AMINOALKYLPYRROLIDINE SEROTONIN RECEPTOR LIGANDS AND COMPOSITIONS, THEIR PHARMACEUTICAL USES, AND METHODS FOR THEIR SYNTHESIS

Abstract: Novel aminoalkylpyrrolidine 5-HT7 receptor ligands, methods of preparing such ligands, intermediate compounds useful in the preparation of the receptor ligands, pharmaceutical compositions comprising the receptor ligands, and methods of treating sleep disorders, pain, depression, and schizophrenia employing the receptor ligands are disclosed. The receptor ligands have formula (1): wherein the formula variables are as defined herein, and pharmaceutically acceptable salts, solvates, active metabolites, or prodrugs thereof.

Description: TITLE AMINOALKYLPYRROLIDINE SEROTONIN RECEPTOR LIGANDS AND COMPOSITIONS, THEIR PHARMACEUTICAL USES, AND METHODS FOR THEIR SYNTHESIS BACKGROUND OF THE INVENTION Field ofthe Invention The invention relates to aminoalkylpyrrolidine 5-HT receptor ligands, methods of preparing such ligands and intermediates useful in such preparation, and pharmaceutical compositions and treatment methods employing the ligands. Description of the Field of the Invention The neurotransmitter serotonin (5-hydroxytryptamine, or "5-HT") has been the subject of substantial research, and abnormalities in serotonin processing are implicated in diverse disease states. Serotonin exerts its effects mainly in the central nervous, cardiovascular, and gastrointestinal systems through binding to a number of discrete 5-HT receptor types, which are assigned to classes and subclasses, e.g., 5-HTι, 5-HTIA, 5-HT 3 , etc., based on their pharmacological properties such as ligand binding profiles, coupling to second messenger systems, functional activity, and protein structures. The properties, functions, and pharmacology of these receptor subtypes have been reviewed by (a) Kennett, G. A., "Serotomn Receptors and Their Function," TOCRIS Review (http://www.tocris.com/serotonin.htm). published May, 1997; (b) Peroutka, S. J., 1994, "Molecular Biology of Serotonin (5-HT) Receptors, Synapse 18, 241-260; and (c) Eglen, R. et al., 1997, "The 5-HT 7 Receptor: Orphan Found, TiPs, April 1997 (Vol. 18), pp. 104-107. While the 5-HT 3 receptor forms a ligand-gated ion channel, most ofthe other serotonin receptor types are linked to increases or decreases of cyclic AMP production. Receptors ofthe 5-HTι family are negatively coupled to adenylyl cyclase through guanine-nucleotide-binding (G) proteins; those ofthe 5-HT 2 family stimulate phospholipase C. The 5-HT , 5-HT 6 , and 5-HT 7 receptors stimulate adenylyl cyclase via G s coupling. Cloning and function of these receptor types are reviewed by Lucas, J. J. and Hen, R, 1995, "New Players in the 5-HT Receptor Field: Genes and Knockouts," TiPS, July, 1995 (Vol. 16) pp. 246-252. The 5-HT 7 receptors form a distinct family of G-protein coupled receptors positively coupled to adenylyl cyclase. The 5-HT 7 receptor has been cloned from rat, mouse, guinea pig, and human cDNA. Despite a high degree of inter-species homology (95%), the receptor has low homology (<40%) with other 5-HT receptor subtypes. The pharmacological profile ofthe receptor is also consistent across species and is characterized by a high affinity for the 5-HTι agonists, 5-carboxyamidotryptamine (5-CT), 5-HT, and 5-methoxytryptamine. 5-HT receptors are expressed in hypothalamus, hippocampus, thalamus, and other limbic areas and may be involved in regulation of circadian rhythms. 5-HT receptors have high affinity for certain antidepressant and antipsychotic drugs, including pimozide, an antipsychotic used to treat Tourette syndrome, and the atypical antipsychotic drug, clozapine. Biochemical and pharmacologic studies have pointed to the role of 5-HT in the following conditions: • depression (Sleight, A. J., et al., 1995, "Identification of 5-Hydroxytryptamine 7 Receptor Binding Sites in Rat Hypothalamus: Sensitivity to Chronic Antidepressant Treatment," Molecular Pharmacol. 47:99-103; Shimizu, M. et al., 1996, "Chronic Antidepressant Exposure Enhances 5-Hydroxytryptamine 7 Receptor-Mediated Cyclic Adenosine Monophosphate Accumulation in Rat Frontocortical Astrocytes," J. Pharmacol. Exper. Therapeutics 279 :1551-1558); • psychosis (Roth, B. L. et al., 1994, "Binding of Typical and Atypical Antipsychotic Agents to 5-Hydroxytryptamine-6 and 5-Hydroxytryptamine-7 Receptors," J. Pharmacol. Exper. Therapeutics 268: 1403-1410); • cardiovascular disease (Gushing, D. J. et al., 1996, "LY215840, a High-Affinity 5-HT 7 Receptor Ligand, Blocks Serotonin-induced Relaxation in Canine Coronary Artery," J. Pharmacol. Exper. Ther. 277:1560-1566; Terron, J., 1998, "The Relaxant 5-HT Receptor in the Dog Coronary Artery Smooth Muscle: Pharmacological Resemblance to the Cloned 5-ht 7 Receptor Subtype," Proc. West. Pharmacol. Soc. 41:129-30); and • affective behaviors and modulation of sensory information (To, Z. et al., 1995, "Characterization and Distribution of Putative 5-ht 7 Receptors in Guinea Pig Brains," Brit. J. Pharmacol. 