.4, 26.6. Crude product contained -25% ('H-NMR) starting material (l-Benzyl-4-pxperidane). 4 4-MeAyn>enzylainmo>l4-buryl-prperidine (47AKU-48) 4-MethyIbenzylamme (268 mg, 2.2 mmol) was dissolved in 5 ml methanol and placed in 50 ml flask. 47AKU-47 (305 mg, 2.0 mmol) in 5 ml methanol was added. Acetic acid (0.3 ml) was added until pH 5. NaCNBHj (250 mg, 4.0 mmol) was slowly added. Gas evolution obscaved. After 4 hrs magnetic stirring 114 WO 01/66521 PCT/US01/07I87 dichloromethane, 2M NaOH and water were added until pH 10. Phases were separated and aq. phase was then re-extracted with dichloromethane and ethylacetate. Combined organic phases were dried over MgSO4. Concentration on Rotavapor (40°Q yielded 556 mg crude 47AKU-48. TLC (20% methanol in dichloromethane): Rf = 0.4. HPLC-MS (MethodA): M = 261.2 (MS(%)=57). 2-(4-Methoxyphenyl)44-(4-jnethylbenzyl)-N-( 1 -t-butylpiperidin-4-yl)-acetamide (47AKU-49) 47AKU-48 (556 mg, 2.1 mraol) was placed in 50 ml flask and 5 ml dichloromethane was added. 4-MethoxyphenylacetyI chloride (739 mg, 4.0 mmol) in 10 ml dichloromethane was added. After 4 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 124 mg (15%) product. Further purification by ion exchange chromatography (washout with 10% aq. NH4OH (25%) in methanol) gave 91mg (11%) 47AKU-49. HCl-salt was prepared from 2M HCl/di ethyl ether in dichloromethane/ heptane. TLC (10% methanol in dichloromethane): R = 0.5. HPLC-MS (Method A): M = 409.4 (UV/MS(%)=100/90). 'H-NMR (400 MHz, CDC13): 6= 7.11 (4H, m); 7.03 (2H, d); 6.79 Example 131 - AK4-Meth>lbeazy\|)-AKlHDethylpiperidiB-4-yi)- r- phcnvkthyJ-carbamide (58AKU-1) 47AKU-5-2 (219 mg, 1.0 mmol) was dissolved in 5 ml dichloromethane and placed in 50 ml flask. Pbenethylisocyanate (177 mg, \2 mmol) in 5 ml dichloromethane was added. After 6 his magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-15% methanol in dichloromethane) giving 134 mg (37%) 58AXU-1. HCl-salt was prepared from 2M HCl/dictbyktber in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf = 0.5. HPLC-MS (Method A): M = 366.3 (UV/MS(%H>9/96). !H-NMR (400 MHz, CDC]3): 6-7.21-6.97 (9H, m); 4.33 (1H, m); 4.26 (1H, m); 4.21 (2H, s); 3.39 (2H, q); 2.85 (2H, 115 WO 01/66521 PCT/US01/07187 m); 2.67 (2H, t); 2.31 (3H, s); 2:24 (3H, s); 2.06 (2H, m); 1.73-1.57 (4H, m). 13C-NMR(CDC13): 6= 158.7,139.5,137.0,135.4,129.7, 128.8,128.6, 126.3, 126.1, 55.6, 52.2, 46.2, 45.8, 42.2, 36.4, 30.2,21.2. Example 132 -A-Phenylethyl-AKl-metbylpipcridiii -yl A -phenethyl-carbamide (58AKU-2) 4-(2-Pbenylemyl)amino-l-methylpiperidine (131 nig, 0.6 mmol) was dissolved in 5 ml dichloromethane and placed in 50 ml flask. Phenethylisocyanate (103 mg, 0.7 mmol) in 5 ml dichloromethane was added. After 4 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (45 °C) Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 198 mg (90%) 58AKU-1. HCl-salt was prepared fix>m 2M HCl/diethylether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf = 0.3. HPLC-MS (Method A): M = 3663 (UV/MS(%)=100/100). 'H-NMR (400 MHz, CDCI3): 6= 7.33-7.16 (SH, m); 7.01 (2H, m); 4.23 (1H, t); 4.04 (1H, m); 3.47 (2H, q); 3.17 (2H, t); 2.89 (2H, m); 2.78 (2H, t); 2.66 (2H, t); 2.28 (3H, s); 2 05 (2H, m); 1.79-1.59 (4H, m). "C-NMR (CDC13): 5= 157.8, 139.6,139.0, 129.0, 128.9,128.8, 126.8, 126.7, 55.7, 52.5, 46.2,44.6,42.0, 37.3,36.4, 30.5. Example 133 -7V-(4-MethyIbenzy!)- -(l-t-but>ipiperidin -yl)-iV-(4-methoxybenzyl) carbamide (58AKTI-3) 47AKU-5-2 (404 mg, 1.6 mmol) was dissolved in 5 ml dichloromethane and placed in 50 ml flask. 4-Methoxyben2ylisocyanatc (326 ing, 2.0 mmol) in 5 ml dichloromethane was added. Aiter 20 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (45°C). Ciiide product was purified three times by flash chromatography (0-20% methanol in 116 WO 01/66521 PCT/US01/07187 Example 134 - 2-(4-Ethoxyphenyl)-7V-(4-metbylbenzyl)-N-(l-metbylpiperidin-4-yI) acetaraide (58AKU-4) 4-Ethoxyphenylacetic add (270 mg, 1.5 mmol) was dissolved in 2 ml thionylchloride and placed in 50 ml flask. Mixture was heated to reflux for 2 hrs and then concentrated on Rotavapor (45°C). The acid chloride (1.5 mmol) in 5 ml dichloromethane was added to 47AKU-5-2 (262 mg, 1.2 mmol) in 5 ml dichloromethane. After 20 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 272 mg (60%) 58AKU-4. HCl-salt was prepared from 2M HCl/diethylether in dichlororaethane/ heptane. TLC (10% methanol in dichloromethane): Rf = 0.4. HPLC-MS (Method A): M = 381.2 (UV/MS(%)=98/9I). 'H-NMR (400 MHz, CDCI3): 6= 7.17-6.99 (6H, m); 6.82-6.76 (2H, m); 4.73 (1H, m); 4.48 (2H, s); 3.98 (2H, q); 3.52 (2H, s); 3.22 (2a d); 2.61 (2H, t); 2.54 (3H, s); 2.32 (3H, s); 2.14 (2H, s); 1.71 (2H, d); 1.38 (3H, t). "ONMR (CDC13): 6= 172.9, 158.2,137.3,135.0, 129.9,129.8,126.8, 125.S, 114.9,63.7,54.6,49.8,46.7,44.1,40.6,27.2,21.2, 15.0. Example 135 - 2-(4-ButoxypbenyI>-7V-(4-methylben2yl>-7V-(l-methylpiperidin-4-yl) acetaraide (58AKU-5) 4-Butoxyphenylacetic acid (317 mg, 1.5 mmol) was dissolved in 2 ml thionylchloride and placed in 50 ml flask. Mixture was heated to reflux for 2 hrs and then concentrated on Rotavapor (45 °C). The acid chloride (1.5 mmol) in 5 ml mchloromethane was added to 47AKU-5-2 (262 mg, 1.2 mmol) in 5 ml dichJoromethanc. After 20 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°Q. Crude product was purified by flash cfaromatography (0-10% methanol in dichloromethane) giving 230 mg (47%) 58AKU-5. HCI-salt was prepared from 2M HCl/diethylether in dichloromethane/ heptane. TXC (10% methanol in dichloromethane): Rf= 0.5. HPLC-MS (Method A): M = 409.2 (UV/MS(%)=98/93). lH-NMR (400 MHz, CDCI3): &= 7.15-6.96 (6H, m); 6.78 (2H, m); 4.74 (1H, m); 4.48 (2H, s); 3.91 (2H, t); 3.52 (2H, s); 3 7 (2H, d); 2.72 (2H, t); 2.58 (3H, s); 2.32 (3H, s); 2.23 (2H, m); 1.72 (4H, d); 1.45 (2H,m); 0-95 (3H, t). I3C-KMR (CDC13): S= 173.0, 158.4, 137.3,135.0, 129.8,126.6, 125.8,115.0, 67.9, 54.4,49.5, 46.7,43.8,40.6, 31.5, 26.8, 21.2, 19.4,14.0. 117 WO 01/66521 PCT/US01/07187 Example 136 - 2-{4-i- ropoxyphctiyl)'N-(4-mcthy}benzy\)-N-(\' raetbylpiperidin-4-yI) acetamfde (S8AKU-6) 47AKU-29-2 (245 ing, 0.7 mmol) was dissolved in 10 ml dimethylformamide and placed in 50 ml flask. KOH (196 mg, 3.5 mmol) and Isopropylbromide (200 u,l, 2.1 mmol) were added. Mixture was heated to 50°C and stiired for 24 hrs. After cooling water and ethylacetate were added. Phases were separated and aq. phase was then re-extracted with dichloromethane. Combined organic phases were washed with brine, dried overMgSO4 and concentrated on Rotavapor (40°C) giving 188 mg. Crude product was purified by flash chromatography (0-10% methanol in dichioromethane) yielding 136 mg (49%) 58AKU-6. HCl-salt was prepared from 2M HCl/di ethyl ether in dichloromethane/ heptane. TLC (10% methanol in dichioromethane): Rf- 0.3. HPLC-MS (Method D): M = 395 (UV/MS(%)=95/91). 'H-NMR (400 MHz, CDC13, retainers): 6= 7.23-7.01 (6H, m); 6.79 (2H, m); 4.60 (1H, m); 4.51 (1H, m); 4 44 (IH, s); 3.77 (1H, s); 3.52 (IH, s); 2.83 (2H, m); 2.76 (2H, m); 2.28 and 2.34 (3H, 2s); 2.19 and 2.22 (3H, 2s); 2.05 (IH, m); 1.86-1.55 (4H, m); 1.32 (6H, d). nC-NMR (CDC13): 6= 172.6, 157.0, 137.1,135.6, 129.8, 129.7,125.8, 116.2, 70.1, 55.3, 51.6, 46,6, 46.1, 40.8,29.6,22.3,21.2. Example 137 - Receptor Selection and Amplification (R-SAT) Assays. The functional receptor assay, Receptor Selection and Amplification Technology (R-SAT), was used (with minor modifications from that previously described US 5,707,798) to screen compounds for efficacy at the 5-HT2A receptor. Briefly. NIH3T3 cells were grown in 96 well tissue culture plates to 70-80% confluence. Cells were transfected for 12-16 hours with plasnrid DNAs using supcrfect (Qiagen Inc.) as per manufacture's protocols."R-SAT's were generally performed with 50 ng/well of receptor and 20 ng/well of Beta-galactosidase plasmid DNA. All receptor and G-protein constructs used were in the pSI mammalian expression vector (Promega Lac) as described in U.S. 5,707,798. The 5HT2A receptor gene was amplified by nested PCR from brain cDNA using the oligodeoxynucleotides based on the published sequence (see Saltzman et al Biochem. Biophys. Res. Comm. 181:1469-78 (1991)). Large-scale transfections, cells were transfected for 12-16 hours, then trypsinized and frozen in DMSO. Frozen cells were later thawed, plated at 10,000-40,000 cells per well of a 96 well plate that contained drug. With both 118 WO 01/66521 PCT/US01/07187 methods, cells were then grown in a humidified atmosphere with 5% ambient CO2 for five days. Media was then removed from the plates and maricer gene activity was measured by the addition of the beta-galactosidase substrate ONPG (in PBS with 5% NP-40). The resulting colorimetric reaction was measured in a spectrophotometric plate reader (Titertek Inc.) at 420 nM. All data were analyzed using the computer program XLFh (IDBSm). Efficacy is the percent maximal repression compared to repression by a control compound (ritanserin in the case of 5HT2A). pIC50 is the negative of the log(IC50), where IC50 is the calculated concentration in Molar that produces 50% maximal repression. The results obtained for several compounds of the invention are presented in Table 4, below. 119 WO 01/66521 PCTAJS01/07187 Table 4. Efficiency and pIC50 of Compounds at the 5-HT2A Receptor Compared to Ritanserin Compound Percent Efficacy p)C50 26HCH17 94 8.3 26HCH65 103 8.2 26HCH66-05 126 8.1 26HCH79-5 94 8.2 26HCH79-6 83 8.3 26HCH79-10 102 7.8 26HCH71B 124 7.9 42ELH45 108 9.0 50ELH27 108 8.7 47AKU-7 120 8.1 42ELH80 122 8.5 42ELH79 t10 8.5 42ELH91 108 8.0 42ELH85 118 7.8 42ELH75 109 8.3 47AKU-12 112 8.1 47AKU-8 113 8.1 47AKU-22 117 7.9 47AKU-21 117 7.9 47AKU-2O 120 8.0 50ELH8 129 7.8 50ELH68 96 8.4 50ELH65 92 7.9 47AKU-44 112 8.5 57MBT12B 75 7.7 58AKU-4 110 9.6 58AKU-3 111 81 58AKU-5 99 95 58AKU-6 101 9.8 57MBT54B 95 7.9 50ELH95B 119 8.0 50B.H93E 72 8.1 5OELH93D 58 7.8 50ELH93A 106 8.7 63ELH1A 104 8.3 50B.H89 111 9.7 63S.H20 95 9.0 57MBT7O-6D 119 7.7 57MBT70-5D 105 8.4 57MBT70-4D 98 8.5 57MBT70-3D 87 8.9 57MBT70-2O 105 8.2 57MBT70-1D 120 7.9 63Q_H21 100 8.5 57MBT62B 119 7.9 57MBT70-6E 115 8.0 120 WO 01/66521 PCT/US01/07187 Example 138 Selectivity Profile for 2-(4-Metboxyphenyl)-;V-{4-raethylbenzyI)-iV-(l-methyIpiperidin-4-yI)acetamidehydrochioride The R-SAT assay (described above in example 137) was used to investigate the selectivity of 2-(4-Methoxyphenyl)-JV-(4-methylbeiizyl)-A'-(l-methylpiperidin-4-yl)acetamide hydrochloride. The results from a broad profiling of this compound at a variety of receptors are reported in Table 4 below. NR means No Response, i.e. the compound investigated showed no effect at the receptor studied. 121 WO 01/6652] PCT/US01/07187 Table 4 - Selectivity of 2-(4-Metboxypbenyl>A44-metbyIbenzy1)-/V-0-m ethylpiperi dro-4-y))aceta mide RECEPTOR ASSAY pEC50/plC50 5-HT1A agonist NR antagonist NR 5-HT1B agonist NR antagonist NR 5-HT1D agonist NR antagonist NR 5-HTtE agonist NR antagonist NR 5-HT1F agonist NR antagonist NR 5-HTZA agonist NR inverse agonist 8.8 5-HTa agonist NR inverse agonist 6.9 5-HTac agonist NR inverse agonist 7 5-HT4 agonist NR inverse agonist NR 5-HT6 agonist NR Inv. Agonist 6.8 5-HT7 agonist NR inverse agonist 6.9 ml agonist NR antagonist . NR m2 agonist NR antagonist NR m3 agonist NR antagonist NR m4 agonist NR antagonist NR m5 agonist NR antagonist NR D1 agonist NR 122 WO 01/66521 PCT/US01/07187 antagonist NR D2 agonist NR antagonist NR D3 agonist NR antagonist NR D5 agonist NR antagonist NR Histamme 1 agonist NR Inv. agonist NR Histamine 2 agonist NR antagonist NR Histamme 3 agonist NR antagonist NR alpha-1A(a/c) agonist NR antagonist NR alpha- 1B agonist NR In. Agonist NR alpha-2A agonist NR antagonist NR alpha-2B agonist NR antagonist NR alpha-2C agonist NR antagonist NR betai agonist NR antagonist NR beta2 agonist NR ¦ antagonist NR endothefinB agonist NR CCK-A agonist NR NK-1 agonist NR VasopressJniA agonist NR K-opiod agonist NR 123 WO 01/66521 PCTAJS01/07187 Example 139 In Vivo Pharmacology of 2-(4-Methoxyphenyl)-iV-(4- metbylbenzyI)-iV-(l-methy]piperidm-4-yI)acetamidehydrochloride(AC-90,179) Methods Animals and apparatus Instruments) were used for rat experiments (details on startle apparatus and measures, see Male Non-Swiss Albmo mice and male Sprague-Dawley rats (Harlan Sprague-Dawley) were housed (4 mice/cage; 2 rats/cage) in rooms with temperature and humidity controlled and water and food (Harlan Teklad) freely available. Mice were kept on a 12-hr lightrdark cycle, whereas rats were kept on a 12- hr reverse light:dark cycle. For locomotor and observation experiments in mice, plastic 20x20x30cm activity cages were equipped with photocell beams (AccuScan Instruments). Startle chambers (San Diego Instruments) were used for rat experiments (for details on startle apparatus and measures, see Mansbach et al., (1988) PsycJiopharmacology 94:507-14). Procedore Observation for Head Twitches Mice were treated with 2.5 mg/kg DOI i.p. Five min later, mice were treated with AC-90179 s.c. and placed into activity cages. Ten min later, mice were observed using a repeated sampling technique. Each mouse was observed for 10 sec and rated for presence (1) or absence (0) of head twitch behavior for a total of 6 observations in 15 min and a total head twitch score of 0-6. Each dose combination was tested in a separate group of animals (n=8) and the experimenter was blind to drug conditions. Head twitch scores were averaged followed by analysis of variance (ANOVA) and post-hoc Durmett's t-test comparisons. Locomotor Activity For hyperactivity experiments, mice were treated with 0.3 mg/kg dizocilpine or 3.0 mg/kg d-amphetamine i.p. 15 min before the session. Five minutes after the pretreatment, mice were treated with AC-90179 s.c. and placed into the activity cages. For spontaneous activity, AC-90179 was administered alone. Locomotor data were collected during a 15 min session without habituan'on in a lit room. Each dose combination was tested in a separate group of animals (n=8). Distance traveled (cm) was calculated and averaged followed by ANOVA and post-hoc Dunnett's t-test comparisons. 124 WO 01/66521 PCT/US01/07187 Startle Testing Rats were tested and groups (n=l 0) matched for levels of startle reactivity and prepulse inhibition (PH; see Mansbach et al, (1988) Psychopharmacology 94:507-14). Two days later, test sessions started and consisted of a 5-min acclimation period with a constant background noise (65 dB), followed by 60 presentations of acoustic stimuli to measure acoustic startle responses. The 60 trials consisted of: twenty two 40-ms presentations of a 120 dB broadband pulse, ten 20-ms presentations of each prepulse intensity (68, 71, 77 dB) 100 ms prior to a 40-msec presentation of a 120 dB broadband pulse, and 8 NOSTIM trials in which no stimuli were delivered in order to assess general motor activation in the rats. Thirty min before testing, rats were treated with sterile water (s.c.), risperidone (1.0 mg/kg, i.p.), or AC-90179 (s.c). Five min later, rats were administered DOI (0.5 mg/kg, s.c.) or 0.9% saline (s.c). One-week later, rats were administered the same pretreatment drug or vehicle and crossed over to receive the treatment opposite to that they received the previous week. Startle magnitudes and percent PPI for the three prepulse intensities were calculated as described elsewhere (Bakshi, et al, (1994) J. Pharmacol Exp. Ther. 271:787-94) and ANOVAs with repeated measures performed. Res alts To further characterize the clinical utility of a selective 5-HT2A receptor inverse agonist as a novel antipsychotic agent, AC-90179 was tested in head twitch, locomotOT and pre pulse inhibition behavioral models. DOI-trcatcd (2.5 mg/kg, i.p., 15 mm) mice exhibited an average head twitch score of 2.6 (± 03, S.E-M.). AC-90179 (0.1 - 30 mg/kg, ex., 10 min) caused a dose-related decrease in DOI-induced bead-twitches with a minimum effective dose of 1 mg/kg and with higher doses completely eliminating head twitch behavior (Figure 2 A). In tbe locomotor experiments (Figure 2 B), mice traveled an average of 794 cm (± 122 S.E.M.) after vehicle administration. Dizocilpinc (03 mg/kg, i-p., 15 min) and J-amphetamine (3.0 mg/kg, i.p., 15 min) caused increases in distance traveled with averages of 2625 cm (± 312) and 3367 cm (± 532), respectively. AC-90179 (03 -10 mg/kg, s.c., 10 mm) attenuated the hyperactivity induced by dizocirpinc, bat not by d-amphetarnine. The minimum effective dose against dizocilpine was 1 mg/kg, whereas AC-90179 reduced spontaneous locomotor activity only at the highest dose tested (30 mg/kg). 125 WO 01/66521 PCT/US01/07187 The 3-way repeated measures ANOVA on the PPI data from the AC-90179 groups revealed an overall effect of treatment [F(l,37) - 27.73, p 0.05) on percent PPI. Risperidone was used as a positive control because previous studies in our laboratory have suggested that it is effective in blocking the PPI-disrupbive effects of DOI. The 3-way repeated measures ANOVA on the PPI data from the risperidone group also revealed a significant effect of treatment [F(l,18)= 14.08, p 0.05). Since there were no significant interactions with prepulse intensity, title data were collapsed across the three prepulse intensities for graphical purposes. Since there was a significant pretreatment by treatment interaction, pair-wise 2-way repeated measures ANOVAs were conducted on the saline- and DOI-treated groups. In the vehicle-treated rats, there was no effect of AC-90179 (p > 0.025) or risperidone (p > 0.025) on PPI. hi the DOI-treated groups, there were significant effects of AC-90179 [F(3,37) = 5.68, p The 3-way repeated measures ANOVA on startle magnitude from the AC-90179 groups revealed a significant effect of pretreatment [F(3,37) 2.89, p = 0.048) and treatment [F(137) - 10.27, p 0.05; Fif jure 1, panel C inset). Risperidone, on fee other hand, had no effect on startle magnitude (p > 0.05). Example 140 - In Vivo Pharmacology of Additional Compounds The effect of various compounds on head twitch behavior in mice treated with DOI was observed as described above in Example 139. The results are summarized below in Table 5. Toe effect of various compounds on btwid twitch behavior in mice treated wth DOI was observed as described in Example 139. Animals received 0.1 -30 rag/kg of the compound indicated via subcutaneous injection. MED indicates the minirmim 126 WO 01/66521 PCT/US01/07187 effective dose at which a statistically significant reduction m head twitching score (described above) was observed. MED = minimum effective dose in vrvo. Table 5. Comparison Of Analogs For Their Ability To Attenuate DOI-lnduced Head Twitches In Mice. CompooD MED 26HCH1 30 44ELH45 30 50ELH27 1 42ELH80 42ELH79 47AKU-7 42ELH85 47AKU-8 47AKU-12 47AKU-13 42ELH91 >10 42ELH90 -10 47AKU-20 47AKU-19 >10 47AKU-22 \| 47AKU-21 >10 \| 42ELH75 47AKU-11 -10 47AKU-14 47AKU-18 >1O 50ELH6 47AKU-33 >10 47AKU-25 >10 5OELH65 5OELH68 47AKU-49 47AKU-44 58AKU-4 58AKU-5 50ELH93A 58AKU-6 63ELH20 63ELH21 MED = minimum effective dose in vivo. 127 WO 01/66521 PCT/US01/07187 The invention described and claimed herein is not to be limited in scope by the specific embodiments herein disclosed, since these embodiments are intended as illustrations of several aspects of the invention. Any equivalent embodiments are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications arc also intended to fall within the scope of the appended claims. The disclosures of all references cited herein are incorporated by reference in their entireties. 128 1. A compound of formula (I) in which R is a hydrogen, a cyclic or straight-chained or branched acyclic organyl group, a lower hydroxyalkyl group, a lower aminoalkyl group, or an aralkyl or heteroaralkyl group; nisO, 1, or 2; Xi is methylene, vinylene, or an NH or N(lower alkyl) group; and X2 is methylene , or, when Xi is methylene or vinylene, X2 is methylene or a bond; or when X] is methylene, X2 is O, S, NH, or N(lower alkyl) or a bond; Yi is methylene and Y2 is methylene, vinylene, ethylene, propylene, or a bond; or Yi is a bond and Y2 is vinylene; or Yi is ethylene and Y2 is O, S, NH, or N(lower alkyl); Ari and Ar2 independently are unsubstituted or substituted aryl or heteroaryl groups, provided that Ari and Ar2 are not simultaneously phenyl; and W is oxygen or sulfur. 2. A compound according to claim 1, wherein Y] is methylene and Y2 is a bond, methylene, ethylene, or vinylene; or Yi is ethylene and Y2 is O or S; 129 and X\| is methylene and X2 is a bond, methylene, O, or S; or Xi is NH or N(lower alkyl) and X2 is methylene, 3. A compound according to claim 2, wherein Zis R and W is oxygen. 4. A compound according to claim 3, wherein Ari and Ar2 independently are mono- or disubstituted phenyl groups. 5. A compound according to claim 4, wherein R is a hydrogen, a lower alkyl group, a cyclic organyl group, or a substituted or unsubstituted aralkyl or heteroaralkyl group; n is 1; Yi is methylene, Y2 is a bond, methylene, ethylene, or vinylene; X] is methylene and X2 is a bond, or. X\| is NH or N(lower alkyl) and X2 is methylene; and An and Ao are phenyl groups, independently p-substituted with groups selected from lower alkyl, lower alkoxy and halogen. 6. A compound according to claim 1, having a formula (II) wherein RN is hydrogen, lower alkyl, aralkyl, or heteroaralkyl; ArL is selected from lower alkyl, lower alkoxy and halogen 130 ArR is selected from lower alkyl, lower alkoxy and halogen; k is 1 or 2 and A" is a suitable anion. 7. The compound according to claim 1, wherein the compound is selected from the group consisting of: N-(l-(l-methylethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide; N-(l-(2)2-dimethylethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide; N-(l-pentylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide; N-(l-hexylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide; N-(l-cyclohexylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxy pheny lacetamid e; N-(l-cyclopentyIpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxypheny 1 acetamide; N-(l-cyclobutylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide; N-(l-cyclopropylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide; N-(l-(cyclopentylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxy phenylacetamide; N-(l-(cyclobutylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide; N-(l-(cyclopropylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxy phenylacetamide; N-(l-(2-hydroxyethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4- methoxy pheny 1 acetamide; N-(l-(3-hydroxypropyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4- methoxy phenylacetamide; jV_((4-methylphenyl)methyl)-JV-(piperidin-4-yl)-N'-phenylmethylcarbamide; A -((4-methylphenyl)methyl)-A -(l-(2-methylpropyl)piperidin-4-yl)-W-phenylmethylcarbamide; 131 A -(l-((2-bromophenyl)niethyl)piperidin-4-yl)-JV-((4-methyIphenyl)methyl)-W-phenylmethylcarbarnide; -(l-((4-hydroxy-3-methoxyphenyl)methyl)piperidin-4-yl)-M((4-methylphenyl)methyl)-W-phenylmethylcarbamide; M-(l-((5-ethylthien-2-yl)methyl)piperidin-4-yl)-N-((4-niethylphenyl)rnethyl)-N)-phenylmethylcarbamide; N-( 1 -(imidazol-2-ylmethyl)piperidin-4-y l)-N-((4-methylphenyl)rnethyl)-N' -phenylmethylcarbamide; N (l-(cycIohexylmethyl)piperidm-4-yl)-N-((4-methylphenyl)methyl)-N'-phenylmethylcarbamide; N-(l-((4-fluorophenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N'-phenylmethylcarbamide; N-((4-methylphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide; N-((4-methylphenyl)methyI)-N-(l-methylpiperidin-4-yl)-4-methoxyphenyIacetamide; N-(l-ethylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide; N-((4-methylphcnyl)methyl)-N-(l-propylpiperidin-4-yl)-4-methoxyphenylacetamide; N-(l-butylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide; N-(l-(3,3-tiimethylbutyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxypheny lacetamide; //-(l-(cyclohexylmethyl)piperidin-4-yl)-N-((4-methyIphenyl)methyl)-4-methoxyphenylacetamide; N-((4-methylphenyl)methyl)-N-(l-(2-methylpropyl)piperidin-4-yl)-4-methoxyphenylacetamide; N-((4-methylphenyl)methyl)-N-(l-((4-methylphenyl)methyl)piperidin-4-yl)-4- methoxyphenylacetamide; N-(l-((4-hydroxyphenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4- methoxyphenylacetamide; N-(l-((2-hydroxyphenyl)methyl)piperidin-4-yl)-N-((4-methyIphenyl)methyl)-4- methoxyphenylacetamide; N-(3-phenylpropyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide; N-(2-phenylethyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide; 132 N-((2-methoxyphenyl)raethyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide; N-((2-chlorophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide; N-((3,4-di-methoxyphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide; N-((4-fluorophenyI)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide; N-((234-di-chlorophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide; N-((3-methylphenyl)methyl)TN-(piperidin-4-yl)-4-methoxyphenyIacetamide; N-((3-bromophenyl)methyI)-N-(piperiidin-4-yl)-4-methoxyphenylacetamide; N-( 1 -(phenylmethyl)piperidin-4-yl)-N-(3-phenyl-2-propen-l -yl)-4-methoxyphenylacetamide; N-((4-methylphenyl)methyl)-N-(l-piperidin-4-yl)-phenylacetamide; N-((4-methylphenyl)methyl)-N-(l-piperidin-4-yl)-3-phenylpropionamide; N-((4-methylphenyl)methyl)-N-(l-piperidm-4-yl)-(phenylthio)acetamide; N-((4-methylphenyl)methyl)-N-(l-piperidin-4-yl)-phenoxyacetamide; N-((4-methylphenyl)methyl)-N-(l-piperidin-4-yI)-(4-chlorophenoxy)acetamide; N-((4-methylphenyl)methyl)-N-(l-piperidin-4-yl)-3-methoxyphenylacetamide; N-((4-methylphenyl)methyl)-N-(l-piperidin-4-yI)-4-fluorophenylacetamide; N-((4-methylphenyl)methyl)-N-(l-piperidin-4-yl)-2,5-di-methoxyphenyiacetamide; N-((4-methylphenyl)methyl)-N-(l-piperidin-4-yl)-4-chlorophenylacetamide; N-((4-methyIphenyl)methyl)-N-(l-(phenylmethyl)pyrrolidin-3-yl)-N -phenylmethylcarbamide; N-((4-methylphenyl)methyl)-N-(l-(phenyImethyl)pyrroIidin-3-yI)-4-methoxyphenylacetamide; 2-(4-methoxyphenyl)- -(4-methylbenzyl)-N-(piperidin-4-yl) acetamide; 2-(4-methoxyphenyl)-A -(4-methylbenzy\)-N-( 1 -methylpiperidin-4-y 1) acetamide; 2-(4-methoxypheny])-N-(4-methylbenzyl)-Ar-(l-ethylpiperidin-4-yl) acetamide; 2-(4-methoxyphenyI)-AT-(4-chlorbenzyl)-A -( 1 -ethylpiperidin-4-yl) acetamide. 2-(4-methoxyphenyl)-N-(4-chlorbenzy\)-N-( 1 -isopropylpiperidin-4-y 1) acetamide; 2-(4-methoxyphenyl)-A -(4-chlorobenzyl)-A'-(piperidin-4-yl) acetamide; 2-(4-methoxyphenyl)-7l/-(4-chlorbenzyl)-M-(l-cyclopentylpiperidin-4-yl) acetamide; 2-(4-methoxyphenyl)-A (4-chIorbenzyl)-W-( 1 -isopropylpiperidin-4-yI) acetamide; 2-(phenyl)- -(4-trifluoromethylbenzyl)-Ar-(l-methylpiperidin-4-yl) acetamide; 133 2-(4-fluorophenyl)- (4-trifluoromethylbenzyl)-//-(l-methylpiperidin-4-yI)acetamide; 2-(4-Methoxyphenyl)-A -(4-trifluoromethylbenzyl)-A'-(l-methyIpiperidin-4-yl) acetamide; 2-(4-Trifluoromethylphenyl)-W-(4-trifiuoromethyIbenzyl)-7 -(l-methylpiperidin-4-yl) acetamide; 2-(4-Fluorophenyl)- V-(4-fluorobenzy])-N-(l-methylpiperidin-4-yl) acetamide; 2-(4-Methoxyphenyl)-iV-(4-fluoroben2yl)-Ar-( 1 -methylpiperidin-4-y 1) acetamide; 2-(phenyl)-//-(4-fluorobenzyl)-7V-(l-methylpiperidin-4-yl) acetamide; 2-(4-Trifluoromethylphenyl)-7 -(4-fluorobenzyl)-AT-( 1 -methylpiperidin-4-yl) acetamide; 2-(44rifIuoromethylphenyl)-A -[4-(methoxycarbonyl)benzyl]-iV'-(l-methyIpiperidin-4-yl) acetamide; 2-PhenyI-A/-[4-(methoxycarbonyl)benzyi]-A'-(l-methylpiperidin-4-yl) acetamide; 2-(4-Chlorophenyl)-A [4-(methoxycarbonyl)benzyl]-A -(l-methylpiperidin-4-yl) acetamide; 2-(4-MethoxyphenyI)-A -[4-(methoxycarbonyl)benzyl]-7V-(l-methylpiperidin-4-yl) acetamide; 2-(4-trifluoromethylphenyl)-A/-[4-(methoxycarbonyl)benzyl]-7V-(l-methylpiperidin-4-yI) acetamide; 2-Phenyl-A'-[4-(methoxycarbonyl)benzyl]-7V-(l-methylpiperidm-4-yl) acetamide; 2-(4-Chlorophenyl)-A -[4-(methoxycarbonyl)benzyl]-A -(l-methylpiperidin-4-yl) acetamide; 2-(4-Methoxyphenyl)-A -[4-(methoxycarbonyI)benzyI]-M-(l-methylpiperidin-4-yl) acetamide; 2-(4methoxyphenyl)-N-(4-methylbenzyl)-Ar-[l-(4-chloromethyl-2-thiazolylmethyl) piperidin-4-yl] acetamide; 2-(4 methoxyphenyl)-A -(4-methylbenzyl)-A'-{ 1 -[3(1,3 dihydro-2H-benzimidazol-2-on-1 - yl)propyl] piperidin-4-yl} acetamide; 2-(4-methoxyphenyl)-A -(2-4(fluorophenyl)ethyl)-A -(l-methylpiperidin-4-yl) acetamide; 2-(4-methoxyphenyl)-Ar-[2-(2)5-dimethoxyphenyl)ethyl]- -(l-methylpiperidin-4-yI) acetamide; 134 2-(4-methoxyphenyI)-iV-[2-(2s4-dichlorophenyI)ethyl]-A (l-methylpiperidin-4-yl) acetamide; 2-(4-methoxyphenyl)-A [2-(3-chlorophenyl)ethyll-//-(l-methylpiperidin-4-yl) acetamide; 2-(4-methoxyphenyl)- -[2-(4-methoxyphenyl)ethyl]-iV-(l-methylpiperidin-4-yl) acetamide; 2-(4-methoxyphenyI)-A [2-(3-fluorophetiyl)ethyI]-M(l-methylpiperidin-4-yI) acetamide; 2-(4-ethoxyphenyl)-//-[2-(4-fluorophenethyl]-7V-(l-methylpiperidin-4-yl) acetamide; 2-(4-ethoxyphenyl)-7V-(4-fluorobenzyl)-N-(l-methylpiperidin-4-yl) acetamide; 2-(4-methoxyphenyl)-A/"-(4-methyIbenzyl)-//-{l [2-(2-hydroxyethoxy)ethyl]piperidin-4-yl} acetamide; 2-(4-methoxyphenyl)-A -(4-methylben:syI)-A'-[l-((2-chioro-5-thienyl)inethyl)piperidin-4-yl] acetamide; 2-(4-methoxyphcnyl)-Ar-(4-methylbenzyl)-A -tl-(2-(imida2olidinon-l-yl)ethyl)piperidin-4-yl] acetamide; 2"(4 methoxyphenyl)-7V-(4-memylbenzyl)-A -{l-[2-(214(lH,3H)quina2olinedion-3-yl)ethyl] piperidin-4-yl} acetamide; 2-(4-methoxyphenyI)-//-(4-methyibenzyl)- -{ 1 -[2-(l ,3-dioxolan-2-yl)ethyl]piperidin-4-yl} acetamide; 2-(4-methoxyphenyl)-Af-(4-methylberi2yl)-A {l-[2-(3-indolyl)ethyl] piperidin-4-yl} acetamide; 2-(4-methoxyphenyl)-A/'-(4-methylberi2yl)-A -{I-[3-(l>2,4-triazol-l-yl)propyl]piperidin-4- yl} acetamide; 2-(4-methoxyphenyl)-//-(4-methylberizyl)-A'r-[l-(5-benzofurazanylmethyl)piperidin-4-yl] acetamide; 2-(4-methoxyphenyl)-Af 4-methylbenzyl)- -[l]thien-3-ylmethyl) piperidin-4-yl] acetamide; 2-(4-methoxyphenyl)-iV-(4-methylbenzyl)-A -[l-(S-phenyl-l,2s4-oxadiazol-3- ylmethyl)piperidin-4-yl] acetamide; 2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(l-isopropylpiperidin-4-yl)-acetamide; 135 2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(l-ethylpiperidin-4-yl)-acetamide; 2-Phenyl-N-(4-methylbenzyl)-N-(l-methylpiperidin-4-yl)-acetamide,2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(l-methylpiperidin-4-yl)-acetamide; 2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(l-cyclopentylpiperidin-4-yl)-acetamide; 2-(4-Fluorophenyl)-N-(4-methyIbenzyl)-N-(l-methylpiperidin-4-yl)-acetamide; 2-(4-Chlorophenyl)-N-(4-methyIben2yI)-N-(l-(2-hydroxyethyl)-piperidin-4-yl)-acetamide; 2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(l-cyclobutylpiperidin-4-yl)-acetamide; 2-(4-MethoxyphenyI)-N-(4 methylben2yl)-N-(l-cyclobutylpiperidin-4-yl)-acetamide1 N-(4-Methylbenzyl)-N-(l-methylpiperidin-4-yl)-N'-benzyI-carbamide; N-(4-Methylbenzy l)-N-( 1 -methy lpiperidin-4-y 1)-N '-pheny 1-carbamide; N-Phenethyl-N-(l-methylpiperidin-4-yl)-N'-benzyl-carbamide; 2-Phenyl-N-(4-methoxybenzyI)-N-(l-methylpiperidin-4-yl)-acetamide; 2-(4-Trifluoromethylphenyl)-N-(4-niethoxybenzyI)-N-(l-methylp)peridin-4-yl)-acetamide; 2-(4-Fluorophenyl)-N-(4-methoxyben2yl)-N-(l-methyIpiperidin-4-yl)-acetamide; 2-(4-Methoxyphenyl)-N-(4-methoxybenzyl)-N-(l-raethylpiperidin-4-yl)-acetamide; 2-(4-Methylphenyl)-N-(4-chlorobenzyl)-N-(l-methylpiperidin-4-yl)-acetamide; 2-(4-Hydroxyphenyl)-N-(4-methylbenzyl)-N-(l-methylpiperidin-4-yl)-acetamide; N-Phenethyl-N-(l-methylpiperidin-4-yl)-N'-phenyl-carbamide; N-(3-Phenylpropyl)-N-(l-methylpiperidin-4-yl)-N'-benzyl-carbamide; N-(3-PhenylpropyI)-N-(l-methylpiperidin-4-yl)-N'-phenyl-carbamide; 2-(4-Methoxyphenyl)-2,2-ethylene-N-(4-methylbenzyI)-N-(l-methylpiperidin-4-yl) acetamide; 2-(4-Methoxyphenyl)-N-alpha-methylbenzyl-N-(l-methylpiperidin-4-yI) acetamide; 2-(4-Methoxyphenyl) N-(4-methylbenzyl)-N-(3-tropen-4-yl) acetamide; 2-Phenyl-2-ethyl-N-(4-methylbenzyl)-N-(l-methylpiperidin-4-yl) acetamide; N-Phenethyl-N-(4-methylbenzyl)-N-(l-methylpiperidin-4-yl)-amine; 2-(4-MethoxyphenyI)-N-(l-indanyl)-N-(l-methylpiperidin-4-yl) acetamide; N-(4-Methylbenzyl)-N-(l-methylpiperidin-4-yl)-N'-(4-methoxybenzyl)-carbamide; 136 2-(3,4-dimethoxyphenyl)-N-(4-methylbenzyl)-N-(l-methyIpiperidin-4-yl)acetamide; 2-(3,4-Methylenedioxyphenyl)-N-(4-niethylbenzyl)-N-(l-methylpiperidin-4-yl) acetamide; 2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(l-t-butylpiperidin-4-yl)-acetatnide; N-(4-Methylbenzyl)-N-(l-methylpiperidin-4-yl)-N'-phencthyl-carbamide; N-Phenethyl-N-(l-methylpiperidin-4-yl)-N'-phenethy!-carbamide; N-(4-Methylbenzyl)-N-(l-t-butylpiperidin-4-yl)-N'-(4-methoxybenzyl)-carbamide; 2-(4-Ethoxyphenyl)-N-(4-methylbenzyl)-N-(l-methylpiperidin-4-yl) acetamide; 2-(4-Butoxyphenyl)-N-(4-methylbenzyl)-N-(l-methylpiperidin-4-yI) acetamide; 2-(4-i-Propoxyphenyl)-N-(4-methylbenzyl)-N-(l-methylpiperidin-4-yl) acetamide; 2-(4-t-Butoxyphenyl)-N-(4-methylbenzyl)-N-(l-methylpiperidin-4-yl) acetamide; 2-(4-ButoxyphenyI)-N-(4-fluorobenzyl)-N-(l-metliylpiperidin-4-yl) acetamide; 2-(4-PropoxyphenyI)-N-(4-fiourobenzyl)-N-(l-methylpiperidin-4-yI) acetamide; 2-(4-i-Propoxyphenyl)-N-(4-fluorobenzyl)-N-(l-methylpiperidin-4-yl) acetamide; and 2-(4-t-Butoxyphenyl)-N-(4-fluorobenzyl)-N-(l-methylpiperidin-4-yl) acetamide. 8. A compound of formula (I) in which R is a hydrogen, a cyclic or straight-chained or branched acyclic organyl group, a lower hydroxyalkyl group, a lower aminoalkyl group, or an aralkyl or heteroaralkyl group; and nisO, 1, or 2; 137 Xj is methylene, vinylene, or an NH orN(lower alkyl) group; and X2 is methylene, or, when X] is methylene or vinylene, X2 is methylene Or a bond; or when Xi is methylene, X2 is O, S, NH, or N(lower alkyl) or a bond; Yj is methylene and Y2 is methylene, vinylene, ethylene, propylene, or a bond; or Yi is a bond and Y2 is vinylene; or Yi is ethylene and Y2 is O, S, NH, or N(lower alkyl); Ari and A12 are different unsubstituted or substituted aryl or heteroaryl groups; and W is oxygen or sulfur. 9. A compound according to claim 8, wherein Yj is methylene and Y2 is a bond, methylene, ethylene, or vinylene; or Yi is ethylene and Y2 is 0 or S; and Xi is methylene and X2 is a bond, methylene, O, or S; or Xj is NH or N(lower alkyl) and X2 is a methylene . 10. A compound according to claim 9, wherein Zis and W is oxygen. 11. A compound according to claim 10, wherein Ari and Ar2 independently are mono- or disubstituted phenyl groups. 12. A compound according to claim 11, wherein R is a hydrogen, a lower alkyl group, a cyclic organyl group, or an, optionally substituted, alalkyl or heteroaralkyl group; nis 1; Yi is methylene, Y2 is a bond, methylene, ethylene, or vinylene; X] is methylene and X2 is a bond, or Xi is NH or N(lower alkyl) and X2 is methylene; and 138 Ari and A12 are phenyl groups, independently p-substituted with groups selected from alkyl, lower alkoxy and halogen. 13. A compound according to claim 7, having a formula (II): wherein RN is hydrogen, lower alkyl, aralkyl, or heteroaralkyl; Ar1' is selected from lower alkyl, lower alkoxy and halogen ArR is selected from lower alkyl, lower alkoxy and halogen; k is 1 or 2 and A" is a suitable anion. 14. A pharmaceutical composition comprising an effective amount of a compound of formula 139 R is a hydrogen, a cyclic or stral$it chained or branched acyclic organyl group, a lower hydroxyalkyl group, a Uwver aminoalkyl group, or an aralkyl or heteroaralkyl group; and nfsO, 1, or2; Xi is methylene, vinylene, or an NH or N(lower a&yl) cjoup; and X2 is methylene, or, when Xi is methylene or vinylene, X2 is methylene or a bond; or when Xt is methylene, X2 is O, S, NH, or N(lower alkyl) or a bond; YT is methylene and Y2 is methylene, vinylene, ethylene, propylene. or a bond; or Y! Is a bond and Y2 Is vinylene; or Yt Is ethylene and Y2 Is O, S, NH, or N(lower alkyl): Ari and Ar2 independently are unsubstituted or substituted aryl or heteroaryi groups, provided that Art and Ar2 are not simultaneously phenyl; and W is oxygen or sulfur; or a pharmaceutically acceptable salt ester orprodrug thereof, and a pharmaceutica&y acceptable diluent or excipient, 15. The pharmaceutical compostiort of claim 14 for inhibiting the activity of a monoamlrte receptor. 16. The pharmaceutical composition of claim 15 wherein the monoamlrte receptor is a serotonin receptor. 17. The pharmaceutical composlion of daim 16 wherein the serotonin receptor is the 5-HT2A subclass. 18. The pharmaceutical composition of claim 16 wherein the serotonin receptor is in the central nervous system, 19. The pharmaceutical composition of claim 16 wherein me serotonin receptor Is in die peripheral nervous system. 20. The pharmaceutical compostlon of claim 16 wherein the serotonin receptor Is fn blood ceils or platelets. 21. The pharmaceutical composition of claim 16 wherein the serotonin receptor Is mutated or modified. 140 22. The pharmaceutical composWon of claim 15 wherein die actMty Is signaling activity. 23. The pharmaceutical composition of claim 15 wherein the activity is constitutive. 24. The pharmaceutical composition of claim 15 wherein the activity is associated wth serotonin receptor activation. 25. The pharmaceutical composition of claim 14 for inhbiting the activation of a monoamlne receptor. 26. The pharmaceutical composition of claim 25 wherein the activation Is by an agonistic agent. 27. The pharmaceutical composition of claim 26 wherein the agonistic agent is exogenous. 28. The pharmaceutical composition of claim 26 wherein the agonistic agent is endogenous. 29. The pharmaceutical composition of claim 25 wherein the activation is constitutive. 30. . The pharmaceutical composition of claim 25 wherein the monoamlne receptor is a serotonin receptor. 31. The pharmaceutical composition of claim 30 wherein the serotonin receptor Is the 5-HT2A subclass. 32. The pharmaceutical composition of claim 30 wherein the serotonin receptor is in the central nervous system. 33. The pharmaceutical composition of claim 30 wherein the serotonin receptor Is In the peripheral nervous system. 34. The pharmaceutical composition of claim 30 wherein the serotonin receptor is In blood cells or platelets. 35. The pharmaceutical composition of claim 30 wherein the serotonin receptor Is mutated or modified. 141 36. The pharmaceutical composition of claim 14 for the treatment of a disease condition associated with a monoamlne reactor. 37. The pharmaceutical composition of claim 36 wherein the disease condition is selected from the group consisting of schizophrenia, psychosis, migraine, hypertension, thrombosis, vasospasm, ischemia, depression, anxiety, sleep disorders and appetite disorders. 38. The pharmaceutical composition of claim 36 wherein the disease condition is associated with dysfunction of a monoamine receptor. 39. The pharmaceutical composition of claim 36 wherein the disease condition is associated with activation of a monoamine receptor. 40. The pharmaceutical composition of claim 36 wherein the disease condition is associated with increased activity of monoamine receptor. 41. The pharmaceutical composition of claim 36 wherein the monoamine receptor is a serotonin receptor. 42. The pharmaceutical composition of claim 41 wherein the serotonin receptor is the 5-HT2A subclass. 43. The pharmaceutical composition of claim 41 wherein the serotonin receptor Is in the central nervous system. 44. The pharmaceutical composition of claim 41 wherein the serotonin receptor is 'm peripheral nervous system. 45. The pharmaceutical composition of claim 41 wherein the serotonin receptor is in blood ceils or platelets. 46. The pharmaceutical composition of claim 41 wherein the serotonin receptor Is mutated or modified 47. The pharmaceiiical composition of claim 14 for the treatment of schizophrenia. 48. The pharmaceutical composition of claim 14 for the treatement of a migraine. 142 143 49. The pharmaceutical composition of claim 14 for the treatment of psychosis. 50. The pharmaceutical composition of claim 14 for ttie Identification of a genetic polymorphism in a subject, wherein the genetic polymorphism predisposes the subject to being responsive to the compound. 51. The pharmaceutical composition of claim 50 wherein the ameliorated disease condition is associated win the 5-HT class or 5-HT2A subclass of monoaminergic receptors. 52. The pharmaceutical composition of claim 50, wherein the presence of the polymorphism Indicates mat the subject Is suitable for treatment with the pharmaceutical composition of claim 14. 53. The pharmaceutical composition of clain 14 for alleviating a side effect of an antipsychotjc drug. R is a hydrogen, a cyclic or straight-chained or branched acyclic organyl group, a lower hydroxyalkyl group, a lower aminoalkyl group, or an aralkyl or heteroaralkyl group; nisO, 1, or 2; X1 is methylene, vinylene, or an NH or N(lower alkyl) group; and X2 is methylene , or, when X1 is methylene or vinylene, X2 is methylene or a bond; or when X1 is methylene, X2 is O, S, NH, or N(lower alkyl) or a bond; Y1 is methylene and Y2 is methylene, vinylene, ethylene, propylene, or a bond; or Y1 is a bond and Y2 is vinylene; or Y1 is ethylene and Y2 is O, S, NH, or N(lower alkyl); Ar1 and Ar2 independently are unsubstituted or substituted aryl or heteroaryl groups, provided that Ar1 and Ar2 are not simultaneously phenyl; and W is oxygen or sulfur.