115:107-116). At present, very few selective ligands for 5-HT 7 receptors have been reported (Forbes, I. T. et al., "(R)-3-N-Dimethyl-N[l-methyl-3(4-methyl-piperidin-l-yl)propyl]benzene- sulfonamide: The First Selective 5-HT Receptor Antagonist," J. Med. Chem. 41, 655- 657 (1998); Kikuchi et al., "Tetrahydrobenzindoles: Selective Antagonists of the 5-HT 7 Receptor," J. Med. Chem. 42, 533-535 (1999); Lovell et al., "A Novel Potent, and Selective 5-HT 7 Antagonist: (R)-3-(2-(2-(4-Methylρiperidinyl-l-yl)-ethyl)pyrrolidine-l- sulfonyl)phenol (SB-269970)," J. Med. Chem. 43, 342-345, (2000); "Functional Characteristics ofthe Human Cloned 5-HT 7 Receptor (long form) Antagonist Profile of SB-258719," British J. Pharm, 124, 1300-1306 (1998); Proos Science (abstracts) of Asai et al., 72 nd Annual Meet Jpn. Pharmacol. Soc. (March 23-25, Sapporo), 1999 - Abst. P- 496, Needham et al., Eur. Neuropsychopharmacol. [12 th Cong. Eur. Coll. Neuropsychopharmacol. (Sept. 21-25, London)] 1999, 9, (Supρl.5) - Abst. P.2.021; WO 99/31062 and WO/00/0472). The 5-HT receptor may be involved in the pathophysiology of sleep disorders, depression, pain, and schizophrenia. Potent and selective ligands active at 5-HT 7 receptors are needed to provide novel pharmaceutical approaches to treatment of these disorders. SUMMARY OF THE INVENTION This invention is directed to compounds represented by Formula I: I wherein: 1, m, and n are independently 1 or 2; R 1 is lower alkyl; R 2 and R 3 may be the same or different and are independently selected from substituted or unsubstituted aryl, heteroaryl, arylalkyl, heteroarylalkyl, and cycloalkenyl, provided that when R 1 is ethyl and 1, m and n are each 1, R 2 and R 3 are not both unsubstituted phenyl. These compounds are potent antagonists for 5-HT 7 receptors and show selectivity for 5-HT 7 receptors over other serotonin receptor subtypes and over other receptors such as D 2 dopamine, αi adrenergic (OC JA , o , OC ID ), 012 adrenergic (α A , «2 B . «2c). hGalanin, opiate (5, μ, K), GABA-B, and muscarinic (Mi, M 2 , M 3 , M 4 , M 5 ). The compounds have potential utility in the treatment of pain, depression, sleep disorders, and schizophrenia. The invention also encompasses pharmaceutically acceptable salts, solvates, active metabolites, or prodrugs comprising the compounds of Formula I, and includes pharmaceutical compositions comprising the compounds of Formula I as well as pharmaceutically acceptable salts, solvates, active metabolites, or prodrugs thereof. The invention is also related to a method of treatment of a patient in need thereof with a pharmaceutical composition comprising an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, active metabolite, or prodrug thereof. The invention is also directed to methods of preparation ofthe compounds represented by Formula I by reductive animation of aminoalkylpyrrolidines with aldehydes. The invention also comprises intermediates and pharmaceutically acceptable salts thereof, useful in the synthesis of compounds of Formula I. DETAILED DESCRIPTION OF THE INVENTION As used herein, the term "alkyl" represents a straight- or branched-chain saturated hydrocarbon group, containing 1 to 20 carbon atoms, which may be unsubstituted or substituted by one or more ofthe substituents described below. Exemplary alkyl groups include, but are not limited to methyl (Me), ethyl (Et), propyl, isopropyl, butyl, isobutyl, t-butyl^ and the like. The term Alower alkyl© refers to an alkyl group having from 1 to 6 carbon atoms in its chain. "Cycloalkyl" represents a group comprising a saturated monocyclic, bicyclic, or tricyclic hydrocarbon containing from 3 to 14 carbon atoms that may be a mono- or poly-carbocyclic ring, preferably having 5-14 ring carbon atoms. Exemplary cycloalkyl groups include monocyclic rings having from 3-7, preferably 3-6, carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Exemplary bicyclic and tricyclic cycloalkyls include groups having from 10-14 carbon atoms. Illustrative examples of cycloalkyl groups include the following: "Cycloalkenyl" represents a group comprising a partially saturated, non-aromatic monocyclic, bicyclic, or tricyclic hydrocarbon containing from 3 to 14 carbon atoms that may be a mono- or poly-carbocyclic ring, preferably