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Field of the Invention
AZACYCLIC-COMPOUNDS FOR USE, IN THE TREATMENT OP SEROTONIN RELATED Dlb'KAbES

The present invention relates to novel compounds tnat arteci monoamine receptors, including serotonin receptors. The invention specifically provides compounds that are active as inverse agonists, and therefore also as antagonists, at the 5-HT2A subtype of human serotonin receptors. The invention also provides methods, utilizing the compounds of the invention for modulating 5-HT2A receptor-mediated events, that are useful for treating or alleviating disease conditions in which modification of the activity of these receptors is beneficial.
Background of the Invention
Serotonin or 5-hydroxytryptamine (5-HT) plays a significant role in^he functioning of the mammalian body. In the central nervous system, 5-HT is an important neurotransmitter and neioromodulator that is implicated in such diverse behaviors and responses as sleeping, eating, locomotion, perceiving pain, learning and memory, sexual behavior, controlling body temperature and blood pressure. In the spinal column, serotonin plays an .important role m the control systems of the afferent peripheral nociceptors (Moulignier, Rev. Neurol 150:3-15,(1994)). Peripheral functions in the cardiovascular, hematological and gastrointestinal systems have also been ascribed to 5-HT. 5-HT has been found to mediate a variety of contractile, secretory, and elcctraphysiologic effects including vascular and nonvascular smooth muscle contraction, and platelet aj^regan'on. (Fuller, Biology ofSerotonergic Transmission, 1982; BouHin, Serotonin In Mental Abnormalities 1:316 (197S); Barenas, et al., Serotonin and Behavior, (1973)) The 5-HT2A receptor subtype (also referered to as subclass) is widely yet discretely expressed in the human brain, including many cortical, limbic, and forebram regions postulated to be involved in the modulation of higher cognitive and affective functions. This receptor subtype is also expressed on mature platelets where it mediates, in part, platelet aggregation, one of the initial steps in the process of vascular thrombosis.
Given the broad distribution of serotonin within the body, it is understandable that tremendous interest in drugs that affect serotonergic systems exists (Gershon, et
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al.. The Peripheral Actions of 5-Hydroxytryptamine, 246 (1989); Saxena, et aL, J Cardiovascular Pharmacol 15: Supp. 7 (1990)) Serotonin receptors are members of a large human gene family of membrane-spanning proteins that function as transducers of intercellular communication. They exist on the surface of various cell types, including neurons and platelets, where, upon their activation by either their endogenous Hgand serotonin or exogenously administered drugs, they change their conformational structure and subsequently interact with downstream mediators of cellular signaling. Many of these receptors, including the 5-HT2A subclass, are G-protein coupled receptors (GPCRs) that signal by activating guanine nucleotide binding proteins (G-proteins), resulting in the generation, or inhibition of, second messenger molecules such as cyclic AMP, inositol phosphates, and diacylglyceroL These second messengers then modulate the function of a variety of intracellular enzymes, including kinases and ion channels, -which ultimately affect cellular excitability and function.
At least 15 genetically distinct 5-HT receptor subtypes have been identified and assigned to one of seven families (5-HT1-7) Each subtype displays a unique distribution, preference for various Ugands, and functional correlate^).
Serotonin may be an important component in various types of pathological conditions such as certain psychiatric disorders (depression, aggressiveness, panic attacks, obsessive compulsive disorders, psychosis, schizophrenia, suicidal tendency), certain neurodegenerarjve disorders (Alzheimer-type dementia, Parkinsonism, Hnntington's chorea), anorexia, bulimia, disorders associated with alcoholism, cerebral vascular accidents, and migraine (Mcltzcr, Netiropsychopharmocology, 21:106S-l I5S (1999); Barnes & Sharp, S&trani'Mrmncoloty, 38:1033-1152 (1999); Gknnon. Neurpsd. BiobekavioraJ Rev^ 14:35 (1990)). Rscert evidence strongh-implicates the 5-HT2 receptor subtype in the etiology of such medical conditions as hypertension, thrombosis, migraine, vasospasm, ischemia, depression, anxiety, psychosis, schizophrenia, sleep disorders and appetite disorders.
Schizophrenia is a particularly devastating neuropsychiatric disorder that affects approximately 1% of the human population. It has been estimated that the total financial cost for the diagnosis, treatment, and lost societal productivity of individnals affected by this disease exceeds 2% of the gross national product (GNP) of the United States. Current treatment primarily involves phannacotherapy with a class of drugs known as antipsychotics. Antipsychotics are effective in ameliorating
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positive symptoms (e.g., hallucinations and delusions), yet tiaey frequently do not improve negative symptoms (e.g., social and emotional withdrawal, apathy, and poverty of speech).
Cwrently, nine major classes of antipsychotics are prescribed to treat psychotic symptoms. Use of these compounds is limited, however, by their side effect profiles. Nearly all of the "typical" or older generation compounds have significant adverse effects on human motor function. These "extrapyramidal" side effects, so termed due to their effects on modulatory human motor systems, can be both acute (e.g., dystonic reactions, a potentially life threatening but rare neuroleptic malignant syndrome) and chronic (e.g., akathisias, tremors, and tardive dyskinesia). Drug development efforts have, therefore, focused on newer "atypical" agents free of these adverse effects.
Antipsychotic drugs have been shown to interact with a large number of central monoaminergic neurotransmitter receptors, including dopaminergic, serotonergic, adrecergic, muscarinic, and histammergic receptors. It is likely that the therapeutic and adverse effects of these drugs are mediated by distinct receptor subtypes. The high degree of genetic and pharmacological homology between these receptor subtypes has hampered the development of subtype-selective compounds, as well as the determination of the normal physiologic 6i pathophysiologic role of any particular receptor subtype. Thus there is a need to develop drugs that are selective for individual receptor classes and subclasses amongst monoaminergic nemotransiintter receptors.
The prevailing theory for the mechanism of action of antipsychotic drugs involves antagonism of dopanrine D2 receptors. UcfaitmiatdY, it is likely that atssgerrism of depamine TO receptors-also mediates the extrapyrainidal^ide effects. Antagonism of 5-HT2A is an alternate molecular mechanism for drugs with antipsychotic efficacy, possibly ihrough antagonism of heightened or exaggerated signal transduction through seroionergic systems. 5-HT2A antagonists are therefore good candidates fox treating psychosis without extrapyramidal side effects.
Traditionally, these recejitors have been assumed to exist in a quiescent state unless activated by the binding of an agonist (a drug that activates a receptor). It is now appreciated that many, if not most, of the GPCR rnonoamine receptors, including serotonin receptors, can exist in a partially activated state in the absence of their endogenous agonists. This increased basal activity (constitutive activity) can be
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inhibited by compounds called inverse agonists. Both agonists and inverse agonists possess intrinsic activity at a receptor, in that they alone can activate or inactivate these molecules, respectively. In contrast, classic or neutral antagonists compete against agonists and inverse agonists for access to the receptor, but do not possess the intrinsic ability to inhibit elevated basal or constitutive receptor responses.
We have recently elucidated an important aspect of 5-HT2A receptor function by applying the Receptor Selection and Amplification Technology (U.S. Patent 5,707,798,1998; CkemAbstr. 128:111548 (1998) and citations therein), to the study of the 5-HT2 subclass of serotonin receptors. R-SAT is a phenotypic assay of receptor ftmction that involves the beterologous expression of receptors in mammalian fibroblasts. Using this technology we were able to demonstrate that native 5-HT2A receptors possess significant constitutive, or agonist-independent, receptor activity (U.S. Patent Application Ser. No. 60/103,317, herein incorportated by reference). Furthermore, by directly testing a large number of centrally acting medicinal compounds with known clinical activity in neuropsychiatric disease, we determined that compounds with anlipsychotic efficacy all shared a common molecular property. Nearly all of these compounds, which are used by psychiatrists to treat psychosis, were found to be ]x>tent 5-HT2A inverse agonists. This unique clinico-pharmacologic correlation at a single receptor subtype is compelling evidence that 5-HT2A receptor inverse agonism is a molecular mechanism of antipsychotic efficacy in humans.
Detailed pharmacological chiiracterization of a large number of antxDsvchotic compounds revealed that they possess broad activity at multiple related receptor subtypes. Most of tbese compounds display agonist, competitive antagonist, or inverse agonist activity at multiple monoaminergic receptor subtypes, including serotoninergic, dopaminergic, adrcncrgic, muscarinic and fcist&ninergic receptors. Tins broad activity is likely responsible for the sedating, hypotensive, and motor side effects of these compounds. It would therefore be of great advantage to develop compounds that are selective inverse agonists of the 5-HT2A receptor, but which have little or no activity on other monaminie receptors subtypes, especially dopamme D2 receptors. Such compounds may be useful in the treatment of human disease (e.g., as anti-psychotics), and may avoid the adverse side effects associated with non-selective receptor interactions.
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Summary of the Invention
The present invention provides compounds of the general formula (I) that affect monoamine receptors, especially serotonin receptors, and share as a common property inverse agonist activity at the 5-HT2A subtype of human serotonin receptors:

R is hydrogen, a cyclic or straight-chained or branched acyclic organyl group, a low er hydroxyaflcyl group, a lower aminoalkv] group, or an aralkyl or heteroaralkyl group;
nisO, I,or2;
Xi is methylene, vinylene,or an NH or K(lower alkyl) group;and
Xj is methylene, or, when X\ is methylene or vinylene, X2 is methylene or a bond, or whec Xi is methylene, X2 is O, S, NH. or N(lower alkyl) or a bond;
Yj is methylene and Y2 is methylene, vinylene, ethylene, propyiene, OT a bond;
Yi is a bond and Y2 is vinylene; or
Yi is ethylene and Y2 is O, S, NH, or NQower alkyl);
Ai] and Ar2 independently are unsubstituted or substituted aryl or heteroaryl groups;
W is oxygen or sulibr; or
a phannaceuticalry acccpta3>Ie salt, ester, or prodrug thereof.
The present invention also provides pharmaceutical compositions comprising an effective amount of a compound of formula (I) or phannaceutically acceptable salts, esters, or prodrugs thereof.
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Also provided are methods of inhibiting an activity of a monoamine receptor comprising contacting the monoamine receptor or a system containing the monoamine receptor with an effective amount of a compound of formula (I), as well as kits for performing the same. Preferably, the receptor is a serotonin receptor of the 5-HT2A subclass. Tlie receptor may be located in either the central or peripheral nervous system, blood cells or platelets, and may be mutated or modified. In a preferred embodiment, the receptor is constitutively active.
Furthermore, the present invention relates to a method of inhibiting an activation of a monoamine receptor comprising contacting the monoamine receptor or a system containing the monoamine receptor with an effective amount of compound of formula (I), as well as kits for performing the same In a preferred embodiment, the compound is selective for the 5-HT2A serotonin receptor. In another preferred embodiment, the compound has little or substantially no anti-dopaminergic activity. The receptor may be constitutively active or may be activated by an endogenous or exogenous agonistic agent.
Another aspect of the present invention relates to a method of treating a disease condition associated with a monoamine receptor comprising administering to a mammal in need of such treatment an effective amount of a compound of formula (I), and kits for performing the same. Examples of disease conditions for which such treannent using the compounds of the invention, cr phannaceuticaj compositions comprising them, is useful include, but are not Umited to, neuropsychiatric diseases such as schizophrenia and related idiopathic psychoses, depression, anxiety, sleep disorders, appetite disorders, affective disorders such as major depression, bipolar disorder, and depression with psychotic features, and Tourette's Syndrome. Said compounds may also be beneficial for the tresanem of drug-induced psychoses as well as psychoses secondary to neurodegencrauve disorders such as Alzheimer's or Huntington s Disease. The compounds of the invention may also be useful in treating hypertension, migraine, vasospasm, ischemia and the primary treatment and secondary prevention of various thrombotic conditions including myocardial infarction, thrombotic or ischemic stroke, idiopathic and thrombotic thrombocytopexoc purpma, and peripteral vascular disease.
Further provided is a method for identifying a genetic polymorphism predisposing a subject to being responsive to a compound of formula (I), comprising administering to a subject an effective amount of the compound; identifying a
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responsive subject having an ameliorated disease condition associated with a roonoamine receptor; and identifying a genetic polymorphism in the responsive subject, wherein the genetic polymorphism predisposes a subject to being responsive to the compound. Also provided are kits for performing the same.
A method for identifying a subject suitable for treatment with the compound of formula (I) and kits for identifying the same, is also provided. According to the method, the presence of a polymorphism that predisposes the subject to being responsive to the compound is detected, wherein the presence of the polymorphism indicates that the subject is suitable for treatment.
Brief Description of the Drawings
Figure 1 is a graph showing data obtained from a dose response analysis of 26HCH17 and ritanserin as 5-FfT2A receptor inverse agonists.
Figure 2 is a graphic representation of in vivo pharmacology data obtained in mice with 2-(4-methoxyphenyl)-Ar-(4-methylben2yl)-W-(l-methylpiperidin-4-yl)acetamide hydrochloride. Figure 2A shows the effects of this novel antipsychotic agent compound in a head twitch behavioral model; Figure 2B shows the results of locomotor experiments; and in Figure 2C pre-pulse inhibition study results are shown. Detailed Description of the Invention
Definitions
For the purpose of the current disclosure, the following definitions shall in their entireties be used to define technical terms, and shall also, in their entireties, be used to define the scope of the composition of matter for which protection is sought in the claims.
"Constitutive activity" is defined as the elevated basal activity of a receptor which is independent of the presence of an agonist Constitutive activity of a receptor may be measured using a number of different methods, including cellular (e.g., membrane) preparations (see, e.g., Barr &. Manning, J. Biol. Chem. 272:32979-87 (1997)), purified reconstituted receptors with or without the associated G-protein in pbospbofipid vesicles (Cerionc et aL, Biochemistry 23:4519-25 (1984)), and functional cellular assays (U.S. Patent Application Ser. No. 60/103,317)-
" Agonist" is defined as a compound that increases the activity of a receptor when it contacts the receptor.
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An "antagonist" is defined as a compound that competes with an agonist or inverse agonist for binding to a receptor, thereby blocking the action of an agonist or inverse agonist on the receptor. However, an antagonist (also known as a '"neutral" antagonist) has no effect on constitutive receptor activity.
An "inverse agonist is defined as a compound that decreases the basal activity of a receptor (i.e., signalling mediated by the receptor). Such compounds are also known as negative antagonists. An inverse agonist is a ligand for a receptor that causes the receptor to adopt an inactive state relative to a basal state occurring in the absence of any ligand. Thus, while an antagonist can inhibit the activity of an agonist, an inverse agonist is a ligand that can alter the conformation of the receptor in the absence of an agonist. The concept of an inverse agonist has been explored by Bond et al. in Nature 374:272 (1995). More specifically, Bond et al. have proposed that unliganded p 2-adrenoceptor exists in an equilibrium between an inactive conformation and a spontaneously active conformation. Agonists are proposed to stabilize the receptor in an active confonnation. Conversely, inverse agonists are believed to stabilize an inactive receptor conformation. Thus, while an antagonist manifests its activity by virtue of inhibiting an agonist, an inverse agonist can additionally manifest its activity in the absence of an agonist by inhibiting the spontaneous conversion of an unliganded receptor to an active confonnation.
The "5-HT2A receptor" is defined as a receptor, having an activity corresponding to the activity of the human serotonin receptor subtype, which was characterized through molecular cloning and pharmacology as detailed in Saltzman et al., Biochem. Biophys. Res. Comm. 181:1469-78; and Julius et al., Proc. Natl Acad. Sci. USA 87:928-932.
The term "subject refers to sn animal^ preferably a mammal, most preferably a human, who is the object of treafcrsnt, observation or experiment
"Selective" is defined as a property of a compound whereby an amount of the compound sufficient to effect a desired response from a particular receptor type, subtype, class or subclass with substantially little or no effect upon the activity other receptor types. "Selectivity or "selective, as an inverse agonist is understood as a property of a compound of the invention whereby an amount of compound that effectively inversely agonises the 5-HT2A receptor, and thereby decreases its activity, causes little or no inverse agonistic or antagonistic activity at other, related or
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unrelated, receptors. In particular, the compounds of the invention have surprisingly been found not to interact strongly with other serotonin receptors (5-HT 1A, IB, ID, IE, IF, 2B, 2C, 4A, 6, and 7) at concentrations where the signalling of the 5-HT2A receptor is strongly or completely inhibited. Preferably, the compounds of the invention are also selective with respect to other monoamine-binding receptors, such as the dopaminergic, histaminergic, adrenergic and muscarinic receptors. Compounds that are highly selective for 5-HT2A receptors may have a beneficial effect in the treatment of psychosis, schizophrenia or similar neuropsychiatric disorders, while avoiding adverse effects associated with drugs hitherto suggested for this purpose. EC50 for an agonist is intended to denote the concentration of a compound needed to achieve 50% of a maximal response seen in R-SAT. For inverse agonists, EC50 is intended to denote the concentration of a compound needed to achieve 50% inhibition of an R-SAT response from basal, no compound, levels.
As used herein, "coadministration" of pharmacologically active compounds refers to the dehvery of two or more separate chemical entities, whether in vitro or in vivo. Coadministration refers to the simultaneous delivery of separate agents; to the simultaneous delivery of a mixture of agents; as well as to the delivery of one agent followed by delivery of a second agent or additional agents. In all cases, agents that are coadministered are intended to work in conjunction with each other.
"Cyclic organyl groups' are aliphatic, alicyclic groups in which carbon atoms form a ring. In preferred embodiments containing four, five, six or seven carbon atoms, the ring, as a substituent, is connected either directly via one of the ring atoms or via one or more appended carbon atoms. Particular examples of such groups include cyclopentyl, cyclohexyl, cycioheptyl, cyclopentylmethyl, cyclohexymiemyi, cyclohexylethyl groups, and the like.
"Straight-chained acyclic orjjanyl groups" are substituent groups consisting of a linear arrangement of carbon atoms, where accordingly each carbon atom binds a maximum of two other carbon atom ;, connected through single, double, or triple bonds. The straight-chained organy] groups may contain none, one, or several multiple bonds, and are, for example, commonly referred to as alkyl, alkenyl or alkynyl, or alkadieiryl groups, respectively. Examples of straight-chained organyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, propenyl, butenyl, pentadienyl, propargyl, butynyl.
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"Branched acyclic organyi groups" are substituent groups consisting of a branched arrangement of carbon atoms, where accordingly one or more carbon atoms may bind more than two other carbon atoms, connected through single, double, or triple bonds. The branched organyi groups may contain none, one, or several multiple bonds. Examples of branched organyi groups include iso-propyl, iso-butyl, tor-butyl, methylbutyL methylbatenyl, methylburynyl.
"Lower alkoxy groups" are Cm cyclic or acyclic organyi groups connected, as substituents, via an oxygen atom. Examples of lower alkoxy groups include methoxy, ethoxy, iso-propoxy, butoxy, tert-butoxy.
"Lower alkyl groups" are Ci_6 cyclic, straight-chained or branched aliphatic substituent groups connected via a carbon atom. Examples include methyl, ethyl, propyl, butyl, methylbutyl, cyclopropyl, cyclohexyl, tro-propvl, tert-butyl.
"Lower alkylamino groups" are understood as lower alkyl groups connected, as substituents, via a nitrogen atom, which may cany one or two lower alkyl groups. Particular examples include methylamino, dimethylamino, iso-propylamino. Optionally, lower aminoalkyi groups may consist of 4-6 membered nitrogen-containing rings, such as pytrolidino.
"Lower anunoalkyl groups" are lower alkyl groups carrying, as a substituent, an additional amino group. Examples include aminomethyl and arninoethyl.
"Lower hydroxyalkyi groups" are understood as lower alkyl groups carrying, as a substituent, an additional hydroxy group. Examples include bydroxymetnyL bydroxyethyL 24rydroxy-2-propyt hydroxypentyL
"Acyl groups" are hydrogen or lower alkyl groups connected, as substituents, via a carbonyl group. Example;; include formyi, acetyl, propanoyL
"Halo groups" are understood to be fiuoro, chloro, bromo, or iodo substituents, with fluoro and chloro being generally preferred.
"Lower alkylene groups" are straight-chained tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples inr.rndrs methylene (-CH2-), etbytene (-CHjCHr), propylene (-CH2CH2CH2-) or butylene (-(CHik-) groups.
"Vinylene groups" are ethene-l,2-diyl groups (-CHCH-) having (E) or (Z) configuration.
"Aralkyl groups" are aryl groups connected, as substituents, via a lower alkykne group. The aryl groups of aralkyl groups may be substituted or unsubstituted.
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Examples include benzyl, substituted benzyl, 2-phcnylethyl, 3-phenylpropyl, naphthylalkyl.
'Hcteroaralkyl groups' are understood as heteroaiyl groups connected, as substituents, via a lower alkylene group. The heteroaryl groups of heteroaralkyl groups may be substituted or unsubstituted. Examples include 2-tbienylroethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, imidazolylaltyl, and their substituted as well as benzo-fused analog.
"Aryl groups" are aromatic, preferably benzenoid or naphthoid, groups connected via one of the ring-forming carbon atoms, and optionally carrying one or more substituents selected from halo, hydroxy, amino, cyano, nitro, aDcylamido, acyl, lower alkoxy, lower alkyl, lower hydroxyalkyl, lower aminoalkyl, lower alkylamino, alkylsulfenyl, aDcylsulfinyl, alkylsulfonyl, sulfaraoyl, or trifluoromethyl. Preferred aryl groups are phenyl, and, most suitably, substituted phenyl groups, carrying one or two, same or different, of the substituents listed above. The preferred pattern of substitution hpara and/or meta. Representative examples of aryl groups include, but are not limited to, phenyl, 3-balophenyl, 4-halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-anunophenyl, 4-aminophenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphtbyi, hydroxynaphtfayl, hydrox^miethyipbenyl, trifluoroinethylphenyL
"Heteroaryl groups" are understood as aromatic, Cj^ cyclic groups containing one O or S atom or up to four N atoms, or a combination of one O or S atom with up to two N atoms, and their substituted as well as benzo- and pyrido-fosed derivatives, preferably connected via one of the ring-forming carbon atoms. Heteroaryi groups may carry one or more substituents, selected from halo, hydroxy, amino, cyano. nitio. alkylamidQ, acyl, lower alkoxy, lower alkyl, lower hydroxyalkyl, lower aminoalkyl, lower alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. Preferred heteroaryl groups are five- and six-membered aromatic heterocyclic systems carrying 0,1, or 2 substituents, which may be the same as OT different from one another, selected from the list above. Representative examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofurac, thiophene, benzotbiopbene, pyrrole, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzotbiazole, isothiazole, imidazole, benziinidazole, pyrazole, mdazole, and tetrazole, which are all preferred as well as furazan, 1,2,3-oxadiaaote, V^3-thiadiazole, l,2,4 tbiadiazole,
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triazole, benzotriazole, pyndine, quionohne, isoquinohne, pyridazine, pyrimidine, purine, pyrazine, ptcridine, and triazine. The most preferred substituents are halo, hydroxy, cyano, lower alkoxy, lower alkyl, lower hydroxyalkyl, lower alkylamino, and lower aminoalkyl.
The present invention provides compounds preferably showing a realtively high selectivity toward serotonin receptors, particularly, 5-HT2A receptors, which may have a beneficial effect in the treatment of neuropsychiatric disorders.
According to one embodiment, the present invention provides compounds of the general formula (I):

in which
R is a hydrogen, a cyclic or straight-chained or branched acyclic organyl group, a lower hydroxyaHcyl group, a lower aminoalkyl group, or an aralkyl or beteroaraBcyl group;
nisO, 1,OT2;
XI is methylene, vinylene,or an NH or N (lower alkyl) group; and
X2 is methylene, or, when Xi is methylene or vinylene, X2 is methylene or a bond; or when Xi is methylene, X2 is O, S, NH, or NGower alkyl) or 2 bond;
X
Yi is methylene and Y2 is methylene, vinylene, ethylene, propylene, or a bond; or
Yi is a bond and Y2 is vinylene; or
Y] is ethylene and Y2 is O, S, NH, or N(lower alkyl);
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Ari and Ar2 independently are unsubstituted or substituted aryl or heteroaryl groups; and
W is oxygen or sulfur;
or a pharmacologically acceptable salt, ester, or prodrug thereof.
In general, compounds of formula (I) are active at monoamine receptors, specifically serotonin receptors. Preferred compounds share the common property of acting as inverse agonists at fee 5-HT2A receptor. Thus, experiments performed on cells transiently expressing the human phenotype of said receptor have shown that the compounds of general formula (I) attenuate the signalling of such receptors in the absence of additional ligands acting upon the Teceptor. The compounds have thus been found to possess intrinsic activity at this receptor and are able to attenuate the basal, non-agonist-stimulated, constitutive signalling responses that the 5-HT2A receptor displays. The observation that the compunds of general formula (I) are inverse agonists also indicates that these compounds have the ability to antagonize the activation of 5-HT2A receptors that is mediated by endogenous agonists or exogenous synthetic agonist ligands.
In a preferred embodiment, the present invention provides compounds that preferably show a relatively high degree of selectivity towards the 5-HT2A subtype of serotonin receptors relative to other subtypes of the serotonin (5-HT) family of receptors as well as to other receptors, most particularly the roonoammergic G-protein coupled receptors, such as dopamine receptors. In another preferred embodiment, the compounds of the present invention act as inverse agonists at the 5-HT2A subtype of serotonin receptors.
The compoonds of genera] formula (I) znzy therefore be useful for treating or alienating symptoms of disease condraons associated with impaired function, in particular elevated levels of activity, of especially 5-HT2A receptors, whether this impaired function is associated with improper levels of receptor stimulation or phenotypicaJ aberrations.
Others have previously hypothesised that certain neuropsychological diseases might be caused by altered levels of constitutive activity of monoamine receptors. Such constitutive activity might be modified via contacting the relevant receptor with a synthetic inverse agonist. By directly testing a large number of centrally acting medicinal compounds with known clinical activity in neuropsychiatric disease, we determined that compounds with antipsychotic efficacy all shared a common
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molecular property. Nearly all of these compounds that are used by psychiatrists to treat psychosis were found to be potent 5-HT2A inverse agonists. This correlation is compelling evidence that 5-HT2A receptor inverse agonism is a molecular mechanism of antipsychotic efficacy in humans
Detailed pharmacological characterization of a large number of antipsychotic compounds in our laboratory revealed that they possess broad activity at multiple related receptor subtypes. Most of these compounds display either agonist, competitive antagonist, or inverse agonist activity at multiple monoarninergic receptor subtypes including serotoninergic, dopaminergic. adrenergic, muscarinic and histaminergic receptors. This broad activity is likely responsible for the sedating, hypotensive, and motor side effects of these compounds. It follows that the compounds disclosed herein will possess efficacy as, for example, novel antipsychotics, but will have fewer or less severe side effects than existing compounds.
The present invention also provides pharmaceutical compositions comprising an effective amount of a compound of general formula (I).
In a preferred embodiment of the compounds of formula (I), Yj is methylene and Y2 is a bond, methylene, ethylene, or vinylene, or Yj is ethylene and Y2 is O or S, and Xi is methylene and X2 is a bond, methylene, O, or S, or X] is NH or NQower alkyl).
In a further preferred embodiment of the compounds of formula (I), Z is
aid W is oxygen.
In a more preferred embodiment of the compounds of formula (I), n is r, Yi is methylene, Y2 is a bond, methylene, ethylene, or vinylene, Xiis methylene andX2 is a bond, or Xi is NH or N(lower alkyl) and X2 is methylene. In a further preferred embodiment of the compounds of formula (I), W is oxygen and An and Ar2 are different aryl or heteroary] groups, with different mono-substituted phenyl groups being particularly preferred. Preferably, An and A12 are not simultaneousry phenyl
Also preferred compounds of formula (I) are those where Z is l-(organyl or araIkyI)-4-piperidinyl.
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In another embodiment, the invention provides preferred compounds ot the formula (II):

in which RN is hydrogen, lower alkyl, aralkyl, or heteroaralkyl;
Ai " is selected from lower alkyl, lower alkoxy and halogen
ArSs selected from lower alkyl, lower alkoxy and halogen;
k is 1 or 2
and A is a suitable anion.
According to the invention, a suitable anion may be any anion capable of forming a pharmaceuticaily acceptable salt of the compound, as described in further detail below.
The present invention also provides a method of inhibiting an activity of a monoamine receptor. This method comprises contacting a monoamine receptor or a system containg the monamine receptor, wi:b an effective amount of a compound of formula (I). Accoding to one embodiment, the monamine receptor is a serotonin receptor. In a preferred embodiment, tbe compound is selective for the 5-HT2A receptor subclass. In another preferred embodiment, the compound has little or substantially no activity to other types of receptors, incrariing other serotonergic receptors and most particularly, monoaminergic G-protein coupled receptors, such as dopaminergic receptors.
The system containing the monoamine receptor may, for example, be a subject such as a mammal, non-human primate or a human. The receptor may be located in the central or peripheral nervous system, blood cells or platelets.
The system may also be an in vivo or in vitro experimental model, such as a cell culture model system that expresses a monamine receptor, a cell-free extract thereof that contains a monoamine receptor, or a purified receptor. Non-limiting examples of such systems are tissue culture cells expressing the receptor or extracts or lysates thereof. Cells that may be used in the present method include any cells
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capable of mediating signal transaction via monoamine receptors, expecially the 5-HT2A receptor, either via endogenous expression of this receptor (e.g., certain types of neuronal cells lines, for example, natively express the 5-HT2A receptor), or following transfection of cells with plasrnids containing the receptor gene. Such cells are typically mammalian cells (or other eukaryotic cells, such as insect cells or Xenopus oocytes), because cells of lower organisms generally lack the appropriate signal transduction pathways for the present purpose. Examples of suitable cells include: the mouse fibroblast cell line NIH 3T3 (ATCC CRL 1658), which responds to transfected 5-HT2A receptors by stimulating growth; RAT 1 cells (Pace et al., Proc. Natl. Acad Sci. USA 88:7031-35 (1991)); and pituitary cells (Vallar et al, Nature 330:556-58 (1987)). Other useful mammalian cells for the present method include HEK 293 cells, CHO cells and COS cells.
The invention specifically provides methods of inhibiting an activity of a native, mutated or modified monoamine receptor. Also provided are kits for performing the same. In a preferred embodiment, the activity of the receptor is a signalling activity. In another preferred embodiment^ the activiny of the receptor is the constitutive basal activity of the receptor. Preferrably, the compound is an inverse agonist selective for the 5-HT2A receptor. Most preferably, the compound has little or substantially no activity toward other serotonergic or other monoaminergic receptors, such as dopamraergic receptors.
In one embodiment, the activity of the receptor is a response, such as a signalling response, to an endogenous agonist, such as 5-HT, or an exogenous agonistic agent, such as a drug or other synthetic ligand. The compound of formula (I) preferably acts by inversely agonising or antagonising the receptor.
Furthermore, the present invention relates to a method of inhibiting an activation of a monoamine receptor ramprising contacting the monoamine receptor, or a system containing the monoamine receptor, with one or more compounds of the invention. The activation of the receptor may be due to an exogenous or endogenous agonist agent, or may be the constitutive activation associated with a native, mutated or modified receptor. The receptor may purified or present in an in vitro or in vivo system. The receptor may also be present in the central or peripheral nervous system, blood cells or platelets of a nonhuman or human subject. Also provided are kits for performing the same.
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In a preferred embodiment, the compound is selective for 5-HT class serotonin receptors, more preferably, the 5-HT2A sublass of serotonin receptors. In another preferred embodiment, the compound has little or substantially no anti-dopaminergic activity.
The present invention provides methods of treating a disease condition associated with a monoamine receptor comprising administering to a mammal in need of such treatment an effective amount of a compound of formula (I). The invention specifically provides methods for treating or alleviating disease conditions associated with improper function or stimulation of native, as well as mutated or otherwise modified, forms of central serotonin receptors, particularly the 5-HT class of such receptors, comprising administration of an effective amount of a selective inverse agonist of the general formula (I) to a host in need of such treatment. Also provided are kits for performing the same.
In a preferred embodiment, ihe receptor is the 5-HT2A subclass. In one embodiment, the disease condition is associated with dysfunction of the serotonin receptor. In another embodiment, the disease condition is associated with activation of the serotonin receptor, preferably inappropriately elevated or constitutive activation, elevated serotonergic tone, as well as disease conditions associated with secondary cellular functions imparicd by such pathologies.
Examples of diseases for which such treatment using the compounds of the im eniioo, or pharmaceutical compositions comprising such compounds, is useful include, but arc not limited to, neuropsychiatric diseases such schizophrenia and related idiopathic psychoses, anxiety, sleep disorders, appetite disorders, affective disorders such as major depression, bipolar disorder, and depression with psychotic features, and Tourette's Syndrome, cirug-induced psychoses, psychoses secondary to neurodegenerative disorders such as Alzheimer's or Huntington's Disease. It is anticipated that the compounds of this invention, particularly selective inverse agonists of 5-HT2A that show little or no activity on dopaminergic receptors, may be especially useful for treating schizophrenia. Treament using the compounds of the invention may also be useful in treating migraine, vasospasm, hypertension, various thrombotic conditions including myocardial infarction, thrombotic or ischenric stroke, idiopathic and thrombotic thrombocytopenic purpura, and peripheral vascular disease. In a further embodiment the present invention provides methods for treating or alleviating a disease condition associated with improper function, dysfunction, or
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stimulation of native, as well as mutated or otherwise modified, forms of central or peripheral monoamine receptors, such methods comprising administration of an effective amount of a compound of the general formula (I) to a host in need of such treatment. Preferably the monaminc receptor is serotonin receptor in the peripheral nervous system, blood or platelets; more preferably a 5-HT2A subclass receptor. In additional embodiments, the disease condition is associated with increased activity or activation of a serotonin receptor. AJso provided are kits for performing the same.
The present invention also pertains to the field of predictive medicine in which pharmacogenomics is used for prognostic (predictive) purposes. Pharmacogenomics deals with clinically significant hereditary variations in the response to drugs due to altered drug disposition and abnormal action in affected persons. See e g., Eichelbaum, Clin Exp Pharmacol PhysioL, 23:983-985 (1996), and Under, Clin. Chem. 43:254-66(1997). In general, two types of pharmacogenetic conditions can be differentiated: genetic conditions n-ansmitted as a single factor altering the way drugs act on the body (altered drug action), and genetic conditions transmitted as single factors altering the way the body acts on drugs (altered drug metabolism). These pharmacogenetic conditions can occur as naturally occurring polymorphisms.
One pharmacogenomics approach to identifying genes that predict drug response, known as "a genome-wide association," relies primarily on a high-resolution map of the human genome consisting of already known gene-related markers (e.g., a "bi-allelic" gene marker map that consists of 60,000-100,000 polymorphic or variable sites on the human genome, each of which has two variants). Such a high-resolution genetic map can be compared to a map of the genome of each of a statistically significant number of patients taking part in a Phase U/IH drug trial to identify markers associated with a particular observed drug response or side effect. Alternatively, such a high-resolution map can be generated from a combination of some ten-million known single nucleotide polymorphisms (SNPs) in the human genome. As used herein, a "SNP is a common alteration mat occurs in a single nucleotide base in a stretch of DNA. For example, a SNP may occur once per every 1,000 bases of DNA. A SNP may be involved in a disease process; however, the vast majority may not be disease-associated. Given a genetic map based on the occurrence of such SNPs, individuals can be grouped into genetic categories depending on a particular pattern of SNPs in their individual genome. In such a manner, treatment
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regimens can be tailored to groups of genetically similar individuals, taking into account traits that maybe common among such genetically similar individuals.
Alternatively, a method termed the "candidate gene approach" can be utilized to identify genes that predict drug response. According to this method, if a gene that encodes a drug's target is known (e.g., a protein or a receptor of the present invention), all common variants of that gene can be fairly easily identified in the population and it can be determined if having one version of the gene versus another is associated with a particular drug response.
Alternatively, a method termed the "gene expression profiling", can be utilized to identify genes that predict drug response. For example, the gene expression of an animal dosed with a drug (e.g., a molecule or modulator of the present invention) can give an indication whether gene pathways related to toxicity have been turned on.
Information generated from more than one of the above phannacogenomics approaches can be used to determine appropriate dosage and treatment regimens for prophylactic or therapeutic treatment of an individual. This knowledge, when applied to dosing or drug selection, can avoid adverse reactions or therapeutic failure and thus enhance therapeutic or prophylactic efficiency when treating a subject with a molecule or modulator of the invention, such as a modulator identified by one of the exemplary screening assays descril>ed herein. As we have described previously, this approach can also be used to identify novel candidate receptor or other genes suitable for further pharmacological characterization in vitro and in vivo.
Accordingly, the present invention also provides methods and kits for identifying a genetic polymorphism predisposing a subject to being responsive to a compound described herein. The zrtethcxi comprises administering to & subject an effective amount of a compound^ identiiying a responsive subject having'an ameliorated disease condition associated with a monamine receptor; and identifying a genetic polymorphism in the responsive subject, wherein the genetic polymorphism predisposes a subject to being responsive to the compound. It is anticipated mat this method may be useful both for predicting which individuals are responsive to therapeutic effects of a compound and also for predicting those likely to experience adverse side effect responses. This approach may be useful for identifying, for exampie, polymorphisms in a serotonin receptor that lead to constitutive activation and are thus amenable to inverse agonist therapy. In addition, this method may be useful for identifying polymorphisms that lead to altered drug metabolism whereby
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toxic byproducts are generated in the body Such a mechanism has been implicated in the rare, but potentially life threatening side effects of the atypical antipsychotic, clozapine.
In a related embodiment, a method for identifying a subject suitable for treatment with a compound of the present invention is provided. According to the method, the presence of a polymorphism that predisposes the subject to being responsive to the compound is detected, the presence of the polymorphism indicating that the subject is suitable for treatment. AJso provided are kits for performing the same.
The compounds of this invention preferably show selective inverse agonist activity towards the 5-HT2A receptor. Such activity is defined by an ability of the ligand to attenuate or abolish the constitutive signaling activity of this receptor. Selectivity in the present context is understood as a property of a compound of the invention whereby an amount of compound that effectively inversely agonizes the 5-HT2A receptor and thereby decreases its activity causes httle or no inverse agonistic or antagonistic activity at other, related or unrelated, receptors. In particular, the compounds of the invention ha\e surprisingly been found not to interact strongly with otheT serotonin receptors (5-HT 1A, IB, ID. IE, IF, 2B, 2C, 4A, 6, and 7) at concentrations where the signaling of the 5-HT2A receptor is strongly or completely inhibited. Preferably, the compounds of tbe invention are also selective with respect to other monoamine-bicding receptors, such as the dopaminergk, histaminergic, adrencrgic and nrascarinic receptors.
A particularly preferred embodimeni of this invention includes: N^l^l-^nethylctny0piperidm-4-yf)-N-((4-methy^icnyi)memyl)-4-methoxyphenylacetamide;
N-( 1 --4-methoxyphenylacetamide;
N^l-penty^iperidiiH4-yl)-N-^(4-^DethylphenyI^nethyl)-4-methoxyphenyiacetamide;
N-(l -hexy!piperidm-4-yi)-N-((4-me&ylphenyl)methy l>-4-methoxyphenylacetamidc;
N-(l-cyclohexylpiperidin-4-yi>N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;
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N-(l-cyclopentylpiperidiD-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacet amide;
N-(l-cyclobutylpiperidm-4-yl)-N-((4-methylphenyl)methy])-4-methoxyphenylacetamide;
N-(l-cyclopropylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;
N-(l-(cyclopentylmethyI)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-m ethoxyphenyl acetamide;
N-(I-(cycIobutylmethyl)piperidiD-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;
N-(l-(cyclopropylmcthyI)piperidiii-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;
N-{l-(2-hydroxyethyl)piperidin-4-yI)-N-((4-methylphenyl)methyl)-4-methoxyphenylacctamide;
N-(H3-hydroxypropyl)piperidin-4-yl)-N-((4-methylphenyl)methyI)-4-methoxyphenylacetamide;
K-((4-Methy]phenyl)methy])-N-(pipendin-4-y])-N>-phenyhneihylcarbamide;
N-((4-MetfaylphenyI)methyl)-N-(l-(2-methylpropyI)piperidin-4-yI)-N'-phenylmethylcarbamide;
K-(H(2-BromopheDyl)me1hyl)pipericTn-4-yJ>N-((4-nietfaylphenyl)methyl)-N' -pheny lmethylcaibainidc;
N-(l-((4-Hydroxy-3-methoxypheJiyI)methyl)piperi N NT -phenyhnethylcarbamidc;
N^l-(Imida2o]-2-ylmcthy])piperidin^yI>N-((4-methylphCTyl)methyl)-N'-pheDylmethylcarbaraide;
N^HCyclohexyhnethyl)piperidin-4-yl>-N-((4-iDethylphenyl)metfayl)-N>-
phcnylmetbylcaibazmde;
N^H(4-HuoropbcnyI)mcaiyI)pipciidiiHV-yl)-NK(4-mcthyipfacaj^^^ N1 -phenyhnethylcart>amidc;
N-((4-Methylphenyl)methyl)-N-(piperidiB-4-yl)-4-methoxypheny]acetamide;
N-((4-MctbyIphcnyI)mcthyl)-N-(l-inethyIpipcridiD-4-yI)-4-methoxyphenylacetamide;
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N-(l-Ethylpiperidin-4-y])-N-((4-methylphenyl)methyl)-4-methoxyphcnylacetamide;
N-((4-Methy]phenyl)methyl)-N-(l-prapylpipendin-4-y!)-4-methoxypbenylacetamide;
N-(l-Butylpiperidui-4-yl)-N-((4-methylphenyl)niethyI>4-rnethoxyphenylacetamide;
N-(l-(3)3-Diinethy]butyl)piperidiii-4-yl)-N-((4-inethylphenyl)methyl)-4-methoxypbenylacetamide;
N-(l-(Cyclohexylinethy])piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;
N-((4-Methylpheayl)mettiyl)-N-(l-(2-inetliylpropyl)pipendin-4-yl)-4-methoxyphenyl acetam ide;
N-((4-Methylphenyl)metbyl)-N-(l-((4-methylphenyl)methyl)piperidin-4-yl)-4-methoxyphenylacetamide;
N-(l ((4-Hydroxyphenyl)methyl)piperidiii-4-yl)-N-((4-methyIphenyl)niethyl)-4-methoxyphenylacetamide;
N-(l-((2-Hydroxyphenyl)methy!)piperidin-4'yI)-N-((4-tnethylph6nyl)methyl)-4-Di ethoxyphcnylacetamidc;
N-(3-Plienylprapyl)-N-(ptp eri din-4-yl)-4-methoxyphenylacetamide;
N-(2-Pheny]ethy])-N-(piperidin-4-y])-4-methoxypheiiylac6taiiude;
N^(2-Mcthoxyphcnyl)mcthyl)-N-(piperidin-4-yl>4-methoxyphenylacetamide;
K-((2-Ch!orophenyl)metiiy])-N-^> iped din -4-yl)-4-methoxypbenylacetami de;
N^(3,4-DiHnethoxyphcnyI)mcthyI)-N-(pq)cridin-4-yl)-4-methoxyphenylacetamide;
N^(4-Fluorophenyl)methyI>N^iperidjm-4-yl>4-methoxypheiiylacetaiDide;
N- NK(3-Metfay^enyl)methyl>-N^p6ridin-4-yl>^-methoxyphCTylacctainide;
N^(3-BromophcnyI)mcthyI)-N^ipcridin-4-yI)^mctiioxyphenylacetamide;
N-(l -(Phenylmethyl)piperidin-4-yl)-N-(3-plienyl-2-propen-l -yiy4-m ethoxyphcnylacetami de;
N-((4-Mcthy Iphcny I)tncthyl)-N-( I -piperidin-4-yI)-phenylacctamidc;
N-{(4-MethyIphenyl)inethyl)-N- 22

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N-((4-Methylpheny])methyI)-N-{l-pipendin-4-yl)-(phenylthio)acctamide; N-((4-Methylpheny1)methyl)-N-{l-pjperidin-4-yl)-phenoxyacetamide;
N-((4-Methylphenyl)metliyl)-N-(l-piperidin-4-yl)-(4-chlorophenoxy)acetamide;
N-((4-Methylphenyl)methyl)-N-(l-piperidin-4-yl)-3-methoxyphenylacetamide;
N-((4-Methylphenyl)methyl)-N-{l-pipendin-4-yl)-4-fluorophenylacetanude;
N-((4-Methy]pheny])methy1)-N-(l-piperidin-4-y])-2,5-di-methoxyphenylacetamide;
N-((4-Methylphenyl)methyI)-N-(l-pipcridin-4-yI)-4-chlorophenylacetamide;
N-((4-MethylphenyI)methy])-N-(l-(phenylmethyl)pyn-oIidin-3-yI)-N'-phenylmethylcarbamide;
N-((4-Methylpheny])inethyl)-N-(l-(phenylmethyl)pyrrolidin-3-yl)-4-methoxyphenylacetamide;
2-(4-methoxyphenyl)-N-(4-methylbenzyl)-N-(piperidin-4-yl)acetamide;
2-(4-methoxyphenyI>N-(4-methylbenzyl)-N-( 1 -methy lpiperidin-4-yl) acetamide;
2-(4-methoxyphenyI)-N-(4-rnethylbenzyl)-N-(l-ethyIpiperidin-4-yl) acctanide;
2-(4-methoxyphsnyl>N-(4-c.hlorbenzyl)-N-(l -ethylpiperidin-4-yI) acetamide;
2-(4-methoxypheoyl)-N-(4-ch]orbenzy])-N-(l-isopropylpiperidin-4-yl) acetamide;
2-(4-metlioxyphenyI)-N-{4-chlorobeiizyl)-N-(piperidiii-4-yl) acetamide;
2-(4-me1iioxyphenyI>N-(4-chIorben2>'!>N-( 1 -cycI 2-(4-methoxypheny])-N-(4-cliIorben2yl)-N-(l-isopropylpiperidin-4-yI) acetamide;
2-(phenyl>N-{4-trifluoromethyJben2yI)-N-(l-methyIpiperidin-4-yl) acetamide;
2-{4-3uorophenyl)-N-(4-trifluoTX5methyIbeiizyl)-N-(l -methylpiperidm-4-yI) acetamide;
2-(4-Methoxyphenyl)-N-(4-tiifluoromethylbeiizyl)-N-(l-mcthylpiperidin-4-yl)
acetamide;
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2-(4-TrifluororaethyIphenyi[)-N-(4-triiluoromethyIbenzyl)-N-(l-methylpiperidin-4-yl) acetamide;
2-(4-Fluorophenyl)-N-(4-fluoroben23'l)-N-(l-inethylpiperidin-4-yl)acetanude;
2-(4-Methoxypbenyl)-N-(4 -iluorobenzyl)-N-(l -methylpiperidin-4-yl) acetamide;
2-(phenyl) N-(4-fluorobenzyI)-N-(l -methylpiperidin-4-yl) acetamide;
2-(4-Trifluoromethylphenyl)-N-(4-fluorobenzyI)-N-(l-methylpiperidui-4-yI) acetamide;
2-(4-trifluoromethyIphenyl)-N-[4-(rDethoxycarbonyl)benzyl]-N-(l-methylpiperidin-4-yI) acetamide;
2-Phenyl-N-[4-(methoxycarboiiyl)ben2yl3-N-(l-methylpiperidin-4-yl) acetamide;
2-(4-ChlorophenyI)-N-t4-(methoxycarbonyI)ben2yl]-N-(l-methyIpiperidin-4-
yl) acetamide;
2-(4-MethoxyphejiyI)-N-[4-(methoxycarbon\l)ben2yl]-N-(l-n)emylpiperidin-
4-yl) acetamide;
2-(4-trifiuoromethylpheDyl)-N-[4-(methoxycarbonyl)benzyI]-N-(l-methylpiperidin-4-yI) acetamide;
2-PheuyI-N'[4-(inetboxycari>onyl)benz>l]-K-{l-methylpiperidin-4-yl)
acetamide;
2^4l)benzyl]-N-(l-methylpiperidin-4-
yl) acetamide;
2^4 Me&oxypbenyl)-N-[4-(methoxycajbo^ 4-yI) acetamide;
2-(4methoxypbenyI)-N-(4-methylben2y I>N-[ 1 - 2- 2phenyI)-NK2^(fluoropbenyl)emyI)-N^l-methylpiperidin-4-yl)
acetamide;
2-(4-methox>-phenyl}-N-[2-{2,5-dimemoxyphenyl)ethyl]-N-(l-methylpiperidin-4-yI) acetamide;
2-{4-methoxyphenyl)-N-[2-(2s4-dich]orophenyl)ethyl]-N-(l-methylpiperidin-
4-,yl) acetamide;
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2-(4-methoxyphenyl)-N-[2 -(3-cttorophenyl) ethyl]-N-(l -methylpiperidin-4-y]) acetamide;
2-(4-methoxyphenyI)-N-[2- (4-methoxyphenyl) ethyl]-N-(l -methylpiperidin-4-yl) acetamide;
2-(4-methoxyphenyl)-N-[2-(3-fluoropheny])ethyIJ-N-(l-methyIpiperidin-4-yl) acetamide;
2-(4-ethoxyphenyI)-N-[2-(4-fluorophenethyl]-N-(l-methylpiperidin-4-yl) acetamide;
2-(4-ethoxyphenyl)-N-(4-fluorobenz>i)-N-(l-methylpiperidin-4-yl) acetamide, 2-(4-methoxyphenyI)-N-(4-methylbenzy3)-N- {1 -[2-(2-hydroxyethoxy)ethyl] piperidin-4-yl} acetamide;
2-(4-methoxyphenyl>N-(4-![nethyIbenzyl)-N-[l-((2-ch3oro-5-thienyI)methyl) piperidin-4-yl] acetamide;
2-(4-methoxyphenyl)-N-(4-3iiethy]benzy l)-N-[ 1 -(2-(imidazolidinon-1 -yl)ethyI)piperidm-4-yl] acetamide;
2-(4-methoxyphenyl)-N-(4-methyIbenzyI)-N- {1 -[2-(2,4(lH,3H)quina2olinedion-3-yl)e1hyl] piperidin-4-yl} acetamide;
2-{4-methoxypheny])-N--K-{l-[2-(l^-dioxolan-2-yl)ethyl3piperidin-4-yI} acetamide;
2-(4-methoxyphenyl)-N-(4-inethy]benzyl)-N- {1 -[2-(3"mdoly3)ethyl] piperidin-4-yl} acetamide;
2-{4-metboxyphenyI>-N- 2-(4H0ietboxyphenyI>-N-(4-rnethylbenzyI>-N-[ 1 - 2-{4-methoxyphenyl)-N-(4-methylbeiizyl)-N-[l- 2-(4-methoxypheay]>-N- 2-{4-Chlorophenyl)-N-(4-mc:thy Ibenzy I>N-( 1 -isopropylpiperidin-4-yl)-acetamide;
2-(4-Chlorophenyl)-N-(4-methy lbenzy l)-N-( 1 -ethylpiperidin-4-yl)-acetamide; 2-Phcnyl-N-{4-methylbenzy])-N-(l-methylpiperidin-4-yl)-acctamide^-(4-Chlorophenyl)-N-(4-methyIbeiizyl)-N-{l-methylpipeiidin-4-yl>-^;etainide;
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2-(4-Chloropheny])-N-(4-methy]benzy])-N-(l-cyc]opentylpipendin-4-yl)-acetamide;
2- 2-(4-Chlorophenyl)-N-(4-methyIbenz>'l)-N-(l-(2-hydroxyethyl)-piperidin-4-yl)-acetamide;
2-(4-Ch]orophenyl)-N-(4-niethyIbenzyl)-N-(l-cyclobutylpipendiji-4-yl)-acetamide;
2-(4-Methox>fphenyI)-N-(4-inethyIben2yI)-N-(l-cyclobutyIpiperidin-4-yl)-acetamide;
2 -(4-Methoxjphenyl>-N-(4-methylben2y 1)-N -(tropin-4-yl)-acetamide;
N_(4-Methylbenzyl)-N-(l-methylpiperidin-4-yl)-N'-benzyl-cart) amide;
N- N-Phcnethyl-N-(l-mcthylpiperidin-4-yl)-N'-benzyl-cart) amide;
2-Phenyl-N-(4-methoxybenzyI)-N-(l-me(hy]piperidin-4-yI)-acetaraide;
2-(4-TrifluoromethyIphenyl)-N-(4-methoxybenz>'l)-N-(l-mcthylpiperidin-4-yl)-acetamide;
2-(4-FIuorophenyl)-N-(4-methoxyben2yl)-N-(l-raethylpiperidin'4-yl)-acetaznide;
2-(4-Methoxj-phenyl)-N-(4-methoxybciiz>l}-N- 2-(4-MethyIphen3d)-N^4-chlorobenzyI)--N- acetamide;
2-(4-HydroxypbenyI)-N-(4-incihyIbenz>'I>N- acetamide;
N-Phenetb}'I-N-(l-methyJpiperidiii-4-yI)-N'-pheDy]-cari) amide;
N-(3-Phenylpropy I)-N-( 1 -mcthyIpiperidin-4-yl)-N '-benzyl-carbamide;
N-(3-Phenylpiopyl>-N^l-methyIpiperidm-4-yO-N -pheiiyl--carbamide;
2-(4-MethoxyphcnyI)-2^- tbylcne-N^4-methylbenzyI)-N-(l-methylpiperidi3-4-yl) acetamide;
2-{4-Methoxyphenyl)-N-alpha-methyIben2yI-N-{ 1 -methylpiperidin-4-yl) acetamide;
2-(4-MethoxyphenyI)-N-(4-methylben2yI)-N-(3-tropen-4-yl) acetamide;
2-PhenyI-2-elhyl-N-(4-methylbenzyl)-N-( 1 -methylpiperidin-4-yl) acetamide;
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N-PhenetbyJ-N-(4-methyJbenzy]>N-( 1 -methylpiperidin-4-y])-amine; 2-(4-Methoxyphenyl>N-(l-indanyl)-N-(l -methylpipendin-4-yI) acetamide; N-(4-MethyIbenzyl)-N- 2-(3J4-dimethoxyphenyl)->J-(4-raethylbenzyl)-N- 2-(3,4-MethylenedioxyphenyI>-N-(4 methy]benzy])-N-(l-methy]piperidin-4 y]) acetamide;
2-(4-MethoxyphenyI)-N-(4-methyIbenzyI)-N-(l-t-but>'Ipiperidin-4-yI)-acetamide;
N-(4-MethyIbenzyl)-N-(l-inethylpiperidin-4-yl)-N'-phenethyl-carbaiiiide;
N-Phenethyl-N-(l-methylpipKidin-4-yl)-N'-phenethyl-carbaraide;
N-(4-MethyIbenzyl)-N-(l-l-butylpiperidin-4-yl)-N'-(4-methoxybenzyl)-carbamide;
2-(4-Ethoxyphenyi)-N-(4-niethy!benzyl)-N-(l-metfayIpiperidi3i-4-yl) acetamide;
2-(4-Butoxyphenyl)-N-(4-methylbenzyn-N-( 1 -methylpiperidin-4-yl) acetamide;
2-{4-i-Propoxypheny3)-N-(^methyIbenzyl)-N-(l-methylpiperidm-4-yl) acetamide;
2-(4-t-Butoxyphenyl)-N-{4-methyIbenzyI)-N-( 1 -methylpiperidin-4-yl) acetamide;
2^4-ButoxyphenyI)-N^4-fluorc4>eiizyIVN^l-tnethylpipeiidiD-4-yI) acetamide;
2-(4-Propoxyphenyl)-N-(4- flourobenzyI)-N-(l -methylpiperidin-4-yl) acetamide;
2-{4-i-Propoxyphenyl)-N-(4-fluoroben2y l)-N-{ 1 -methylpiperidin-4-y I) acetamide;
and, 2-(4-t-ButoxyphenyI)-N-{4-fluorobenzyl)-N-eridin-4-yl) acetamide.
Suitable phannaceutically acceptable salts of the compounds of this invention include acid addition salts that may,, for example, be formed by mixing a solution of the compound according to the invention with a solution of a phannaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid,
27

succinic acid, acetic acid, bcnzoic acid, oxalic acid, citric acid, tartanc acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof nay include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts, and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. Examples of pharmaceutically acceptable salts include the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium, carbonate, chloride, cla>rulanate, citrate, dihydrochloride, fumarate, gluconate, glutamate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malcate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, phosphate/diphosphate, salicylate, stearate, sulfate, succinate, tannate, tartrate, tosylate, triethiodide and valerate salt.
The present invention includes within its scope prodrugs of the compounds of this invention. In general, such prodrugs are inactive derivatives of the compounds of this invention that are readily co avertible in vivo into the required compound. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, (ed. H. Bundgaard, Elsevier, 1985). Metabolites o^Jjffe n^KrarK3s"in^Iu^e^ctive species mat are produced upon introduction of compounds of this invention into the biological milieu.
Where the compounds according to the invention have at least one crural center, they may exist as a raccinate or as enantiomers. It should be noted mat all such isomers and mixtures (hereof are included in the scope of the present invention. Furthermore, some of the crystalline forms for compounds of the present invention may exist as poryraorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates are also included in the scope of this invention.
Where the processes for the preparation of the compounds according to the invention give rise to mixtures of stereoi&omers, such isomers may be separated by conventional techniques such as preparative chiral chromatography. The compounds may be prepared in racemic fonn or individual enantiomers may be prepared by stereoselective synthesis or by resolution. The compounds may be resolved into their component cnantiomers by standard techniques, such as the formation of
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diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-dj-p-toluoyl-I-tartaric acid, followed by fractional crystallization and regeneration of the free base. The compound's may also be resolved by formation of diastereomeric esters or amides followed by chromatographic separation and removal of the chiral auxiliary.
Compounds of the present invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever specific pharmacological modification of the activity of monoamine receptors is required.
The present invention also provides pharmaceutical compositions comprising one or more compounds of the invention together with a pharmaceutically acceptable diluent or excipient. Preferably such compositions are in unit dosage forms such as tablets, pills, capsules (including sustained-release or delayed-release formulations), powders, granules, elixirs, tinctures, syrups and emulsions, sterile parenteral solutions or suspensions, aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral (e.g., intravenous, intramuscular or subcutaneous), intraiusal, sublingual or rectal administration, or for administration by inhalation or insufflation, and may be formulated in an appropriate manner and in accordance with accepted practices such as those disclosed in Remington's Pharmaceutical Sciences, (Gennaro, ed., Mack Publishing Co., Easton PA, 1990, herein incorportated by reference). Alternatively, the compositions may be in sustained-release form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decaiioate salt, may be adapted to provide a depot preparation for intramuscular injection. The present invention also contemplates providing suitable topical formulations for administration to, e.g., eye or skin or mucusa.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, flavoring agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in
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WO 01/66521 PCT/US01/07187
these dosage forms include, without limitation, sodium oleate, sodium stearatc, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentomte, xantban gum and the like.
For preparing solid compositions such as tablets, the active ingredient is mixed with a suitable pharmaceutical excipient such as the ones described above and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention or a pharmaceutically acceptable salt thereof. By the term "homogeneous" is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdhided into equally effective unit dosage forms such as tablets, pills and capsules. The solid preformulation composition may then be subdivided into unit dosage forms of the type described above containing from O.I to about 50 mg of the active ingredient of the present invention. The tablets or pills of the present composition may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner core containing Ihe active compound and an outer layer as a coating surrounding the core. The outer coating may be an enteric layer that serves to resist disintegration in the stomach and permits the inner core to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings including a number of polymeric acids and mixtures of polymeric acids with conventional :EBaterials such as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the present compositions may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical carriers. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanm, acacia, algmaie, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose or polyvinylpyrrolidone. Other dispersing agents that may be employed include glycerin and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations that gisnerally contain suitable preservatives are employed when intravenous administration is desired. The compositions can also be
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formulated as an ophthalmic solution or suspension formation, i.e., eye drops, for ocular administration
Consequently, the present invention also relates to a method of alleviating or treating a disease condition in which modification of monoamine receptor activity, in particular 5-HT2A serotonergic receptor activity, has a beneficial effect by administering a therapeutically effective amount of a compound of the present invention to a subject in need of such treatment. Such diseases or conditions may, for instance arise from inappropriate stimulation or activation of serotonergic receptors. It is anticipated that by using compounds that are selective for a particular serotonin receptor subtype, m particular 5-HT2A, the problems with adverse side effects observed with the known antipsychotic drugs, such as extrapyramidal effects, may be avoided substantially.
The term "therapeuhcally effective amount" as used herein means an amount of an active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated.
Advantageously, compounds of the present invention may be administered in a smgle daily dose, or the total daily dosage may be administered in divided doses, for example, two, three or four times daily. Furthermore, compounds of the present invention may be administered in intranasal form via topical use of suitable intranasal vehicles, via transdermal routes, using those forms of transderxnal skin patches well known to persons skilled in the art, by implantable pumps; or by any other suitable means of administration. To be administered in the form of a transdennal delivery system, for example, the dosage administration wiD,-of course, be continuous rather than intermittent throughout the dosage regimen.
The dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound employed. A physician or veterinarian of ordmary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the disease or disorder that is being treated.
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The daily dosage of the products may be varied over a wide range from about 0.01 mg to about 100 mg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing 0.01,0.05, 0.1, 0.5, 1.0,2.5, 5.0,10.0,15.0, 25.0 or 50.0 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. A unit dose typically contains from about 0.001 mg to about 50 mg of the active ingredient, preferably from about 1 mg to about 10 mg of active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0001 mg/kg to about 25 mg/kg of body weight per day. Preferably, the range is from about 0.001 to 10 mg/kg of body weight per day, and especially from about 0.001 mg/kg to 1 mg/kg of body weight per day.
Compounds according to the present invention may be used alone at appropriate dosages defined by routine testing in order to obtain optimal pharmacological effect on a monoaininergic receptor, in particular the 5-HT2A serotonergic receptor subtype, while minimizing any potential toxic or otherwise unwanted effects. In addition, co-administration or sequential administration of other agcnis that improve the effect of the compound may, in some cases, be desirable
The pharmacological properties and the selectivity of the compounds of this invention for specific serotonergic receptor subtypes may be demonstrated by a number of different assay methods using recombinant receptor subtypes, preferably of the human receptors if these are available, e.g. conventional second messenger or binding assays. A particularly convenient functional assay system is the receptor selection and amplifJcatioG assay disclosed in U.S. Pat No. 5,707,798, which describes a method of screening for bioactive compounds by utilizing the ability of cells transfected with receptor DNA, e.g., coding for the different serotonergic subtypes, to amplify in the presence of a ligand of the receptor. Cell amplification is detected as increased levels of a marker also expressed by the cells. Methods o/preparation
The compounds in accordance with the present invention may be synthesized by methods described below, or by modification of these methods. Ways of modifying the methodology include, among others, temperature, solvent, reagents etc, and will be obvious to those skilled in the art
For instance, compounds of the formula C may be synthesized from the corresponding ketone A by reductive aminatjon utilizing any primary amine. The
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WO 01/66521 PCTAJS01/07187
reaction is conveniently carried out by stirring the reactants in an inert solvent such as methanol or ethanol containing acetic acid. As reducing agent NaBHU, NaCNBH3, BH3 pyridine or any related reagent may be used including solid-supported reagents. The reaction is typically carried out at room temperature. The ketone A, as exemplified by the piperidone, may be chosen from a list of compounds corresponding to the Z-group listed in formula (I). The ketones can either be obtained commercially or synthesized by methodology disclosed in Lowe et al. J. Med. Chem. 37: 2831-40 (1994); Carroll et al J.Med Chem 35:2184-91 (1992); or Rubiralta et al. Pipendine - Structure, Perparation, Reactivity and Synthetic Applications of Piperidine and its Derivatives. (Studies in Organic Chemistry 43, Elsevier, Amsterdam, 1991). The protecting group P includes groups such as those described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Chemistry; 3. Ed. John Wiley & Sons, 1999, and they should be chosen in such a way, that they are stable to the reaction conditions applied and readily removed at a convenient stage using methodology known from the art. Typical protecting groups are N-Boc, N-Cbz, N-Bn.
Alternatively, the amine C c;an be synthesized from the primary amine B by reductive amination with any aldehyde. The reaction is conveniently carried out by stirring the reactants in an inert solvent such as methanol or ethanol containing acetic acid. As reducing agent NaBH4, NaCNBH3, BH3-pyridine or any related reagent may be used including solid-supported reagents. The reaction is typically carried out at room temperature. The primary amine B, as exemplified by the 4-aminopiperidine, may be chosen from a list of compounds corresponding to the Z-groups listed in formula (I). The amines can either be obtained commercially or synthesized from the corresponding ketones. The protecting group P may be chosen as stated above.
Alternatively, the amine C can be synthesized from the primary amine B by alkylation with any alkylating agent (R-Lj)- The leaving group Li is suitably a halogen atom, e.g., bromine or iodine, or a sulfonate, e.g. tosylate or mesylate, or another leaving group favoring the reaction. The reaction is conveniently carried out by stirring the reagents under basic conditions in an inert solvent, e.g., diisopropylethyiamme in acetonitrilc, or K2CO3 in A'.A^-dimethylformamide. The reaction is typically carried out at temperatures between room temperature and 80°C. The primary amine B, as exemplified by the 4-aminopiperidine, may be chosen from a list of compounds corresponding to the Z-groups listed in formula (I). The amines
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WO 01/66521 PCT/US01/07187
can either be obtained commercially or synthesized from the corresponding ketones. The protecting group P may be chosen as stated above.

Wherein R and R are defined in agreement with formula (I), and P represents a suitable protecting group, and Lt represents a suitable leaving group.
The secondary amine C may be acylated using any isocyanate or isothiocyanate (Qi-NO=W) to give the cotiesponduig ureas or thioureas D. The reaction is typically carried out by stirring the reactants, using an excess of isocyanate or isothiocyanate in an inert solvent, e.g-, dicfclsroaethane at a temperature,between 0°C and room temperature and under dry conditions. The amine C may also be acylated using any carboxylic acid halide (QsCOX), e.g., chloride, or carboxylic anhydride ((QtfXykO) to give amides of the general structure E. The reaction is typically carried out using an excess of the acylating agent and a suitable base, e.g., triethylamine or diisopropylethylamine in an inert solvent, e.g., dichJoromethane, at a temperature between 0°C and room temperature and under dry conditions. As an alternative to the carboxylic acid halides and carboxylic acid anhydrides, the amine C may be acylated using a carboxylic acid (Q2COOH) and a suitable coupling reagent e.g. DCC or EDCI. The reaction is typically carried out using an excess of the
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WO 01/66521 PCT/US01/07187
acylating agent and the coupling reagent in an mert solvent, e.g., dichloromethane at a temperature between 0°C and room temperature and under dry conditions. The compounds of the general structure (E) may be converted into the corresponding thioamides using methodology disclosed in Varraa et al, Org. Lett. 1: 697-700 (1999); Cherkasov et al. Tetrahedron 412567 (1985); or Scheibye et al Bull. Soc. Chim. Belg. 87229 (1978).