having 5-14 ring carbon atoms. Exemplary cycloalkenyl groups include monocyclic rings having from 3-7, preferably 3-6, carbon atoms, such as cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl and the like. Illustrative examples of cycloalkenyl groups include the following: "Heterocycloalkyl" represents a group comprising a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or partially unsaturated, containing 3 to 18 ring atoms, which includes 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, and which may be unsubstituted or substituted by one or more ofthe substituents described below. Illustrative examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-2H-l,4-thiazinyl, tetrahydrofuryl, dihydrofuryl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, azabicylo[3.2.1]octyl, azabicylo[3.3.1 ]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2. l]heptyl, 1,5,9-triazacyclododecyl, and the like. Illustrative examples of heterocycloalkyl groups include the following moieties: "Aryl® represents a group comprising an aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing from 6 to 18 carbon ring atoms, which may be unsubstituted or substituted by one or more ofthe substituents described below. Illustrative examples of aryl groups include the following: "Heteroaryl® represents a group comprising an aromatic monovalent monocyclic, bicyclic, or tricyclic radical, containing 5 to 18 ring atoms, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, which may be unsubstituted or substituted by one or more ofthe substituents described below. Illustrative examples of heteroaryl groups include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzo[b]thienyl, naphtho[2,3-b]tbianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxyalinyl, quinzolinyl, benzothiazolyl, benzimidazolyl, tetrahydroquinolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, and phenoxazinyl. Further examples of heteroaryl groups include the following moieties: As indicated herein, the alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl groups may be optionally substituted by one or more substituents. The term "optionally substituted" is intended to expressly indicate that the specified group is unsubstituted or substituted by one or more suitable substituents. The term "substituent" or "suitable substituent" is intended to mean any suitable substituent that may be recognized or selected, such as through routine testing, by those skilled in the art. Exemplary Asuitable substituents® that may be present on any ofthe above alkyl, aryl, cycloalkyl, heterocycloalkyl or heteroaryl groups are described herein and include alkyl (except for alkyl), aryl, cycloalkyl, heterocycloalkyl, heteroaryl, nitro, amino, cyano, halo, hydroxyl, alkoxy, alkylenedioxy, aryloxy, cycloalkoxy, heterocycloalkoxy, heteroaryloxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, arylcarbonyl, arylcarbonyloxy, aryloxycarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyloxy, cycloalkyoxycarbonyl, heteroarylcarbonyl, heteroarylcarbonyloxy, heteroaryloxycarbonyl, heterocycloalkylcarbonyl, heterocycloalkylcarbonyloxy, heterocycloalkyoxycarbonyl, carboxyl, carbamoyl, formyl, keto (oxo), thioketo, sulfo, alkylamino, cycloalkylamino, arylamino, heterocycloalkylamino, heteroarylamino, dialkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, heterocycloalkylaminocarbonyl, heteroarylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, cycloalkylaminothiocarbonyl, arylaminothiocarbonyl, heterocycloalkylaminothiocarbonyl, heteroarylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfenyl, arylsulfenyl, alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heterocycloalkylcarbonylamino, heteroarylcarbonylamino, alkylthiocarbonylamino, cycloalkylthiocarbonylamino, arylthiocarbonylamino, heterocycloalkylthiocarbonylamino, heteroarylt ocarbonylamino, alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonylamino, arylsulfonylamino, mercapto, alkylthio, arylthio, heteroarylthio, wherein any ofthe alkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, heteroaryl moieties present in the above substituents may be further substituted. The alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl moieties of any ofthe above substituents may be optionally substituted by one or more of alkyl (except for alkyl), haloalkyl, aryl, nitro, amino, alkylamino, dialkylamino, halo, hydroxyl, alkoxy, haloalkoxy, aryloxy, mercapto, alkylthio or arylthio groups. Preferred "suitable substituents" in the compounds of this invention include lower alkyl, substituted or unsubstituted