Wherein R^ Qu Q^ and W lire defined m agreement wife formula (I), P represents a suitable protecting group, and X represents a halide.
The substituent G on the ring nitrogen can be introduced by g. two step procedure. First, the protecting group on the urea D or the amide E is removed using well-known methods. For example., the N-Boc group is removed by treating the protected compound with 4 M HC1 in dioxane or trifluoroaceu'c acid in dichloromethane. Second, the secondary amines obtained from D and £ can be alkylated by reductive aminan'on wring any aldehyde (T-CHO). The reaction is conveniently carried out by stirring the reactsnts in an inert solvent such as methanol or ethanol. As a reducing agent, solid-supported borohydride, NaBH . NaCNBEb, BHspyridine or any related reagent may be used, including solid-supported reagents. The reaction is typically carried out at room temperature.
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Alternatively, the compounds F and G can be synthesized from the secondary amine obtained from D or E as described above by alkylation with any aKcylating agent (T- Li). The leaving group Lj is suitably a halogen atom, e.g., bromine or iodine, or a sulfonate, e.g., tosylate or mesylate, or another leaving group favoring the reaction. The reaction is conveniently carried out by stirring the reagents under basic conditions in an inert solvent, for example diisopropylethyl amine in acetonitrile, or K2CO3 in K N-dunethylfonnamidc. The reaction is typically carried out at temperatures between room temperature and 80°C.
Alternatively, the T-group can be introduced in the first step of the synthetic sequence leading to the compounds in accordance with the present invention by A-alkylation of compound H with any alkylating agent (T- Li). The leaving group Li is suitably a halogen atom, e.g., bromine or iodine, or a sulfonate, e.g., tosylate or mesylate, or another leaving group favoring the reaction. The reaction is conveniently carried out by stirring the reagent under basic conditions in an inert solvent, e g., diisopropylethylamine in acetonitrile, or K2CO3 in yV.W-dimethylformamide. The reaction is typically carried out at temperatures between room temperature and 80°C. The secondary amine H, as exemplified by 4-piperidone, may be chosen from a list of compounds corresponding to the Z-groups listed in formula (I). The amines can either be obtained commercially or synthesized from methodology disclosed in Lowe et al., J, Med. Chem. 37.2831-40 (1994); and Carroll et al., J. Med. Chem. 35:2184-91 (1992).
Alternatively, compounds of the general structure J may be synthesized starting from K using the method disclosed m: Kuehne et aL, J. Org. Chem. 56:2701 (1991); and Kuehne et al, J. Org. Chem. (1991), 56:513.
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wherein R, Qi, Qi, W, and T are defined in agreement with formula (I), and Li
is a suitable leaving group.
In general, dining any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of tbe molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J.F.W. McGmie, Plenum Press, 1973); and Greene & Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
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Examples
The invention is disclosed in further detail in the following examples that are not in any way intended to limit the scope of the invention as claimed.
General LC-MS procedure for Examples 1-41: All spectra were obtained using an HP 1100 LC/MSD-instrument A setup with a binary pump, autosampler, column oven, diode array detecter, and electrospray ionization interface was used. A reversed phase column (CIS Luna 3mm particle size, 7.5 cm x 4.6 mm ID) with a guard cartridge system was used. The column was maintained at a temperature of 30°C. The mobile phase was acetonitrile/8 mM aqueous ammonium acetate. A 15 minute gradient program was used, starting at 70% acetonitrile, over 12 minutes to 95 % acetonitrile, over 1 minute back to 70% acetonitrile, where it stayed for 2 minutes. The flow rate was 0.6 ml/min. The tj- values reported in the specific examples below
were obtained using this procedure.
Example 1 - AH(4-Methylphenyl)methyl)-Ar-(piperidin-4-yI)-Ar'-phenylmethylcarbamide (26HCH65)
To a solution of commercially available rer;-butyl 4-oxo-l-piperidine carboxylate (1.75 g, 8.S mmol) and 4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added acetic acid in methanol Q M, 6.7 mj) followed by NaCNBH3 in methanol (0.3 M, 30 ml). The resulting solution was stored at room
temperature. After 20 h, water (5 ml) was added, and the mixture was stirred for 1 h before it was concentrated. Flash chromatography in dichloromethanermethanol 10:1 gave tert-butyl 4^4-melhylphetiyI)memyI)amino-piperidme carboxylate. Yield: 2.4 g, 98%. To a solution of tert-butyl 4^4-memy^heo>1)methyl>ainmo-piperidme carboxyiate (800 mg, 2.63 mmol) in dry dichloromethape (20 ml) was added benzylisocyanate (0.65 ml, 5.26 mmol). The solution was stiued at room temperature. After 48 h, an excess of 2-dimethylaminoethylanaine was added. The mixture was stirred for another 24 h, before it was concentrated. The resulting solid was rtdissolved in dichloromcthane (20 ml), sequentially washed with HC1 (0.2 N, 3x30 ml), and water (20 ml), dried (Na2SO4), filtered and concentrated. Flash
chromatograpfay in dichloromethanermethanol 10:1 gave A^-((4-methylphenyI)methyI)-Ar-( l-(/err-butyloxycari>onyl)pip eridin-4-y 1)-W -phenylmethylcarbamide (760 mg, 66 %), which was dissolved in diethyl ether (5 ml). HC1 (4 M) in dioxane (3 ml) was added, and the solution was stirred at room
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temperature for 60 min, then concentrated The resulting oil was redissolved in a mixture of dichJoromethanc and diethyl ether (4.1). The organic layer was extracted with HC1 (0.2 M, 3x20 ml). The combined aqueous layers were treated with NaOH (0.2 M) until basic (pH>8), then extracted with dichloromethane (3x20 ml). The combined organic layers were dried (Na2SC>4), filtered, and concentrated to give the
title compound Yield: 406 mg, 70%; 13C-NMR (CDCI3): 6 21.3, 31.6, 45.0, 45.9, 46.4, 53.0, 126.3,127.2,127.4, 128.6, 129.8, 135.3, 137.4, 139.7, 158.5.
Example 2 - - -MethylpbenyOmetbyl -fl -methylpropyOpiperidin-4-yl)-iV-pheiiy]inethylcarbamide (26HCH66-02)
The product from example 1 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 2-MethylpropionaJdehyde (0.08 ml, 0.6 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in
methanol, and concentrated to give the title compound IR: 1640, 1185, IIIOCTT ; LC-MS: (M+H)+ 394.2, t,- 5.60 mis.
Example 3 - Ar- The product from example 1 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 2-Bromdbenzaldehyde (0.07 ml, 0.6 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (03 mmol/g resin), which was washed with methanol (3x6 ml), and elated with 10% NH3 in
methanol, and concentrated to give the title compound. IR: 1635,1180, lllOcm" ; LC-MS: (M+H)+ 506.1, tr 8.37 min.
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Example 4 - A4l-((4-Hydroxy-3-methox>'pheny])methyl)piperidin-4-yl)-^-((^niethylpbenyOmethyiy-A^-pbenylniethylcarbainide (26HCH66-04)
The product from example 1 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 4-Hydroxy-3-methoxybenzaldehyde (91 mg, 0.6 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 4S h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed wife methanol (3x6 ml), and eluted with 10% NH3 in
methanol, and concentrated to give the title compound. 13C-NMR (CD3OD, selected): 6 19.9,55.4, 126.5,127.0,128.1,129.0, 140.3, 148.0, 148.1, 158.8. Example 5 - N-(l-((5-EthyJthien-2-yi)methyI)piperidin-4-yl)-N-((4-methylpbenyl)methyI)-N'-phenyImethylcarbamide (26HCH66-05)
The product from example 1 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 5-Ethyl-2-thiophencarboxaldehyde (84 mg, 0.6 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken al room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed wife methanol (3x6 ml), and eroted with 10% NH3 in methanol, and concentrated to give the title compound. IR: 1640,1185,1110, 805, 700,620 cm"3; LC-MS: (M+H)+462.3, ^ 7.52 min.
Example 6 - N-(l-(Inudazo^ylmethyI)piperidiii-4-yI)-N-((4-methy]pheny!)methyl)-N'-pfaenylmethyIcarbamide (2 6H CH 66-06)
The product from example 1 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). Imidazole-2-carboxaMehyde (58 rag, 0.6 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was
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added on to a column carrying strongly acidic cation exchange resin (0 3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. IR: 1620,1190,1100, 805, 700, 620 cm"1; LC-MS: (M+H)+ 418.2, tr 2.05 min.
Example 7 - ;V-(l-(QcJohexyJroethy])piperidin -yl)-;V-((4-methylphenyl)methyl)-iV-phenylmethylcarbamide (26HCH66-09)
The product from example 1 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). Cyclohexanecarboxaldehyde (67 mg, 0.6 mmol) was added followed by solid-supported borohydridc (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. IR: 1635,1175,1100, 805, 695, 620 cm"3; LC-MS: (M+H)+ 434.4, tr 7.44 min.
Example 8 - 7V-(l-((4-F!uorophenyi)methyl)piperidiii-4-yI>A'-((4-roethylphenyI)metbyI)-Aw-pbenylmetbvicarb amide (26HCH66-10)
The product from example 1 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 4-Fluorobenzaldehyde (0-08 ml, 0.6 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 02 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissorved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound IR: 1640,1175,1110, 805, 700,620 cm"1; LC-MS: (M+H)+ 4463, t, 5.62 min.
Example 9 - N-((4-MetbylphenyI)methyI>N-(l-{pbeiiylniethyI)piperidiii-4-yI)-N'-phenyImethylcarbamide kydrochloride (26HCH16D)
To a solution of l-benzyl-4-piperidone (1.74 g, 9.2 mmol) and 4-methylbenzylamine (0.97 g, 8 mmol) in methanol (30 ml) was added sodium
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borohydride (525 mg) in small portions over 30 min. The reaction mixture was stirred at room temperature. After 16 h, the mixture was concentrated. Water (30 ml) was added, and the mixture was extracted with dichloromethane (2x20 ml). The combined organic layers were dried O SC ), filtered, and concentrated to give 4-((4-
methylphenyl)methyl)ammo-l-phenylmethylpiperidme. The crude product was used without further purification.
4-((4-Methylphenyl)methyl)amino-l-phenylmethylpiperiduie (800 mg, 2.7 rnmol) was dissolved in dry dichloromethane (30 ml). Benzylisocyanate (543 mg, 4.1 mmol) was added. The reaction mixture was stirred at room temperature. After 16 h, water (10 ml) was added followed by NaOH (6 N, 2 ml). After additional 30 minutes of stirring the white crystals were filtered off The organic layer was isolated and dried (Na2SC>4), filtered, and concentrated. Flash chromatography in
dichloroniethane/methanol 10/1 leftiV-((4-Methylphenyl)methyl)-A'--(l-(phenylmethyI)piperidin-4-yl)-A -phenylinethylcarbamide Yield: 820 mg, 71%; A sample was concentrated with HC1 (4 M in dioxane) followed by recrystallization
from dichloromethane/diethyl ether leaving the title compound. H-NMR (CDCI3): 5
1.87 (br d, 2 H), 2.30 (s, 3 H), 2.59 (dq, 2 H), 2.76 (br q, 2 H), 3.44 (br d, 2 H), 4.09 (d, 2 H), 4.30 (d, 2 H), 4.40 (s, 2 H), 4.64-4.76 (in, 2 H), 6.98-7.64 (Aromatic protons, 14 H); I3C-NMR (CDCI3): 5 21.2, 26.7,45.0, 46.0, 49.7, 52.2, 61.0,126.2, 127.26,
126.31, 128-2, 128.6, 229.6,129.9,130.4, 131.6,134.4, 137.6, 139.3,158.5; (tm)C-NMR (CD3OD, rotamers): 6 19.8,26.4,27.8,40.3, 443, 51.6, 51.9, 54.5, 60.5,110.0, 112-1.114.0,114.2, 117.5, 125.9, 126.2,126.7, 126.8,128.9, 129.1,129.2,129.4,
129.7,130.1,131 , 134.5,137.4,159.1,173.8,175.0; Mp. l09-112oC; Eleinental analysis: Found Q 70.06; H, 7.62; N, 8.60; calcd for monohydrale: C, 69.76; H, 7.53; N,8.7Z
Example 10 - N-((4-Methylphcny0metbyl)-N-(l-{phenylmetfayl)piperidiii-4-yl>-N'-pbeDyliDcthylcarbainide oxalatc (34JJ59oxaI)
H( Methylphenyl)methyi)-iV l henymiethyI iperi6U&4-yI)-A -pbenybnethylcarbamide was prepared as described in example 9 above. A sample was precipitated as the ox al ate and reciystallizcd from ethyl acetate to give the title
compound. 13C-NMR (CDCI3): 6 21.2,27.0,45.0, 45.9,49.9, 52.1,60.6,126.1, 127.3,127.4,128.5,128.7,129.6, 130.0,130.4, 131.2,134.3,137.7,1393,158.4,
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163.4; Mp. 18O-1S2°C; ElementaJ analysis: Found C, 69.54; H, 6.73; N, 7.96; calcd formonooxalate: C, 69.61; H, 6.82; N, 8.12
Example 11 - N-((4-Methyipbenyl)methy])-N-(l-(phenylmetbyI)piperidin-4-yI) 4-metboxyphenylacetamide faydrochloride (26HCH17)
To a solution of l-benzyl-4-piperidone (1.74 g, 9.2 mmol) and 4-methylbenzylamine (0.97 g, 8 mmol) in methanol (30 ml) was added sodium borohydride (525 mg) in small poiiions over 30 min. The reaction mixture was stirred at room temperature. After 16 h, the mixture was concentrated. Water (30 ml) was added, and the mixture was extracted with dichloromethane (2x20 ml). The combined organic layers were dried (Na2SC>4), filtered, and concentrated to give 4-((4-
methylphenyl)methyl)amino-l-phenylmcthylpiperidine. The crude product was used without further purification.
To a solution of 4-((4-Meti"yIphenyl)methyI)amino-l-phenylmethyIpiperidine (800 mg, 2.7 mmol) in dry dichloromethane (30 ml) was added diisopropylethylamine (1.5 ml) followed by 4-methoxyphenylacetyl chloride (997 mg, 5.4 mmol). The reaction mixture was stirred at room temperature. After 16 h, the reaction mixture was concentrated, redissolved in diethyl ether, and extracted with HC1 (0.6 N). The aqueous layer was isolated, treated with NaOH (1 N) until basic, and extracted with dichloromethane (20 ml). The organic layer was isolated and dried (Na2SO4),
filtered, and concentrated, and redissolved in diethyl ether. The hydrochloride was formed by addition of HC1 (4 M in dioxane), and recrystallized mam diethyl ether to
give the title compound. TieW: 600 mg, 50%; iH-NMR (CDCI3): 6 1.75 (d, 2 H), 232 (s. 3 H), 2.50 (q, 2 H), 2.70 (q, 2 H), 338 (d, 2 H), 3.54 (s, 2 H), 3.78 (s, 3 H), 4.06 (d, 2 H), 4.54 (s, 2 H), 4.82 (m, 1 H), 6.78-7.60 (aromatic protons, 13 K); 13C-NMR (CDCI3): 5 21.0, 26.0,40.3, 46.3,49.0, 51.8, 55.3, 60.8, 114.2,125.6, 126.6, 127.9,129.4,129.60,129.62,130.3,131.4,134.8,137.1,158.7,172.9; Mp. 197-
200C; Elemental analysis: Found C, 71.29; H, 7.25; N, 5.73; calcd for hydrate: C, 7137; H, 7.43; N, 5.74.
Example 12 - N- Ar-((4-Methylphenyl)methyl)- -( 2 -(phenyImethyl)piperidin-4-yl)-4-methoxyphenylacetamide was prepiao d as described in example 11 above. A sample
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was precipitated as the oxalate and recrystallized from tetrahydrofuran to give the title compound. 13C-NMR(CDC13): 821.2, 26.4, 40.6, 52.0, 55.5, 114.4, 125.9, 126.7, 128.4,129.6, 129.8,129.9,130.4,131.2,134.6,137.6, 158.9,163 3,172 9; Mp. 171-
173°C; Elemental analysis: Found C, 69.56; H, 6.74; N, 5.16; calcd for monooxalate: C, 69.48; H, 6.61; N, 5.40.
Example 13 - N-((4-MethylpheByI)methyI)-N-(piperidin-4-yl)-4-raethoxypbenylacetaniide (26HCH71B)
To a solution of commercially available /erf-butyl 4-oxo-l-piperidine carboxylate (1.75 g, 8.8 mmol) and 4-methylbenzylamine (970 rug, 8.0 mmol) in methanol (7 ml) was added acetic acid in methanol (I M, 6.7 ml) followed by NaCNBEb in methanol (0.3 M, 30 ml). The resulting solution was stirred at room temperature. After 20 h, water (5 ml) was added, and the mixture was stirred for 1 h before it was concentrated. Flash chromatography in dichloromethane:methanol 10:1 gave tert-butyl 4-(4-methylphenyl)methyl)amino-piperidine carboxylate. Yield: 2.4 g, 98%. To a solution of tert-butyl 4-(4-methylphenyl)methyl)amino-piperidine carboxylate (862 mg, 2.83 mmol) in dry dichloromethane (10 ml) was-added diisopropylethylamine (1.1 ml, 6.5 mmol) followed by 4-methoxyphenylacety3 chloride (0.66 mi, 4.3 mmol). The reaction mixture was stirred at room temperature. After 48 h, water (5 ml) was added, and the mixture was stirred for additional 2 h before extracted with NaOH (0.2 N, 2x15 ml), HC1 (0.2 N, 2x15 ml), and water (15 ml). The organic layer was dried (SH2SO4) and concentrated to give -((4-methy enyl)memyl)- l rert4}urykacycarbonyi)piperidm-4-yl>4-methoxypbenylacetamide. The crude product was used without any further purification. -((4-Methylphenyl)mcth3'l>-A'-( 1 -( erf-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetainide was dissolved in ether (2 ml) and HC1 (3 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2 h, water (5 ml) was added, and the mixture was extracted with HC1 (0.1 N, 3x30 ml). Ike combined aqueous layers were treated with NaOH (0.2 N) until basic (pH > 8). The aqueous layer was extracted with diethyl ether (2x20 ml). The combined organic layers were dried (Na2SO4) and concentrated, before dissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated. Additional flash chromatography in
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dichloromethane/methanol 1/1 - methanol containing 2% NH3 gave the title compound. Yield: 466mg, 47%; i3C-NMR (CD3OD, rotamers): 5 19.9,27.8,29.7, 40.2,40.3, 44.4,44.45, 44.50, 52.4, 54.5, 55.5, 114.0, 114.1, 126.0,126.7, 126.9, 127.3, 12S.7, 129.3,129.6,129.7,135.1,136.1, 136.2, 137.1, 159.0, 159.1, 173.1, 173.7.
Example 14 - A -(l-(3"3-Diniethylbutyl)piperidiD-4-yI)-iV-((4-methvlphenyl)mcthyl>-4-methoxyphenylacetamide (26HCH79-5)
The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 3,3-DimethylbutyraIdehyde (0.143 ml, 1.1 mmol) was added followed by solid-supported borohydride (150 ing, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temptsrature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0i2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in
methanol, and concentrated to give the title compound. Yield: 26 mg; C-NMR (CD3OD, rotamers): 6 19.9,27.4, 2S.4, 2S.8, 29.2, 29.3, 38.3, 38.4,40.2, 40.3, 44.3,
52.0, 52.3, 52.4, 53.9, 54.6,54.9,114.0,114.1, 126.0, 126.8, 127.0,127.3, 128.8, 129.4,129.8,129.9,135.0,136.1,136.3,137.1,158.96,159.05,173.2,173.8.
Example IS - -(l-(CycIobexylroetbyI)piperidin-4-yI)-Ar-((4-m thylpbenyr)methyI)-4-methoiyphenylacettmide (26HCH79-6)
The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). CydohacanecarfxJxaJdehyde (0.138 ml. 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aidrich'32,864-2). The mixture was shaken at room temperature. After 48 b, the resin was filtered off and acetic anhydride (0.02 ml, 02 mmol) was added to the organic solution. After 24 b, the mixture was concentrated and redissolved in methanol (2 ml). The solution was &lded on to a column carrying strongly acidic cation exchange resin (03 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 17 mg; HRMS (FAB , NBA) (M+H)+ 4493163, C29H41N2O2 requires 4493168; LC-MS: (M+H)+ 449.2, Xj. 7.92 min.
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Example 16 - A4(4-Methy]phenyI)methyl)-;V-(l-(2-methyJpropyJ)piperidin-4-yl)-4-inethoxj'phenylacelamide (26HCH79-7)
The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs, ethanol (2 ml).). 2-Methylpropionaldehyde (0.104 ml, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 19 mg; HRMS (FAB+, NBA) (M+H)+ 409.2858, C2 H37N2O2 requires 409.2855; LC-MS: (M+H)+ 409-2, tr
5.97 min.
Example 17 - A -((4-Methylphenyl)methyl)-Ar-(l-((4-metbylpbenyI)methyI)piperidiD-4-yI)-4-methoxyphenylacetainide (26HCH79-8)
The product from example 13 above (20 mg3 0.06 mmol) was dissolved in abs. ethanol (2 ml). 4-MetbyIbenzaldehyde (0.134 ml, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2 5 mmoL'g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 45 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 mi). The solution was added on to a column carrying stronjUy acidic cation exchange resin (03 mmol/g resin), which was washed with methanol (3x6 raJ). and eluted wiifa 10% NH3 in
methanol, and concentrated to give the title compound- Yield: 22 mg; HRMS (FAB+, NBA) (M+H)+ 457.2853, C30H37N2O2 requires 457.2855; LC-MS: (M+H)+ 457.2, t,-
6.97 min.
Example 18 - iV l (4-Hyd )iyphenvI)methyI)piperidin-4-yI>-iV-4-met]ioxypbcBylacctanude (26HCH79-9)
The product from example 13 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 4-Hydroxybenzaldehyde (139 mg, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h,
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the mixture was concentrated and redissolved m methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 19 rug; HRMS (FAB+, NBA) (M+H)+ 459.2655, C29H35N2O3 requires 459.2648; LC-MS: (M+H)+ 459.1, tr 2.84 min.
Example 19 - AHH(2-Hydroxyphen>DmethyI)piperidin-4-yI)-Ar-((4-methylphenyl)methyI)-4-methox3'phenylacetamide (26HCH79-10)
The product from example L3 above (20 mg, 0.06 mmol) was dissolved in abs. ethanol (2 ml). 2-Hydroxybenzaldehyde (0.122 ml, 1.1 mmol) was added followed by solid-supported borohydride (150 mg, 2.5 mmol/g resin; Aldrich 32,864-2). The mixture was shaken at room temperature. After 48 h, the resin was filtered off and acetic anhydride (0.02 ml, 0.2 mmol) was added to the organic solution. After 24 h, the mixture was concentrated and redissolved in methanol (2 ml). The solution was added on to a column carrying strongly acidic cation exchange resin (03 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 16 mg; HRMS (FAB+, NBA) (M+H)+ 459.2633, QpH Oj requires 459.2648; LC-MS: (M-r-HT 459.2, V
5.81 mm
Example 20 -AH3-PbenyIpropyl>7V-(piperidin-4-y()-4-metboxyphenyUcetamide (26HCH80-1)
To a solution of commercially available tert-butyl 4-oxo-l-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 3-phcnyipropylana3e (0.143 ml, 1 mmol) in methanol (1 ml) was added 'acetic add in methanol (1 M, 1.34" ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was
stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HC1 (0.1 N, 1x15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SC>4),
filtered, and concentrated to give /erf-butyl 4-(3-pbenylpropyl)arnino-piperidme carboxylate. Yield: 110 mg. To a solution of tert-butyl 4-(3-phenylpropyl)amino-
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piperidine carboxylate (50 mg, 0.16 mmol) in dichloromethane (6 ml) was added diisopropylethylaminc (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HC1 (0 2 N, 2x15 ml), NaOH (0.2 N, 2x15 ml), and water (10 ml), dried (Na2SC>4), filtered and concentrated to give N-(3-
pheny!propyl)-7V-( 1 -(/ert-butyIoxycarbonyl)piperidin-4-yI)-4-methoxyphenylacetamide. The crude product was used without any further purification. W-(3-PhenylpropyI)-#-( 1 -(tert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HC1 (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichJoromethane (10 mi). The mixture was extracted with water (2x15 ml), dried (Na2SO4), filtered to give a clear solution.
The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 61 mg; l C-NMR (CD3OD, rotamers): 6 27.8,29.4, 30.8, 32.3, 32.7: 33.3, 40.2, 40.5,42.0,44.5,
44.6,44.9, 52.7, 54.56, 54.57, 54.9,114.0, 114.1, 125.7, 126.1, 127.0, 127.4,128.2, 128.3,128.5, 129.47,129.55, 141.2,141.8,158.9, 159.0,172.5,172.7.
Example 21 - A'-(2-PhenylethyI)-Ar-(piperidin-4-yI)-4-metboiyphenyimethylacetamide (26HCH80-2)
To a solution of commercially available /erf-butyl 4-oxo-l-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 2-phenylsthylamine (0.143 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 m methanol (0.3 M, 4.4 ml). The resulting solution was
stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in dietfayl ether (20 ml), extracted with HC1 (0.1 N, 1x15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4),
filtered, and concentrated to give tert-buty] 4-(2-phenylethyl)amino-piperidine carboxylate. Yield: 221 mg. To a solution of tert-butyl 4-{2-phenylethyl)amino-
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piperidine carboxylatc (50 mg, 0.16 mmol) in dichloromcthane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HCl (0 2 N, 2x15 ml), NaOH (0.2 N, 2x 15 ml), and water (10 ml), dried (Na2SC>4), filtered and concentrated to give //-(2-
phenylethyl)- l-(/er?-butyloxycarbonyI)piperidm y]) -memoxyphenylacetamide. The crude product was used without any further purification. iV-(2-PhenylethyI)-JV-(l -((ert-butyloxycarbonyl)piperidm-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HCl (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2x15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to
give the title compound. Yield: 52 mg; 3C-NMR (CD3OD, retainers): 6 27.1, 28.5,
34.9, 36.6,40.2, 40.4, 44.1,44.2,44.4, 53.3, 54.2, 54.6,114.0,114.1,126.2,126.6, 127.2, 127.4,128.3, 128.6,128.79, 128.82, 129.7, 138.5, 1393,158.96, 159.0, 172.7, 173.1
Example 22 - A (2-MetfaoxyphenyI)methyI)-AHpiperidiii-4--yl>- -methoxypbenylmethyiacetamide (26HCH80-4)
To a solution of commercially available rerf-butyi 4-oxo-l -piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 2-methoxybenzylamine (0.130 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was
stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HCl (0.1 N, 1x15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 02 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4),
filtered, and concentrated to give /er/-butyl 4-((2-methoxyphenyl)methyl)amino-piperidine carboxylate. Yield: 211 mg. To a solution of fert-butyl 4-((2-
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methoxyphenyl)methyl)amino-piperidiiie carboxylate (50 ing, 0.16 rnmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture" was stiired at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HC1 (0.2 N, 2x15 ml), NaOH (0.2 N, 2x15 ml), and water (10 ml), dried (Na2SO4),
filtered and concentrated to give 7V-((2-methoxyphenyl)methyl)-77-(l-(terf-butyloxycarbonyl)piperidin-4-yl)-4--methoxyphenylacetamide. The crude product was used without any further purification. N-((2-Meihoxyphenyl)meihyl)-N-(l-(tert-buryloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HC1 (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. AAer 2.5 h, NaOH (I ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2x15 ml), dried (Na2SO4), filtered to give a clear solution. The soluton was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and cluted with 10% NH3 in methanol, and concentrated to
give the title compound. Yield: 40 mg; J3C-NMR (CD3OD, retainers). 6 26.1,27.4,
40.0, 40.1, 43.5, 43.9, 51.5, 53.4, 54.5,54.58, 54.63, 54.78, 54.83, 110.1, 110.5, 113.76, 113.78, 113.84, 114.0,114.1, 120.1, 120.5, 125.4, 126.0, 126.5, 126.7, 127.1, 1273,127.7,128.8,129.8,130.0,130.08,130.14, 156.5,157.0,159.0,159.1,173.2, 173.8.
Example 23 - AH(2-Chlon he )i)meth>1KV-4-metboxypbenyiacetamide (26HCH80-5)
To a solution of commercially available ferr-butyl 4-oxo-l-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 2-chIorobenzylamine (0.121 ml, 1 mmol) in methanol (I ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCN6H3 in methanol (03 M, 4.4 ml). The resulting solution was
stirred at room temperature. After 24 b, water (2 ml) was added, and the mixture was stirred for 1 h before it was concentrated. The resulting oil was rcdissolved in dicthyl ether (20 ml), extracted with HC1 (0.1 N, 1 x 15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4),
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filtered, and concentrated to give tert-butyl 4-((2-chlorophenyl)methyI)amino-piperidine carboxylate. Yield: 137 mg. To a solution of tert-butyl 4-((2-chlorophenyl)methyl)amino-piperi ime carboxylate (50 tng, 0.15 rmnol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HC1 (0.2 N, 2x15 ml), NaOH (0.2 N, 2x 15 ml), and water (10 ml), dned (Na2SO4),
filtered and concentrated to give 7V- give the title compound. Yield: 45 rag; I3C-KMR (CD3OD, rotamers): 5 25.8,26.9,
40.0,40.1,42.9,43.4,43.7,46.0,51.1,53.0,54.6, 113.77, 113.84,114.0, 114.1, 126.6,126.8,127.08,127.13,1273,127.4,128.1,129.0,129.2,129.8,130.0,130.2, 131.9,132.2,135.0,1353,159.1,173.4,173.8.
Example 24 - N (3 AD"-(tm)BdioiyplieoyI)roethyI)-N pip€ridHi-4-yI>-t-methoxypbenylacetamide (26HCH80-6)
To a solution of commercially available tert-butyl 4-oxo-l-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 3,4-di-methoxybenzylamine (0.151 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was
stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HC1 (0.1 N, 1 x 15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before
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extracted with dichioromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-((3,4-di-memoxyphenyl)methyl)aniino-piperidine carboxylate. Yield: 162 mg. To a solution of tert-butyl 4-((3,4-di-methoxyphenyl)methyl)amino-piperidine carboxylate (50 mg, 0.14 ramol) in dichioromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HC1 (0.2 N, 2x15 ml), NaOH (0.2 N, 2 15 ml), and water (10 ml), dried (Na2SO4),
filtered and concentrated to give7V-((3,4-di-methoxyphenyl)methyl)-7V-(l-(/er/-butyloxycarbonyl)pipendin-4-yl)-4-methoxyphenylacetamide. The crude product was
used without any further purification. iVX(3,4-Di-methoxypheoyI)memyl)-AHH'ert-buty!oxycarbonyl)piperidin-4-yl)-4-meuioxvphenylacetamide was dissolved in diethyl ether (2 ml) and HC1 (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichioromethane (10 ml). The mixture was extracted with water (2x15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and ehited with 10% NH3 in methanol, and concentrated to
give the title compound. Yield: 54 mg; 13C-NMR (CD3OD, rotamers): 6 25.9,27.3, 40.0,40.1,43.5,43.8,44.1,51.4,53.5,54.6,55.4, no.2, 111.0,113.9, 112.2, 114.0, 114.2,118.6, 119.4,127.1,127.4,129.9,130.0,130.5,132.1, 148.2,148.7, 149.2, 149.7,158.98,159.05,173.3,173.6.
Example 25 - N (4-FlDOropbeny!)iDctfayI>-N-(piperidhi-4-yI>4-methoxyphenylacetamide (26HCH80-7)
To a solution of commercially available tert-butyl 4-oxo-l-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 4-fluorobenzylamine(0.114 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was
stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for I h, before it was concentrated. The resulting oil was rcdissorved in diethyl ether (20 ml), extracted with HC1 (0.1 N, 1 x 15 ml). The aqueous layer was washed
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with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-((4-fluorophenyl)methyl)amino-piperidine carboxylate. Yield: 130 mg. To a solution of tert-butyl 4-((4 fluorophenyl)methyl)amino-piperidine carboxylate (50 mg, 0.16 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After IS h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HC1 (0.2 N, 2x15 ml), NaOH (0.2 N, 2x15 ml), and water (10 ml), dried (Na2SO4),
filtered and concentrated to give W-((4-fluorophenyl)memyl)-tf- give the title compound Yield: 45 mg; 13C-NMR (CD3OD, rotamers): 5 26.1,27.5,
40.1,43.6,43.8, 44.0, 51.6,53.6,54.6,113.77, 113.84,114.0,114.1,114.7,114.9, 115-3, 115.6,126.8,127.2,128.1,128.6,128.7,129.8, 130.0, 130.1,130.6, 131.0, 133.8, 159.1,173.3, 173.6.
Example 26 - N-((2,4-Di-chIorophenyI)methyl)-N-{piperidin-4-yI>-4-methoxyphenylacetamide (2 6H CH 80-8)
To a solution of commercially available tert-butyl 4-oxo-l-piperidine carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 2,4-di-chlorobenzyiamine (0.135 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was
stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl
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ether (20 ml), extracted witfaHCi (0.1 N, 1x15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treaicd with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give /ert-butyl 4-((2J4-di-chlorophenyl)methyl)amino-piperidine carboxylate. Yield: 97 mg. To a solution of tert-butyl 4-((2,4-di-chJorophenyl)methyl)amino-piperidine carboxylate (50 mg, 0.14 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0 4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HC1 (0.2 N, 2x15 ml), NaOH (0.2 N, 2x15 ml), and water (10 ml), dried (Na2SO4);
filtered and concentrated to give Al(G2 abfihlgj toyJ)me butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. //-{ Di-chlorophenytym ethyI)-.7V-(l-(/£7?-butyloxycarbonyl)piperidin-4-yI)-4-methoxyphenyIacetamide was dissolved in diethyl ether (2 ml) and HC1 (1 ml, 4 M in dioxanc) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2x 15 ml), dried (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and ehited with 10% NH3 in methanol, and concentrated to
give the title compound. Yield: 39 mg I3C-NMR (CD3OD, rotamers): S 25.7,26.8,
40.0,42.6, 43.3,43.7, 51.2, 53.0, 54.-5, 54.6, 113.8, 113.8, 134.0, 114.1-, 127.0, 12S.4, 128.8, 129.8,130.0,130.1,131.0,132.7,132.9,134.5, 159.1,173.4,173.6.
Example 27 - N-((3-Methylphcny0methyi)-N-(piperidin-4-yI)-4-methoryphcnylacetamide (26HCH80-9)
To a solution of commercially available tert-butyl 4-oxo-l-piperidme carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 3-methylbeczylamine (0.125 ml, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The resulting solution was
stirred at room temperature. After 24 h, water (2 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl
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ether (20 ml), extracted with HC1 (0.1 N, 1 x 15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SC>4), filtered, and concentrated to give tert-butyl 4 ((3-methyIphenyl)methyI)animo-piperidine carboxylate. Yield: 136 mg. To a solution of tert-butyl 4-((3-methylphenyl)methyl)amino-piperidine carboxylate (50 mg, 0.16 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenylacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with HC1 (0.2 N, 2x15 ml), NaOH (02 N, 2x15 ml), and water (10 ml), dried (Na2SO4),
filtered and concentrated to give A (3-methylphenyl)methyl)-JV-(l-(tert-butyloxycarbonyl)piperidm-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. M((3-Methylphenyl)methyl)-W-(l-(ferr-but>loxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HC1 (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 >3) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2 15 ml), dried (Na SCj), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and ehited with 10% NH3 in methanol, and concentrated to
give the title compound. Yield: 48 mg; 13c-NMR (CD3OD, retainers): 8 20.4, 26.8,
2S.3,40.2,43.9, 44.1,44.5,51.8, 54.2, 54.57, 54.61, 114.0, 114.1,123.2.123.7, 126.7,127.0,127.1,127.3,128.0,128.1,128.7,129.8,129.9,137.9,138.6,138.9, 159.0,159.1,173.1,173.7.
Example 28 - N-((3-Bromophenyl)raethyI)-N-{piperidin-4-yl>-4-methovypbenylacetamide (26HCH80-10)
To a solution of commercially available rerz-butyl 4-oxo-l-pipcridinc carboxylate (400 mg, 2 mmol) in methanol (1 ml) and 3-bromobenzylamioe hydrobromide (222 nag, 1 mmol) in methanol (1 ml) was added acetic acid in methanol (1 M, 1.34 ml) followed by NaCNBH3 in methanol (0.3 M, 4.4 ml). The
resulting solution was stirred at room temperature. After 24 h, water (2 ml) was
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added, and the mixture was stirred for 1 h, before it was concentrated. The resulting oil was redissolved in diethyl ether (20 ml), extracted with HC1 (0.1 N, 1x15 ml). The aqueous layer was washed with diethyl ether (10 ml) and treated with 0.2 N NaOH until basic (pH>8), before extracted with dichloromethane (20 ml). The organic layer was dried (Na2SO4), filtered, and concentrated to give tert-butyl 4-((3-bromophenyl)methyl)amino-piperidine carboxylate. Yield: 142 mg. To a solution of tert-butyl 4-((3-bromophenyl)methyl)amino-piperidine carboxylate (50 mg, 0.14 mmol) in dichloromethane (6 ml) was added diisopropylethylamine (0.070 ml, 0.4 mmol) followed by 4-methoxyphenyIacetyl chloride (0.055 ml, 0.35 mmol). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. The mixture was stirred for another 2 h. The mixture was sequentially washed with UCl (0.2 N, 2x15 ml), NaOH (0.2 N, 2x15 ml), and water (10 ml), dried (Na2SO4),
filtered and concentrated to give 7/-((3-bromophenyl)methyl)- -(l-(zert-butyloxycarbonyl)piperidin-4-yl)-4-methoxyphenylacetamide. The crude product was used without any further purification. AH(3-Bromopheny!)methyl)-J\r-(l-(tert-butyloxycarbonyl)piperidin-4-yl>4 methoxyphenylacetamide was dissolved in diethyl ether (2 ml) and HC1 (1 ml, 4 M in dioxane) was added. The reaction mixture was stirred at room temperature. After 2.5 h, NaOH (1 ml, 6 N) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2x 15 ml), cMed (Na2SO4), filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to
give the title compound. Yield: 49 rag; 13C-NMR (CD3OD, retainers): 6 26.6,28.2, 40.2,43.9,44.0,51.8,54.1,54.6,113.76,113.84, 114.1,114.2,122.2,125.0,125.5, 126.7,127.1,129.2,129.5,129.7,129.8,129.9,130.0,130.5,130.6,140.8,141.8,
159.1,1733,173.7.
Example 29 - N- l-yD-4-methoiypbenyUcetamidc (26HCH76B)
To a solution of 4-amino-N-benzylpiperidnie (200 mg, 1.05 mmol) in methanol (2 ml) was added trans-cinnamaldehyde (211 mg, 1.6 mmol), followed by Acetic acid in methanol (1 M, 1.4 ml) and sodiumcyanoborohydridc in methanol (0.3 M, 4.4 ml). The reaction mixture was stirred at room temperature. After 48 h, water (2
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ml) was added. The mixture was stirred for another 2 h before concentrated and redissolved in diethyl ether (20 ml). The organic layer was extracted with HC1 (0.1 N, 2 l o ml). The combined aqueous layers were treated with NaOH (0.2 N) until basic (pH>8). The mixture was extracted with dichloromethane (2x10 ml). The combined organic layers were dried (NB2SO4) and concentrated. The crude product, which was
used without any further purification, was dissolved in dichloromethane (5 ml). Diisopropylethylamine (284 ing, 2.1 eq.) was added, followed by 4-methoxyphenylacetyl chloride (387 ing, 2.0 eq). The reaction mixture was stirred at room temperature. After 18 h, water (2 ml) was added. After additional 2 h dichloromethane (10 ml) was added. The mixture was extracted with NaOH (0.2 N, 3x15 ml), and water (15 ml). The organic layer was dried (Na2SO4) and
concentrated. The crude product was redissolved in methanol (2 ml) and added on to a column carrying strongly acidic cation excnange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and
concentrated to give the title compound. 13C-NMR (CDCI3): 5 28-5>381" 46-6> 47-4> 50.9, 54.7, 62.9, 113.7, 125.5,126.4, 126.6, 127.4, 127.9, 12S.5, 128.6, 129.6, 130.0, 135.2,135.3,138.0,158.2,173.2.
Example 30 - iV--pbenylacetamide (26HCH78-1)
To a solution of commercially available tert-butyl 4-oxo-l-piperidine carboxylate (1.75 g, 8.8 mmol) and 4-methyIberizylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH3 in methanol (03 M, 30 ml). The resulting solution was stirred at room temperatme. After 20 h, water (5 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. Flash chromatography in dichloromethane:methanol 10:1 gave i£rr-butyl 4-(4-methylphenyl)methyl)araino-piperidine carboxylate. Yield: 2.4 g, 98%. To a solution of/crt-butyl 4 4-memylphenyI)merayI)amino-piperidine carboxylate (80 mg, 0.26 mmol) in dichloromethane (1.8 ml) was added diisopropylethylamme (0.11 ml, 2.4 eq.) followed by pbenylacetyl chloride (81 mg, 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 h, water (1 ml) was added. The mixture was stirred for another 2 h, before diethyl ether (20 ml) was added. The mixture was sequentially extracted with HC1 (0.2 N, 2x15 ml),
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NaOH (0.2 N, 2x15 ml), and H2O (10 ml), dried (Na2SC>4), filtered and concentrated. The crude material was dissolved in diethyl ether (2 ml) and HC1 (4 M in dioxane, 1 ml). The reaction mixture was stored at room tempeiature After 2 h, NaOH (6 N, 1 ml) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2x 10 ml), dried (NajSC ), and filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in
methanol, and concentrated to give the title compound. Yield: 38 nag; C-NMR (CD3OD, rotamers): 5 19.9,26.9, 2S.4, 41.0, 41.1, 44.0,44.1, 44.4, 51.9, 54.4, 126.1,
126.7, 126.8,126.9, 128.5,128.7, 128.78,128.81,128.9,129.4, 129.5, 134.9, 135.2, 135.6, 136.0, 136.3,137.2, 172.8,173.3.
Example 31 - N-((4-MetbyIpbenyl)methyl)-N-(l-piperidin-4-yl)-3-phenylpropiooamide (26HCH78-2)
To a solution of commercially available tert-butyl 4-oxo-l-piperidine carboxyiate (1.75 g, 8.8 mmol) and 4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added acetic acid in methanol (1 M. 6.7 ml) followed by N3CNBH3 in methanol (03 M, 30 ml). The resulting solution was stirred at room temperature. After 20 h, water (5 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. Hash cliromatography in dichloromethanermethanol 10:1 gave tert-butyl 4 4-mcthylphenyl)methyI)amino-piperidine carboxyiate. Yield: 2.4 g, 98%. To a solution of tert-butyl 4 4-methylphenyI)methyi)amino-piperidine carboxyiate (80 mg, 0.26 mmol) in dichloromethane (1.8 ml) was added diisopropylethylamine (0.11 niL 2.4 eq.) followed by 3-pbenylpropionyl .chloride (0.07S ml, 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 h, water (1 ml) was added The mixture was stirred for another 2 h, before diethyl ether (20 ml) was added. The mixture was sequentially extracted with HC1 (0.2 N, 2x15 ml), NaOH (0.2 N, 2x15 ml), and H2O (10 ml), dried (Na2SO4), filtered and
concentrated. The crude material was dissolved in diethyl ether (2 ml) and HC1 (4 M in dioxane, 1 ml). The reaction mixture was stirred at room temperature. After 2 h, NaOH (6 N, 1 ml) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2x10 ml), dried (Na2SO4), and filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin
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(0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 43 mg; 13C-NMR (CD3OD, rotamers): 5 19.9,27.4,29.0, 31.4,31.7,34.7,35.7,44.2,44.3, 51.6,
54.2, 125.9, 126.07,126.15,126.8, 128.3, 128.4, 128.7, 128.8, 129.3,135.1, 136.1, 136.2, 137.0, 141.1,141.2,173.9,174.4.
Example 32 - N-((4-Me(hyIphenyI)methyl>N-(l-piperidin-4-yl> (phenylthio)acetamide (26HCH78-3)
To a solution of commercially available tert-butyl 4-oxo-l-piperidine carboxylate (1.75 g, 8.8 mmol) and 4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH3 in methanol (0.3 M, 30 ml). The resulting solution was stirred at room
temperature. After 20 h, water (5 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. Flash chromatography in dichloromethanermethanol 10:1 gave tert-butyl 4-(4-methylphenyl)methyI)amino-piperidine carboxylate. Yield: 2.4 g, 98%. To a solution of /erf-butyl 4 4-mcthyiphenyl)methyl)amino-piperidine carboxylate (80 mg, 0.26 mmol) in dichloromethane (1.8 ml) was added diisopropylethylamine (0.11 ml, 2.4 eq.) followed by (phenylthio)acetyl chloride (0.07S ml, 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 h, water (1 ml) was added. The mixture was stirred for another 2 h, before diethyl ether (20 ml) was added. The mixture was sequentially extracted with HC1 (0.2 N, 2x15 ml), NaOH (0.2 N, 2x15 ml), and H2O (10 ml), dried (Na2SC>4), filtered and
concentrated. The crude material was dissolved in diethyl ether (2 ml) and HC1 (4 M in dioxane, 1 ml). The reaction mixture was stirred al room temperature. After 2 h, NaOH (6 N, 1 ml) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2x 10 ml), dried (Na2SO4), and filtered to give a clear solution.
The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield; 18 mg; HRMS
(FAB , NBA) (M+H)+ 355.1841, C21H27N2OS requires 355.1844; LC-MS: (M+H)+ 355.1, t,. 2.62 min.
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Example 33 - N (4-MethyIphenyl)methyl)-N-0-piperidin-4-yl)-phenoxyacetarnide (26HCH78-4)
To a solution of conmiercially available tert-butyl 4-oxo-l-piperidine carboxylate (1.75 g, 8.8 mmol) and 4-metbylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH3 in methanol (0.3 M, 30 ml). The resulting solution was stirred at room temperature. After 20 h, water (5 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. Flash chromatography in dichloromethanermethanol 10:1 gave tert-butyl 4-(4-methyIphenyJ)metbyl)amino-piperidine carboxylate. Yield: 2.4 g, 98%. To a solution of tert-butyl 4-(4-methylphenyl)methyl)amino-piperidine carboxylate (80 mg, 0.26 mmol) in dichloromethane (1.8 ml) was added diisopropylethylarmne (0.11 ml, 2.4 eq.) followed by phenoxyacetyl chloride (0.073 ml, 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 h, water (1 ml) was added. The mixture was stirred for another 2 h, before diethyl ether (20 ml) was added. The mixture was sequentially extracted with HC1 (0.2 N, 2x15 ml), NaOH (0.2 N, 2x15 ml), and H2O (10 ml), dried (Na2SO4), filtered and
concentrated. The crude material was dissoh ed in diethyl ether (2 ml) and HC1 (4 M in dioxane, 1 ml). The reaction mixture was snrred at room temperature. After 2 h, NaOH (6 N, 1 ml) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2x10 ml), dried (Na2SO4), and filtered to give a clear solutioa The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 24 mg; C-NMR (CD3OD, rotamers): 5 19.9,25.8,27.4, 43.5, 43.7,44.4, 51.9, 52.3,66.9,
114.7, 114.8, 116.7, 117.0, 121.4,123.6, 126.3, 126.8, 128.4, 128.9,129.3, 129.5, 129.6, 131.0,134.4,136.1,137.4,1583,169.8,170.1.
Example 34 - N-((4-M ethjip ben y1)methy l)-N-(l-pi peri din-4-yI>-ropbeoory) cet3imide (26MCH7&-5)
To a solution of commercially available tert-butyl 4-oxo-l-piperidine carboxylate (1.75 g, 8.8 mmol) and 4-methyIbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH3 in methanol (0.3 M, 30 ml). The resulting solution was stirred at room
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temperature. After 20 h, water (5 nil) was added, and ihc mixture was stirred for 1 h, before it was concentrated. Flash chromatography in dichloromethanermethanol 10:1 gave tert-butyl 4-(4-methylphenyl)methyl)ammo-piperidine carboxylate. Yield: 2.4 g, 98%. To a solution of tert-butyl 4-(4-methy]pheny])methyl)amino-piperidine carboxylate (SO mg, 0.26 mmol) in dichloromethane (1.8 ml) was added diisopropylethylamine (0.11 ml, 2.4 eq.) followed by 4-chlorophenoxyacetyl chloride (0.082 ml, 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 h, water (1 ml) was added. The mixture was stirred for another 2 b, before diethyl ether (20 ml) was added. The mixture was sequentially extracted with HC1 (0.2 N, 2x15 ml), NaOH (0.2 N, 2x15 ml), and H2O (10 ml), dried (Na2SO4), filtered and
concentrated. The crude material was dissolved in diethyl ether (2 ml) and HC1 (4 M in dioxane, 1 ml). The reaction mixture was stirred at room temperature. After 2 h, NaOH (6 N, 1 ml) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2x 10 ml), dried (Na2SO4), and filtered to give a clear solution.
The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield; 21 mg; C-NMR (CD3OD, rotamers): 5 19.9, 26.2, 27.S, 43.6, 43.9, 44.4, 52.2, 52.5, 67.0, 116.2, 116.4, 126.2, 1263, 126.8, 128.6,128.9, 129.1, 129.3, 129.5,131.0, 134.4, 135.6,136.4,137.5,157.1,169.4,169.7.
Example 35 - N-((4-Methylpheny!)inethyl>N-(l-piperidin-4-yI)-3-methoxypbenylacetamide (26HCH78-6)
To a solution of commercially available tert-butyl 4-oxo-l-piperidine carboxylate (1.75 g, 8.8 mmol) and 4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH3 in methanol (03 M, 30 ml). The resulting solution was stirred at room
temperature. After 20 h, water (5 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. Flash chromatography in dichloromcthanc.mcthanol 10:1 gave K7?-butyl 4 4-memy henyl)naethyi)arnino-piperidiiie carboxylate. Yield: 2.4 g, 98%. To a solution of tert-butyl 4-(4-methyIphenyl)methyI)amino-piperidine carboxylate (80 mg, 0.26 mmol) in dichloromethane (1.8 ml) was added diisopropylethylamine (0.11 ml, 2.4 eq.) followed by 3-methoxyphenylacetyl chloride
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(97 mg, 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 h, water (1 ml) was added The mixture was stirred for another 2 h, before diethyl ether (20 ml) was added The mixture was sequentially extracted with HC1 (0.2 N} 2x15 ml), NaOH (0.2 N, 2x15 ml), and H2O (10 ml), dried (Na SO , filtered and
concentrated. The crude material was dissolved in diethyl ether (2 ml) and HC1 (4 M in dioxane, 1 ml). The reaction mixture was stirred at room temperature. After 2 h, NaOH (6 N, 1 ml) was added followed by dichloromethanc (10 ml). The mixture was extracted with water (2x10 ml), dried (Na2SO4), and filtered to give a clear solution.
The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10%
NH3 in methanol, and concentrated to give the title compound. Yield: 26 mg; C-NMR (CD3OD, rotamers): 8 19.9,26.3,27.7, 41.0,43.7,43.9, 44.4, 51.5, 53.8, 54.5,
54.6, 112.2, 112.6, 114.3, 114.5, 121.0, 121.2, 126.1, 126.8, 128.S, 129.4, 129.5, 129.8, 134.8,136.0, 136.3, 136.5, 136.9,137.2, 160.2, 160.3, 172.8, 173.2.
Example 36 - N-((4-Metny]pbenyI)methyI)-N-(l-piperidiii-4-yI)-4-flnorophenylacetamide (26HCH78-7)
To a solution of commercially available terr-butyl 4-oxo-l-piperidine carboxylate (1.75 g, 8.8 mmol) and 4-mcthylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH3 in methanol (0.3 M, 30 ml). The resulting solution was stirred at room
temperature. After 20 h, water (5 ml) was added, and the mixture was stirred for 1 h, before it was concentrated- Flash chromatography in dichlorometbanernietharjol 10:1 gave tert-butyl 4 4-methybphcnyI)mcdryi)arnino-pipcridine carboxylate. Yield: 2.4 g, 98%. To a solution of tert-butyl 4 4-methylphenyI)methyI)ammo-piperidine carboxylate (80 mg, 0.26 mmol) in dichloromethane (1.8 ml) was added diisopropylethylamine (0.12 ml, 2.4 eq.) followed by 4-fluorophenylacetyl chloride (0.072 ml, 0.53 mmol). The reaction mixture was stirred at room temperature. Aiter 20 h, water (1 ml) was added. The mixture was stirred for another 2 h, before diethyl ether (20 ml) was added The mixture was sequentially extracted with HC1 (0.2 N, 2x15 ml), NaOH (0.2 N, 2x15 ml), and H2O (10 ml), dried (Na2SO4), filtered and
concentrated. The crude material was dissolved in diethyl ether (2 ml) and HC1 (4 M in dioxane, 1 ml). The reaction mixture was stirred at room temperature. After 2 h.
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NaOH (6 N, 1 ml) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2x10 ml), dried (Na2SO4), and filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 26 mg; C-NMR (CD3OD, rotamers): 8 19.9, 26.1,27.4, 39.7,39.9,43.5,43.8,44.4,51.3, 53.4,
114.9,115.1,115.3,126.1, 126.7, 128.5,128 S, 129.4, 130 7,130.8,130.9, 131.0, 131.2,131.6, 134.8,136.0,136.3, 137.2,160.9,163.3,172.7,173.2.
Example 37 - N-((4-Methylphenyl)me(hyl>N-(l-piperidin-4-yl)-2 -di-metboxyphenylacetamide (26HCH78-8)
To a solution of commercially available tert-butyl 4-oxo-l-piperidine carboxylate (1.75 g, 8.8 mmol) and 4-mcthyIbenzylamine (970 mg, 8.0 niraol) in methanol (7 ml) was added acetic acid in methanol (1 M, 6.7 ml) followed by NaCNBH3 in methanol (0.3 M, 30 ml). The resulting solution was stirred at room
temperature. After 20 h, water (5 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. Flash chromatography in dichloromethane:methanol 10:1 gave /£7t-butyl 4-(4-methylphenyl)methyl)amnio-piperidine carboxylate. Yield: 2.4 g, 98%. To a solution of tert-hatyl 4 4-methyIphenyl)methyl)amino-piperidine carboxylate (80 mg, 0.26 mmol) in dicbloromethane (1.8 ml) was added diisopropylethylamine (0.11 ml, 2.4 eq.) followed by 2,5-di-methoxyphenylacetyl chloride (0.092 ml, 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 h, water (1 ml) was added. The mixture was stirred for another 2 h, before di ethyl ether (20 ml) was added. The mixture was sequentially extracted witfcHO (0.2 N, 2x15 ml), NaOH (0.2 N, 2x15 ml), andH2O (10ml),dried (Na2SC>4), filtered and concentrated. The crude material was dissolved in diethyl
ether (2 ml) and HC1 (4 M in dioxane, 1 ml). The reaction mixture was stirred at room temperature. After 2 h, NaOH (6 N, 1 ml) was added followed by dichloromethane (10 ml). The mixture was extracted with water (2x10 ml), dried (Na2SO4), and
filtered to give a clear solution. The solution was added on to a column carrying strongly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give
the title compound. 36 mg; 13C-NMR (CD3OD, rotamers): 6 20.0, 26.5,28.2,35.1,
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35.7, 44.0, 44.4, 51.6, 53.8,54.99, 55.03, 55.2, 55.5, 111.4, 111.7, 112.4. 112.9, 116.6,116.9,124.98,125.02,126.L, 126.7, 128.8, 129.3, 135.0, 136.1.. 136.3,137.0, 151.3, 151.7,153.9,154.0,173.1, 173.5.
Example 38 - N-((4-Methylphenyl)methyl)-N-(l-piperidiii-4-yl)-4-
chlorophenylacetamide (26HCH78-9)
To a solution of commercially available tert-butyl 4-oxo-l-piperidine carboxylate (1.75 g, 8.8 mmol) and 4-methylbenzylamine (970 mg, 8.0 mmol) in methanol (7 ml) was added acetic aicid in methanol (1 M, 6.7 ml) followed by NaCNBH3 in methanol (0.3 M, 30 ml). The resulting solution was stiiTed at room
temperature. After 20 h, water (5 ml) was added, and the mixture was stirred for 1 h, before it was concentrated. Flash cliromatography in dichloromethane:methanol 10:1 gave tert-butyl 4-(4-methylphenyI)methyl)amino-piperidine carboxylate. Yield: 2.4 g, 98%. To a solution of tert-butyl 4-(4-methylphenyl)methyl)amino-piperidine carboxylate (80 mg, 0.26 mmol) in dichloromethane (1.8 ml) was added diisopropylethylamine (0.11 ml, 2.4 eq.) followed by 4-chlorophenylacety] chloride (99 mg, 0.53 mmol). The reaction mixture was stirred at room temperature. After 20 h, water (1 ml) was added. The mixture was stirred for another 2 h, before diethyl ether (20 ml) was added. The mixture was sequentially extracted with HC1 (0.2 N, 2x15 ml), NaOH (0.2 N, 2x15 ml), and H2O (10 ml), dried (Na2SO4), filtered and
concentrated. The crude material WJIS dissolved in diethyl ether (2 ml) and HC1 (4 M in dioxane, 1 ml). The reaction mixiure was stirred at room temperature. Afier 2 h, NaOH (6 N, 1 ml) was added followed by dichloromethane (10 ml). TTie mixture was extracted with water (2x 10 ml), dried (Na2SO4), and filtered to give a clear solution.
The solution was added on to a column carrying "strorigly acidic cation exchange resin (0.3 mmol/g resin), which was washed with methanol (3x6 ml), and eluted with 10%
NH3 in methanol, and concentrated to give the title compound. Yield: 22 mg; 13C-NMR (CD3OD, retainers): 6 19.9,263,27.7,39.9,40.0,43.6,43.9,44.4,51.5, 53.6,
126.1,126.7,128.2,128.4,128.6, 128.9,129.4,129.6,130.7,130.9,131.2,131.6, 132.5,132.7,133.9,134.1,134.4,134.8,135.9,136.3,137.2,172.4,172.9.
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Example 39 - A'-((4-MethylphenyI)methyl)-A'-(l-(phenylmethyl)pyrroHdin-3-yl)-7V-pheny]methy]carbainide (26HCH50)
To a solution of 3-amino-l-phenylmethylpyrrolidine (353 mg, 2 mmol) and 4-methylbenzaldehyde (361 mg, 3 mmol) in methanol (20 ml) was added acetic acid in methanol (2 M, 6.7 ml) followed by NaCNBH3 in methanol (0.3 M, 3 nil). The mixture was stirred at room temperature. After 24 h, water (5 ml) was added. The mixture was stirred for another hour before concentrated. Flash chromatography in dichloromethane/methanol 10/1 gaveA (4-methylphenyl)methyl)amino-l-phenylmethylpyrrolidine.
AK(4-MethylphenyI)methyl)aniino-l-phenylmethylpyn'olidine(35 mg, 0.125 mmol) was dissolved in dichloromethane (1.5 ml), and benzylisocyanate (0.09 ml, 0.3 mmol) was added. The reaction mi:icture was stirred at room temperature. After 48 h, the crude reaction mixture was added on to a column carrying strongly acidic cation exchange resin, which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and concentrated to give the title compound. Yield: 48 mg, 92%;
13C-NMR (CD3OD): 5 20.0,29.7, 44.2, 51.3, 53.4, 56.4, 57.8, 58.7, 126.8, 127.1,
127.3, 127.6,128.3, 128.4,128.9,129.1, 135.9, 136.8, 140.3, 158.5.
Example 40 - N- To a solution of 3-amino-I-phenybnethylpvrTolidine (353 mg, 2 mmol) and 4-methylbenzaldefayde (361 mg, 3 mmol) in methanol (20 ml) was added acetic acid in methanol (2 M, 6.7 ml) followed by NaCNBH3 in methanol (0.3 M, 3 ml). The
mixture was sfcrrec at room temperature. After 24 h, water (5 ml) was added. The mixture .was snrred for another hour before concentrated. Flash chroniatography in dicWcTomethane/methanol 10/1 gave? - To a solution of M{(4-Methylphenyl)methyl)amino-1-
phenylmethylpynolidme (35 mg, 0.H25 mmol), diisopropylethylamine (0.14 ml) in dichloromethane (1.5 ml) was added. 4-methoxyphenylacetyl chloride (0.1 ml, 0.5 mmol). The reaction mixture was stirred at room temperature. Aiter 48 h, the crude reaction mixture was concentrated and redissolved in methanol. The solution was added on to a column carrying strongly acidic cation exchange resin, which was washed with methanol (3x6 ml), and eluted with 10% NH3 in methanol, and
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concentrated Flash chromatography in dichloromethane/methanol 10/1 gave the title compound. Yield: 20 mg, 38%; 13C-NMR (CD3OD)- S 21.3, 30.2, 40.8, 47.8, 53.6, 53.9, 55.5, 57.5, 60.2, 114.4,125.7,127.0, 127.1, 127.3, 127.4, 128.4, 128.5, 128.7, 128.9,129.2, 129.8,130.0,135.9,137.0,158.6.
Example 41 - N-((4-Metby1phenyl)methyl)-N-(l-(phenylmethyl)piperidin-4-yl)-4-inethoxyphenyIthioacetamide (RO)
A mixture of 7V-((4-Methylphenyl)methyI)-Ar"(l-(phenylmethyl)pipendin-4-yl)-(4-methoxyphenylmethyl) acetamide (20 mg, 0.045mmol) and Lawesson's reagent (25 mg, 0.062 mmol), was taken in a glass vial and mixed thoroughly with magnetic stirbars. The glass vial was then irradiated in a microwave oven (900 W, Whirlpool M401) for 8 min. Upon completion of the reaction, the yellow-colored material was transferred to an ion-exchange column with the aid of methanol (2 ml). The ion-exchange column was subsequently washed with CH2CI2 (2ml) and methanol (2ml) and the product was thereafter eluted from the ion-exchange column (10% NH3 in methanol, 2 ml) to give 7\/'- Example 42 - Receptor Selection and Amplification (R-SAT) Assays.
The functional receptor assay, Receptor Selection and Amplification Technology (R-SAT), was used (with minor modifications from that previously described US 5,707,798) to screen compounds for efficacy at the 5-HT2A receptor. Briefly, NIH3T3 cells were grown in 96 well tissue culture piaies to 70-80% confluence. Cells were trdnsfected for 12-16 hours with piasmid DNAs using superfect (Qiagen Inc.) as per manufacture's protocols. R-SAT's were generally performed with 50 ng/well of receptor and 20 ng/well of Beta-galactosidase piasmid DNA. All receptor and G-protein constructs used were in the pSI mammalian expression vector (Promega lac) as described in U.S. 5,707,798. The 5HT2A receptor gene was amplified by nested PCR from brain cDNA using the oligodeoxynucleoades based on the published sequence (i5ee Saltzman et al Biochem. Biophys. Res. Comm. 181:1469-78 (1991)). Large-scale transfections, cells were transfected for 12-16 hours, then feypsinized and frozen in DMSO. Frozen cells were later thawed, plated at 10,000-40,000 cells per well of a 96 well plate that contained drug. With both
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methods, cells were then grown in a humidified atmosphere with 5% ambient CO2 for five days. Media was then removed from the plates and marker gene activity was measured by the addition of the beta-galactosidase substrate ONPG (in PBS with 5% NP-40). The resulting colorimetric reaction was measured in a spectrophotometric plate reader (Titertek Inc.) at 420 nM. All data were analyzed using the computer program XLFit (IDBSm). Efficacy is the percent maximal repression compared to repression by a control compound (ritanserin in the case of 5HT2A). pIC50 is the negative of the Iog(IC50), where IC50 is the calculated concentration in Molar that produces 50% maximal repression. The results obtained for six compounds of the invention are presented in the following table. Table I. Efficacy of Compounds at the 5-HT2A Receptor

Compound
Efficacy (average)
Efficacy(s tdev)
pICSO (average)
pICSO (stdev)
26HCH52
98
5.0
7.31
0.16
26HCH66-03
76
13.3
7.42
0.01
| 26HCH66-05
109
3.0
7.55
0.15
1 26HCH8O-2
89
46
7 78
0.17
1 26HCHSO-7
87
3.7
7.70
0.26
26HCHSO-10
91
4.9 7.21
0.05
Example 43 - In Vitro Efficacy of 26HCH17 as an Inverse Agonist at the 5-IIT2A Receptor.
The graph shown in Figure 11 represents the data obtained from a dose response analysis of 26HCH17 and ritanserin as 5-HT2A receptor inverse agonists. Briefly, the 5-HT2A receptor, and the alpha subucit of the guanine nadeotids binding protein Gq were transiently transfected into NIH3T3 cells and assayed using the functional receptor assay, Receptor Selection and Amplification Technology (R-SAT) essentially as disclosed in U.S. Patent No. 5,707,798. Each compound was screened at seven serially diluted concentrations in triplicate. Data were analyzed using least squares fit analysis with GraphPad Prism (San Diego, CA.), and are reported normalized to percent response.
Example 44 - Selectivity Profile of Inverse Agonist 26HCH16D
R-SAT assays (as described in Example 42) were carried out with cells transfected with receptors (listed below) to determine the receptor selectivity profile for compound 26HCH16D. 5HT2A inverse agonist data (IC50 nM; % efficacy) were
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derived from detailed dose response curves (7 points in triplicate). All other data (initial concentration at which at least 30% efficacy observed; actual efficacy figure) derived from the 4 dose profiling protocol in which compounds were tested at 4 doses in duplicate, nr = activity less than 30% at all doses tested (3, 30, 300, 3000QM), therefore EC50AC50 greater than 3000nM). The results are presented in the following table.
Table 2. Profile of 5-HT2A Inverse Agonist 26HCHJ6D

Receptor

Efficacy
5HT2A (human)
Agonist
nr

Inverse A eonist
0 9nM; 79%

5HT2B (human)
Agonist
nr

Antagonist
3000nM; 60%

5HT2C (human)
Agonist
nr

Inverse Agonist
3000nM; 79%

5HT1A (human)
Agonist
nr

Antagonist
nr

5HT1A (rat)
Antagonist
nr

5HTIE (human)
Agonist
nr

P2 (human)
Agonist
nr

Antagonist
3000nM; 73%

HI (bmnwi)
Agonist
nr

Antagonist
3000nM; 33%

alpha la/D (rat)
Agonist
nr

Antagonist
nr

alpha I b/B (hamster)
Agonist
nr

Antagonist >
nr

i
alphalc/A (tmman)
Agocst
nr

Antagonist
3000nM;46%

alph 2A (human)
Agonist
or

Antagonist
m

alpha2B (human)
Agonist
nr

Antagonist

a!pha2C (human)
Agonist
or

Antagonist
m

ml (human)
Agonist
nr

Antagonist
nr
As indicated above, 26HCH16D is a highly selective 5-HT2A inverse agonist
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General LC-MS procedure for Working Examples ELH01-46, MBT01-14 and AKU01-38.
In the following examples, HPLC/MS analyses were performed using either of two general methods (Method A or Method B). The tr values reported below were obtained using one of these procedures, as indicated in the specific examples.
The methods were as follows: Method A: AgUent HP1100 HPLC/MSD.
G1312A Binary pump, G1313A Autosampler, G1316A Column compartment, G1315A Diode array detector (190-450 nm), 1946A MSD, electrospray ionization, Chromatography: 8 mM amnaoniumacetate in water/acetonitrile
Gradient start at 70% org. up to 100 % org. over 12 min, down to 70 % org. over 0.5 min, held for 3.5 min. Total runtime 16 min. Flowrate 1 ml/min
Column, Phenoroenex Lima Cl 8(2) 3um 75x4.6mm. MS parameters:
Drying gas, 10 1/min. Nebulizer pressure, 40 psig. Gas temp, 350 C. VCap, 4000. Method B: Waters/Micromass HPLC/MS
600 LC-pump, 2700 Sample manager, 24S7 Dual absorbance detector (channel A-205 nm, channel B-Z35 nm), Micromass ZMD-mass-spectrometer, electrospray ionization. Chromatography:
0.15%TFA in water/acetonitrile.
Gradient start at 30 % org. up to 100% org. over 10 min, held for 3 min. down to 30 % org. over 0.5 min, held for 4.5 min. Total nm time 18 min. Flowrate, 1 ml/min.
Column, Symmetry Cl8,5fun, 4.6x50 mm. or
10 mM ammoniumacetate in water/acetonitrile.
Gradient start at 30% org. for 2.5 min, up to 100 % org. over 10 min, held for 9 mm, down to 30 % org. over 0.5 min, held for 5 min. Total run time 27 min. Flowrate, 1 ml/min.
Column: Phenomenex Synergi C12,4um, 4.6x50mm. MS parameters:
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Derivation gas, 404 I/H. Capillary, 5.3kV. Cone, 36V. Extractor, 3V. Source block temp, 130 C. Desolvation temp, 250 C
Example 45 - 2-(4-methoxj'phenyI)-Ar-(4-methylbenz>'J)-7V-(piperidiii-4-y]) acetamide (50ELH87)
Reaction step 1: N-trifluoroacetyl-4-piperidone (50ELB84)
4-Piperidone hydrochloridc monohydrate (4.0 g, 26 mmol, 1.0 eq) was dissolved in 130 ml of dichloromethane. After addition of triethylamine (8.66 g, 3.3 eq) the reaction mixture was stirred for 10 min. The mixture was cooled on an ice-bath (0°C). Trifluoroacetic anhydride (12.0 g, 2.2 eq) was added dropwise under stirring. After 2 hours the reaction was quenched by addition of distilled water. The aqueous phase was extracted twice with dichloromethane. The combined organic layers were collected and dried with sodium sulfate. Concentration afforded N-irifl uoroacetyl-4-piperidone. Reaction step 2: 4-(4 Methylbenzylamino)-l-(trifluoroacetyl) piperidin (50ELH85)
Methanol (150 ml) was added to an Erlenmeyer flask and acetic acid was added under stirring until pH 5. 4-Methylbenzylamine (3.14 g, 25.9 mmol) and N-trifluoroaceiyl-4-piperidone(from reaction step 1) (5.065 g, 25.9 mmol) were added to a 250 ml round-bottomed flask and dissolved in the methanol/acetic acid (150 ml) solution previously made. The reaction mixture was stirred for 5 min and NaCNBHa (2.46 g,. 3S.9 mmol) was added slowly under stirring. After 20 hours the reaction was concentrated and transferred to a separatory funnel containing dichloromethane and distilled water. The aqueous phase was made basic by addition of NajCOs. The aqueous phase was extracted twice with dichloromethane. The combined organic layers were collected and dried with Na2SO . Concentration afforded. 4-(4-mrthylbemylanimeVHtrifruoroacctyl) piperidme. UV/MS 60/53 (M 301), tr (A, MS) 3.267.
Reaction step 3:2-(4-Methoxyphenyl)-N-(4-methyIbenzyl) N-(l-trifluoroacetylpiperidin-4-yI) acetamide (50ELH86)
The product from reaction step 2 (7.8 g, 25.9 mmol) was dissolved in 100 ml of dichloromethane and stirred while 4-methoxyphenylacetyl chloride (4.8 g, 25.9 mmol) was added. After 4 hours, heptane was added whereupon the product precipitated as the hydrochloride salt The solvent was removed by evaporation. The crude material was purified by flash chromatography EtOAc/Heptane (1:2) Yield (overall: Reaction steps 1+2+3) 3.912 g (34%), UV/MS 91/58 (M 449), V (A, MS)
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4.319. 'H-NMR (400 MHz, CDC13) 8 6.80-7.15 (Ar, 4H), 4.64 (bit, 1H), 4.4 (s, 2H), 3.95 (d, 2H), 3.72 (s, 3H), 3.50 (s. 2H), 3.09 (t, 2H), 2.7(t, 2H), 2.32 (s, 3H), 1.75 (bit, 2H). "C-NMR 172.5; 158.8; 137 4; 134.9, 129 9; 129.9; 129.8; 127.1; 125.8; 114.3; 55.4; 52.2; 47.3; 45.3; 43.4.40.6; 30,1; 29.2; 21.2.
Reaction step 4: 2-(4 Methoxyphenyl)-N-(4-methylbenzyl) N (piperidin-4-yl) acetamide (50ELH87)
The product from reaction step 3 (3.9 g, 8.7 mmol) was dissolved in methanol (12 ml). In a 250 ml round bottom flask a saturated solution of potassium carbonate in methanol was prepared. To this solution, the 2-(4-methoxyphenyl)-M{4-methylben2yI)-A (A'-trifluoioacetpiperidin-4-yl) acetamide solution was added under stirring. After 4 hours, the solution was concentrated and the remaining solid taken upin base and dichloromethane. The combined organic layers were dried with sodium sulfate and concentrated. UV/MS 91/72 (M 353), tr (A, MS) 2.210.
The corresponding hydrocliloride salt was also prepared, by dissolving the free base in dichlorornethane (1 ml) and HC1 (1 eq. 2 M HC1 in ether) was added with stirring. The salt was precipitated by addition of the dichlorom ethane solution into heptane. Concentration on the rotary evaporator returned the product is white crystals.
Example 46 - 2-(4-Methoxyphenyi)-A (4-methylbenzyl)-iV-(l-metbylpiperidin-4-yI) acetamide (50ELH27) Reaction step 1: 4-(4-Methylbenzylamino)-l-methylpiperidine (50ELH25)
Methanol (50 ml) was added to an Erlenmeyer flask and acetic acid was added under stirring until pH 5. Methyftxazylamine (1.0 g, 8.8 mmol) and I -Methyl-4-piperidone (1.1 g, 8.8 mmol) were added to a 100 ml round-bottomed flask and dissolved in the methanol/acetic acid (40 ml) solution previously made The reaction mixture was snrred for 5 min and NaCNBHa (0.83 g,, 13.2 mmol) was added slowly under stirring. After 20 hours the reaction was concentrated and transferred to a separatory funnel containing dichloromethane and distilled water. The aqueous phase was made basic by addition of Na2CO3. The aqueous phase was extracted twice with dichloromethane. The combined organic layers were collected and dried with Na2SO<. concentration afforded the title compound. yield uv t ms> Reaction step 2; 2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N (l-methylpiperidm-4-yl) acetamide (50ELH27)
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The product from reaction step 1 (1.9 g, S.7 mmol) was dissolved in 40 ml of dichloromethane and stirred while 4-methoxyphenylacetylchloride (1.606 g, 8.7 mmol) was added. After 4 hours, heptane was added whereupon the product precipitated as the hydrochloride salt. The solvent was removed by evaporation. The crude material was purified by flash chromatography first eluting with 10% MeOH in CH2C12 and thereafter eluting with 0-20% MeOH in CH2CI2 and 5% NEt3. Yield (overall: Reaction steps 1+2). 77%. UV/MS: 100/100 (M 367), t, (A, MS) 4.359, Rf 0.15 (2% MeOH in CH2C12). 'H-NMR (400 MHz, CDC13) 5 12.6 (s, 1H), 7.16 (d, 7=7.0 Hz, 2H), 7.10 (d, 7=7 0 Hz, 2H), 7.04 (d, 7=8.0 Hz, 2H), 6.82 (d, 7=8.0 Hz, 2H), 4.87 (tt, 7=1 1.0, 4.0 Hz, 1H), 4.53 ppm (s, 2H), 3.78 (s, 3H), 3.55 (s, 2H), 3.42 (brd, 7=1 1.0 Hz, 2H), 2.80 (brq, 7-11.0 Hz, 2H), 2.7 (d, 7=4.0 Hz, 3H), 2.42 (dq, 7=13.0, 3.0 Hz, 2H), 2.34 (s, 3H), 1.78 (brd,7=13.0 Hz, 2H). "C-NMR173.1,158.9; 137.4; 134.8; 129.9; 126.7; 125.8; 114.4; 76.9; 55.5; 54.6, 48.8; 43.7; 40.5; 26.4; 21.2
Example 47 - 2-(4-MethosypheDyI)-Ar-(4-methyIbenzyl)-A (l-cyclohexylmethylpiperidin-4-yl) iicetamide (42ELH45)
50ELH87 (the hydrochloride salt) (0.5 g, 1.29 mmol, 1.0 eq) was dissolved in ethanol (100 ml). Cyclohexanecarboxaldehyde (2.5 g, 20 eq.) was added followed by addition of sodium borohydride (0.084 g, 2.0 eq.). The reaction was stirred for 36 h and acetic acid (3 ml) was added The reaction was stirred for additionally 2 h and extracted with sodium hydrogen carbonate (3 tunes) and dichloromethane. The organic layers were dried with sodium sulfate and concentrated. The product was purified by flash chromatography (5-10% MeOH in CH2CI2). The resulting product was dissolved m ether (20 ml) and MeOH (added dropwise until dissolved) and HC1 (1 eq. 2 M HC1 in ether) was added under stirring. The hydrochloride salt of 2-{4-methoxyphenyl)-A 4-methyIbenzy!)-A'-(l-cyclohexyImethylpiperidin-4-yl) acetamide precipitated and the white crystals were filtered. Yield 80 mg (16%), UV/MS 100/100 (M+ 449), rt (A, MS) 7.105, mp 133-135°C, Rf 0.25 (2% MeOH/CH2Cl2). 'H-NMR (400 MHz, CDC13) 6 11.9 (brs, 1H), 7.12 (q, 4H), 7.02 (d, 2H), 6.80 (d, 2H), 4.87 (m, 1H), 4.58 (s, 2H), 3.77 (s, 3H), 3.55 (s, 2H), 3.48 (m, 2H), 2.70 (m, 4H), 231 (s, 3H), 1.91 (d, :>H), 1.75 (m, 3H), 1.64 (d, 1H), 1.22 ( d, 2H), 1.13 (tt, 2H), 1.02 (brq, 2H). "C-2HMR 173.1; 15S.8; 137.2; 135.1; 129.9; 129.8; 126.8; 125.8; 114.4; 64.1; 55.5; 53.4; 49.2; 46.5; 40.4; 33.9; 25.9; 25.8; 25.7; 21.2.
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Example 48 - 2-(4-Methoxyphenyl)-AH4-methylbenzyl)-Ar-(l-ethylpiperidin-4-yI) acetamide (42ELH80)
50ELH87 (0.25 g, 0.71 mmol, 1.0 eq) was dissolved in acetorutrile (15 ml) and ethyl bromide (0.232 g, 3.0 eq.) was added under stirring. After 2 min Hfinings base (0.084 g, 10.0 eq.) was added. After 36 hours, the solution was extracted with sodium hydrogen carbonate solution and dichloromethane (3 times). The organic layers were dried with sodium sulfate and concentratedyielding a yellow oiL The product was purified by flash chromatography (2% MeOH in CH2CI2). The resulting product was dissolved in dichloromethane (1 ml) and HCI (1 eq. 2 M HC1 in ether) was added under stirring. The salt was precipitated by addition of the dichloromethane solution into heptane. Concentrationon the rotary evaporator gave the product as white crystals.Yield 170 mg (63%), UV/MS 98/95 (M 381), mp 153-155°C, rt (A, MS) 3.033, Rf 0.35 (3% MeOH/CH2Cl2). 'H-NMK (400 MHz, CDC13) 8 12.2 (s, 1H), 7.15 (d, 2H), 7.12 (d\ 2H), 7.08 (d, 2H), 6.82 (d, 2H), 4.89 (m, 1H), 4.58 (s, 2H), 3.79 (s, 3H), 3.58 (s, 2H), 3.50 (d, 2H), 2.90 (m, 1H), 2.7 (brq, 2H), 2.45 (m, 2H), 2.34 (s, 3H), 1.80 (d, 2H), 1.44 (t, 3H). 13C-NMR 173.1; 158.9; 137.3; 134.9; 129.9; 125.8; 114.4; 55.5; 52.3; 52.0; 492; 46.5; 40.5; 26.2; 21.2; 9.5.
Example 49 - 2 4-MethoxyphenylHV-(4-chlorbenzyl)-A-(l-etfaylpiperidin-4-yl) acetamide (42ELH85).
This compound was prepared similarly to 50ELH27
Reaction-step 1: (42ELH84)
Starting materials: l-Methyl-4-piperidone (0.5 g, 4.4 mnaol, 1.0 eq.), 4-chJorobenzylamine (0.626 g, 1.0 eq.), sodinm cyanoborohydride (0 79 g, 1.5 eq.).
Reaction-step 2: (42ELHB5)
Starting materials: 42ELHS4,4-rcethoxyphenylacetylchloride (0.774 g, 1.0
eq.)-
The procedure was analogous to 50ELH27, but the product was purified by ion-exchange chromatography followed by HPLC. The hydrochloride salt was made by dissolving the free base in dichloromethane (1 ml) and HCI (1 eq. 2 M HCI in ether) was added under stirring. The salt was precipitated by addition of the dichloromethane solution into heptane followed by concentration on the rotary evaporator.
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Product: White crystals. UV/MS 98/97 (M 387), rt (A, MS) 2.953. 'H NMR (400 MHz, CDC13) 5 12.6 (s, 1H), 7.35 (d, 2H), 7.18 (d, 2H), 7.05 (d, 2H), 6.82 (d, 2H), 4.89 (m, 1H), 4.55 (s, 2H), 3.80 (s, 3H), 3.55 (s, 2H), 3.45 (brs, 2H), 2 80 (bis, 2H)} 2.72 (s, 3H), 2.25 (brs, 3H), 1.80 (bis, 2H). UC-NMR 173.0; 158.9; 136.5; 133.6; 129.8; 129.4; 127.3; 126.3; 114.5; 55.5; 54.6; 48.7; 46.3; 43.7; 40.5; 26.3.
50-2-(4-Methoxyphenyl)-?V-(4-chlorbenzyl)-A'-(l-isopropyIpiperidin-4-yl) acetamide(42ELH79).
Procedure as 42ELH80
Starting materials: 50ELHS7 (0.25 g, 0.71 ramol, 1.0 eq.), isopropylbromide (0.262 g, 3.0 eq.,).
Product: Yield 130 mg (46%), UV/MS 100/100 (M 395), r, (A, MS) 3.360. 'H-NMR (400 MHz, CDC13) 6 12.0 (s, 1H), 7.15 (d, 2H), 7.10 (d, 2H), 7.05 (d, 2H), 6.82 (d, 2H), 4.87 (m, 1H), 4.60 (s, 2H), 3.79 (s, 3H), 3.57 (s, 2H), 3.38 (brd, 3H), 2.79 (q, 2H), 2.63 (q, 2H), 2.34 (st 3H), 1.80 (d, 2H), 1.39 (d, 6H). i3C-NMR 173.1; 158.9; 137.3; 135.1; 129.8; 126.8; 125.8; 114.4; 57.9; 49.4; 48.2; 46.5; 40.5; 25.9; 21.2; 16.9.
Example 51 - 2-(4-Metho phenyI)-A'-(4-chJorobenzyI)-A-(piperidiii-4-yI) acetamide (42ELH89) (As starting material in other reactions, used unpurified) Procedure as 50ELH27.
Reaction step 1.- M-Trifluoroacetyl-4-piperidone (42ELH86) Starting materials: 4-Piperidone hydrochloride monohydrate (2.0 g, 13 mmol, 1.0 eq), trifluoroacetic anhydride (6.0, U2 eq.). TLC showed full conversion. Product: RrO.9 (10% MeOH/CHTCb).
Reaction step 2:4 4-Chloroben Iamino)-l-(Erifluoroacetyl) piperidin (42ELH87)
Starting materials: 42ELH86 (2.5 g, 12.8 mmol, 1.0 eq.), 4-Chloroben2ylamine (1.8 g, 1.0 eq.)
Reaction step 3:2 4-Meiho3cyphenyl)-7VL(4-chlorobeiizyl)-iVL Starting materials: 42ELH87 (4.0 g, 12.5 mmol, 1.0 eq.), 4-methoxyphenylaceti cWoride(2Jl g, 1.0 eq.)
Reaction step 4:2-(4-Metho3cyphenyI)-7 4-K oroben2yl)-W-(pipcridin-4-yl) acetamide (42ELH89)
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Product. Yield: 2 g (57%), UV/MS 80/82 (M 373), Rf 0.2 (50% EtOAc/Heptane).
Example 52 - 2-(4-Methoyypheny!)-AK4-chlorbenzyl)- -(l-cycJopenty!piperidin-4-yI) acetamide (42ELH91).
Procedure as 42ELH80, but the product was purified by HPLC. The acidic cluent was made basic with sodium carbonate and extracted with dichloromethane (3 times). The combined organic layers were collected and dried with sodium sulfate and concentrated. The remaining product was dissolved in 1 ml of dichloromethane and HC1 (1 eq. 2 M HC1 in ether) was added under stirring. This solution was added dropwise to a large excess of n-heptane to make the hydrochloride precipitate. The solvent was evaporated off to form white crystals of 2-(4-methoxyphenyl)-#-(4-chlorbenzyI)-iV-(l-cyclopentylpiperidin-4-yl) acetamide, hydrochloride.
Starting materials: 42ELH89 (025 g, 0.67 mmol, 1.0 eq.), cyclopentylbromide (0.3, 3.0 eq.)
Product: Yield: 211.2 mg (76%). Purification by ion-exchange: UWMS 90/98. Purification by HPLC UV7MS 100/J 00 (M 441), Rf 0.2 (3% MeOH/CH2Cl2), r, (A, MS) 4.067. JH-NMR (400 MHz, CDCI3) 5 12.2 (brs, 1H), 7.32 (d, 2H), 7.17 (d, 2H), 7.04 (d, 2H), 6.82 (d, 2H), 4.90 (brt, 1H), 4.58 (s, 2H), 3.79 (s, 3H), 3.58 (brd, 2H), 334 (s, 2H), 3.14 (brq, 2H), 2.58 (brq, 2H), 2.04 (m, 4H), 1.89 (m, 4H), 1.75 (brd, 2H). "C-NMR 173.0; 158.9; 133.5; 129.8; 129.3; 127.3; 126.4; 114.5; 68.4; 55.5; 51.9; 49.1; 462; 40.5; 28.5; 26.0; 23.8.
Example S3 - 2--Ar-(l-feopropylpiperidiD-4-yI) acetamide (42ELH90).
42ELH89(0.25 g, 0.67 mmol, 1.0 eq) was transferred to a 4 ml vial and dissolved in acetonitrile (2 ml). Isopropyl bromide (0.25 g, 3.0 eq.) was added along with Hiinigs base (0.87 g, 10.0 eq.). The vial was sealed and shaken for 4 days at 60°C. The reaction mixture was transferred to a separatory funnel with distilled water and CH2Cl2- The aqueous phase was made basic with sodium hydrogen carbonate and extracted with dichloromethane (3 times). The organic layers were collected and dried with sodium sulfate and concentrated, mis resulted in a yellow oil. The product was purified by flash chromatography (3% MeOH in CH2CI2). The resulting product was dissolved in dichloromethane (1 ml) and HC1 (1 eq. 2 M HC1 in ether) was added under stirring. The salt precipitated by addition of the dichloromethane solution into
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heptane. Concentration on the rotary evaporator returned the product as white crystals.Yield 101.2 mg (63%), UV/MS 94/96 (M 415), Rf 0.25 (3% MeOH/CH2a2).
'H-NMR (400 MHz, CDC13) 8 12.05 (brs, 1H), 7.36 (d, 2H), 7.18 (d, 2H), 7.04 (d, 2H), 6.82 (d, 2H), 4.88(m, 1H), 4.60 (s, 2H), 3.79 (s, 3H), 3.55 (d, 2H), 3.36 (d, 3H), 2.80 (brq, 2H), 2.65 (brq, 2H), 1.76 (brd, 2H), 1.39 (d, 6H). I3C-NMR 173.0; 159.0; 137.0; 136.0; 129.7; 129.3; 127.4; 126.4; 114.5; 57.9; 55.5; 49.2; 48.2; 46.2; 40.5; 25.8; 16.9.
Example 54 - 2-(PhenylHV-(4-trinuoromethylbenzylHV-(l-methylpiperidin-4-y!) acetamidc (50ELH14b)
Procedure as for 50ELH27. Purification was done by HPLC. The hydrochloride salt was made by dissolving the free-base in dichloromethane (1 ml) and HC1 (1 eq. 2 M HC1 in ether) was added under stirring. The salt was precipitated by addition of the dichloromethane solution into heptanefollowed by concentration.
Reaction-step 1: 4-(4-Triflouromethylben2ylamino)-l-methylpiperidin (50ELH2).
Starting materials: 1-Methyl-4-piperidone (1.13 g, 10.0 mmol, 1.0 eq.),4-trifluoromethylbenzylamine (1.75 g, 1.0 eq.). Product: UV/MS 80/92 (M 273).
Reaction-step 2: 2-(Phenyl)-AT-(4-trifluoromethylbenzyl>7 -(l-methylpiperidin-4-yD acetamide (50ELH14b).
Starting materials: 50ELH2 (0.12 g, 0.44 mmol, 1.0 eq.), phenyiacetyichioride (0.068 g, 1.0 cq.).
Product: UV/MS 100/97 a 390), rt (A, MS) 3.797, Rf 0.3 . (5%MeOH/CH2Cl2). 'H-NMR (400 MHz, CDC13, rotamers 54/46) 8 7.52 (d, 2H), 7.42 (d, 2H), 7.12-7.30 (m, 4H,), 4.63 and 3.74 (2m, 1H), 4.38 (brs, 2H), 3.80 and 3.50 (2s, 3H), 3.31 and 2.78 (2d, 2H), 233 and 2.18 (2s, 2H), 2.24 and 1.65-1.90 (t andm,4H), 1.60 and 1.22 (2d,2H), I. "C-NMR 172.3; 171.8; 143.9; 135.1; 134.8; 129.1; 129.0; 128>, 128.7; 127.4; 1273; 127.2; 126.3; 126.1; 126.0; 56.0; 55.2; 54.9; 50.9; 46.8; 45.2; 44 , 42 ; 41.7; 30.6; 28.4.
Example 55 - 2-(4-Fluorophenyl)-7V-(4-trifluoromethylbenzyl)-M 76

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Reaction-step 2: 2-(4-Fluoro-pbenyl)-N-(4-trifluoroiDCthylbcnzyl)-N-(l-methylpiperidin-4-yl) acetamide (50ELH14c).
Starting materials: 50ELH2 (0.12 g, 0.44 mmol, 1.0 eq.), 4-fluorophenylacetylchloride (0.076 g, 1.0 eq.).
Product: Yield 69.7 mg (36%), UV/MS 100/98 (M 409), rt (A, MS) 3.839, Rf 0.3 (5%MeOH/CH2Cl2). 'H-NMR (400 MHZ, DMSO, retainers 65/35) 5 10.80 and 10.60 (2s, 1H), 7.71 and 7.62 (2d, 2H), 7.47 and 7.38 (2d, 2H), 7.00-7.36 (t and m, 4H), 4.70 and 4.50 (2s, 2H), 430 (m, 1H), 3.93 and 3.56 (2s, 2H), 3.34 (s, 2H), 3.00 (brq, 2H), 2.64 (s, 3H), 2.08 (m, 2H), 1.68 and 1.58 (2d, 2H). 13C-NMR 176.8; 176.4; 167.6; 165.3; 150.0; 149.0; 136.6; 132.5; 131.0; 130.5; 120.6; 120.5; 120.5; 120.4; 58.1; 58.0; 57.0; 54.5; 52.0; 49.3; 47.6; 45.0; 32.4; 31.4.
Example 56 - 2-(4-McthoxyphcnyI)-Ar-(4-tri(lnoromethyIbenzyI)-Ar-(l-mcthyIpiperidin-4-yl) acetamide (S0ELH14d) Procedure as 50ELH14B.
Reaction-step 2: 2-(4-Metho?yphenyl)-JV-(4-trifluoromethyIbenzyl)-JV-(l-meih>Ipiperidin-4-yl) acetamide (5035LH14d).
Starting materials: 50ELH2 (0.15 g, 0.55 mmol, 1.0 eq.), 4-mcthencyphcnylacctylchloride (0.1 g, 1.0 eq.).
Product: Yield 57.5 mg (29%), UV/MS 99/100 (M 421), rt (B, MS) 6.30, Rf 0.25 (3%MeOH/CH2CI2). JH-NMR (400 MHz, CDC13) 6 12.4 (brs, 1H), 7.55 (d, 2H), 7.2S (d, 2H), 6.96 (d, 2H), 4.84 (bit, 1H), 4.59 (s, 2H), 3.72 (s, 3H), 3.46 (s, 2H), 3.38 (d, 2HU 2-78 (q, 2H), 2.64 (s, 3H), 2.38 (q, 2H), 1.70 (d, 2H). I3C-NMR 173.0; 159.0; \AZ3; 130.0; 129.8; 1263; 126.2; 114.7; 114 ; 55.5; 54.4; 48.7; 46 ; 43.6; 40.6; 263.
Example 57 - 2-(4-TriflHoromethy1phenyI)-7V-(4-trifluoroinethylbeii2yI)-Ar-(l-metby]piperidin-4-yl) acetamide (50ELH14a) Procedure as 50ELH14B.
Reaction-step 2:244-TriiluoromethvtohcnylVAM 4-trifluoromethylbeDzyl)- -(l-methylpiperidin-4-yl) acetamide (f>0ELH14a).
" Starting materials: 5OELH2 (0.12 g, 0.44 mmol, 1.0 eq.), 4-trifiuoromethylphenylacetylchloride (0.1 g, L0 eq.).
Product: Yield 92.6 mg (42%), UV/MS 89/93 (M 458), rt (A, MS) 4.211, Rf 0.3 (5%MeOH/CH2a2). JH-NMR (400 MHz, CDCI3) 5 12.7 (bis, 1H), 7.56 (d, 2H),
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7.48 (d, 2H), 7.17 (d, 2H), 4.86 (m, 1H), 4.63 (s, 2H), 3.58 (s, 3H), 3.40 (d, 2H), 2.75 (q, 2H), 2.65 (d, 3H), 2.46 (dq, 2H), 1.73 (brs, 2H). "C-NMR 171.8; 141.9; 138.4; 129.4; 127.9; 126.3; 126.3; 126.2; 125.9; 125.8; 54.4; 48.8; 46.6; 43.6; 40.9; 26.2,
Example 58 - Z -HuorophenyO-A -flnorobenzyO-AHl-nietbylpiperidin-4-yJ) acetamide (50ELH6) Procedure as 50ELH14B.
Reaction-step 1:4-(4-HBorobenzylaminoH-niethylpiperidme (50ELH4).
Starting materials: l-Methyl-4-piperidone(1.13 g, 10.0 mmol, 1.0 eq.), 4-fiuorobenzylamine (1.25 g, 1.0 eq.).
Product: Yield 2.154 g (97%), UV/MS 79/89 (M 223).
Reaction-step 2: 2-(4-Flaoropheqyl)-.AK4-fluorobenzyl)-7/-(l-methvlpiperidin-4-yl) acetamide (50E]LH14a).
Starting materials: 50ELH4 (0.12 g, 0.54 mmol, 1.0 eq.), 4-fluoropbenylacetylchloride (0.096 g, 1.0 eq.).
Product: Yield 57 mg (29%), UV/MS 100/100 (M 359), rt (A, MS) 3.763, Rf 0.25 (3% MeOH/CH2CI2). JH-NMR (400 MHz, CDCI3) 5 12.6 (brs, 1H), 7.2 (dd, 2H), 7.06 (m, 4H), 6.98 (t, 2H), 4.88 (tt, 1H), 4.58 (s, 4H), 3.45 (d, 2H), 2.81 (q, 2H), 2.72 (d, 3H), 2.4S (brq, 2H), 1.78 (brs, 2H). 13C-NMR 172.5; 163.4; 160.8; 133.4; 130.6; 130.2; 127.5; 127.4; 116.3; 116.1; 115.9; 115.7; 54.5; 48.8; 46.2; 43.6; 40.3;
26.3.
Example 59 - 2 4-MctlioxypheDyl>-Ar-(4-fluorobeDzyrHV-{l-
metbylpiperidin-4-yJ) acetamide (50ELH8).
Procednre as 50ELH14B
Reaction-step 2:
Starting materials: 50ELH4 (0.12 g, 0.54 mmol, 1.0 eq.), 4-roethoxyphenylacetylchloride (0.1 g, 1.0 eq.).
Product: Yield 54 g (26%), UV/MS 100/100 (M 371), rt (A, MS) 3.257, Rf 0 5 (3%MeOH/CH292). !H-NMR (400 MHz, CDC13) S 12.2 (brs, 1H), 7.12 (m, 2H), 6.97 (m, 4H), 6.75 (d, 2H), 4.80 (brt, 1H), 4.49 (s, 2H), 3.71 (s, 3H), 3.47 (s, 2H), 337 (d, 2H), 2.8 (q, 2H), 2.64 (s, 3H), 235 (q, 2H), 1.69 (d, 2H). "C-NMR 173.0; 163J; 161.1; 158 ; 133.7; 133.6; 129.8; 127.6; 127.5; 126.5; 116.2; 116.0; 114.6; 1143; 55.5; 54.4; 48.8; 46.2; 43.6; 40 ; 26.4.
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Example 60 -2-(Phenyl)-7V-(4-nuorobenz>'])-7V-(l-methylpiperidin-4-yI) acetamide (50ELH1O)
Procedure as 50ELH14B.
Reaction-step 2: 2-(Phenyl)-iV-(4-fluorobenzyl)-7V-(l -methylpiperidin-4-yl) acetamide (50ELH10).
Starting materials: 50ELH4 (0.13 g, 0.59 mmol, 1.0 eq.), phenylacetylchloride (0.091 g, 1.0 eq.).
Product: UV/MS 100/94 (M 341), r, (A, MS) 3.127, Rr0.25
(3%MeOH/CH2CI2). 'H-NMR (400 MHz, DMSO, rotamers 54/56) 5 12.38 (brs, lH), 7.35-7.00 (m, 9H), 4.55 and 4.40 (2s,, 2H), 4.50 and 4.25 (brt, 1H), 3.91 and 3.56 (2s, 2H), 3.30 (Hidden under water signal)(2H), 2.98 (d, 2H), 2.64 (s, 3H), 2.09 (brt, 2H), 1.66 and 1.45 (2brd, 2H). "C-NMR 171.9; 171.6; 162.8; 160.4; 136.5; 136.2; 135.4; 129.9; 129.7; 129.5; 129.2; 129.0; 128.9; 128.7; 127.2; 127.1; 116.2; 116.0; 115.6; 53.2; 52.5; 49.8; 46.9; 44.0; 42.8; 40.9; 40.6; 40.4; 40.2; 40.0; 39.8; 39.6; 27.7; 26.6.
Example 61 - 2-(4-Trifloorometbylpbeny])-Ar-(4-fluorobenzy))-iV-(l-methylpiperidin-4-yI) acetamide (50ELH122)
Procedure as 50ELH14B.
Reaction step 0: 4-TrifluoromethylphenylacetyI chloride (50ELH121)
4-Trifluorophenylacetic acid (1.0 g) and thionyl chloride (15 ml) were refluxed for 1 h. The excess thionyl chloride was evaporated off. NMR showed complete conversion.
Reaction-step 2: 2 4-TrifluoTomethylpbenyl)-7V-(4-floorobqizyI)-Jtf'-(l-methylprperidin-4-yD acetamide (50ELH122).
Starting materials: 50ELH4 (0.12 g. 0.55 mmol, 1.0 eq.), 4-trifluoromethyrphenylacetylchloride (SOELHU1) .] 1 g, 0,5 mmol, 1.0 eq.).
Product: Yield 47.1 mg (24%), UV/MS 96/96 (M 409), rt (A, MS) 4.566, R/ 0.25 (3%MeOH/CH2a2). 'H-NMR (400 MHz, CDC13) 6 7.52 (d, 2H), 7.22 (d, 2H), 7.17 (dd, 2H), 7.04 (t, 2H), 4.86 (bit, 1H), 4.58 (s, 2H), 3.64 (s, 2H), 3.45 (brd, 2H), 2.84 (brq, 2H), 2.71 (d, 3H), 2.45 (brq, 2H). 1.77 (brd, 2H). UC-NMR 171.8; 163.6; 161.2; 138.7; 133J; 129.8; 129.5; 127.5; 127.4; 125.8; 125.7; 116.4; 116.2; 54.4; 48.9; 46.3; 43.6; 40.8; 263.
Example 62 - 4-(4-MetboxybenzylamiDo)-l-metbyIpiperidine (50ELH18). Procedure as 50ELH27.
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Starting materials; l-MethyI-4-piperidone (1.13 g, 10.0 ramol, 1 0 eq.). 4-methoxybenzylaniine (1.37 g, 1.0 eq.).
Product: UV/MS 95/95 (M 235),rt (A,MS) 3.509.'H-NMR (400MHz, CDCh) o 7.3-O.8 (in, 4H), 3.77 (s, 3H), 3.73 (s, 2H), 2.86 (m, 2H), 2.55 (m, 1H), 2.30 (s, 3H), 2.1 (t, 2H), 1.96 (dd, 2H), 1.50 (m, 2H).
Example 63 - 2-(4-TrifluoromethyIphenyl)-iV-[4-
(metboxycarbonyl)benzyl]-iV-(l-niethylpiperidin-4-yl)acetaiiiide(S0ELH20A) Procedure as 50ELH14B.
Reaction-step 1: Methyl 4-(W-ri-methylpiperiding-4-yn aminomcthyl) benzoate (50ELH19).
Starting materials: l-MethyI-4-piperidone (1.13 g, lO.Oinmol, 1.0eq.)> methyl 4-(aminomethyl) benzoate hydrochloride (2.0 g, 1.0 eq.).
Product: UV/MS 81/88 (M 263), rt (A, MS) 3 060. H-NMR (400 MHz, CDCb) 5 S.OO (d, 2H), 7.20 (d, 2H), 3i"0 (s, 3H), 3-85 (s, 2H)( 2.96 (dt, 2H), 2.7 (brs, IH), 2.62 (m, 1H), 2.40 (s, 3H), 2.28 (t, 2H), 1.96 (m, 2H), 1.56 (m, 2H).
Reaction-step 2: 2-(4-Trifluoromethylphenyl)-A f4-(mclhoxycarbonyl)benzyn-N-(l-methylpiperidin-4-yl) acetamide (50EIJH20A).
Starting materials: 50ELH19 (0.20 g, 0.76 mmol, 1.0 eq.), 50ELH121 (0 169 g, 1.0 eq.).
Product: Yield 108.9 mg (32%), UV/MS 100/100 (bt 448), rt (A, MS) 3.327S Rf 0.3 (5% MeOH/CH2Cl2). H-NMR (400 MHzJ>MSO, retainers 56/44) 8 10.7 and 10.4 (2bis, IH), 7.96-72& (m, 8H)f 4.70 and 4.51 (2s, 2H), 430 (brt, IH), 4.06 and 3.69 (2s, 2H), 3.83 and 3.81 (2s, 3H), 3.00 (m, 2H), 2.63 (m, 3H), Z05 (bit, =12 Hz, 2H), 1 9 (brt,>=l2 Hz, 2H). "C-NMR (CrX33) 171.9; 166.7; 142.9; 138.5; 130.7; 130.1; 129.7; 126J2; 1255; 55 ; 52 ; 49.2; 47.4; 4U; 3Z1; 26.6; 222; 14.3.
Kxample 64 - 2-PbenyI-A'-[4-(iDethoxycarbonyObenzyI]-7V-(l-metfaylpiperidin-4-yI) acetamide (50ELH20B) Procedure as 50ELH14B
Reaction-step 2: 2-Phenyl- -f4-(methoyycarbopy3)benzyl]- -(l-methylpipcridin-4-yI) acetamide (50ELH20B)
Starting materials: 50ELH19 (0.2 g, 0.76 mmol, 1.0 eq.), phenylacetyichloride (0.117 g, 1.0 eq.).
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Product: Yield 82.5 g (29%), UV/MS 100/100 (M 381), r, (A, MS) 2.652, Rf 0.25 (3%MeOH/CH2CI2). 'H-NMR (400 MHz, CDC13) 6 12.2 (brs, 1H), 8.00 (d, J=7A, 2H), 7.4-7.2 (m, 4H), 7.08 (d, J 7.4,2H), 4 89 (bit, 1H), 4.62 (s, 2H), 3.90 (s, 3H), 3.56 (s, 2H), 3.42 (d, >11.0, 2H), 2.84 (q, =11.0, 2H), 2.68 (d, J=3.6, 3H), 2.40 (q,J ll.Of 2H), 1.77 (bid, >11.0, 2H). 13C-NMR 173.0; 168.0; 143.3; 136.7; 130.6; 129.0; 127.4; 125.9; 54.5; 52.4; 48.8; 43.6; 41.4; 26.3.
Example 65 - 2-(4-Chlorophenyl)-A [4-(methoxycarbonyI)benzylI-iV-(l-metbylpiperidiD-4-yl) acetamide (50ELH20C). Procedure as 50ELH14B.
Reaction-step 2: 2-(4-ChJoropheiiyl)- '-[4-(inethoxycarfaonyl)benzyl1-A -(l-methylpiperidin-4-yl) acetamide (50ELH20C).
Starting materials: 50ELH19 (0.2 g, 0.76 mmol, 1.0 eq.), 4-cfalorophenylacetylchloride(0.131 g, 1.0 eq.).
Product: Yield 79.2 % (26%), UV/MS 100/96 (M 399), rt (A, MS) 2.333. JH-NMR (400 MHz, DMSO, rotamers 62/38) 5 10.8 and 10.60 (2brs, 1H), 7.95 and 7.85 (2d, =8.6s 2H), 7.4 and 7.28 (2d, 2M), 7.35 and 7.14 (2m, 4H), 4.67 and 4.50 (2s, 2H), 4.29 (m, 1H), 3 93 and 3.84 (2s, 2H), 3.81 (s, 3H), 3 1 (d, >=11.9, 2H), 3.00 (d, J 11.9t 2H), 2.63 (s, 3H), 2.06 (m, :2H), 1.68 and 1.56 (d; J±U.9r 2H). 13C-NMR (CDO3) 172.6; 166.7; 163.4; 161.0; 143.0; 130.7; 130.6; 130.5; 126.0; 115.9; 115.7;; 54.7; 52.4; 48.9; 46.9; 44.0; 40.4; 26.4.
Example 66 - 2-{4-Methox;j henyi}-7V-[4-(inethoxycarbonyI)ben2yI]-JV-(l-metfaylpiperidin-4-y]) acetamide (50ELH20D). Procedure as 50HLH146.
Reaction-step 2:2 4-Metbaxypbeiiyr)-Ar-f4 metboxycaib Starting materials: 50ELH19 (0.2 g, 0.76 mmol, 1.0 eq.), 4-metboxyphenylacetylchloride (0.140 g, 1.0 eq.).
Product: Yield 108.6 g (26%), UV/MS 100/99 (M 410), rt (A, MS) 2 80. 'H-NMR (400 MHz, CDQj) 8 1238 (bis, 1H), 8.00 (d =7 , 2H), 7 8 (d, J=HX 2H), 7.00 (d, J=n2,2H), 6.79 (d, J=72t 2H), 4.88 (bit, 1H), 4.61 (s, 2H), 3.90 (s, 3H), 3.75 (5, 3H), 3.42 (brf, >10.7, 2H), 2.84 (q, J=\0.7,2H), 2.68 (d, >=3.6, 3H), 2.40 (brq, =10.7, 2H), 1.75 (d. 10.7, 2H). I3C NMR 173.0; 166.8; 159.0; 143.3;
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130.5; 129.9; 129.8; 126.3; 125.9; 114.5; 55.5; 54.7; 52.4; 48.7; 46.7; 43 6; 40.6; 32.1; 26.3; 22.9; 14.3.
Example 67 - 2-(4-TMctbyIpbenyJ)-Ar-I4-(methox>'carbonyl)benzyl]-Ar-(l-metbyIpiperidin-4-yl) acetamide (50ELH23) Procedure as 50ELH14B.
Reaction-step 2:1 -Phenyl-.V-f'2-(4-nictbylphenyI)etbyl3-A'-(l -methylpiperidm-4-yI) amide (50ELH23).
Starting materials: 4-(2-Phenylethyl)amino-l-methylpiperidine (0.20 g, 0.86 mmol, 1.0 eq.), benzoylchloridc (0.158 g, 1.0 eq.).
Product; Yield 159 rag (50%), UV/MS 100/100 (M 337), r, (A, MS) 3.289, Rr 0.55 (10% MeOH/CH2Cl2). 'B-NJUR (400 MHz, DMSO (S0°C)) S 10.9 (brs, 1H), 7.44 (s, 2H), 7.34 (d, >=3.0 Hz, 2H), 7.04 (d, 7.0 Hz, 2H), 6.95 (brs, 2H), 4.00 (brs, 1H), 3.40 (d, JM.2 Hz, 2H), 3.35 (d, .£=4.2 Hz, 2H), 2.95 (brs, 2H), 2.77 (t, J==3.2 Hz, 2H), 2.40 (q, J=6A Hz, 2H), 2.24 (s, 3H) 1.83 (d, J=6.4 Hz, 2H). 13C-NMR (CDC13) 171.6; 138.1; 136.3; 136.0; 129.8; 129.6; 129.1; 129.1; 126.7; 53.6; 52.4; 46.1; 42.9; 35.9; 27.3; 21.1.
Example 68 - 2-(4-Metho3ryi"henyl)-Ar-(3-pbenyl-l-propyl)-AKl-methylpiperidin-4-yI) acetamide (5QELH65) Procedure as 50ELH14B.
Reaction-step 1: 4-f3-Pbenylaininopropyl)piperidine (50ELH59) Starting materials: l-Methyl-4-piperidone(l.l ml, 7.4 mmol, 1.0 eq.), 3-pbenylpropylamiDe (1.35 g, 1.0 eq.).
Product: UV/MS 100/94 (M 1133), r, (A, MS) 3.534.). ]H-NMR (400 MHz, CDCI3) 6 7J28-7.12 (m, 5H), 3.40 (tas, 1H), 2.84 (dt, =12J and 3 Hz, 2H), 2.64 (q, J=7.0 Hz ,4H), Z51 (m, 1H), Z27 (s, 3H), 2.05 (brt, =12J Hz, 2H), 1.82 (m, 2H), 1.44 (m, 2H).
Reaction-step 2:2-(4-Methoxyphenyl>//-(3-phenyl--l-propyl)-.Af-(l-methylpiperidin-4-yl) acetamide (50ELH65)
Starting materials: 50ELH59 (0.50 g, 2.2 mmol, 1.0 eq.), 4-methoxypbenylflcetylcbJoride (0398 g, 1.0 eq.).
Product: Yield 153 mg (43%)", UV/MS 100/100 (M 381), rt (A, MS) 2.938. 'H-NMR (400 MHz, DMSO, retainers 55/45) 6 11.0 and 10.90 (2brs, IH), 7.30-7.10 (m, >7.9 Hz, 6H), 6.97 (d, =7.9 Hz, tH), 4.22 and 4.06 (2dt, dH), 3.70 (s, 3H), 3.35
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(t, =10.4 Hz, 2H), 3.15 (m, 2H), 3.00 (q, .M0.4 Hz, 2H), 2.66 (d, 3H), 2.52 (q, J=7.9 Hz, 2H), 2.17 (brq, 12 Hz, 2H) 1.73 (m, 2H), 1.70 and 1.52 (2d, 12 Hz, 2H). 13C-NMR(DMSO) 171.3; 171.0; 158.6; 142.2; 141.7; 130.0; 129.0; 128.0; 128.5; 128.2, 126.6; 114.5; 55.7; 55.7; 53.5; 53.3; 50.1; 44.5; 42.9; 41.9; 33.7; 33.1; 32.9; 31.4; 27.8; 26.8.
Example 69 - 2-(4-Methoryphenyl>A'-[2-(4-methylphenyS)ethyl)-N- Reaction-step 1:4-f2-(4-Mcthylphenyl)ethylamino1-piperidm (50ELH58) Starling materials: l-Methyl-4-piperidone (1.1 ml, 7.4 mmol, 1.0 eq.), 2-(4-methylphenyl)ethylamine (1.0 g, 1.0 eq.).
Product: UV/MS 100/91 (M4 233), n (A, MS) 3.933.). 'H-NMR (400 MHz, CDC13) 5 7.4 (s, 5H), 3.27 (bre, 1H), 2.84 (d, J=7.0 Hz, 4H), 2.75 (m, 2H), 2.54 (m, 1H), 2.29 (2xs, 6H), 2.10 (brt, >12.3 Hz, 2H), 1.86 (brd, 2H), 1.45 (m, 2H).
Reaction-step 2: 2-(4-MethoxypheDyl)-..V-[2-(4-methylpheDyI)ethyl)-? -(l-methylpiperidJD-4-yl) acetamide (50ELH68)
Starting materials: 5OELH58 (0.30 g, 1.3 mmol, 1.0 eq.), 4-methoxypheny!acetylchloride (0 38 g, 1.0 eq.).
Product: Yield 125 mg (26%), UV/MS 100/99 (M 381), r, (A, MS) 3.156. ]B-NMR (400 MHz, DMSO, rotaracre 50/50) 5 11.0 and 10.90 (2brs, IH), 7.25-7.04 (m, 8.7 Hz, 6H), 6.87 and 6.84 (2d, =8.7 Hz, 2H), 4.30 and 4.09 (2dt, Ml 1.5 Hz, dH), 3.73 and 3.58 (2s, 2H), 3.71 and 3.70 (2s, 3H), 3.35 (m, (Underneath waterpeak) 3H), 3 4 (m, IH), 3.02 (m,J=US Hz, 2H), 2.80-2.62 (m, 5H), 2.32 and2.20(2q, >1U Hz, 2H), 2 6 and 2 4 (2s, 3H) 1.78 and 1.49 (2d, >=11.5 Hz, 2H). "C-NMR (DMSO) 171.5; 171.2; 158.6; 136.8; 136.2; 136.0; 135.8; 130.7; 130.5; 129.7; 129.6; 129.4; 129.2; 128.4; 128 J; 114.5; 55.8; 55.7; 53.3; 53.3; 52.2; 50.2; 46.8; 43.9; 42.9; 36.8; 35.2; 27.6; 26.8; 213.
Example 70- 2- Procedure as 50ELH14B
Reaction-step 1:4-f2-(2-Thieir )etfaylamino]piperidin (50ELH67A) Starting materials: l-Methyl-4-piperidone (0.5 g, 4.4 mmol, 1.0 eq.), thiophene-2-ethylamine (0.563 g, 1.0 eq.).
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Product: UV/MS 94/93 (M4 225).
Reaction-step 2:2-(4-Meth'oxvphenyI>7V-f2-(2-tliieDylethyn-//-(l-methylpiperidip-4-yl) acetamide (50ELH71 A)
Starting materials: 50ELH67A (0.243 g, 1.08 mmol, 1 0 eq.), 4-methoxyphenylacetylch]oride(0.2 g, 1.0 eq.).
Product: Yield 80.7 mg (33fl/o), UV/MS 100/100 (M 373), r, (A, MS) 2.613. 'H-NMR (400 MHz, DMSO, rotamcre 50/50) 5 10.8 and 10.6 (2brs, IH), 7.36 and 7.31 (2d, >=4.7 Hz, 1H), 7.20 and 7.06 (2d, >8.3 Hz, 2H), 7.00-6.92 (m, J=4J and 2.8 Hz, 2H), 6.87 and 6.40 (2d, J=&3 Hz, 2H), 4.22 and 4.08 (2dt, J=12.2 Hz, 1H), 3.71 (s, 3H), 3.70 (s, 2H), 3.46-3.30 (m, 4H), 3.10-2.90 (m, 4H), 2.67 (m, 2H), 2.28 and 2.12 (2q, =12 Hz, 2H), 1.80 and 1.50 (2d, J=32 Hz, 2H). I3C-NMR (DMSO) 172.5; 158.9; 139.6; 130.0; 129.6; 126.8; 124.5; 114.5; 55.5; 54.7; 49.3; 45.8; 43.8; 41.3; 31.9; 29.9
Example 71 -2-(4-Methox>-phenyl)-A'-[2-(4-Ditropbeiiyl)ethy]J-AKl-metbyIpiperidin-4-yI) acetamide (50ELH71C) Procedure as 50EIJil4B
Reaction-step 1: 4-f2-f4-nitrophepyl) ethylaminoi-piperidin (50ELH67C) Starting materials: l-Mcthyl-4-pipendone (0.5 g, 4.4 mmol, 1.0 eq.), 4-nitrophenyI-2-ethyIamine (0.897 g, 1.0 eq.).
Product: UV/MS 96/89 (M 264), r, (A, MS) 3.264. Reaction-step 2:2-{4"Methoxifphenyl>Ar-r2-(4-nitrophenyl)e&yl1- -{l-methylpipgridin-4-yI) acetamide (50ELH71A)
Starting materials: 50ELH67C (0 185 g, 1.08 mmol, 1.0 eq.), 4-methoxyphenylacetylchloride (0 g, 1.0 eq.).
Product: Yield 130.9 mg (30%), UV/MS 100/100 (M 412), r, (A, MS) 2.219. 'H-NMR (400 MHz, DMSO, retainers 50/50) 8 10.8 and 10.6 (2bxs, 1H), 8.17 and 8.12 (2d, =8.6 Hz, 2H), 7.58 and 7.48 (2d, >=8.6 Hx, 2H), 12 and 7.1 (2d, =8.6 Hz, 2H), 6.87 and 6.40 (2d, =8.6 Hz, 2H), 4.25 and 4.10 (2dt, J=X2 Hz, 1H), 3.72 (s, 3H). 3.70 (s, 2H)f 3.48-3 JO (m, 4H), 3.10-2.84 (m, 4HX 2.69 and 2.67 (2d, >4.7 Hz, 3H), 234 and 2.15 (2q, =13 Hz, 2H), 1.79 and 1.47 (2d, J=\Z2 Hz, 2H).
Example 72 - MethoxyphenyO-AK -thieayliDethylVAKl-methylpipendin-4-yI) acetamide (50ELH73A) Procedure as 50ELH14B.
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Reaction-step 1: 4-f(2-Thienyhnetfayl)aniino1-l-niethylpiperidine (50ELH66A)
Starting materials: I-MethyI-4-pipcridone (0.5 g, 4.4 mmol, 1.0 eq.), 2-thienylmethylamine(0.52 g, 1.0 eq.).
Product: UV/MS 77/86 (M 211), rt (AMS) 2.739. Reaction-step 2: 2-{4-McthoxypbenylV-A '2-thienylmcthyl)-./V: Starting materials- 50ELH65A (0.228 g, 1.08 mmol, 1.0 eq.), 4-methoxyptaenylacetylchloride (0.2 g, 1.0 eq.).
Product: Yield 178.4 mg (50%), UV/MS 100/9S (M 359), rt (A, MS) 3.117. 'H-NMR (400 MHz, DMSO) 6 10.9 and 10.6 (2brs, 1H), 7.47 and 7.32 (2d, J=4.S Hz, 1H), 7.20 and 7.03 (2d, >=8.4 Hz, 2H), 7.03 and 6.9S (2m, 1H), 6.87 (m, 3H), 4.70 and 4.57 (2s, 2H), 4.42 and 4.16 (2t, =l 1.9 Hz, IH), 3.77 and 3.60 (2s, 2H), 3.51 (s, 3H), 3-15 (m, 2H), 2.98 (m. 11.9 Hz, 2H), 2.65 (2d, >4.5 Hz, 3H), 2.25 and2.17 (2q, =11.9Hz, 2H), 1.69 and 1.44 (2d, J±\\.9 Hz, 2H). I3C-NMR (DMSO) 171.4; 158.6; 143.2; 130.7; 128.1; 126.6; 126.3; 125.9; 114.5; 55.7; 53.3; 52.6; 50.0; 42.8; 27.7; 26-8.
Example 73 - 2-(4-Methoi3/phenyI)-JV-(furfur>'I)-Ar-{I-metbylpiperidiii-4-yl) acetamide (50ELH73B).
Procedure as 50ELH14B.
Reaction-step 1: 4- Product: UV/MS 77/92 (M 195), rt (A, MS) 2.812. \ Reaction-step 2:2-(4-Memo> henylVA -(figmryl)-.?y-(l-metiiylpiperidm--4-yl) acetamide (50ELH73B).
Starting materials: 50ELH66B (0.21 g, 1.08 mmol, 1.0 eq.), 4-metboxyphenylacetyichJoridc (0 g, 1.0 eq.).
Product: Yield 134 mg (36%), UV/MS 100/99 (M 343), rt (A, MS) 2.401. 'H-NMR (400 MHz, DMSO, rotamers 57/43) 5 10 5 and 10.75 (2brs, 1H), 7.63 and 7.48 (s, 1H)S 7.18 and 7.06 (2d, =7.7 Hz, 2H), 6.85 (t, >7.7 Hz, 2H), 6.44 and 633 (2d,. =7.7 Hz, 1H), 6.37 and 6.11 (2K, 1H) 4.5 and 434 (2s, 2H), 4.42 and 4.18 (2dt, J=ll and 2 Hz, 1H), 3.75 and 3.65 (2s, 2H) 3.70 (s, 3H), 3.33 (hidden, 2H), 3.0 (q,
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2H), 2.64 (d,, J=4.1 Hz, 3H), 2.15 (dq, >=11 and 2 Hz, 2H), 1.65 and 1.50 (2d, =11 Hz,2H).
Example 74 - 2(2-thienylmethyI)-Ar-(4-methy]phenylmethyl)-Ar-(l-methylpiperidin-4-yI) acetamide (50ELH82) Procedure as 50ELH14B
Reaction-step 2: 2-(2-lhicnylmctliyl)-//-(4-niethylphenylinethyl)-7V-(l -methylpiperidin-4-yl) acetamide (50ELH82)
Starting materials; 50ELH25 (0.30 g, 1.38 mmol, 1.0 eq.), thiophene-2-acetylchlorid (0.22 g, 1.0 eq.).
Product: Yield 235 mg (62%), UV/MS 97/93 (M 343), rt (A, MS) 2.795. ]H-NMR (400 MHz, DMSO, rotamers 54/46) 5 10.8 and 10.60 (2brs, IH), 7.4 and 7.35 (2d, 1H), 7.2-6.76 (m, 6H), 4.55 and 4.4 (2s, 2H), 4.49 and 4.26 (2dt, J=\ 1 and 2 Hz, 2H), 4.15 and 3.79 (2s, 2H), 3.32 (d, J=\1 Hz, 2H), 2.99 (q, 2H), 2.63 (s, 3H), 2.27 and 2.23 (2s, 3H), 2.09 (q, 11 Hz, 2H), 1.66 and 1.55 (2d, M\ 1 Hz, 2H).
Example 75 - 2-(4-MethoxypbeDyI)"Ar-(4-inethyIbenzyl)-iV-(l-cyclopentylpipcridin-4-yl) acetamide (42ELH75)
Procedxire as for 42ELH80, except that the reaction was run at 60°C for 3 days.
Starting materials: 50ELH87 (0 5 g, 0.71 mmol, 1.0 eq.), Cyclopcntylbromide (0.288 g, 3.0 eq.).
Product: Yield 91.2mg(34%),UV/MS S8/93 (M l), (A,MS) 4.450. Example 76 - 2-(4-MetboxyphenylHV-JV-(l-(3-(l -dibydro-2H-benziniida2ol-2-one-l-yDpropyr)piperidine-4-yi) acetamide (50ELHS9).
5OFJf\K7 (0.05 g, 0.14 mmol, L eq.) was transferred xo a 4 ml vial and dissolved in 1 mJ of acetonitrile. Then, l-(3-chioropropyl)-l,3-dinydro-2H-benzimidazol-2-one (0.032 g, I.I eq.), sodium carbonate (0.022 g, 1.1 eq.) and K3 (one crystal) were added and the vial was sealed and shaken for 20 h at 82°C. The mixture was extracted with distilled water (pH 10, sodium carbonate) and dichloromethane (3 times) the organic layers were dried with sodium sulfate and concentrated. The title compound was purified by HPLC and evaporated to dryness, forming a trifluoroacetic acid salt Yield 8.8 mg (12%). UV/MS 100/100 (M 527), rt (A, MS) 2.851.
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Example 77 - 2-(4-Melhoxyphenyl>-JV-(4-methylbenzyl)-A'-[l-(2-methyltbiazoM-ylroethyl) piperidin-4-yI) acetamide (63ELH1A).
5OELH87 (0.3 g, 0.852 mmol, 1.0 cq) and 4-(chloromethyl)-2-methylthiazole hydrochloride (0.235 g, 1.5 eq) were added to a 7 ml vial and dissolved in acetonitrile (3ml). Potassium carbonate (141.3 g, 1.2 eq) and a crystal of potassium iodide were added and the vial was sealed and shaken for 20 h at 82°C. The reaction mixture was extracted with distilled water (made basic by potassium carbonate, pH 10) and dichloromethane. The crude product was dried with sodium sulfate and concentrated. After purification by HPLC the product was converted into the hydrochloride salt by dissolving the free base in 1 ml dichloromethane and adding 1 eq. HC1 in ether (2M). This mixture was added drop-wise to an excess of heptane where the product precipitated. The solvent was removed by evaporation leaving a white powder as the product, yield 83.8 mg (21%), UV/MS 100/90 (M 463), r, (B, MS) 11.82.
Example 78-2 4-Methoxyphenyl)-JV-(2-HfliiorophenyI) ethyI)-M Reaction-step 1: 4-f2-4-(Fluorophenyl)ethylaminoJ-l-methylpiperidine (50ELH92A)
Starting materials: 1-Methyl-4-piperidone (0.3 g, 2.65 mmol, 1.0 eq.), 4-(fluorophenyl)eaiylamine (0369 g, 1.0 eq.).
Product: UV/MS 60/92 (M 237), r, (A>tS) 3.422. Reaction-step 2:244-MemoxyphgpylVM(2-4KiliK>rophenyl)ethyl>Jvv-(l-mcthYh)iperidm-4-yI) acetamide (50ELH93 A)
Starting materials: 50ELH92A (0.625 g, 2.65 mmoU 1.0 eq.), 4-methoxyphenylacetylchloride (0.488 g, app. 1.0 eq.).
Product: Yield 181 mg (18%), UV/MS 87/97 (M 385), rt (A, MS) 2.783. Rf 0.8 (10% MCOH/CH2CI2). 'H-NMR (400 MHz, DMSO, rotamers 50/50) 6 10 (brs, 1H), 7.56 6.8 (m, 8H), 4 6 and 4.02 (2brt, 2H), 3.70 and 3.95 (2s, 3H), 3.59 and 3.57 (2s, 2H), 3.4-3.15 (m, 5H), 2J96-2.66> (m, 5H), 2.62 and 236 (2s, 3H), 2J 9 and 2.10 (2q,2H), 1.73 ad 1.41 (2d,2H). UC-NMR (DMSO) 172.5; 171.4; 1713; 162.9; 162,7; 1605; 1603; 158.9; 158.6; 136.1; 136.1; 1353; 131.4; 1313; 131.1; 131.0; 131.0; 130.6; 130.5; 128.4; 128.4; 126.9; 115.9; 115.8; 115.7; 115.6; 114.5; 55.7; 53.7; 53.5; 52.7; 523; 50.7; 46.7; 43.8; 43.2; 43.0; 363; 34.7; 27.9; 26.9.
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Example 79 - 2-(4-MethoxyphenyI>7V-[2-(2,5-dimetboxypheDy])ethyI]-Ar-(l-metbylpiperidin-4-yl) acetamide (50ELH93C)
Procedure as 50ELH14B. A small amount was purified by HPLC and evaporated to dryness, fonning the trifluoroacetic acid salt.
Reaction-step 1: 4-[2-(2,5-dimethoxvphenyl)ethylammo] J-methylpiperidine (50ELH92A)
Startiftg materials: Metbyl-4-piperidone (0.3 g, 2.65 mmol, 1.0 eq.), 2,5-(dimethoxvphenyl)ethylamine (0.481 g, 1.0 eq.).
Product: UV/MS 81/90 (M 279), rt (AJrfS) 2.868.
Reaction-step 2:2-(4-Methoyyphenyl)-A -f2-(2,.5-dimethoxyphenyl)ethyll-A (l-methylpiperidin-4-yl) acetamide (5OELH93Q
Starting materials: 5OELH93C (0.737 g, 2.65 mmol, 1.0 eq.). 4-methoxyphenylacetylchJoride (0.488 g, app. 1.0 eq.).
Product: UV/MS 82/100 (M 427), r, (B, MS) 8.44. R,0.8 (10% MeOH/CH2Cl2).
Example 80- 2-(4-Methox>']phenyl)-Ar-[2-(2,4-dich]orophenyl) etfayl]-7V-{l-mcthylpiperidin-4-yl) acetamide (50ELH93D)
Procedure as 50ELH14B, but purified by HPLC and evaporated to dryness forming the trifluoroacetic acid salt
Reaction-step 1:4-[2 2ADic orophenv0emylainmoVl-methylpiperidi2e (50ELH92D)
Starting materials: 1-Metbyl-4-piperidone (03 g, 2.65 mmol, 1.0 eq.), 2 -(dSchlorophenyl) ethylamine (0 0 g, 1.0 eq.).
Product. UV/MS 82/92 (M 287), r, (AMS) 4.875.
Reaction-step 2:2-N-[2-(2T4-dichlorophec>fi emyIl-N-(l-methyIpiperidin-4-yI) acetamide (50ELH93P)
Starting materials: 50ELH93D (0.76 g, 2.65 mmol, 1.0 eq.), 4-metboxyphenylacetylcblohde (0.488 j app. 1.0 eq.)-
Product: UV/MS 100/96 (M 435), rt (A, MS) 4.415. R, 0.8 (10% McOH/CHjCla).
Example 81 - 2-Ar-[2- Procedure as 50ELH14B, but purified on HPLC and evaporated to dryness fonning the trifluoroacetic acid salt.
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Reaction-step 1:4-K3-Ch]orophenyl)ethyI)ainiiiol-l-methylpiperidine (50ELH92E)
Starting materials: 1-Methyl-4-piperidone (0.3 g, 2.65 mmol, 1.0 eq.), 3-(chlorophenyl) ethylaminc (0.413 g, 1.0 eq.).
Product: UV/MS 86/88 (M 253), r, (A IS) 3.175. Reaction-step 2: 2-(4-MethoxyphenyI)-N-r2-(3-chIorophenvO ethyl1-N-(l-methylpiperidin-4-yl) acetamide (5OELH93E)
Starting materials: 50ELH93E (0.67 g, 2.65 mmol, 1.0 eq.), 4-methoxyphenylacetylchloride (0.488 g, app. 1.0 eq.).
Product: UV/MS 100/100 (M 401), r, (A, MS) 3.464. Rf 0.8 (10% MeOH/CH2Cl2).
Example 82 - 2-(4-MethoxypheDyD-W-I2 (4-metboxyphenyI) ettayl]-iV-(l-jnetby)piperidiD-4-yJ) acetamide (50ELH95B)
Procedure as 50ELH14B. Purified by HPLC and evaporated to dryness forming the trifhioroacetic acid salt.
Reaction-step 1: 4-[(4-Mcthoxyphenyl)ethyl)amino]-l-tnethylpiperidine (50ELH94B)
Starting materials: 1 -Methyl-4-piperidone (0.3 g, 2.65 mmol, 1.0 eq.), 4-methoxyphenylethylamine (0.40 g, 1.0 eq.).
Product: UV/MS 74/87 (M 249), rt (A>1S) 2.935.
Reaction-step 2: 2-(4-MethoxyphenyD-A f2-(4-methoxyphenyl) hy\\-N-{\ methy3piperidin-4-yl) acetamide (50ELH95B)
Starting materials: 50ELH94B (0.657 g, 2-65 rnrnol, 1.0 eq.), 4-metlioxyphenylacetylchloride (0.488 %> app. 1.0 eq.).
Product: UV/MS 100/100 (M 397), r, (A, MS) 2389. Rf 0.8 (10% MeOH/CH2a2).
Example 83 - 2-(4-MetfaoxypfaenylHV-[2-(3-nnorophenyI) ethyl]-7V-(l-metbylpiperidin-4-yI) acetamide (50ELH95D)
Procedure as 50ELH14B- Purified on HPLC and evaporated to dryness, forming the trifhioroacetic acid salt.
Reaction-step 1:4-r2 (3-FluoTophcnyI)emyOammo1-l-metbyIpiperidme (5QELH94D)
Starting materials: 1-Methyl-4-piperidone (0.3 g, 2.65 mmol, 1.0 eq.), 3-fluorophenylethylamine (0.369 g, 1.0 eq.).
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Product: UV/MS 74/89 (M4 237), r, (AJtfS) 2.946.
Reaction-step 2: 2-(4-methoixypheDyI)-Af-r2-(3-fluorophenyI) ethyl]-Ar-Q-methylpiperidin-4-yl) acetamide (50ELH95D)
Starting materials: 50ELH94D (0.625 g, 2.65 mmol, 1.0 eq.), 4-methoxyphenylacetylchloride (0.488 g, app. 1.0 eq.).
Product: UV/MS 100/95 (hf 3S5), rt (A, MS) 2.946. R, 0.8 (10% MeOH/CH2a2).
Example 84 - 2-(4-etboxvphenyl)- 12 4-fluoropbenyl)ethylJ-VV-(l-methylpiperidin-4-yI) acetamide (63ELH20)
Reaction step 1:4-EthoxyphenyJacetic acid chloride(63ELHI9)
4-Ethoxyphenylacetic acid (0.5 g, 2.8 mmol) was transferred to a 7 ml vial and dissolved in thionylchloride (3 ml). The reaction mixture was shaken at 70°C for 2V2 hours. Thionylchloride was evaporated off and the resulting product was used unpurified.
Reaction step 2:2-(4-Ethoxy]phenyl)-Ar-[2-(4-fluoropherjyl)ethyl]-Ar-(l-methylpiperidin-4 yl) acetamide (63ELH20)
63ELH17 (0.11 g, 0.47 mmol) was transferred to a 4 ml vial and dissolved in dichlorometbane. 63ELH19 (0.084 mg, 1 eq.) was added and the vial was sealed and the reaction shaken for 20 h. The product was extracted in distilled water (made basic with potassium carbonate, pH 10) and dichloromethane. Dried with sodium sulfate and concentrated. Purified by HPLC. The extraction, drying and concentration was repeatedand the product re-dissolved in dichloromethane (1 ml) and HC1 (1 eq-, 2 M in ether) was added. The mixture was added drop-wise to an excess of heptane whereupon the salt precipitated. Yield 33.4 mg (18%), UV/MS: 92/100 (M 399% t, (B, MS) 10.38-
Example 85- 2--AKl-methylpiperidin-4-yI) acetamide (63ELH21)
50ELH4 (O.llg, 0.49 mmol, 1.0 eq.) was transferred to a 4 ml vial and dissolved in dichloromethane. 63ELH19 (0.089 mg, 1.0 eq.) was added and me vial was sealed and the reaction shaken for 20 h. The product was extracted in distilled water (made basic with potassium carbonate, pH 10) and dichlorometharje. Dried with sodium sulfate and concentrated. Purified by HPLC. The extraction, drying and concentration was repeated and the product dissolved in dichloromethane (1 ml) and HC1 (1 eq., 2 M in ether) is added.This mixture was added drop-wise to an excess of
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heptane whereupon the salt precipitated. Yield 31 1 mg (16%), UV/MS: 94/100 (M 385), tr (A, MS) 2.573.
Example 86 - 7V-((4-methylpbeny])methyI)-Ar-(l-methylpiperidiii-4-yl)-2-(3-hydroxy-4-methoxypbenyl)acetamide (57MBT12B)
AK(4-methylphenyI)methyl)-4-amino-l-methylpiperidine (50ELH25) (105 mg, 0.48 mmol) and 3-hydroxy-4-methoxyphenylacetic acid (88 mg, 0.48 mmol) were dissolved in DMF (10 ml). Diisopropylethylamine (DIEA, 250 uL, 1.44 mmol) was added followed by brorno-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBrOP, 336 mg, 0.72 mmol), and the mixture was stirred at r.t for 1 h. Water (50 mL) was added, and the reaction mixture was extracted with EtOAc (2x50 mL). Drying by NajSO4 and concentration yielded 514 mg crude material, which was purified by flash chromatography (0-30% MeOH in CH2CI2). This gave 105 mg (57%) of the title compound as a white solid. Rf=0.20 (10% MeOH in CH2CI2). HPLC-MS (method A) showed MH+=383. UV/MS(%)=100/92. 'H-NMR (400 MHz, CD3OD, Rotamers 52:48): 8 7.18-6.58 (m, 7H), 4.53 (s, 2H), 4.31 and 3.97 (2m, 1H), 3.82 and 3.81 (2s, 3H), 3.80 and 3.55 (2s, 2H), 3.04 and 2.85 (2m, 2H), 2.41 and 2.32 (2s, 3H), 2.35 and 2.12 (2m, 2H), 2.29 and 2.27 (2s, 3H), 1.83 and 1.74 (2m, 2H), 1.72 and 133 (2m, 2H)
Example 87- (4-metbyIphenyI)mcth>1>-Ar-(3-in€thylpiperidin-4-yI>-2-(3,4-dibydroxypbenyI)acetomide (57MBT24B)
AK(4-memylphen>1)irietnyI> 12 Hz, 2H), 3.02 and 2.95 (2far t, M\2 Hz, 2H), 2.79 (s, 3H), 233 and Z2S (2s, 3H), 2.17 and 1.84 (2dq, >4,12 Hz, 2H), 1.87 and 1.48 (2br d, J=12 Hz, 2H)
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Example 88 - 7V-((3-hydro3[y-4-inetby]pbenyI)methy])-AHl-metbylpiperidui-4-y])-2 4-methoxyphenyl)aceUmide(57MBT54B)
AK(4-melhoxypheoyl)meaij'l)-4-arruno-l -methylpiperidine (lg, 4.27 mmol) was dissolved in 4% formic acid in methanol (60 mL). 10% Pd/C (lg) was added under argon and the reaction mixture was heated to reflux for 24 h. The mixture was filtered through celite and the filtrate was acidified with cone. HC1 to pH 1. Concentration yielded a yellow oil which was purified by flash chromatography (MeOH/CH2Cl2 3:7 + 3.5% NH4OH) to give 249 mg (51%) of 4-amino-l-methylpiperidine (57-MBT36B) as a white solid. RHX13 (10% MeOH in CH2C12 + 3.5% NRtOH). HPLC-MS (method B) showed MH =115. UV/MS(%)=-/100.
4-Amino-l-methylpiperidine (57MBT36B) (26 mg, 0.231 mmol) was dissolved in methanol (1 mL) and 3-hydroxy-4 methylbenzaldehyde (32 mg, 0.231 mmol) and acetic acid (33 jxL) were added. The mixture was cooled to 0 CC. NaBHjCN (29 mg, 0.462 mmol) was; added and the cooling bath was removed. After 3 h the reaction mixture was evaporated and flash chromatography (0-30% MeOH in CH7CI2) gave 27 mg (50%) of tf (3-hydroxy-4-metoyIphenyl)memyl) ainino-l-meihylpiperidine (57MBT44Q as a white solid. R(=0.27 (10% MeOH in CH2C12 + 3.5% NKiOH). HPLC-MS (method A) showed MH =235. UV/MS(%)=99/99.
AH(3-hydroxy-4-methylpheny])methyI)-4-ammo-1 -methylpiperidine (57MBT44Q (27 mg, 0.115 mmol) ivas dissolved in CH2C12 (2 mL). 4-Mcthoxyphenylacetyl chloride (17 ptl-, 0.115 mmol) was added dropwise under argon. After 3 h, n-heptane (3 mL) was added and the mixture was evaporated. Flash chromatography (0-20% MeOH in CH2CI2) B&ve 14 m8 (32%) of the title compound as a white solid. 1 =032 (10% MeOH in OfeCb + 3.5% NH4OH). HPLC-MS (method A) showed MH"=383. UV/MS(%)=99/96. !H-NMR (400 MHz, CD3OD, Rotamers 63:37): 5 7.28-6.55 (m, 7H), 4.48 (s, 2H)S 4.37 and 3.95 (2m, 1H), 3.78 and 3.77 (2s, 3H), 3.06 and 2.89 (2brd, >12 Hz, 2H), 2.42 and 232 (2s, 3H), 2.40 and 2.12 (2m, 2H), 2.18 and 2.12 (2s, 3H), 1.86 and 1.83 (2m, 2H), 1-75 and 135 (2br d, >12Hz,2H)
Example 89 - -.V-(l-mcthy1piperidm-4-yI>2-(4-bromopbenyl)acetamidebydroch)oridc(57MBT70-lD)
4-Bromophenylacetic acid (54 mg, 0.252 mmol) was dissolved in CH2C12 (2 mL), and -((4-metbylphenyl)methyl]h4-ammo-l-methylpiperidine (292 mg/mL
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stock solution in CH2C12) 171 uL, 0.229 mmol) and polystyrene supported diisopropylethylamine (PS-DIEA with a loading of 3.57 mmol/g, 192 rag, 0.687 mmol) was added followed bybromo-tris-pyrrolidirio-phosphonium hexafluorophosphate (PyBrOP, 160 mg/mL stock solution , 1 mL, 0.334 nunol). The reaction mixture was shaken for 1 h at r.t. and filtered onto a prewashed (methanol) ion exchange column (0.88 ramol/g, Ig). The column was washed with methanol (8 4 mL) and the remaining product was eluted off the column with 10% NH4OH in methanol (2 4 mL) and evaporated. The resulting oil was filtered through silica (H=4 cm, P=l cm) with metbanol/CH2Cl;i 1:9 (20 mL), evaporated and subjected to a second ion exchange column (0.8S mmol/g, lg). The column was washed with methanol (8 4 mL) and the remaining product was eluted off the column with 10%
NH4OH in methanol (2 4 mL) and evaporated on rotavap and oil pump. The product
was dissolved in CH2CI2 (0.5 mL) and HCI in diethylether (1.0 M, 0.1 mL, 0.1 mmol)
was added. The solution was added to n-heptanc (3 mL) and evaporation afforded 29
mg (25%) of the title compound as a white solid. Rr=0.31 (10%MeOH in CH2C12).
HPLC-MS (method B) showed MH =416. UV/MS(%)= 100/99.
Example 90 - Ar-((4-methylpheDyI)methyl)-Ar-(l -methyl pipe rid in-4-yl)-2-
(4-iodophcnyI)acetamidehydrochaoride(57MBT70-2D)
The title compound was prepared according to example MBT04. Yield: 33 mg
(26%). RrOJl (10% MeOH in CH2C12). HPLC-MS (method B) showed MH =463.
UV/MS(%)=100/98.
Example 91 -7V (4-inethy]lpbeny0inetfay])-7V -(l-n]etfaylpiperidia-4-yl>-2-
(4-(2-propyf)pheiiyi)acetamide bydrochloride(57MBT70-3D)
The title compound was prepared according to example MBT04. Yield: 36 mg
(34%). R =0.31 (10% MeOH in CR2Ch). HPLC-MS (method B) showed MH =379.
UV/MS(%)-10(V97.
Example 92 -7V-((4-iDethylphenyI)methyl)-JV-(l-methylpiperidiii-4-yI)-2-
(4-tnflaoromethoxypheDy])acetamidebydrDcliloride(57MBT7(MD)
The title compound was prepared according to example MBT04. Yield: 35 mg
(30%). 1 4=0.27 (10% MeOH in CH2O2). HPLC-MS (method B) showed MH 421.
UV/MS(%)=10(V99.
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Example 93 - Ar-((4-nietliy]pheDyI)inetby])-AHl-methylpiperidin-4-yI>-2-(4-methy]tbiopbenyl)acetamidefaydrochIoride(57MBT70-5D)
The title compound was prepared according to example MBT04. Yield: 35 mg (33%). Rf=0.30 (10% MeOH in CH2C12). HPLC-MS (method B) showed MH+=3S3. UV/MS(%)=100/99.
Example 94 -7V-((4-methylphenyI)methyl)-7V-(l-niethyIpiperidin-4-yI)-2-(4-(i\VV-diniethylaiiiiDo)pheDyI)acetamidebydrochloride(57MBT70-6D) The title compound was prepared according to example MBT04. Yield: 16 mg (15%). Rf=0-25 (10% MeOH in CH2C12). HPLC-MS (method A) showed MH+=380. UV/MS(%)=100/100.
Example 95 - AH(4 metbylphenyI)metbyl)-AHl-niethylpiperidin-4-yI)-2-(4-nUropbenyI)acetamidehydrochioride(57MBT70-7I))
The title compound was prep;ared according to example MBT04. Yield: 28 mg (27%). Rj=0.27 (10% MeOH in CH2C12). HPLC-MS (method B) showed MH+=382. UV/MS(%)=100/100.
Example 96-AH(4-metnylpbenyJ)metbyI)rAHl-metbyIpiperidiD-4-yI)-2-(4-metboxy-3-methyIphenyI)acetamidebydrochloride(57MBT70-8D)
The title compound was prepjired according to example MBT04. Yield: 34 mg (32%). R Example 97 - A-{(4-methylphenyI)methyI)-A'-(l-niethyIpiperidiii-4-yf)-2-(4-p>Tidyl)acetamidebydrc)cblorid The title compound was prepared according to example MBT04. Yield: 18 mg (17%). RH>.09 (10% MeOH in CH2C12). HPLC-MS (method A) showed MH -338. UV/MS(%)=100/100.
Example 98-AK(4-metbylpheDyi)inethyI)-AHl-nietbylpiperidin--4-y!>-2-(4-methylphenyl)acetamidehydrocliloride(57MBT62B)
The title compound was prepared according to example MBT04. Yield: 10 mg (35%). R = (10% MeOH in CH2CI2). 13PLC-MS (method A) showed MH =351. UVyMS(%>=100/100.
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Example 99 - A4(4-(hydroxymemy1)pbedy0methyl)-AHl-nietbylpiperiduM-yI>2 4 methoxyphcny])flcetamide hydrochJoride(S7MBT72D)
To a stirred suspension of LiAIH (285 mg, 7.52 mmol) in diethyiether(10 mL) at 0 °C was added a solution of 4-cyanobenzyl alcohol (0.5 g, 3.76 mmol) in diethylether (5 mL) over 15 min. The grey reaction mixture was heated to reflux for 3 h. After cooling to r.t., the mixture was treated successively with water (1 mL), 2M NaOH (2 mL) and water (2 mL) under vigorous stirring. The resulting white slurry was filtered and washed with CH2C12 (20 mL). Extraction with additional CH2C12 (20 mL) and n-butanol (20 mL) and evaporation yielded an oil, which upon flash chromatography (0-15% MeOH in CH2CI2) gave 152 mg (29%) of 4-(aminomethyl)benzylalcohol (57MBT52B) as a white solid. Rf=O.5I (30% MeOH in CH2CI2 + 3.5% NH4OH).
l-Methyl-4-piperidone (84 JJ! 0.73 mmol) was dissolved in methanol (5 mL) and 4-(aniinornethyl)ben2yIalcobol (57MBT52B) (100 mg, 0.73 mmol) was added followed by acetic acid (125 uL). NaBH3CN (92 mg, 1.46 mmol) was added and the mixture was stirred for 3 h. The reaction mixture was evaporated and 2M NaOH (5 mL) was added. Extraction with CH2CI2 (4 5 mL), drying with Na2SO and evaporation gave 152 mg (87%) of A'-((4-{hycToxyiriethyl)phenyl)niethyl>4-amirjo-l-methylpiperidine (57MBT56D) as a white solid. HPLC-MS (method B) showed MH =235. UV/MS(%)=10aa00.
(4- ydroxymethyI)phenyI)methyl) aniino-1 -methylpiperidine (57MBTS6D) (20 mg, 0.0853 mmol) was dissolved in CH2C12 (2 mL) and 4-mcthoxypbcnylacetyi chJoridc (26 pL. 0.171 mmol) was added dropwise- The reaction mixture was stirred for 1 h and water (500 \xL) was added followed by evaporation. A solution of sodium (5 mg, 0.179 mmol) in methanol (2 mL) was added. After stirring for 4 h, the solution was transferred to a prewashed (methanol) ion exchange column (0.88 mmol/g, Ig) and washed with methanol (4 4 mL). The remaining product was ehrted off the column with 10% NH4OH in methanol (2 4 mL) and evaporated. The resulting oil was filtered through silica (H=4 cm, D=l cm) with methanol/CH2d2 2:8 (20 mL), evaporated and subjected to a second ion exchange column (0.88 mmol/g, Ig). The column was washed with methanol (8 4 mL) and the remaining product was eluted off the column with 10% NH OH in
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methanol (2 4 mL) and evaporated on rotavap and oilpurap. The product was dissolved in CH2Q2 (0.5 mL)and HQ in diethylether (1.0 M, 0.1 mL, 0.1 mmol)was added. The solution was added to n-heptane (3 mL) and evaporation afforded 14 mg (39%) of the title compound as a white solid. Rf=O.l6 (10% MeOH in CH2C12). HPLC-MS (method B) showed MHf=383.UV/MS(%)=100/96.
Example 100 - 2-(4-O lor op h enyl>A -(4 -methyl ben zyI)-iV-(l-isopropylpiperidin-4-yl)acetamide(47AJaJ-7) l-Trifluoroacetyl-4-piperidone (47AKU-2) 4-Piperidone hydrochloride monohydrate (3.85 g, 25 mmol) and Triethylamine (10.5 ml, 75 mmol) were partly dissolved in 100 ml of dichloromethane and stirred for 10 min. Reaction mixture was then cooled on ice-bath and trifluoroaceb'c anhydride (7.2 ml, 50 mmol) was slowly added over 10 min. Ice-bath was removed and mixture was stirred overnight. Additional trifhioroacetic anhydride (2 ml) was added and the mixture was stirred for 1 hr. Water (200ml) was added. Phases were separated and aq. phase was re-extracted with dichloromethane. Combined organic phases were washed with brine, dried over MgSC>4 and concentrated (40°C) giving 4.97 g (100%) 47AKU-2 as yellow crystals. TLC (5% methanol in dichloromethane): Rf = 0.8. 'H-NMR (400MHZ, CDCb): &= 3.87-3.99 (4H,m); 2.54-2.61 (4H,m). l3C-NMR(Ct>Cl3): 8-204.7, 118.0, 115.1,44.2,42.8, 41.2,40.5.
4-(4-Methylbenzy!amino)-1 -trifluoroacetyl-piperidine (47 AKU-3) 47AKU-2 (4.97 g, 25 mmol) was dissolved in 100 ml methanol and 4-methylbeozyl-amine (3.2 ml, 25 mmol) was added. Mixture was stirred and acetic acid (-2 ml) was added until pH 5. NaCNBH3 (3.15 g, 50 mmol) was slowly added. After magnetic stirring for 20 hrs the methanol was partly removed on me rotary evaporator (40°C). Dichloromethane, 2M NaOH and water were added until pH 10. Phases were separated and aq. phase was then re-extracted twice with dichloromethane. Combined organic phases were washed with brine and dried over MgSO4. Conccntration(40oC) yielded 6.94 g (92%) 47AKU-3. TLC (10% methanol in dichloromethane): Rf=0.6. HPLC-MS (Method A): M = 301.0 (UV7MS(%)=94/100).
2-(4-Chloit)phenyI)-JV-(4-memyfl>en2yI)- -(l-triiluoroacctylpiperidin-4-yl)acetamide (47AKU-4)
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47AKU-3 (3.01 g, 10 mmol) in 25 ml of dichlorometbane was placed in a 100 ml flask. Triethylamine (1.4 ml, 10 mmol) was added and the mixture was cooled on an ice-bath and stirred for lOmin. 4-Chlorophenyiacetyl chloride (1.90 g, 10 mmol) was dissolved in 10 ml dichlorometliane and added slowly to the ice-cold mixture. After 15 min. the ice-bath was removed and the mixture was left for 1 br. Precipitation was observed. The reaction mixture was then concentrated at aspirator pressure(40°C). TTie crude product was purified by flash chromatography (0-50% ethylacetate in heptane) yielding 2.38 g (53%) 47AKU-4. TLC (100% dichloromethane): Rf= 0.6. HPLC-MS (Method A): Nf=453.0 (UV/MS(%)=89/84).
2-(4-C3ilorophenyI)-7 4-methyIbenzyI)-7 (piperidin-4-yl)acetamide (47AKU-6)
47AKU-4 (2.38 g; 5 mmol) was dissolved in 50 ml of methanol. K2CO3 (3.5 g; 25 mmol) was added in one portion. After magnetic stirring for 20 hrs, additional K2CO3 (1 g) was added. After 4 hrs magnetic stirring methanol was partly removed by evaporation(40°C). Ethyl acetate (100 ml) and water (100 ml) were added. The phases were separated and the aq. phase was then re-extracted with ethylacetate. The combined organic phases were dried over MgSO 2 4-OUorophenyl)-N-(4-methylbeiizyl)-N-(l-isopropylpiperidin-4-yi)-acetamide (47AKU-7)
47AKU-6 (358 ing, 1,0 mmol) was dissolved in 20 ml of acetonitriie, Triethylamine (1.4 ml, 10 mmol) was added and mixture was stirred for 10 mm. Isopropyl bromide (370 mg, 3.0 mmol) was dissolved in 5 ml of acetonitriie and added to the reaction mixturewhich was stirred at room temp, for 20 hrs and then heated to 60°C for 4 hrs. After cooling, ethylacetate (25 ml) and water (25 ml) were added The phases were separated and die aq. phase was then re-extracted with etbylacetate. The combined organic phases were washed with brine, dried over MgSO4 and concentrated(40°C) giving 362 mg of crude product Purification by flash chromatograpby (0-10% methanol in dichloromethane) and HCl-precipitan'on from 2M HCl/diethyl ether in dichloromethane/heptane gave 76 mg (18%) 47AKU-7. TLC (10% methanol in dichloromcthane): Rf •= 0.4. Mp = 223-224°C. HPLC-MS (Method A): M = 399.1 (UV/MS(%)= 100/99). 'H-NMR (400 MHz, CDCI3): 6= 7.03-7.29
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(8H, m); AM (1H, m); 4.61 (2H, m); 3.58 (2H, m); 3.37 (3H, m); 2.82 (2H, m); 2.64 (2H, m); 2.34 (3H, s); 1.80 (2H,m); 1.39 (6H, d). l3C-NMR (CDC13): 5= 172.4, 137.4, 134.8,133.3, 133.1, 130.4,129.9,129.0, 125.8, 58.0, 49.5, 48.2, 46.6,40.4, 26.0,21.2,17.0.
Example 101 - 2-(4-Chloropheny!)- V-(4-methylbenzyl)-Af- 47AKU-6 (358 mg, l.Ommol) was dissolved in 20 ml of acetonitrile. Triethylamine (1.4 ml, 10 mrnol) was added and the mixture was stirred for 10 min. Ethyl bromide (370 ul, 5.0 mnwl) was added. The mixture was then heated to 50°C and stirred overnight. After cooling, water (25 ml) and ethylacetate (25 ml) were added. The phases were separated and the aq. phase was re-extracted with ethylacetate. The combined organic phases were washed with brine and dried over MgSC>4. Evaporation(40°C) yielded 406 mg of crude product. Purification by ion exchange chromatography (washout with 10% aq. NHjOH (25%) in methanol) gave 166 mg (43%) 47AKU-12. The HCl-!>alt was prepared from 2M HO/diethylether in dicbloromethane/heptane. TLC (10% methanol in dichloromethane): Rf = 0.5. HPLC-MS (Method A): M = 385.1 (UV/MS(%)=100/99). lH-NMR (400 MHz, CDC13, rotamers): 5= 7.02-7.34 (8H, m); 4.62 (1H, m); 4.46 and 4.53 (2H, 2s); 3.81 (1H, s); 3.55 (2H, s); 2.92 (2H, m); 2.34 (3H, s); 2 9 (1H, s); 1.98 (2H, m); 1.52-1.84 (4H, m); 1.03 (3H, t). I3C-NMR(CDa3):2i= 171.7,137.2, 135.4,133.9, 132.8,130.4, 129.7, 128.9,125.8, 52.8, 52.4,46.5, 40.8, 31.2,29.8, 21 , 12.4.
Example 102 - 2-Pbe&yK7V 4-metfayIbenzyl)- - 47AKU-5 (218mg, 1.0 mmol) was dissolved in 2 ml of dichlorometiiaDe in a 50-ml flask.l'baryiacetyl chloride (13-4 pi, 1.0mmol) was added:1 After3"nts stnring at room temp, mixture was concentrated on Rotavapor (40°Q. Crude product was purified by ion exchange chromatography (washout with 10% aq. NHiOH (25%) in methanol) and flash chromatography ('3-10% methanol in dichloromethane) giving 48 mg (14%) 47AKU-13. HCl-salt was prepared from 2M HCl/diethylether in dichtorome&ane/heptaiie. TLC (10% methanol in dichloromethane): Rf 0.4. HPLC-MS (Memod A): M = 337.1 (UV/MS(%>=98/98). !H-NMR (400 MHz, CDCI3, rotamers): 5= 7.01-7.40 (9H, m); 4.63 (1H, m); 4.53 and 4.45 (2H, 2s); 3.85 and 3.61 (2H, 2s); 2.86 and 2.77 (2H, 2m); 2.35 and 2.29 (3H, 2s); 2.25 and 2.20 (3H, 2s); 2.09
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(2H,m); 1.61-1.86 (4H, m). 13C-N]vtR (CDC13): 5= 172.2, 137.1, 135.5,129.7,128.9, 128.8,127.2,126.9,125.8,55.3,51.6,46.6,46.1,41.6,29.5,21.2.
Example 103 - 2-(4-Chlorophenyl)-AH4-niethylbenzyI)-Ar-(l-methylpiperidin-4-yl)-acetamide(47AiaJ-8)
4-(4-MethyIbenzylamino)-1 -methyl-piperidine (47AKU-5) l-Methyl-4-piperidone (1.13 g, 10 mmol) was dissolved in 20 ml of methanol and added to a 100 ml flask. 4-MemylbenzyIamine (1.21 g, 10 mmol) in 10 ml of methanol was added. Acetic acid (-1.5 ml) was added until pH 5. NaCNBH3 (1.26 g, 20 mmol) was slowly added. After 20 hrs magnetic stirring methanol was partly removed on Rotavapor (40°C). Dicliloromethane, water and 2M NaOH were added until pH l 0. The phases were separated and aq. phase was extracted twice with dichloromethane. The combined organic phases were washed with brine and dried over MgSO4. Concentration on Rotavapor (40cC) yielded 2.06 g crude (93%) 47AKU-5. TLC (20% methanol in dichloromethane): Rr = 0.3. HPLC-MS (Method A):M =219.1 (UV/MS(%)=89/98).
2-(4-ChlorophenyI)-N-(4-methyIbenzyI)-N-(l-methylpiperidin-4-yl)-acetamide
(47AKU-8)
47AKU-5 (437 ing, 2.0 mmol) was dissolved in 10 ml of dichloromethane in a 50 ml flask. Triethylamine (280 JJJ, 2.0 mmol) was added and the mixture was cooled to 0°C on an ice bath and stirred for 10 min. 4-Chlorophcnylacetyl chloride (380 mg, 2.0 mmol) was dissolved in 10 ml of dichforomethaoe and added to the cooled mixture. After 2 hrs stirring al room temp, additional dichJoromethane (10 ml) and water (20 ml) were added. The phases were separated and the aq. phase was re-extracted with dichloromethane. The combined organic phases were dried over MgSO4 and concentrated on the Rotavapor (40°C) giving 755 mg of crude product Purification by flash chromatography (0-10% methanol in dichloromethane) gave 485 mg (65%) product Further purification by ion exchange chromatography (washout with 10% aq. NH4OH (25%) in mettianol) gave 239 mg (32%) 47AKU-8. The HC1-salt was prepared from 2M HCI/diethyiether in dichlorometfaane/heptane. TLC (10% methanol in dichloromethane): Rf = 0.4. Mp = 217-219°C. HPLC-MS (Method A): M = 371.1 (UV/MS(%)=99/99). 'H-NMR (400 MHz, CD3OD): 5= 7.05-7.39 (8H, m); 4.80 (3H, s); 4.62 + 4.56 (2H, 2s); 4.35 (1H, m); 4.00 (1H, s); 3.71 (1H, s); 3.46
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(2H, m); 3.06 (2H, m); 2.80 (3H, s); 2.32 + 2.27 (3H, 2s); 2.19 (lH n) 13C-NMR (CD3OD): 5= 173.0,137.5,134.5,133.9,132.6,130.6,129.5,128.5,126.2, 54.0, 51.4, 42.6, 40.2, 31.8, 26.6,19.9.
Example 104 - 2-(4-Ch]orophenyI>- -(4-methyIbenzyI)-iV-{l-cyc1opent>'1piperidin-4-yI)-acetamiide(47AKU-ll)
47AKU-6 (358 mg, 1,0 mmol) was dissolved in 20 ml of acetonitrile. Trietbylamine (1.4 ml, 10 mmol) was added and mixture was stirred for 10 min. Cyclopentylbromide (540 pi, 5.0 mmol) was added and the mixture was stirred at room temp. After 20 hrs the mixture was heated to 50°C for an additional 24 hrs. The reaction mixture was then cooled and water (25 ml) and ethylacetate (25 ml) were added. The phases were separated and the aq. phase was re-extracted with ethylacetate. The combined organic jihases were washed with brine and dried over MgSO<. concentration on rotavapor yielded mg of crude product. purification by ion exchange chromatography with aq. nh4oh in methanol and flash dichlorometfaane gave the hcl-salt was prepared from hcl dichloromethane tlc rf hplc-ms a m="425.1" mhz cdci3 rotamers s> Example 105 - 2H4-Rouropfaeny9-AK4-raethyn>enzyI)-A-(l-metfcyipiperidm-4-yI)-acetamide (47AKU-14)
47AKU-S (218mg, 1.0 mmol) was dissolved in 3 ml of dichloromethane in a 50 ml flask. 4-FIuorophenyIacetyl chloride (150 pi, 1.1 mmol) was added. After 4 hrs stirring at room temp, the mixture was concentrated on Rotavapor (40°C). The crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 243 mg (68%) 47AKU-14. The HCI-salt was prepared from 2M HCl/diethyletber in dichlorornethane/lieptane. TLC (10% methanol in dichloromethane): Rf = 0.5. HPLC-MS (Method A): M = 355.1 (UV/MS(%)=100/100). 'H-NMR (400 MHz, CDC13): 5= 6.92-7.33 (8H, m); 4.73
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(IH, m); 4.52 (2H, s); 3.56 (2H, 2s); 3.44 (5H, m); 3.25 (2H, m); 2.52-2.67 (4H, m); 2.33 (3H, s). 13C-NMR (CDC13): 5= 172.5,163.3, 160.9, 139.5, 134.8,130.6, 129.8, 125.8, 115.8, 54.6, 50.8,49.9,46.7,40.4,27.2, 21.2.
Example 106 - 2 4-A44-methylbenzyI>-;V-{l-(2-bydroxyetbyl>piperidin-4-yl)-acetaiiude(47AKlM8)
47AKU-6-2 (358 mg, 1,0 mmol) was dissolved in 10 ml ofacctonitrilcin 50 ml flask. Tri ethyl amine (1.4 ml, 10 mmol) was added and mixture was stirred for 10 min.
2-Bromoethanol (215 ui, 3.0 mmol) was added Reaction mixture was then heated to 60°C and stirred overnight. After cooling ethylacetate (25 ml) and water (25 ml) were added. Phases were separated and aq. phase was re-extracted with ethylacetate. Combined organic phases were washed with brine, dried over MgSC>4 and concentrated on Rotavapor (40°C) giving 406 mg crude product. Purification by flash chromatography (0-10% methanol in dichloromethane) afforded 253 mg (63%) 47AKU-18. HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC (10% methanol in dichJoromethane): R = 0.4. HPLC-MS (Method A): M = 401.1 (UV/MS(%)=100/100). 'H-NMR (400 MHz, CDC13, rotamers): 5- 7.04-7.34 (8H, m); 4.60 (IH, m); 4.52 and 4.45 (2H, 2s); 3.55 (4H, m); 3.03 (IH, bs); 2.92 (2H, m); 2.52 (2H, m); 2.36 and 231 (3H, 2s); 2.19 (2H, m); 1.66 (4H, m).). 13C-KMR (CDClj): 5= 171.7,1373,135J2, 133.8,132.9,130.4,129.8, 128.9,125.8, 59.4,58.1, 53.1,52.3,46.8, 40.8,29.7,21.2.
Example 107 - 2-(4-Ch Jorophcny I>A'--acctainide (47AKU-19)
l-Cyclobrtyi-4 npcridone (47AKU-1S)
Partly dissolved quartenary salt (1.23 g, 3.7 mmol) (prepared according to the procedure outlined in the synthesis of 47AKU-47) was slowly added to a rcfluxing solution of Cyclobutylamine (178 nig, 2.5 mmol) and Potassium carbonate (48 mg, 0.34 mmol) in ethanol. The mixture was refhixed for 1.5 hrs. After cooling to room temp, water (10 ml) and dicMoromethane (25 ml) were added. Phases were separated and aq. phase was re-extracted with dichloromethane- Combined organic phases were dried over MgSO4 and concentrated on Rotavapor (40°Q giving 419 mg crude 47AKU-1S. TLC (10% methanol in dichloromethane): Rf = 0.4. HPLC-MS (Method A): M = 154.1 (MS(%)=75).
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4-(4-MethyIbenzylamino)-]-cyclobutyl-pipCTidiiie(47AKU-16) 4-Methylbenzylamine (215 ing, 1.8 mmol) was dissolved in 5 ml methanol and placed in 50 ml flask. 47AKU-15 (270 mg, 1.8 mmol) in 5 ml methanol was added. Acetic acid (0.3 ml) was addisd until pH 5. NaCNBH3 (226 mg, 3.6 mmol) was slowly added. Gas evolution observed. After 24 hrs magnetic stilling dichloromethane, 2M NaOH and water were added until pH 10. Phases were separated and aq. phase was then re-extracted with dichloromethane. Combined organic phases were dried over MgSO4 and concentrated on Rotavapor (40°C) yielding 419 mg crude 47AKU-16. TLC (10% methanol in dichloromethane): Rf = 0.3. HPLC-MS (Method A): M = 259.1 (UV/MS(%) 44/87).
2-(4-Chlorophenyl)-N-(4-melhylbenzyl)-N-(l-cyclobutylpiperidm-4-yl)-acetamidc (47AKU-19)
47AKU-16 (209 mg, 0.8 mraol) was placed in 50 ml flask and 5 ml dichloromethane was added. 4-Chlorophenylacetyl chlonde (171 mg, 0.9 mmol) in 5 ml dichloromethane was added. After 5 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 101 mg (31%) product. Further purification by ion exchange chromatography (washout with 10% aq. NH4OH (25%) in methanol) gave 55 mg (17%) 47AKU-19. Oxalate-salt was prepared from Oxalic acid (1.1 cq) in dichloromethame/ heptane. TLC (10% methanol in dichloromethane): R, = 0.6. HPLC-MS (Method B): M = 411.2 (UV/MS(%)==91/86). 'H-NMR (400 MHz, CDCU, retainers): S= 7.33-7.01 (8H, m); 4.62 (1H, m); 4.52 and 4.46 (2H, 2s); 3.80 (1H, s); 3.45 and 3.54 (2H, 2s); 2.86 (2H, m); 2.66 (2H, m); 2.28 and 234 (3H, 2s); 13$ (2H, m); 1.80 (2H, m); 1.70-1.52 (6H n). "C-NMR (CDa3): 5= 171.7,137.2,135.4,133.9,1323,130.4,129.7,128.9,125.7,60.4; 523. 49.4, 46.5,40.7,29.4,27.6,21.2, 14.2.
Example 108 - 2-p hen yI>.V-(4-methyl ben zyl)-AKl cydobatylpiperidiB-4-yI)acetamide (47AKU-20)
47AKU-16 (209 mg, 0.8 mmol) was placed in 50 ml flask and 5 ml dichloromethane was added. 4-Methoxyphcnylacetyl chloride (167 mg, 0.9 mmol) in 5 ml dictJorometbane was added. After 5 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°Q. Crude product was purified by flash chromatograpby (0-10% methanol in dichloromethane) giving 72 mg (22%) product
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Further purification by ion exchange chromatography (washout with 10% aq. NH4OH (25%) in methanol) gave 67 mg (20%) 47AKU-20. Oxalate-salt was prepared from Oxalic acid (1.1 eq) in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf = 0.6. HPLC-MS (Method B): M = 407.3 (UV/MS(%)=93/77). 'H-NMR (400 MHz, CDCI3, rotamers): 6= 7.26-6.79 (SH, m); 4.62 (1H, m); 4.52 and 4.45 (2H, 2s); 3.79 (1H, m); 3.77 (3H, s); 3.52 and 3.45 (2H, 2s); 2.84 (2H, m); 2.66 (2H, m); 2.34 and 2.28 (3H, 2s); 1.98 (2H, m); 1.81 (2H, m); 1.72-1.51 (6H,m). 13C-NMR(CDa3): 5= 172.5,158.7,137.0,135.7, 130.4, 129.8, 127.4, 125.8,114.3, 60.4, 55.5, 52.1,49.4, 46.4, 40.6,29.4, 27.6,21.2,14.2.
Example 109 - (47AKU-21) 2-(4-Metboxypbeoyl)-;V-(4-methylbenzyJ)-Ar-(tropin-4-yI)acetamide (47AKU-21)
4-(4-Methylbenzylamino)-tropane (47AKU-17)
4-MethyIbenzylamine (607 mg, 5.0 mmol) was dissolved in 10 ml methanol and placed in 100 ml flask. Tropinone (697 mg, 5.0 mmol) in 10 ml methanol was added. Acetic acid (0.75 ml) was added until pH 5. NaCNBH3 (628 mg, 10 mmol) was slowly added. Gas evolution observed. After 20 hrs magnetic stirring dichloromethane, 2M NaOH and waier were added until pH-10. Phases were separated and aq. phase was then re-extracted with dichloromethane. Combined organic phases were dried over MgSO . Concentration on Rotavapor (40°Q yielded 1.14 g crude 47AKU-17. TLC (10% methanol in dichloromethane): R = 0.4. HPLC-MS (Method A): M = 245.2 {UV/MJH%>=65/96).
2 4-Methoxyphenyl)-N-(4-memyIbenzyI)-NKtropm-4-yl)-acetamidc (47AKU-21)
47AKU-17 (244 mg, 1.0 mmol) was placed in 50 ml flask and 5 ml dichloromethane was added. 4-Methoxyphenylacetyl chloride (203 mg, 1.1 mmol) in 10 ml dichloromethane was added. After 3 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°Q. Crude product was purified by ion exchange chromatography (washout with 10% aq. NH OH (25%) in methanol) and flash chromatography (0-10% methanol in dichloromethane) giving 202 mg (51 %) 47AKU-21. Oxalate-salt was prepared from Oxalic acid (1.1 eq) in dichloromethane/heptane. TLC (10% methanol in dichloromethane): R = 0.4. HPLC-MS (Method B): M% 393.3 (UV/MS(%)=94/92). !H-NMR (400 MHz, CDCb, isomers): 5= 7.02-7.17 (6H, m); 6.78-6.87 (2H, m); 4.74 (1H, s); 4.44 (1H, s); 3.78
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and 3.77 (3H, 2s); 3.68 (1H, m); 3.66 and 3.55 (3H, 2s); 2.65 (2H, m); 2.56 (2H, m); 2.32 (3H, s); 2.12-2.26 (6H, m); 2.05 (2H, m). 13C-NMR (CDC13): S= 173.2,171.4, 158.8,137.1, 129.7,127.6,126.9,126.0,114.4, 63.4, 60.9, 55.5, 54 6, 47.5, 41.5, 40.4, 32.8, 31.1, 27.5, 24.9, 21.2.
Example 110 - A-(4-MethyIbenzyI)-A'-(l-mcthyIpiperidin-4-yl)-Ar'-beii2yI-carbamide (47AKU-22)
47AKU-5 (219 mg, l.OmmoI) was dissolved in 5 ml dichloromethane and placed in 50 ml flask. Benzylisocyanate (160 mg, 1.2 mmol) in 5 ml dichloromethane was added. After 16 his magnetic stiining the reaction mixture was concentrated on Rotavapor (40°Q. Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 236 mg (67%) 47AKU-22. Oxalate-salt was prepared from Oxalic acid (1.1 eq) in dichlorom ethane/heptane. TLC (10% methanol in dichloromethane): R/= 0.5. HPLC-MS (Method B): M = 352.3 (UV/MS(%)=100/100). 'H-NMR (400 MHz, CDCI3): 6= 7.26-7.02 (9H, m); 4.61 (1H, m); 4.41 (1H, m); 4.33 (4H, m); 2.87 (2H, m); 2.32 (3H, s); 2.25 (3H, s); 2.09 (2H,m); 1.79-1.62 (4H,m). I3C-NMR(CDC13) 5= 158.6,139.7,137.3,135.4,129.8, 128.6, 127.4, 127.2, 126.2, 55.5, 52.2, 46.2,45.8, 45.0, 30.2, 21.2.
Example 111 - Ar-(4-MethylbenzyI)-AL(l-niethylpiperidin-4-yl)-7Vr-pbenyl carbamide (47AKU-24)
47AKU-5 (219 mg, 1.0 mmol) was dissolved in 5 ml dichloromethane and placed in 50 ml flask. Phenylisocyanale (143 mg, 1.2 mmol) in 5 ml dichloromethane was added. After 4 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was. purified by flash chromatograpby (0-10% methanol in dichloromethane) giving 181 mg (54%) 47AKU-24. HCI-saxt was prepared from 2M HCl/dietbyJethex in dichloroxnethane/heptane 3XC (10% methanol in dichloromethane): Rf •= 0.4. HPLC-MS (Method A): M = 338.3 (UV/MS(%)=100/100). 'H-NMR (400 MHz, CDC13): 5= 7.12-7.24 (8H, m); 6.93-6.98 (1H, m); 6.26 (1H, s); 4.45 (3H, s); 2.90 (2H, d); 2.36 (3H, s); 2.28 (3H, s); 2.12 (2H,m); 1.69-1.85 (4H,m). I3C-NMP.(CDQ3): 6= 156.1,139.3,137.8,134.9,130.1, 128.9, 1263, 123.1,119.9, 55.5, 52.3, 46.3, 46.2, 30.3, 213.
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Example 112 - Ar-l henetbyl-Ar--Ar'-ben2yl-carbamide (47AKU-25)
4-(2-Phenyletoyl)amiiH>-l-methylpiperidine (110 mg, 0.5 mmol) was dissolved in 5 ml dichloromethane and placed in 50 ml flask. Benzylisocyanatc (80 mg, 0.6 mmol) in 5 ml dichloromethane was added. After 20 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatograpby (0-10% methanol in dichloromethane) giving 164 mg (84%) 47AKU-25. HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/beptane. TLC (10% methanol in dichloromethane): Rf 0.4. HPLC-MS (Method A): M = 3523 (UV/MS(%)= 100/100). 'H-NMR (400 MHz, CDC13): 5= 7.34-7.09 (10H, m); 4.52 (1H, m); 4.35 (2H, d); 4.08 (1H, m); 3.33 (2H, t); 2.92 (2H, m); 2.82 (2H, t); 2.28 (3H, s); 2.07 (2H, m); 1 84-1.66 (4H, m). I3C-NMR (CDC13): 5= 157.9, 139.8,139.1, 129.0,128.9,128.8, 127.8,127.4, 126.9, 55.7, 52.8, 46.2, 45.3,44.8,37.5,30.6.
Example 113 - 2-PhenyI-7Nr-(4-metho>r>benzyI)-7V-(l-methylpiperidin-4-yI)-acctamide (47AKU-26a)
50ELH-18 (118 mg, 0.5 mmol) was dissolved in 5 ml dichloromethane in 50 ml flask.
4-Fmoropbenylacctyl chloride (104 mg, 0.6 mmol) was added. After 20 hrs stirring at room temp, mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 87 mg (49%) 47AKU-26 . HCl-saH was prepared from 2M HCl/dicthylethcr in dichloromethane/
heptane. HPLC-MS (Method A): M = 353.1 (UV/MS(%)=96V88). Example 114 - 2-(4-Trintioroincthylphenyl)-iV-(4-raetho3r)'benzyI)-iV-(l-metbylpiperidiB-4-y])-acetamidf! (47AKU-26b)
50ELH-18 (118 mg, 0.5 mmol) was dissolved in 5 ml dichloromethane in 50 ml flask.
4-TriihiOTDmethyiphenylacetyl chloride (134 mg, 0.6 mmol) was added After 20 hrs stirring at room temp, mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 81 mg (39%) 47AKU-26b. HCl-salt was prepared from 2M HCl/diethylether
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in dichloromethane/heptane. HPLC-MS (Method A): M = 421.1 (UV/MS(%)=90/100).
Example 115 - 2-(4-Flooropbenyl)-JV-(4-niethoxybeiizyl)-7V-(l-metbylpiperidin-4-yl)-acetamide(47AKU-26c)
50ELH-18 (118 mg, 0.5 mmol) was dissolved in 5 ml dichloromethane in 50 ml flask.
4-FIuorophenylacetyl chloride (104 nig, 0.6 mmol) was added. After 20 hrs stirring at room temp, mixture was concentrated on Rotavapor (40°Q. Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 68 mg (37%) 47AKU-26c. HQ-salt was prepared from 2M HCl/diethylether in dichloromethane/heptane. HPLC-MS (Method A): M = 371.1 (UV/MS(%) 100/97).
Example 116 - 2-(4-MethoxyphenyI)-Ar-(4-methoxybenzyl)-A'-(l-me(bylpiperidiD-4-yl)-acetaniide(47AKU-26d)
50ELH-18 (118 mg, 0.5 mmol) was dissolved in 5 ml dichloromethane in 50 ml flask.
4-Methoxyphenylacetylchloride (111 mg, 0.6 mmol) was added. Aiter 20 hrs stirring at room temp, mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-10% methanol in dichJoromethane) giving 77 mg (40%) 47AKU-26d. HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/heptane. HPLC-MS (Method A): M = 383.1 (UV/MS(%)=100/100).
Example 117 - 2-(4-Metbylpbenyl>7V-{4-ch]orobenzyl)-7V-{l-metbyipiperidin-4-yI)-acetainide (4 7AKU-28)
4-(4-CbJorobenzylaiiiino)-l-me&yl-piperidme (47AKU-27) 1 -Methyl-4-piperidone (566 nig, 5.0 mmol) was dissolved in 10 ml methanol and placed in 200 ml flask. 4-Chlorobenzylamine (708 mg, 5.0 mmol) was added. Mixture was stirred and Acetic acid (-0.75 ml) was added until pH 5. NaCNBH3 (628 mg, 10 mmol) was slowly added. Gas evolution observed. After magnetic stirring for 16 hrs methanol was partly removed on Rotavapor (40°C). Dichloromethane, 2M NaOH and water were added until pH 10. Phases were separated and aq. phase was then re-extracted with dichloromethane. Combined organic phases were dried over MgSCU. Concentration on Rotavapor (40°C) yielded 1.14 g crude 47AKU-27. TLC (10% methanol in dichloromethane): Rf = 0.3. HPLC-MS (Method A): M = 239.1 (MS(%)-96).
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2-(4-Methylphenyl)-N-(4-c1ilorobenzyl)-N-(]-methylpiperidin-4-yl)-acetamidc
(47AKU-28)
p-Tolylacetic acid (1.50 g) was dissolved in 10 ml thionylchloride and placed in 50 ml flask. Mixture was heated to reflux for 2 hrs and then concentrated on Rotavapor (40°C).
p-Tolylacetic chloride (202 mg, 1.2 mmol) in 5 ml dichloromethane was added to 47AKU-27 (239 mg, 1.0 nunol) in 5 ml dichloromethane. After 4 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 104 mg (28%) 47AKU-28. HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/
heptane. TLC (10% methanol in dichloromethane): Rf= 0.5. HPLC-MS (Method A): M = 371.1 (UV/MS(%)=100/90). 'H-NMR (400 MHz; CDC13, rotamers): 6= 7.34-6.99 (SH, m); 4.57 (1H, m); 4.50 and 4.44 (2H, 2s); 3.80 (1H, s); 3.55 (1H, s); 2.96 and 2.82 (2H, 2m); 2.34 (1H, m); 2.32 (3H, s); 2.24 and 2.15 (3H, 2s); 1.91 (lH,m); l.Sl-1.59(4H,m). 13C-NMR(CDC13):S= 172.5,138.2, 136.8, 133.4,131.8,129.7,129.2,128.6,127.4,54.9, 51.3,46.7, 41.3, 30.6,28.6, 21.2.
Example 118 - 2- 42ELH-77 (41 mg, 0.1 mmol) was dissolved in 1 ml dry dichloromethane and placed in oven-dried 10 ml flask. Mixture was cooled to -78°C on a dry-ice/isupropanol bath. Borontribromide (1.0 M in dkhloromcfliane, 150 nU 0.15 mmol) was slowry added at
-78°C. Ice-bath was removed and mixture was left at room temp, for 2 hrs. Water (3 ml) and saturated NaCI (aq.) were added and aq. phase was extracted with dichloromethane, ethylacetate and n-butanol. Combined organic phases were dried over MgSO4 and concentrated on Rotavapor (40°Q. Crude product was purified by flash chrotnatography (0-20% methanol in dichloromethane) giving 22 mg (63%) 47AKD-29. HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf = 0.3. HPLC-MS (Method A): M = 353.2 (UV/MS(%)=100/100). -NMR (400 MHz, CDCI3, rotamers): 5= 7.07-6.60 (8H, m); 4.48 (1H, m); 4.39 (2H, s); 3.76 and 3.66 (4H, 2bs);
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3.41 (2H, s); 3.08 (2H, m); 2.49 (1H, m); 2.42 (2H, bs); 2.22 and 2.16 (3HT 2s); 1.96-1.82 (2H, m); 1.66-1.56 (lH,m). 13C-NMR (CDCb): 5= 173.7, 156.0,137.3,134.6, 129.7, 129.6, 125.7,125.4,115.7, 54.4,50.4, 46.8,44.0,40.5, 27.3,20.9.
Example 119 - JV-Phenethyl-JV--JV'-phenyl-carbamide (47AKU-30)
4-{2-Phenylethyl)ammo-l-methylpiperidine (110 it"g, 0.5 mmol) was dissolved in 5 ml dichloromethane mi placed in 50 ml flask. Phetiylisocyanate (71 mg, 0.6 mmol) in 5 ml dichloromethane was added. After 16 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified twice by ilash chrpmatography (0-10% methanol in dichloromethane) giving 131 mg (78%) 47AKU-30. HCl-salt was prq)ared fit>m 2M HCl/diethyJether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf= 0.4. HPLC-MS (Method A): M = 338.1 (UV/MS(%)=99/100). H-NMR (400 MHz, CDC13): 6= 7.36-6.93 (10H, m); 6.24 (1H, s); 4J1 (1H, m); 3.50 (2H, t); 3.20 (2H, d); 2.89 (2H, t); 2.57 (2H, m); 2.50 (3H, s); 2-26 (2Rt m); 1.79 (2H, m). 13C-NMR (CDC13): 5= 155.8,139.2,139.0,129.4,129.3, 12S.9,127.3,123.2,120.4, 54.9, 51.3,45.5,44.3, 37.6,28.3.
Example 120 - A'- 4 3-Phenylpropy])atniiK)-l-memylpiperidine(l 60 mg. 0.7 mmol) was dissolved in 5 ml dichloromethane and placed m 50 nil flask. Benzylisocyanate (107 mg, 0.8 mmol) in 5 ml dichloromethane was added. After 2 his magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified twice by flash cbxomatography (0-10% methanol m dichlaromethane) giving 156 mg (61%) 47AKU-31. Hd-salt was preparaJ fiom 2M HO/diemyfctha in dicbloromethane/heptane. TLC (10% methanol in dichloromethane): Rf = 0.3. HPLC-MS (Method A): M = 366.1 (UV/MS(%)=100/100). 'H-KMR (400 MHz, CDClj): 6= 734-7.07 (10H, m); 4.33 (3H, m); 4.14 (1H, m); 3.04 (2H, m); 2.89 (2H, d); 2.57 (2H, t); 2.28 (3H, s); 2.06 (2H, m); 1.87 (2H, m); 1.75-1.62 (4H, m). 13C-NMR (CDCU): 5= 157.5,141.0,140.0,129.0, 128.6,1283,128.0, 127.6,126.6, 55.6,52.1,463, 45.1.41.6,33.4,32.2,30.6.
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Example 121 - Ar-(3-PbenylpropyI)-7V-(l-methyJpiperidin-4-y])-JV'-phenyI-carbamide (47AKU-32)
4-(3-Phenylpropyl)amino-l-methylpipcridine (160 mg, 0.7 mmol) was dissolved in 5 ml dichlaronaethane and placed in 50 ml flask. Phenyhsocyanate (95 mg, 0.8 mmol) in 5 ml dichlorometbane was added. After 20 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 106 mg (43%) 47AKU-32. HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC (10% methanol in dichJoromethane): Rf = 0.3. HPLC-MS (Method A): M = 352.1 (UV/MS(%)=100/100). ]H-NMR (400 MHz, CDC13): &= 7.35-6.95 (10H, tn); 5.99 (1H, s); 4.18 (1H, m); 3.17 (2H, t); 2.91 (2H, d); 2.65 (2H, t); 2.28 (3H, s); 2.07 (2H, m); 1.97 (2H, m); 1.81-1.66 (4H, m). I3C-NMR(CDC13): 5= 154.9,141.0,139.3,129.2,129.0,129A 126.8,123.1, 120.0,55.6,52.2, 46.2, 41.8,33.4,32.3,30.6.
Example 122 - 2-(4-Methoiyphenyl)-2,2-etbyIene-AK4-niethylbeDzy!)-A'-(l-metbylpiperidin-4-yI) acetamide (47AKU-33)
l-(4-Methoxyphenyl)-l-cyclopropane carboxylic acid (230 mg, 1.2 mmol) was dissolved in 2 ml thionylchloride and placed in 50 ml flask. Mixture was heated to reflux for 2 hrs and then concentrated on Rotavapor (40°Q. Tee acid chloride (250 mg, 12 mmol) in 5 ml dichloromethane was added to 47AKU-5 (220 mg, 1.0 mmol) in 5 ml dichloromethane. After 2 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°Q. Crude product was purified twice by flash chromatography (0-10% methanol in dichloromethane) giving 201 mg (51%) 47AKD-33. HCl-salt was prepared from 2M HO/'diethYiether in dichlotomethane/heptane. TLC (10% methanol in dichloromethane): Rf = 0.6. HPLC-MS (Method A): M = 3932 (UV/MS(%)-95/88).
lH-NMR (400 MHz, CDCI3, retainers): 8= 7J22-6.70 (8H, m); 4.44 (2H, s); 4 6 (1H, m); 3.74 (3H, s); 3.12 and 2-89 (2H, 2m); 2 1 (1H, m); 2.32 (3H. m); 226 (3H, s); 2.08-1.52 (4H, m); 1.36 (2H, bs); 1.15-0.95 (3H, m). "C-NMR 109

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Example 123 - 2-(4-MethoxyphenyI>- -(I-phenylethy))-Ar-(i-metbylpiperidin-4-yI) acetamide (47AKU-37)
4-Alpha-mcthylbcnzylamin(>-l-mcthy]-piperidine(47AKU-36)
DL-Phenylethylamine (606 mg, 5.0 mmol) was dissolved in 10 ml methanol and l-MethyI-4-piperidone (566 mg, 5.0 mmol) in 10 ml methanol was added Mixture was stirred and Acetic acid (-0.75 ml) was added until pH 5. NaCNBH3 (628 g, 10 mmol) was slowly added. Gas evolution observed. After magnetic stirring for 20 hrs methanol was partly removed on Rotavapor (40°C). Ethylacetate, 2M NaOH and water were added until pH 10. Phases were separated and aq. phase was then re-extracted with ethylacetate and dichloromethane. Combined organic phases were dried overMgSCV Concentration on Rotavapor (40°C) yielded 838 mg crude 47AKU-36. TLC (10% methanol in dichloromethane): Rf = 0.3. HPLC-MS (Method A): M " 219.1 (UWMS(%)=100/94).
2-(4-Methoxyphenyl)-N-alpha-methylbenzyl-N-(l-methylpiperidin-4-yl) acetamide (47AKU-37)
47AKU-36(218mg, 1.0 mmol) was dissolved in 10 ml dichlorometbane and placed in 50 ml flask. 4-Methoxyphenylacetyl chloride (185 mg, 1.2 mmol) in 10 ml dichloromethane was added. After 16 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 256 mg (70%) 47AKU-37. HCl-salt was prepared from 2M HCl/diethylether in dichloTomcthane/beptanc TLC (10% methanol in dichloromethane): Rf= 0.5. HPLC-MS (Method A): M = 3673 (\JV/MS(%y=l(W99)-
'H-NMR (400 MHz, CDCI3, retainers): 5= 734-7.06 (7H, m); 6.84 (2H, d); 5.10 (1H, m); 3.77 (3H, s); 3.67 (2H, m); 3.17 (IH, m); 3.03-2.75 (3H, m); 2.64 (3H, s); 2.38 (2H, m); 1.77-1.05 (6H, m). I3C-NMR (CDC13): 5= 172.0,158.9,139.9, 130.0, 129-0, 128.2,127.1, 114.5, 55.5,53.1, 51.4,42.4, 41.3, 31.1,29.5, 24.9, 18.1.
Example 124 - 2 MethbxypbenyI)- -(4-methylbeDzyl)-AK3-tn>P -4-ji) acetamide (47AKU-39)
4-MethyIbenzjdimmo-tiopane (47AKU-38)
4-Methylbenzylamine(1.21 g, lOmmoI) andTropinone(139g, lOmmol) were placed in 100 ml flask and dissolved in 50 ml toluene. Mixture was heated to reflux for 3 hrs and water was removed using a Dean/Stark water-separator. Crude
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product was concentrated onRotavapor (40°C) giving 47AKU-38. TLC (10% methanol in dichloromethanc): Rf- 0.3. lH-NMR (400 MHz, CDC13, isomers): 7.20-7.09 (4H, m); 4.47 (1H, m); 3.81 (1H, s); 3.42 (1H, m); 3.31 (1H, m); 2.77- 2.56 (2H, m); 2.47 and 2.41 (3H, 2s); 2.33 and 231 (3H, 2s); 2.27-1.97 (4H, m); 1.69-1.54 (2H, m).
2-(4-Methoxyphenyl>N-(4-methylbeiizyl>N-(3-tropen-4-yl)acetamide (47AKU-39)
47AKU-38 (242 ing, 1.0 mmol) was dissolved in 5 ml dichloromethanc and placed in 50 ml flask. 4-Methoxyphenylacetyl chloride (185 mg, 1.2 mmol) in 10 ml dichloromethane was added. After 16 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-10% methanol ira dichloromethane) giving 69 mg (18%) 47AKU-39. HCl-salt was prepared from 2M HCl/diethylcther in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf = 0.4. HPLC-MS (Method A): M = 391.2 (UV/MS(%>91/86).
'H-NMR (400 MHz, CDCI3, rotamers)- &= 7.22-6.82 (8H, m); 5.41 (1H, bs); 4.71-4.52 (2H, m); 3.78 (3H, s); 3.68 (2H, m); 3.44-3.24 (2H, m); 2.72-2.36 (5Ht m); 232 (3H, s); 2.25-2.00 (2H, m); 1.80-1.54 (2H, m). 13C-NMR (CDCI3): 6= 170.8, 158.7,137.4, 134.9,130.1, 1293,128.9,126.9, 114 , 59.0, 58.0, 55.5, 49.5, 463, 39.7,35.9,33.8,29.7,213.
Example 125 - 2-PfaeDyi-2-ctfayWV 4-metbyIbenzyI)-A-(l-metbylprperidnM-ji) acetamide (47AKU-40)
2-PhenyIbmyric acid (197 mg, 1 mmol) was dissolved in 2 ml thionyfchloridcand placed in 50 ml flask. Mixture was heated to reflux for-2 hrs and then concentrated on Rotavapor (50oQ. The acid chloride (1.2 mmol) in 5 ml dichloromethane was added to 47AKU-5 (158 mg, 0.72 mmol) in 5 ml dichloromethane. After 20 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 196 mg (74%) 47AKU-40. HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/
heptane. TLC (10% methanol in dichloromethane): Rf = 0.5. HPLC-MS (Method A): M = 365.4 (UV/MS(%)=99/100). 'H-NMR (400 MHz, CDC13, rotamers): 6= 732-6.98 (8H, m); 4.77 (1H, bs); 4.50 (1H, d); 4.29 (1H, d); 3.43 and
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3.21 (3H, 2m); 2.72 (2H, m); 2.62 (3H, s); 2.43 (1H, m); 2.32 Example 126- 2-(4-Methoxyphenyl)- -(l-indanyl)-Ar-(l-methylpipcridin-4-yl) acetamide (47AKU-43)
4-0 -lndanamino)-l -methyl-piperidine (47AKU-42) 1 -Aminoindane (666 mg, 5.0 mmol) was dissolved in 10 ml methanol and placed in 100 ml flask. l-Methyl-4-piperidone (566 mg, 5.0 mmol) in 10 ml methanol was added. Mixture was stirred and Acetic acid (-0.75 ml) was added until pH 5. NaCNBHs (628 g, 10 mmol) was slowly added. Gas evolution observed. After magnetic stiiring for 16 hrs methanol was partly removed on Rotavapor (40°C). Dichloromethane, 2M NaOH and water were added until pH l 0. Phases were separated and aq. phase was then re-extracted with ethylacetate and dichloromethane. Combined organic phases were dried over MgSO4. Concentration on Rotavapor (40°C) yielded 1.06 g 47AKU-42. TLC (10% methanol in dichloromethane): Rf = 0.3. HPLC-MS (Method A): M "= 231.1 (UVYMS(%)=72/91).
2-(4-Methoxyphenyl)-N-(l-mdanyl)-N-(l-methylpiperidin-4-yl) acetamide (47AKU-43)
47AKU-42 (230 mg, 1.0 mmol) was dissolved in 10 ml dichloromethane and placed in 50 ml flask. 4-Methoxyphenylacetyl chloride (185 mg, 12 mmol) in 10 ml dichloromethane was added. After 16 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°Q. Ciude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 194 mg (51%) 47AKU-43. HCi-saK was prepared from 2M HCI/diemylether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf = 0.5. HPLC-MS (Method A): M = 379.2 (UV/MS(%>=$4/90).
Example 127 - (47AKU-44VV -carbamide (47AKU-44)
47AKU-5 (219 mg, 1.0 mmol) was dissolved in 5 ml dichloromethane and placed in 50 ml flask. 4-MethoxybenzyKsocyanate (196 mg, 1.2 mmol) in 10 ml dichloromethane was added. After 16 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash
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chromatography (0-10% methanol in dichloromethane) giving 192 mg (50%) 47AKU-44. HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf 0.3. HPLC-MS (Method A): M 382.3 (UV/MS(%>=100/94). 'H-NMR (400 MHz, CDC13): 5= 7.10 (4H, m); 6.98 (2H, m); 6.76 (2H, m); 4.58 (1H, t); 4.45 (1H, m); 4.33 (2H, s); 4.25 (2H, d); 3.76 (3H, s); 2.97 (2H, m); 2.34 (3H, s); 2.32 (3H, s); 2.24 (2H, m); 1.78 (4H, m). 13C-NMR (CDCI3): 6= 158.9,158.5,137.3, 135.2,131.8,129.8,128.8, 126.2, 114.1, 55.5, 55.4, 51.7,45.8,45.7, 44.5,29.7, 21.2.
Example 128 - 2-(3,4-dimetboxypbeEyl>A44-methyIbenzyl)-JV-(l-metbylpiperidin-4-yI) a c et amide (47AKU-45)
3,4-DimethoxyphenyIbutyric acid (235 mg, 1.2 mmol) was dissolved in 2 mi thionylchloride and placed in 50 ml flask. Mixture was heated to reflux for 2 hrs and then concentrated on Rotavapor (50°C). The acid chloride (1.2 mmoi) in 5 ml dichloromethane was added to 47AKU-S (219 mg, 1.0 mmol) in 10ml dichloromethane. After 16 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°Q. Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 129 mg (33%) 47AKU-4S. HCl-saK was prepared from 2M HCl/diethylether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf= 0.4. HPLC-MS (Method A): M = 397.4 (UV/MS(%)=98/89). 'H-NMR (400 MHz, CDCI3, rotamers): 5= 7.17-6.60 (7H, m); 4.75 (1H, m); 4.51 (2H, s); 3.83 (3H, s); 3.79 (3H, s); 3.53 (2H, s); 3.27 (2H, d); 2.65 (2H, t); 2L58 (3H, s); 2.32 (3H, s); 2J24 (2H, m); 1.72 (2H, d). UC-NMR (Cr>Cb): 6= 172 , 1493, 1483,137.4,135.0,129.8, 127.4,125.8,121.0,112.2,111.6, 56.2,36.1, 54.6,49.6,46.7,44.0, 40 , 27.0,212.
Example 129 - 2-'phenyI>Ar-Ar-(3-methylpfperidin-4-yI) acetamlde (47AKU-46)
3,4-Methylenedioxyphenylacetic acid (216 mg, 1.2 mmol) was dissolved in 2 ml thionylchloride and placed in 50 ;ml flask. Mixture was heated to reflux for 2 hrs and mol concentrated on Rotavapor (50°C). The acid chloride (1.2 mmol) in 5 ml dicbloromethane was added to 47AKU-5 (219 rug, 1.0 mmol) in 10 ml dichloromethane. After 2 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 188 mg (49%) product. Further purification by
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ion exchange cbromatography (washout with 10% aq. NH4OH (25%) in methanol) yielded 149 mg (39%) 47AKU-46. HCl-salt was prepared from 2M HCl/diethylether in dichloromethane/
heptane. TLC (10% methanol in dichloromethane): Rf = 0.4. HPLC-MS (Method A): M = 381.2 (UV/MS(%)=96/95). 'H-NMR (400 MHz, CDC13, rotamers): 5- 7.17-7.02 (4H, m); 6.77-6.51 (3H, m); 5.91 and 5.93 (2H, 2s); 4.70 (1H, m); 4.52 and 4.49 (2H, 2s); 3.51 (2H, s); 3.26 (2H, d); 2.49 (3H, s); 2.33 (3H, s); 2.14-1.66 (6H, m) 13C-NMR(CDC13):5= 172.5,148.1,146.8, 137.3,135.1,129.8, 128.6,125.8, 121.9, 109.4, 108.5, 101.2,54.8,50.2,46.7,44.6,41.1,27.7,21.2.
Example 130 - 2-(4-Methoxypheny])-A 4-methylbenzyl)-A'- l-BenzyI-4-piperidone(I.89g, 10 mmol) was dissolved in 15 ml acetone. Metbyliodide (0.90 ml, 15 mmol) was slowly added over 5 min. After 2 hrs magnetic stirring additional Methyliodide (1.8 ml, 30 mmo!) was added. After 1 hr magnetic stirring 20 ml diethyl-ether was added. Crude product was collected by filtration and washed with acetone/diethylether. White crystals were dried under vacuum giving 806 mg quartenary salt TLC (10% methanol in dichloromethane): Rf = 0.7. Partly dissolved salt in 5 ml water was added to 50°C hot mixture of t-Butylamine (120 mg, 1.6 mmol) and Potassiumcarbonate (32 mg, 0.22 mmol) in 3 ml ethanol. The resulting mixture was stirred and heated to reflux ( 80°C) for 1 hr. After cooling water (20 ml) and dichloromethane (20 ml) were added. Phases were separated and aq. phase was re-extracted with dichloromethane and ethylaceiate. Combined organic phases were dried ovcx MgSO4 and concentrated cm Roiavapor (40°Q giving 496 mg 47AKU-47. TLC (lOftmeOunol in dicfaloromeftiane): Rf = 0.3; 'H-NMR (400MHz,-CDCi ): 5= 2.82 (4H, t); 2.41 (4H, t); 1.12 (9H, s). 13C-NMR (CDC13): 6= 210SL, 54.3, 46.4, 42.4, 26.6. Crude product contained -25% ('H-NMR) starting material (l-Benzyl-4-pxperidane).
4 4-MeAyn>enzylainmo>l4-buryl-prperidine (47AKU-48) 4-MethyIbenzylamme (268 mg, 2.2 mmol) was dissolved in 5 ml methanol and placed in 50 ml flask. 47AKU-47 (305 mg, 2.0 mmol) in 5 ml methanol was added. Acetic acid (0.3 ml) was added until pH 5. NaCNBHj (250 mg, 4.0 mmol) was slowly added. Gas evolution obscaved. After 4 hrs magnetic stirring
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dichloromethane, 2M NaOH and water were added until pH 10. Phases were separated and aq. phase was then re-extracted with dichloromethane and ethylacetate. Combined organic phases were dried over MgSO4. Concentration on Rotavapor (40°Q yielded 556 mg crude 47AKU-48. TLC (20% methanol in dichloromethane): Rf = 0.4. HPLC-MS (MethodA): M = 261.2 (MS(%)=57).
2-(4-Methoxyphenyl)44-(4-jnethylbenzyl)-N-( 1 -t-butylpiperidin-4-yl)-acetamide
(47AKU-49)
47AKU-48 (556 mg, 2.1 mraol) was placed in 50 ml flask and 5 ml dichloromethane was added. 4-MethoxyphenylacetyI chloride (739 mg, 4.0 mmol) in 10 ml dichloromethane was added. After 4 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 124 mg (15%) product. Further purification by ion exchange chromatography (washout with 10% aq. NH4OH (25%) in methanol) gave 91mg (11%) 47AKU-49. HCl-salt was prepared from 2M HCl/di ethyl ether in dichloromethane/ heptane. TLC (10% methanol in dichloromethane): R = 0.5. HPLC-MS (Method A): M = 409.4 (UV/MS(%)=100/90). 'H-NMR (400 MHz, CDC13): 6= 7.11 (4H, m); 7.03 (2H, d); 6.79 Example 131 - AK4-Meth>lbeazy|)-AKlHDethylpiperidiB-4-yi)- r-
phcnvkthyJ-carbamide (58AKU-1)
47AKU-5-2 (219 mg, 1.0 mmol) was dissolved in 5 ml dichloromethane and placed in 50 ml flask. Pbenethylisocyanate (177 mg, \2 mmol) in 5 ml dichloromethane was added. After 6 his magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-15% methanol in dichloromethane) giving 134 mg (37%) 58AXU-1. HCl-salt was prepared from 2M HCl/dictbyktber in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf = 0.5. HPLC-MS (Method A): M = 366.3 (UV/MS(%H>9/96). !H-NMR (400 MHz, CDC]3): 6-7.21-6.97 (9H, m); 4.33 (1H, m); 4.26 (1H, m); 4.21 (2H, s); 3.39 (2H, q); 2.85 (2H,
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m); 2.67 (2H, t); 2.31 (3H, s); 2:24 (3H, s); 2.06 (2H, m); 1.73-1.57 (4H, m). 13C-NMR(CDC13): 6= 158.7,139.5,137.0,135.4,129.7, 128.8,128.6, 126.3, 126.1, 55.6, 52.2, 46.2, 45.8, 42.2, 36.4, 30.2,21.2.
Example 132 -A-Phenylethyl-AKl-metbylpipcridiii -yl A -phenethyl-carbamide (58AKU-2)
4-(2-Pbenylemyl)amino-l-methylpiperidine (131 nig, 0.6 mmol) was dissolved in 5 ml dichloromethane and placed in 50 ml flask. Phenethylisocyanate (103 mg, 0.7 mmol) in 5 ml dichloromethane was added. After 4 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (45 °C) Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 198 mg (90%) 58AKU-1. HCl-salt was prepared fix>m 2M HCl/diethylether in dichloromethane/heptane. TLC (10% methanol in dichloromethane): Rf = 0.3. HPLC-MS (Method A): M = 3663 (UV/MS(%)=100/100). 'H-NMR (400 MHz, CDCI3): 6= 7.33-7.16 (SH, m); 7.01 (2H, m); 4.23 (1H, t); 4.04 (1H, m); 3.47 (2H, q); 3.17 (2H, t); 2.89 (2H, m); 2.78 (2H, t); 2.66 (2H, t); 2.28 (3H, s); 2 05 (2H, m); 1.79-1.59 (4H, m). "C-NMR (CDC13): 5= 157.8, 139.6,139.0, 129.0, 128.9,128.8, 126.8, 126.7, 55.7, 52.5, 46.2,44.6,42.0, 37.3,36.4, 30.5.
Example 133 -7V-(4-MethyIbenzy!)- -(l-t-but>ipiperidin -yl)-iV-(4-methoxybenzyl) carbamide (58AKTI-3)
47AKU-5-2 (404 mg, 1.6 mmol) was dissolved in 5 ml dichloromethane and placed in 50 ml flask. 4-Methoxyben2ylisocyanatc (326 ing, 2.0 mmol) in 5 ml dichloromethane was added. Aiter 20 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (45°C). Ciiide product was purified three times by flash chromatography (0-20% methanol in 116

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Example 134 - 2-(4-Ethoxyphenyl)-7V-(4-metbylbenzyl)-N-(l-metbylpiperidin-4-yI) acetaraide (58AKU-4)
4-Ethoxyphenylacetic add (270 mg, 1.5 mmol) was dissolved in 2 ml thionylchloride and placed in 50 ml flask. Mixture was heated to reflux for 2 hrs and then concentrated on Rotavapor (45°C). The acid chloride (1.5 mmol) in 5 ml dichloromethane was added to 47AKU-5-2 (262 mg, 1.2 mmol) in 5 ml dichloromethane. After 20 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°C). Crude product was purified by flash chromatography (0-10% methanol in dichloromethane) giving 272 mg (60%) 58AKU-4. HCl-salt was prepared from 2M HCl/diethylether in dichlororaethane/
heptane. TLC (10% methanol in dichloromethane): Rf = 0.4. HPLC-MS (Method A): M = 381.2 (UV/MS(%)=98/9I). 'H-NMR (400 MHz, CDCI3): 6= 7.17-6.99 (6H, m); 6.82-6.76 (2H, m); 4.73 (1H, m); 4.48 (2H, s); 3.98 (2H, q); 3.52 (2H, s); 3.22 (2a d); 2.61 (2H, t); 2.54 (3H, s); 2.32 (3H, s); 2.14 (2H, s); 1.71 (2H, d); 1.38 (3H, t). "ONMR (CDC13): 6= 172.9, 158.2,137.3,135.0, 129.9,129.8,126.8, 125.S, 114.9,63.7,54.6,49.8,46.7,44.1,40.6,27.2,21.2, 15.0.
Example 135 - 2-(4-ButoxypbenyI>-7V-(4-methylben2yl>-7V-(l-methylpiperidin-4-yl) acetaraide (58AKU-5)
4-Butoxyphenylacetic acid (317 mg, 1.5 mmol) was dissolved in 2 ml thionylchloride and placed in 50 ml flask. Mixture was heated to reflux for 2 hrs and then concentrated on Rotavapor (45 °C). The acid chloride (1.5 mmol) in 5 ml mchloromethane was added to 47AKU-5-2 (262 mg, 1.2 mmol) in 5 ml dichJoromethanc. After 20 hrs magnetic stirring the reaction mixture was concentrated on Rotavapor (40°Q. Crude product was purified by flash cfaromatography (0-10% methanol in dichloromethane) giving 230 mg (47%) 58AKU-5. HCI-salt was prepared from 2M HCl/diethylether in dichloromethane/
heptane. TXC (10% methanol in dichloromethane): Rf= 0.5. HPLC-MS (Method A): M = 409.2 (UV/MS(%)=98/93). lH-NMR (400 MHz, CDCI3): &= 7.15-6.96 (6H, m); 6.78 (2H, m); 4.74 (1H, m); 4.48 (2H, s); 3.91 (2H, t); 3.52 (2H, s); 3 7 (2H, d); 2.72 (2H, t); 2.58 (3H, s); 2.32 (3H, s); 2.23 (2H, m); 1.72 (4H, d); 1.45 (2H,m); 0-95 (3H, t). I3C-KMR (CDC13): S= 173.0, 158.4, 137.3,135.0, 129.8,126.6, 125.8,115.0, 67.9, 54.4,49.5, 46.7,43.8,40.6, 31.5, 26.8, 21.2, 19.4,14.0.
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Example 136 - 2-{4-i- ropoxyphctiyl)'N-(4-mcthy}benzy\)-N-(\' raetbylpiperidin-4-yI) acetamfde (S8AKU-6)
47AKU-29-2 (245 ing, 0.7 mmol) was dissolved in 10 ml dimethylformamide and placed in 50 ml flask. KOH (196 mg, 3.5 mmol) and Isopropylbromide (200 u,l, 2.1 mmol) were added. Mixture was heated to 50°C and stiired for 24 hrs. After cooling water and ethylacetate were added. Phases were separated and aq. phase was then re-extracted with dichloromethane. Combined organic phases were washed with brine, dried overMgSO4 and concentrated on Rotavapor (40°C) giving 188 mg. Crude product was purified by flash chromatography (0-10% methanol in dichioromethane) yielding 136 mg (49%) 58AKU-6. HCl-salt was prepared from 2M HCl/di ethyl ether in dichloromethane/
heptane. TLC (10% methanol in dichioromethane): Rf- 0.3. HPLC-MS (Method D): M = 395 (UV/MS(%)=95/91). 'H-NMR (400 MHz, CDC13, retainers): 6= 7.23-7.01 (6H, m); 6.79 (2H, m); 4.60 (1H, m); 4.51 (1H, m); 4 44 (IH, s); 3.77 (1H, s); 3.52 (IH, s); 2.83 (2H, m); 2.76 (2H, m); 2.28 and 2.34 (3H, 2s); 2.19 and 2.22 (3H, 2s); 2.05 (IH, m); 1.86-1.55 (4H, m); 1.32 (6H, d). nC-NMR (CDC13): 6=
172.6, 157.0, 137.1,135.6, 129.8, 129.7,125.8, 116.2, 70.1, 55.3, 51.6, 46,6, 46.1, 40.8,29.6,22.3,21.2.
Example 137 - Receptor Selection and Amplification (R-SAT) Assays.
The functional receptor assay, Receptor Selection and Amplification Technology (R-SAT), was used (with minor modifications from that previously described US 5,707,798) to screen compounds for efficacy at the 5-HT2A receptor. Briefly. NIH3T3 cells were grown in 96 well tissue culture plates to 70-80% confluence. Cells were transfected for 12-16 hours with plasnrid DNAs using supcrfect (Qiagen Inc.) as per manufacture's protocols."R-SAT's were generally performed with 50 ng/well of receptor and 20 ng/well of Beta-galactosidase plasmid DNA. All receptor and G-protein constructs used were in the pSI mammalian expression vector (Promega Lac) as described in U.S. 5,707,798. The 5HT2A receptor gene was amplified by nested PCR from brain cDNA using the oligodeoxynucleotides based on the published sequence (see Saltzman et al Biochem. Biophys. Res. Comm. 181:1469-78 (1991)). Large-scale transfections, cells were transfected for 12-16 hours, then trypsinized and frozen in DMSO. Frozen cells were later thawed, plated at 10,000-40,000 cells per well of a 96 well plate that contained drug. With both
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methods, cells were then grown in a humidified atmosphere with 5% ambient CO2 for five days. Media was then removed from the plates and maricer gene activity was measured by the addition of the beta-galactosidase substrate ONPG (in PBS with 5% NP-40). The resulting colorimetric reaction was measured in a spectrophotometric plate reader (Titertek Inc.) at 420 nM. All data were analyzed using the computer program XLFh (IDBSm). Efficacy is the percent maximal repression compared to repression by a control compound (ritanserin in the case of 5HT2A). pIC50 is the negative of the log(IC50), where IC50 is the calculated concentration in Molar that produces 50% maximal repression. The results obtained for several compounds of the invention are presented in Table 4, below.
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Table 4. Efficiency and pIC50 of Compounds at the 5-HT2A Receptor Compared to Ritanserin
Compound Percent Efficacy p)C50

26HCH17
94
8.3
26HCH65
103
8.2
26HCH66-05
126
8.1
26HCH79-5
94
8.2
26HCH79-6
83
8.3
26HCH79-10
102
7.8
26HCH71B
124
7.9
42ELH45
108
9.0
50ELH27
108
8.7
47AKU-7
120
8.1
42ELH80
122
8.5
42ELH79
t10
8.5
42ELH91
108
8.0
42ELH85
118
7.8
42ELH75
109
8.3
47AKU-12
112
8.1
47AKU-8
113
8.1
47AKU-22
117
7.9
47AKU-21
117
7.9
47AKU-2O
120
8.0
50ELH8
129
7.8
50ELH68
96
8.4
50ELH65
92
7.9
47AKU-44
112
8.5
57MBT12B
75
7.7
58AKU-4
110
9.6
58AKU-3
111
81
58AKU-5
99
95
58AKU-6
101
9.8
57MBT54B
95
7.9
50ELH95B
119
8.0
50B.H93E
72
8.1
5OELH93D
58
7.8
50ELH93A
106
8.7
63ELH1A
104
8.3
50B.H89
111
9.7
63S.H20
95
9.0
57MBT7O-6D
119
7.7
57MBT70-5D
105
8.4
57MBT70-4D
98
8.5
57MBT70-3D
87
8.9
57MBT70-2O
105
8.2
57MBT70-1D
120
7.9
63Q_H21
100
8.5
57MBT62B
119
7.9
57MBT70-6E
115
8.0
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Example 138 Selectivity Profile for 2-(4-Metboxyphenyl)-;V-{4-raethylbenzyI)-iV-(l-methyIpiperidin-4-yI)acetamidehydrochioride
The R-SAT assay (described above in example 137) was used to investigate the selectivity of 2-(4-Methoxyphenyl)-JV-(4-methylbeiizyl)-A'-(l-methylpiperidin-4-yl)acetamide hydrochloride. The results from a broad profiling of this compound at a variety of receptors are reported in Table 4 below. NR means No Response, i.e. the compound investigated showed no effect at the receptor studied.
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Table 4 - Selectivity of 2-(4-Metboxypbenyl>A44-metbyIbenzy1)-/V-0-m ethylpiperi dro-4-y))aceta mide
RECEPTOR
ASSAY
pEC50/plC50
5-HT1A
agonist
NR

antagonist
NR
5-HT1B
agonist
NR

antagonist
NR
5-HT1D
agonist
NR

antagonist
NR
5-HTtE
agonist
NR

antagonist
NR
5-HT1F
agonist
NR

antagonist
NR
5-HTZA
agonist
NR

inverse agonist
8.8
5-HTa
agonist
NR

inverse agonist
6.9
5-HTac
agonist
NR

inverse agonist
7
5-HT4
agonist
NR

inverse agonist
NR
5-HT6
agonist
NR

Inv. Agonist
6.8
5-HT7
agonist
NR

inverse agonist
6.9
ml
agonist
NR

antagonist
. NR
m2
agonist
NR

antagonist
NR
m3
agonist
NR

antagonist
NR
m4
agonist
NR

antagonist
NR
m5
agonist
NR

antagonist
NR
D1
agonist
NR
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antagonist
NR
D2
agonist
NR

antagonist
NR
D3
agonist
NR

antagonist
NR
D5
agonist
NR

antagonist
NR
Histamme 1
agonist
NR

Inv. agonist
NR
Histamine 2
agonist
NR

antagonist
NR
Histamme 3
agonist
NR

antagonist
NR
alpha-1A(a/c)
agonist
NR

antagonist
NR
alpha- 1B
agonist
NR

In. Agonist
NR
alpha-2A
agonist
NR

antagonist
NR
alpha-2B
agonist
NR

antagonist
NR
alpha-2C
agonist
NR

antagonist
NR
betai
agonist
NR

antagonist
NR
beta2
agonist
NR ¦

antagonist
NR
endothefinB
agonist
NR
CCK-A
agonist
NR
NK-1
agonist
NR
VasopressJniA
agonist
NR
K-opiod
agonist
NR
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Example 139 In Vivo Pharmacology of 2-(4-Methoxyphenyl)-iV-(4-
metbylbenzyI)-iV-(l-methy]piperidm-4-yI)acetamidehydrochloride(AC-90,179) Methods
Animals and apparatus
Instruments) were used for rat experiments (details on startle apparatus and measures, see Male Non-Swiss Albmo mice and male Sprague-Dawley rats (Harlan Sprague-Dawley) were housed (4 mice/cage; 2 rats/cage) in rooms with temperature and humidity controlled and water and food (Harlan Teklad) freely available. Mice were kept on a 12-hr lightrdark cycle, whereas rats were kept on a 12- hr reverse light:dark cycle. For locomotor and observation experiments in mice, plastic 20x20x30cm activity cages were equipped with photocell beams (AccuScan Instruments). Startle chambers (San Diego Instruments) were used for rat experiments (for details on startle apparatus and measures, see Mansbach et al., (1988) PsycJiopharmacology 94:507-14).
Procedore
Observation for Head Twitches
Mice were treated with 2.5 mg/kg DOI i.p. Five min later, mice were treated with AC-90179 s.c. and placed into activity cages. Ten min later, mice were observed using a repeated sampling technique. Each mouse was observed for 10 sec and rated for presence (1) or absence (0) of head twitch behavior for a total of 6 observations in 15 min and a total head twitch score of 0-6. Each dose combination was tested in a separate group of animals (n=8) and the experimenter was blind to drug conditions. Head twitch scores were averaged followed by analysis of variance (ANOVA) and post-hoc Durmett's t-test comparisons.
Locomotor Activity
For hyperactivity experiments, mice were treated with 0.3 mg/kg dizocilpine or 3.0 mg/kg d-amphetamine i.p. 15 min before the session. Five minutes after the pretreatment, mice were treated with AC-90179 s.c. and placed into the activity cages. For spontaneous activity, AC-90179 was administered alone. Locomotor data were collected during a 15 min session without habituan'on in a lit room. Each dose combination was tested in a separate group of animals (n=8). Distance traveled (cm) was calculated and averaged followed by ANOVA and post-hoc Dunnett's t-test comparisons.
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Startle Testing
Rats were tested and groups (n=l 0) matched for levels of startle reactivity and prepulse inhibition (PH; see Mansbach et al, (1988) Psychopharmacology 94:507-14). Two days later, test sessions started and consisted of a 5-min acclimation period with a constant background noise (65 dB), followed by 60 presentations of acoustic stimuli to measure acoustic startle responses. The 60 trials consisted of: twenty two 40-ms presentations of a 120 dB broadband pulse, ten 20-ms presentations of each prepulse intensity (68, 71, 77 dB) 100 ms prior to a 40-msec presentation of a 120 dB broadband pulse, and 8 NOSTIM trials in which no stimuli were delivered in order to assess general motor activation in the rats. Thirty min before testing, rats were treated with sterile water (s.c.), risperidone (1.0 mg/kg, i.p.), or AC-90179 (s.c). Five min later, rats were administered DOI (0.5 mg/kg, s.c.) or 0.9% saline (s.c). One-week later, rats were administered the same pretreatment drug or vehicle and crossed over to receive the treatment opposite to that they received the previous week. Startle magnitudes and percent PPI for the three prepulse intensities were calculated as described elsewhere (Bakshi, et al, (1994) J. Pharmacol Exp. Ther. 271:787-94) and ANOVAs with repeated measures performed. Res alts
To further characterize the clinical utility of a selective 5-HT2A receptor inverse agonist as a novel antipsychotic agent, AC-90179 was tested in head twitch, locomotOT and pre pulse inhibition behavioral models. DOI-trcatcd (2.5 mg/kg, i.p., 15 mm) mice exhibited an average head twitch score of 2.6 (± 03, S.E-M.). AC-90179 (0.1 - 30 mg/kg, ex., 10 min) caused a dose-related decrease in DOI-induced bead-twitches with a minimum effective dose of 1 mg/kg and with higher doses completely eliminating head twitch behavior (Figure 2 A).
In tbe locomotor experiments (Figure 2 B), mice traveled an average of 794 cm (± 122 S.E.M.) after vehicle administration. Dizocilpinc (03 mg/kg, i-p., 15 min) and J-amphetamine (3.0 mg/kg, i.p., 15 min) caused increases in distance traveled with averages of 2625 cm (± 312) and 3367 cm (± 532), respectively. AC-90179 (03 -10 mg/kg, s.c., 10 mm) attenuated the hyperactivity induced by dizocirpinc, bat not by d-amphetarnine. The minimum effective dose against dizocilpine was 1 mg/kg, whereas AC-90179 reduced spontaneous locomotor activity only at the highest dose tested (30 mg/kg).
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The 3-way repeated measures ANOVA on the PPI data from the AC-90179 groups revealed an overall effect of treatment [F(l,37) - 27.73, p 0.05) on percent PPI. Risperidone was used as a positive control because previous studies in our laboratory have suggested that it is effective in blocking the PPI-disrupbive effects of DOI. The 3-way repeated measures ANOVA on the PPI data from the risperidone group also revealed a significant effect of treatment [F(l,18)= 14.08, p 0.05). Since there were no significant interactions with prepulse intensity, title data were collapsed across the three prepulse intensities for graphical purposes.
Since there was a significant pretreatment by treatment interaction, pair-wise 2-way repeated measures ANOVAs were conducted on the saline- and DOI-treated groups. In the vehicle-treated rats, there was no effect of AC-90179 (p > 0.025) or risperidone (p > 0.025) on PPI. hi the DOI-treated groups, there were significant effects of AC-90179 [F(3,37) = 5.68, p The 3-way repeated measures ANOVA on startle magnitude from the AC-90179 groups revealed a significant effect of pretreatment [F(3,37) 2.89, p = 0.048) and treatment [F(137) - 10.27, p 0.05; Fif jure 1, panel C inset). Risperidone, on fee other hand, had no effect on startle magnitude (p > 0.05).
Example 140 - In Vivo Pharmacology of Additional Compounds
The effect of various compounds on head twitch behavior in mice treated with DOI was observed as described above in Example 139. The results are summarized below in Table 5.
Toe effect of various compounds on btwid twitch behavior in mice treated wth DOI was observed as described in Example 139. Animals received 0.1 -30 rag/kg of the compound indicated via subcutaneous injection. MED indicates the minirmim
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effective dose at which a statistically significant reduction m head twitching score (described above) was observed. MED = minimum effective dose in vrvo. Table 5. Comparison Of Analogs For Their Ability To Attenuate DOI-lnduced Head Twitches In Mice.

CompooD
MED
26HCH1
30
44ELH45
30
50ELH27
1
42ELH80
42ELH79
47AKU-7
42ELH85
47AKU-8
47AKU-12
47AKU-13
42ELH91
>10
42ELH90
-10
47AKU-20
47AKU-19
>10
47AKU-22
| 47AKU-21
>10
| 42ELH75
47AKU-11
-10
47AKU-14
47AKU-18
>1O
50ELH6
47AKU-33
>10
47AKU-25
>10
5OELH65
5OELH68
47AKU-49
47AKU-44
58AKU-4
58AKU-5
50ELH93A
58AKU-6
63ELH20
63ELH21
MED = minimum effective dose in vivo.
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The invention described and claimed herein is not to be limited in scope by the specific embodiments herein disclosed, since these embodiments are intended as illustrations of several aspects of the invention. Any equivalent embodiments are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications arc also intended to fall within the scope of the appended claims.
The disclosures of all references cited herein are incorporated by reference in their entireties.
128

1. A compound of formula (I)

in which
R is a hydrogen, a cyclic or straight-chained or branched acyclic organyl group, a lower hydroxyalkyl group, a lower aminoalkyl group, or an aralkyl or heteroaralkyl group;
nisO, 1, or 2;
Xi is methylene, vinylene, or an NH or N(lower alkyl) group; and
X2 is methylene , or, when Xi is methylene or vinylene, X2 is methylene or a bond; or when X] is methylene, X2 is O, S, NH, or N(lower alkyl) or a bond;
Yi is methylene and Y2 is methylene, vinylene, ethylene, propylene, or a bond; or
Yi is a bond and Y2 is vinylene; or
Yi is ethylene and Y2 is O, S, NH, or N(lower alkyl);
Ari and Ar2 independently are unsubstituted or substituted aryl or heteroaryl groups, provided that Ari and Ar2 are not simultaneously phenyl; and
W is oxygen or sulfur. 2. A compound according to claim 1, wherein
Y] is methylene and Y2 is a bond, methylene, ethylene, or vinylene; or
Yi is ethylene and Y2 is O or S;
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and
X| is methylene and X2 is a bond, methylene, O, or S; or Xi is NH or N(lower alkyl) and X2 is methylene,
3. A compound according to claim 2, wherein
Zis
R
and W is oxygen.
4. A compound according to claim 3, wherein
Ari and Ar2 independently are mono- or disubstituted phenyl groups.
5. A compound according to claim 4, wherein
R is a hydrogen, a lower alkyl group, a cyclic organyl group, or a substituted or unsubstituted aralkyl or heteroaralkyl group;
n is 1;
Yi is methylene, Y2 is a bond, methylene, ethylene, or vinylene;
X] is methylene and X2 is a bond, or.
X| is NH or N(lower alkyl) and X2 is methylene; and
An and Ao are phenyl groups, independently p-substituted with groups selected from lower alkyl, lower alkoxy and halogen.
6. A compound according to claim 1, having a formula (II)

wherein RN is hydrogen, lower alkyl, aralkyl, or heteroaralkyl; ArL is selected from lower alkyl, lower alkoxy and halogen
130

ArR is selected from lower alkyl, lower alkoxy and halogen;
k is 1 or 2
and A" is a suitable anion. 7. The compound according to claim 1, wherein the compound is selected from the group
consisting of:
N-(l-(l-methylethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;
N-(l-(2)2-dimethylethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;
N-(l-pentylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;
N-(l-hexylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;
N-(l-cyclohexylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxy pheny lacetamid e;
N-(l-cyclopentyIpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxypheny 1 acetamide;
N-(l-cyclobutylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;
N-(l-cyclopropylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;
N-(l-(cyclopentylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxy phenylacetamide;
N-(l-(cyclobutylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;
N-(l-(cyclopropylmethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxy phenylacetamide;
N-(l-(2-hydroxyethyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-
methoxy pheny 1 acetamide;
N-(l-(3-hydroxypropyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-
methoxy phenylacetamide;
jV_((4-methylphenyl)methyl)-JV-(piperidin-4-yl)-N'-phenylmethylcarbamide; A -((4-methylphenyl)methyl)-A -(l-(2-methylpropyl)piperidin-4-yl)-W-phenylmethylcarbamide;
131

A -(l-((2-bromophenyl)niethyl)piperidin-4-yl)-JV-((4-methyIphenyl)methyl)-W-phenylmethylcarbarnide;
-(l-((4-hydroxy-3-methoxyphenyl)methyl)piperidin-4-yl)-M((4-methylphenyl)methyl)-W-phenylmethylcarbamide;
M-(l-((5-ethylthien-2-yl)methyl)piperidin-4-yl)-N-((4-niethylphenyl)rnethyl)-N)-phenylmethylcarbamide;
N-( 1 -(imidazol-2-ylmethyl)piperidin-4-y l)-N-((4-methylphenyl)rnethyl)-N' -phenylmethylcarbamide;
N (l-(cycIohexylmethyl)piperidm-4-yl)-N-((4-methylphenyl)methyl)-N'-phenylmethylcarbamide;
N-(l-((4-fluorophenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-N'-phenylmethylcarbamide;
N-((4-methylphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;
N-((4-methylphenyl)methyI)-N-(l-methylpiperidin-4-yl)-4-methoxyphenyIacetamide;
N-(l-ethylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;
N-((4-methylphcnyl)methyl)-N-(l-propylpiperidin-4-yl)-4-methoxyphenylacetamide;
N-(l-butylpiperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxyphenylacetamide;
N-(l-(3,3-tiimethylbutyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-methoxypheny lacetamide;
//-(l-(cyclohexylmethyl)piperidin-4-yl)-N-((4-methyIphenyl)methyl)-4-methoxyphenylacetamide;
N-((4-methylphenyl)methyl)-N-(l-(2-methylpropyl)piperidin-4-yl)-4-methoxyphenylacetamide;
N-((4-methylphenyl)methyl)-N-(l-((4-methylphenyl)methyl)piperidin-4-yl)-4-
methoxyphenylacetamide;
N-(l-((4-hydroxyphenyl)methyl)piperidin-4-yl)-N-((4-methylphenyl)methyl)-4-
methoxyphenylacetamide;
N-(l-((2-hydroxyphenyl)methyl)piperidin-4-yl)-N-((4-methyIphenyl)methyl)-4-
methoxyphenylacetamide;
N-(3-phenylpropyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;
N-(2-phenylethyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;
132

N-((2-methoxyphenyl)raethyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;
N-((2-chlorophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;
N-((3,4-di-methoxyphenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;
N-((4-fluorophenyI)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;
N-((234-di-chlorophenyl)methyl)-N-(piperidin-4-yl)-4-methoxyphenylacetamide;
N-((3-methylphenyl)methyl)TN-(piperidin-4-yl)-4-methoxyphenyIacetamide;
N-((3-bromophenyl)methyI)-N-(piperiidin-4-yl)-4-methoxyphenylacetamide;
N-( 1 -(phenylmethyl)piperidin-4-yl)-N-(3-phenyl-2-propen-l -yl)-4-methoxyphenylacetamide;
N-((4-methylphenyl)methyl)-N-(l-piperidin-4-yl)-phenylacetamide;
N-((4-methylphenyl)methyl)-N-(l-piperidin-4-yl)-3-phenylpropionamide;
N-((4-methylphenyl)methyl)-N-(l-piperidm-4-yl)-(phenylthio)acetamide;
N-((4-methylphenyl)methyl)-N-(l-piperidin-4-yl)-phenoxyacetamide;
N-((4-methylphenyl)methyl)-N-(l-piperidin-4-yI)-(4-chlorophenoxy)acetamide;
N-((4-methylphenyl)methyl)-N-(l-piperidin-4-yl)-3-methoxyphenylacetamide;
N-((4-methylphenyl)methyl)-N-(l-piperidin-4-yI)-4-fluorophenylacetamide;
N-((4-methylphenyl)methyl)-N-(l-piperidin-4-yl)-2,5-di-methoxyphenyiacetamide;
N-((4-methylphenyl)methyl)-N-(l-piperidin-4-yl)-4-chlorophenylacetamide;
N-((4-methyIphenyl)methyl)-N-(l-(phenylmethyl)pyrrolidin-3-yl)-N -phenylmethylcarbamide;
N-((4-methylphenyl)methyl)-N-(l-(phenyImethyl)pyrroIidin-3-yI)-4-methoxyphenylacetamide;
2-(4-methoxyphenyl)- -(4-methylbenzyl)-N-(piperidin-4-yl) acetamide;
2-(4-methoxyphenyl)-A -(4-methylbenzy\)-N-( 1 -methylpiperidin-4-y 1) acetamide;
2-(4-methoxypheny])-N-(4-methylbenzyl)-Ar-(l-ethylpiperidin-4-yl) acetamide;
2-(4-methoxyphenyI)-AT-(4-chlorbenzyl)-A -( 1 -ethylpiperidin-4-yl) acetamide.
2-(4-methoxyphenyl)-N-(4-chlorbenzy\)-N-( 1 -isopropylpiperidin-4-y 1) acetamide;
2-(4-methoxyphenyl)-A -(4-chlorobenzyl)-A'-(piperidin-4-yl) acetamide;
2-(4-methoxyphenyl)-7l/-(4-chlorbenzyl)-M-(l-cyclopentylpiperidin-4-yl) acetamide;
2-(4-methoxyphenyl)-A (4-chIorbenzyl)-W-( 1 -isopropylpiperidin-4-yI) acetamide;
2-(phenyl)- -(4-trifluoromethylbenzyl)-Ar-(l-methylpiperidin-4-yl) acetamide;
133

2-(4-fluorophenyl)- (4-trifluoromethylbenzyl)-//-(l-methylpiperidin-4-yI)acetamide;
2-(4-Methoxyphenyl)-A -(4-trifluoromethylbenzyl)-A'-(l-methyIpiperidin-4-yl) acetamide;
2-(4-Trifluoromethylphenyl)-W-(4-trifiuoromethyIbenzyl)-7 -(l-methylpiperidin-4-yl) acetamide;
2-(4-Fluorophenyl)- V-(4-fluorobenzy])-N-(l-methylpiperidin-4-yl) acetamide;
2-(4-Methoxyphenyl)-iV-(4-fluoroben2yl)-Ar-( 1 -methylpiperidin-4-y 1) acetamide;
2-(phenyl)-//-(4-fluorobenzyl)-7V-(l-methylpiperidin-4-yl) acetamide;
2-(4-Trifluoromethylphenyl)-7 -(4-fluorobenzyl)-AT-( 1 -methylpiperidin-4-yl) acetamide;
2-(44rifIuoromethylphenyl)-A -[4-(methoxycarbonyl)benzyl]-iV'-(l-methyIpiperidin-4-yl) acetamide;
2-PhenyI-A/-[4-(methoxycarbonyl)benzyi]-A'-(l-methylpiperidin-4-yl) acetamide;
2-(4-Chlorophenyl)-A [4-(methoxycarbonyl)benzyl]-A -(l-methylpiperidin-4-yl) acetamide;
2-(4-MethoxyphenyI)-A -[4-(methoxycarbonyl)benzyl]-7V-(l-methylpiperidin-4-yl) acetamide;
2-(4-trifluoromethylphenyl)-A/-[4-(methoxycarbonyl)benzyl]-7V-(l-methylpiperidin-4-yI)
acetamide;
2-Phenyl-A'-[4-(methoxycarbonyl)benzyl]-7V-(l-methylpiperidm-4-yl) acetamide; 2-(4-Chlorophenyl)-A -[4-(methoxycarbonyl)benzyl]-A -(l-methylpiperidin-4-yl)
acetamide;
2-(4-Methoxyphenyl)-A -[4-(methoxycarbonyI)benzyI]-M-(l-methylpiperidin-4-yl)
acetamide;
2-(4methoxyphenyl)-N-(4-methylbenzyl)-Ar-[l-(4-chloromethyl-2-thiazolylmethyl)
piperidin-4-yl] acetamide;
2-(4 methoxyphenyl)-A -(4-methylbenzyl)-A'-{ 1 -[3(1,3 dihydro-2H-benzimidazol-2-on-1 -
yl)propyl] piperidin-4-yl} acetamide;
2-(4-methoxyphenyl)-A -(2-4(fluorophenyl)ethyl)-A -(l-methylpiperidin-4-yl) acetamide;
2-(4-methoxyphenyl)-Ar-[2-(2)5-dimethoxyphenyl)ethyl]- -(l-methylpiperidin-4-yI) acetamide;
134

2-(4-methoxyphenyI)-iV-[2-(2s4-dichlorophenyI)ethyl]-A (l-methylpiperidin-4-yl) acetamide;
2-(4-methoxyphenyl)-A [2-(3-chlorophenyl)ethyll-//-(l-methylpiperidin-4-yl) acetamide;
2-(4-methoxyphenyl)- -[2-(4-methoxyphenyl)ethyl]-iV-(l-methylpiperidin-4-yl) acetamide;
2-(4-methoxyphenyI)-A [2-(3-fluorophetiyl)ethyI]-M(l-methylpiperidin-4-yI)
acetamide;
2-(4-ethoxyphenyl)-//-[2-(4-fluorophenethyl]-7V-(l-methylpiperidin-4-yl) acetamide;
2-(4-ethoxyphenyl)-7V-(4-fluorobenzyl)-N-(l-methylpiperidin-4-yl) acetamide;
2-(4-methoxyphenyl)-A/"-(4-methyIbenzyl)-//-{l [2-(2-hydroxyethoxy)ethyl]piperidin-4-yl} acetamide;
2-(4-methoxyphenyl)-A -(4-methylben:syI)-A'-[l-((2-chioro-5-thienyl)inethyl)piperidin-4-yl] acetamide;
2-(4-methoxyphcnyl)-Ar-(4-methylbenzyl)-A -tl-(2-(imida2olidinon-l-yl)ethyl)piperidin-4-yl] acetamide;
2"(4 methoxyphenyl)-7V-(4-memylbenzyl)-A -{l-[2-(214(lH,3H)quina2olinedion-3-yl)ethyl] piperidin-4-yl} acetamide;
2-(4-methoxyphenyI)-//-(4-methyibenzyl)- -{ 1 -[2-(l ,3-dioxolan-2-yl)ethyl]piperidin-4-yl} acetamide;
2-(4-methoxyphenyl)-Af-(4-methylberi2yl)-A {l-[2-(3-indolyl)ethyl] piperidin-4-yl}
acetamide;
2-(4-methoxyphenyl)-A/'-(4-methylberi2yl)-A -{I-[3-(l>2,4-triazol-l-yl)propyl]piperidin-4-
yl} acetamide;
2-(4-methoxyphenyl)-//-(4-methylberizyl)-A'r-[l-(5-benzofurazanylmethyl)piperidin-4-yl]
acetamide;
2-(4-methoxyphenyl)-Af 4-methylbenzyl)- -[l]thien-3-ylmethyl)
piperidin-4-yl] acetamide;
2-(4-methoxyphenyl)-iV-(4-methylbenzyl)-A -[l-(S-phenyl-l,2s4-oxadiazol-3-
ylmethyl)piperidin-4-yl] acetamide;
2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(l-isopropylpiperidin-4-yl)-acetamide;
135

2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(l-ethylpiperidin-4-yl)-acetamide;
2-Phenyl-N-(4-methylbenzyl)-N-(l-methylpiperidin-4-yl)-acetamide,2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(l-methylpiperidin-4-yl)-acetamide;
2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(l-cyclopentylpiperidin-4-yl)-acetamide;
2-(4-Fluorophenyl)-N-(4-methyIbenzyl)-N-(l-methylpiperidin-4-yl)-acetamide;
2-(4-Chlorophenyl)-N-(4-methyIben2yI)-N-(l-(2-hydroxyethyl)-piperidin-4-yl)-acetamide;
2-(4-Chlorophenyl)-N-(4-methylbenzyl)-N-(l-cyclobutylpiperidin-4-yl)-acetamide;
2-(4-MethoxyphenyI)-N-(4 methylben2yl)-N-(l-cyclobutylpiperidin-4-yl)-acetamide1
N-(4-Methylbenzyl)-N-(l-methylpiperidin-4-yl)-N'-benzyI-carbamide;
N-(4-Methylbenzy l)-N-( 1 -methy lpiperidin-4-y 1)-N '-pheny 1-carbamide;
N-Phenethyl-N-(l-methylpiperidin-4-yl)-N'-benzyl-carbamide;
2-Phenyl-N-(4-methoxybenzyI)-N-(l-methylpiperidin-4-yl)-acetamide;
2-(4-Trifluoromethylphenyl)-N-(4-niethoxybenzyI)-N-(l-methylp)peridin-4-yl)-acetamide;
2-(4-Fluorophenyl)-N-(4-methoxyben2yl)-N-(l-methyIpiperidin-4-yl)-acetamide;
2-(4-Methoxyphenyl)-N-(4-methoxybenzyl)-N-(l-raethylpiperidin-4-yl)-acetamide;
2-(4-Methylphenyl)-N-(4-chlorobenzyl)-N-(l-methylpiperidin-4-yl)-acetamide;
2-(4-Hydroxyphenyl)-N-(4-methylbenzyl)-N-(l-methylpiperidin-4-yl)-acetamide;
N-Phenethyl-N-(l-methylpiperidin-4-yl)-N'-phenyl-carbamide;
N-(3-Phenylpropyl)-N-(l-methylpiperidin-4-yl)-N'-benzyl-carbamide;
N-(3-PhenylpropyI)-N-(l-methylpiperidin-4-yl)-N'-phenyl-carbamide;
2-(4-Methoxyphenyl)-2,2-ethylene-N-(4-methylbenzyI)-N-(l-methylpiperidin-4-yl) acetamide;
2-(4-Methoxyphenyl)-N-alpha-methylbenzyl-N-(l-methylpiperidin-4-yI) acetamide;
2-(4-Methoxyphenyl) N-(4-methylbenzyl)-N-(3-tropen-4-yl) acetamide;
2-Phenyl-2-ethyl-N-(4-methylbenzyl)-N-(l-methylpiperidin-4-yl) acetamide;
N-Phenethyl-N-(4-methylbenzyl)-N-(l-methylpiperidin-4-yl)-amine;
2-(4-MethoxyphenyI)-N-(l-indanyl)-N-(l-methylpiperidin-4-yl) acetamide;
N-(4-Methylbenzyl)-N-(l-methylpiperidin-4-yl)-N'-(4-methoxybenzyl)-carbamide;
136

2-(3,4-dimethoxyphenyl)-N-(4-methylbenzyl)-N-(l-methyIpiperidin-4-yl)acetamide;
2-(3,4-Methylenedioxyphenyl)-N-(4-niethylbenzyl)-N-(l-methylpiperidin-4-yl) acetamide;
2-(4-Methoxyphenyl)-N-(4-methylbenzyl)-N-(l-t-butylpiperidin-4-yl)-acetatnide;
N-(4-Methylbenzyl)-N-(l-methylpiperidin-4-yl)-N'-phencthyl-carbamide;
N-Phenethyl-N-(l-methylpiperidin-4-yl)-N'-phenethy!-carbamide;
N-(4-Methylbenzyl)-N-(l-t-butylpiperidin-4-yl)-N'-(4-methoxybenzyl)-carbamide;
2-(4-Ethoxyphenyl)-N-(4-methylbenzyl)-N-(l-methylpiperidin-4-yl) acetamide;
2-(4-Butoxyphenyl)-N-(4-methylbenzyl)-N-(l-methylpiperidin-4-yI) acetamide;
2-(4-i-Propoxyphenyl)-N-(4-methylbenzyl)-N-(l-methylpiperidin-4-yl) acetamide;
2-(4-t-Butoxyphenyl)-N-(4-methylbenzyl)-N-(l-methylpiperidin-4-yl) acetamide;
2-(4-ButoxyphenyI)-N-(4-fluorobenzyl)-N-(l-metliylpiperidin-4-yl) acetamide;
2-(4-PropoxyphenyI)-N-(4-fiourobenzyl)-N-(l-methylpiperidin-4-yI) acetamide;
2-(4-i-Propoxyphenyl)-N-(4-fluorobenzyl)-N-(l-methylpiperidin-4-yl) acetamide; and
2-(4-t-Butoxyphenyl)-N-(4-fluorobenzyl)-N-(l-methylpiperidin-4-yl) acetamide. 8. A compound of formula (I)

in which
R is a hydrogen, a cyclic or straight-chained or branched acyclic organyl group, a lower hydroxyalkyl group, a lower aminoalkyl group, or an aralkyl or heteroaralkyl group; and nisO, 1, or 2;
137

Xj is methylene, vinylene, or an NH orN(lower alkyl) group; and X2 is methylene, or, when X] is methylene or vinylene, X2 is methylene Or a bond; or when Xi is methylene, X2 is O, S, NH, or N(lower alkyl) or a bond;
Yj is methylene and Y2 is methylene, vinylene, ethylene, propylene, or a bond; or
Yi is a bond and Y2 is vinylene; or
Yi is ethylene and Y2 is O, S, NH, or N(lower alkyl);
Ari and A12 are different unsubstituted or substituted aryl or heteroaryl groups; and
W is oxygen or sulfur.
9. A compound according to claim 8, wherein
Yj is methylene and Y2 is a bond, methylene, ethylene, or vinylene; or
Yi is ethylene and Y2 is 0 or S; and
Xi is methylene and X2 is a bond, methylene, O, or S; or
Xj is NH or N(lower alkyl) and X2 is a methylene .
10. A compound according to claim 9, wherein
Zis

and W is oxygen.
11. A compound according to claim 10, wherein
Ari and Ar2 independently are mono- or disubstituted phenyl groups.
12. A compound according to claim 11, wherein
R is a hydrogen, a lower alkyl group, a cyclic organyl group, or an, optionally substituted, alalkyl or heteroaralkyl group; nis 1;
Yi is methylene, Y2 is a bond, methylene, ethylene, or vinylene; X] is methylene and X2 is a bond, or Xi is NH or N(lower alkyl) and X2 is methylene; and
138

Ari and A12 are phenyl groups, independently p-substituted with groups selected from alkyl, lower alkoxy and halogen. 13. A compound according to claim 7, having a formula (II):

wherein RN is hydrogen, lower alkyl, aralkyl, or heteroaralkyl; Ar1' is selected from lower alkyl, lower alkoxy and halogen ArR is selected from lower alkyl, lower alkoxy and halogen; k is 1 or 2
and A" is a suitable anion. 14. A pharmaceutical composition comprising an effective amount of a compound of formula

139

R is a hydrogen, a cyclic or stral$it chained or branched acyclic organyl group, a
lower hydroxyalkyl group, a Uwver aminoalkyl group, or an aralkyl or heteroaralkyl
group; and
nfsO, 1, or2;
Xi is methylene, vinylene, or an NH or N(lower a&yl) cjoup; and
X2 is methylene, or, when Xi is methylene or vinylene, X2 is methylene or a bond;
or
when Xt is methylene, X2 is O, S, NH, or N(lower alkyl) or a bond;
YT is methylene and Y2 is methylene, vinylene, ethylene, propylene. or a bond; or
Y! Is a bond and Y2 Is vinylene; or
Yt Is ethylene and Y2 Is O, S, NH, or N(lower alkyl):
Ari and Ar2 independently are unsubstituted or substituted aryl or heteroaryi
groups, provided that Art and Ar2 are not simultaneously phenyl; and
W is oxygen or sulfur;
or a pharmaceutically acceptable salt ester orprodrug thereof, and
a pharmaceutica&y acceptable diluent or excipient,
15. The pharmaceutical compostiort of claim 14 for inhibiting the activity of
a monoamlrte receptor.
16. The pharmaceutical composition of claim 15 wherein the monoamlrte
receptor is a serotonin receptor.
17. The pharmaceutical composlion of daim 16 wherein the serotonin
receptor is the 5-HT2A subclass.
18. The pharmaceutical composition of claim 16 wherein the serotonin
receptor is in the central nervous system,
19. The pharmaceutical composition of claim 16 wherein me serotonin
receptor Is in die peripheral nervous system.
20. The pharmaceutical compostlon of claim 16 wherein the serotonin
receptor Is fn blood ceils or platelets.
21. The pharmaceutical composition of claim 16 wherein the serotonin
receptor Is mutated or modified.
140

22. The pharmaceutical composWon of claim 15 wherein die actMty Is
signaling activity.
23. The pharmaceutical composition of claim 15 wherein the activity is
constitutive.
24. The pharmaceutical composition of claim 15 wherein the activity is
associated wth serotonin receptor activation.
25. The pharmaceutical composition of claim 14 for inhbiting the activation
of a monoamlne receptor.
26. The pharmaceutical composition of claim 25 wherein the activation Is
by an agonistic agent.
27. The pharmaceutical composition of claim 26 wherein the agonistic
agent is exogenous.
28. The pharmaceutical composition of claim 26 wherein the agonistic
agent is endogenous.
29. The pharmaceutical composition of claim 25 wherein the activation is
constitutive.
30. . The pharmaceutical composition of claim 25 wherein the monoamlne
receptor is a serotonin receptor.
31. The pharmaceutical composition of claim 30 wherein the serotonin
receptor Is the 5-HT2A subclass.
32. The pharmaceutical composition of claim 30 wherein the serotonin
receptor is in the central nervous system.
33. The pharmaceutical composition of claim 30 wherein the serotonin
receptor Is In the peripheral nervous system.
34. The pharmaceutical composition of claim 30 wherein the serotonin
receptor is In blood cells or platelets.
35. The pharmaceutical composition of claim 30 wherein the serotonin
receptor Is mutated or modified.
141

36. The pharmaceutical composition of claim 14 for the treatment of a
disease condition associated with a monoamlne reactor.
37. The pharmaceutical composition of claim 36 wherein the disease
condition is selected from the group consisting of schizophrenia,
psychosis, migraine, hypertension, thrombosis, vasospasm, ischemia,
depression, anxiety, sleep disorders and appetite disorders.
38. The pharmaceutical composition of claim 36 wherein the disease
condition is associated with dysfunction of a monoamine receptor.
39. The pharmaceutical composition of claim 36 wherein the disease
condition is associated with activation of a monoamine receptor.
40. The pharmaceutical composition of claim 36 wherein the disease
condition is associated with increased activity of monoamine receptor.
41. The pharmaceutical composition of claim 36 wherein the monoamine
receptor is a serotonin receptor.
42. The pharmaceutical composition of claim 41 wherein the serotonin
receptor is the 5-HT2A subclass.
43. The pharmaceutical composition of claim 41 wherein the serotonin
receptor Is in the central nervous system.
44. The pharmaceutical composition of claim 41 wherein the serotonin
receptor is 'm peripheral nervous system.
45. The pharmaceutical composition of claim 41 wherein the serotonin
receptor is in blood ceils or platelets.
46. The pharmaceutical composition of claim 41 wherein the serotonin
receptor Is mutated or modified
47. The pharmaceiiical composition of claim 14 for the treatment of
schizophrenia.
48. The pharmaceutical composition of claim 14 for the treatement of a
migraine.
142

143
49. The pharmaceutical composition of claim 14 for the treatment of
psychosis.
50. The pharmaceutical composition of claim 14 for ttie Identification of a
genetic polymorphism in a subject, wherein the genetic polymorphism
predisposes the subject to being responsive to the compound.
51. The pharmaceutical composition of claim 50 wherein the ameliorated
disease condition is associated win the 5-HT class or 5-HT2A
subclass of monoaminergic receptors.
52. The pharmaceutical composition of claim 50, wherein the presence of
the polymorphism Indicates mat the subject Is suitable for treatment
with the pharmaceutical composition of claim 14.
53. The pharmaceutical composition of clain 14 for alleviating a side effect
of an antipsychotjc drug.
R is a hydrogen, a cyclic or straight-chained or branched acyclic organyl group, a lower hydroxyalkyl group, a lower aminoalkyl group, or an aralkyl or heteroaralkyl group;
nisO, 1, or 2;
X1 is methylene, vinylene, or an NH or N(lower alkyl) group; and
X2 is methylene , or, when X1 is methylene or vinylene, X2 is methylene or a bond; or when X1 is methylene, X2 is O, S, NH, or N(lower alkyl) or a bond;
Y1 is methylene and Y2 is methylene, vinylene, ethylene, propylene, or a bond; or
Y1 is a bond and Y2 is vinylene; or
Y1 is ethylene and Y2 is O, S, NH, or N(lower alkyl);
Ar1 and Ar2 independently are unsubstituted or substituted aryl or heteroaryl groups, provided that Ar1 and Ar2 are not simultaneously phenyl; and
W is oxygen or sulfur.

Documents:

in-pct-2002-01019-kol abstract.pdf

in-pct-2002-01019-kol assignment.pdf

in-pct-2002-01019-kol claims.pdf

in-pct-2002-01019-kol correspondence.pdf

in-pct-2002-01019-kol description(complete).pdf

in-pct-2002-01019-kol drawings.pdf

in-pct-2002-01019-kol form-1.pdf

in-pct-2002-01019-kol form-18.pdf

in-pct-2002-01019-kol form-2.pdf

in-pct-2002-01019-kol form-26.pdf

in-pct-2002-01019-kol form-3.pdf

in-pct-2002-01019-kol form-5.pdf

in-pct-2002-01019-kol letters patent.pdf

in-pct-2002-01019-kol reply f.e.r.pdf

IN-PCT-2002-1019-KOL-FORM 27.pdf

IN-PCT-2002-1019-KOL-FORM-27-1.pdf

in-pct-2002-1019-kol-granted-abstract.pdf

in-pct-2002-1019-kol-granted-assignment.pdf

in-pct-2002-1019-kol-granted-claims.pdf

in-pct-2002-1019-kol-granted-correspondence.pdf

in-pct-2002-1019-kol-granted-description (complete).pdf

in-pct-2002-1019-kol-granted-drawings.pdf

in-pct-2002-1019-kol-granted-form 1.pdf

in-pct-2002-1019-kol-granted-form 18.pdf

in-pct-2002-1019-kol-granted-form 2.pdf

in-pct-2002-1019-kol-granted-form 26.pdf

in-pct-2002-1019-kol-granted-form 3.pdf

in-pct-2002-1019-kol-granted-form 5.pdf

in-pct-2002-1019-kol-granted-letter patent.pdf

in-pct-2002-1019-kol-granted-reply to examination report.pdf

in-pct-2002-1019-kol-granted-specification.pdf

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Patent Number

213446

Indian Patent Application Number

IN/PCT/2002/1019/KOL

PG Journal Number

01/2008

Publication Date

04-Jan-2008

Grant Date

02-Jan-2008

Date of Filing

08-Aug-2002

Name of Patentee

ACADIA PHARMACEUTICALS, INC.,

Applicant Address

3911 SORRENTO VALLEY BOULEVARD, SAN DIEGO, CA 92121,

Inventors:

#	Inventor's Name	Inventor's Address
1	ANDERSSON CARL M	DAHLVANGVEJ 81.2 MF, DK-2600 GLOSTRUP,
2	CROSTON GLENN	7882 CAMINO TRANQUILO, SAN DIEGO CA 92122, USA.
3	HANSEN E.L.	DENMARK, FABRIKSPARKEN 58, DK-2600 GLOSTRUP;
4	ULDAM A.K.	DENMARK RAEVEHOJPARKEN 4, 2TV, DK-2800 LYNGBY.

PCT International Classification Number

A61K31/44,C07D211/00

PCT International Application Number

PCT/US01/07187

PCT International Filing date

2001-03-06

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/187,289	2000-03-06	U.S.A.