aryl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, halo, hydroxyl, alkoxy, aryloxy, cycloalkoxy, heteroaryloxy, nitro, alkylthio, arylthio and aminocarboxyl. The terms "halogen" and "halo" represent chloro, fluoro, bromo or iodo substituents. AHeterocycle® is intended to mean a heteroaryl or heterocycloalkyl group. "Acyl® is intended to mean a -C(O)-R radical, wherein R is an alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group. "Acyloxy® is intended to mean an -OC(O)-R radical, wherein R is an alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group. AThioacyl® is intended to mean a -C(S)-R radical, wherein R is an alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroaryl group. ASulfonyl® is intended to mean an -SO 2 - biradical. ASulfenyl® is intended to mean an -SO- biradical. ASulfo® is intended to mean an -SO 2 H radical. AHydroxy® is intended to mean the radical -OH. AAmine® or Aamino® is intended to mean the radical -NH 2 . AAlkylamino® is intended to mean the radical -NHRa, wherein R a is an alkyl group. ADialkylamino® is intended to mean the radical -NR a Rb, wherein R a and Rb are each independently an alkyl group, and is intended to include heterocycloalkyl groups, wherein Ra and Rb, taken together, form a heterocyclic ring that includes the amine nitrogen. AAikoxy® is intended to mean the radical -ORg, wherein Ra is an alkyl group. Exemplary alkoxy groups include methoxy, ethoxy, propoxy, and the like. ALower alkoxy® groups have alkyl moieties having from 1 to 4 carbons. AAlkylenedioxy® is intended to mean the divalent radical -ORgO- which is bonded to adjacent atoms (e.g., adjacent atoms on a phenyl or naphthyl ring) , wherein R a is a lower alkyl group. AAlkoxycarbonyl® is intended to mean the radical -C(O)OR a , wherein Ra is an alkyl group. AAlkylsulfonyl® is intended to mean the radical -SO 2 R a , wherein Ra is an alkyl group. "Alkylaminocarbonyl" is intended to mean the radical -C(O)NHRa, wherein R a is an alkyl group. ADialkylaminocarbonyl" is intended to mean the radical -C(O)NR a Rb. wherein Ra and Rb are each independently an alkyl group. "Mercapto" is intended to mean the radical -SH. "Alkylthio" is intended to mean the radical -SR a , wherein R a is an alkyl group. "Carboxyl" is intended to mean the radical -C(O)OH. AKeto® or Aoxo® is intended to mean the radical =O. AThioketo® is intended to mean the radical =S. "Carbamoyl" is intended to mean the radical -C(O)NH 2 . ACycloalkylalkyl® is intended to mean the radical Balkyl-cycloalkyl, wherein alkyl and cycloalkyl are defined as above, and is represented by the bonding arrangement present in the groups -CH -cyclohexane or -CH 2 -cyclohexene. AArylalkyl® is intended to mean the radical Balkylaryl, wherein the alkyl and aryl moieties thereof are defined as above (e.g., wherein "alkyl" represents a straight- or branched-chain saturated hydrocarbon group, containing 1 to 20 carbon atoms, which may be unsubstituted or substituted by one or more substituents) and is represented by the bonding arrangement present in a benzyl group. "Heteroarylalkyl" is intended to mean the radical Balkyl-heteroaryl, wherein the alkyl and heteroaryl moieties thereof are defined as above and is represented by the bonding arrangement present in an α-methylfuranyl group. AAminocarbonylalkyl® is intended to mean the radical BalkylC(O) NH 2 and is represented by the bonding arrangement present in the group -CH 2 CH 2 C(O)NH 2 . AAlkylaminocarbonylalkyl® is intended to mean the radical BalkylC(O)NHR a , wherein R a is an alkyl group and is represented by the bonding arrangement present in the group -CH 2 CH 2 C(O)NHCH 3 . AAlkylcarbonylaminoalkyl is intended to mean the radical BalkylNHC(O)-alkyl and is represented by the bonding arrangement present in the group -CH 2 NHC(O)CH 3 . ADialkylaminocarbonylalkyl® is intended to mean the radical BalkylC(O)NR a R b , wherein R a and Rb are each independently an alkyl group. "Aryloxy" is intended to mean the radical -ORc, wherein Re is an aryl group. "Heteroaryloxy" is intended to mean the radical -OR < _, wherein Rd is a heteroaryl group. "Arylthio" is intended to mean the radical -SRc, wherein Re is an aryl group. "Heteroarylthio" is intended to mean the radical -SRd, wherein R_ is a heteroaryl group. If the substituents themselves are not compatible with the synthetic methods of this invention, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions used in these methods. The protecting group may be removed at a suitable point in the reaction sequence ofthe method to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiley & Sons, NY (1999), which is incorporated herein by reference in its entirety. In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used in the methods of this invention. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful in an intermediate compound in the methods of this invention or is a desired substituent in a target compound. If an inventive compound is a base, a desired salt may be prepared by any suitable method known in the art, including treatment ofthe free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like. The inventive compounds may exist as single stereoisomers and/or diastereomers, racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, diastereomers, racemates, and mixtures thereof are intended to be encompassed within the broad scope ofthe present invention. Where the stereochemistry ofthe chiral carbons present in the chemical structures illustrated herein is not specified, the chemical structure is intended to encompass compounds containing either stereoisomer of each chiral carbon. Preferably, however, the inventive compounds are used in optically pure form. When used describe a particular compound, the term "optically pure" is used herein to that the compound is substantially enantiomerically or diastereomerically pure. Compounds that are substantially enatiomerically pure contain at least 90% ofa single isomer and preferably contain at least 95% ofa single isomer. Compounds that are substantially diastereomerically pure contain at least 90% ofa single isomer of each chiral carbon center present in the diastereomer, and preferably contain at least 95% ofa single isomer of each chiral carbon. More preferably, the optically active compounds in this invention contain at least 97.5% ofa single isomer and most preferably contain at least 99% ofa single isomer. Compounds identified herein as single stereoisomers are meant to describe compounds that are present in a form that contains at least 90% ofa single isomer. The term Aracemic® or Aracemic mixture® refers to a mixture of equal amounts of enantiomeric compounds, which encompasses mixtures of enantiomers and mixtures of enantiomeric diastereomers. Preferred embodiments ofthe compounds of this invention are represented by the Formula: wherein R and R are as defined above. Exemplary R 2 and R 3 groups include, but are not limited to substituted or unsubstituted benzyl, methyldibenzofbranyl, cyclohexenyl, fluorenyl, phenyl, naphthyl, furanyl, benzofuranyl, benzothienyl, dibenzofuranyl and the like, wherein any alkyl (-CH 2 -), alkenyl (~CH=) or aryl (-CH=) moiety thereof may be independently substituted by one or more suitable substitutents. Exemplary groups suitable as substitutents for the above-described substituted R 2 and R 3 groups (e.g., substituted benzyl, etc.) include, but are not limited to, lower alkyl, substituted or unsubstituted aryl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, halo, hydroxyl, alkoxy, aryloxy, cycloalkoxy, heteroaryloxy, nitro, alkylthio, arylthio and aminocarboxyl. In especially preferred embodiments, the absolute stereochemistry at the point of attachment ofthe side-chain to the pyrrolidine ring is as shown in Formula I-b: Preferably, in the compounds of this invention represented by Formulas I, I-a, or I-b, R 2 and R 3 are substituted phenyl which may be independently substituted by one or more lower alkyl, halo, hydroxyl, alkoxy, nitro, alkylthio, or aminocarbonyl. This invention also encompasses methods for preparing the compounds shown above. The compounds may be prepared by reductive amination comprising treatment of an aminoalkylpyrrolidine with aldehydes, under conventional reducing conditions. The reductive amination reactions may be conducted in a stepwise manner, for example: R 3 -(CH 2 ) q -CHO where 1, m, R , R , and R have the meanings given above, p is equal to (1-1), and q is equal to (m-1). However, when R 2 and R 3 are the same, the reductive amination may be conducted in a single step: The compounds may also be prepared by amino-alkyϊation comprising treatment ofthe aminoalkylpyrrolidine with a suitable alkylating agent under conventional conditions. Symmetrically substituted compounds, wherein the added substituents on nitrogen are the same, may be prepared by conducting the alkylation ofthe aminoalkylpyrrolidine in a single step: where 1, n, R and R have the meanings given above and X is a suitable halogen or leaving group. Unsymmetrically substituted compounds may be prepared by treatment of an alkylated aminoalkylpyrrolidine (e.g., which may be prepared as described above by reductive amination of an aminoalkylpyrrolidine) with a suitable alkylating agent, for example: R 3 (CH 2 ) m X where 1, m, n, R 1 , R 2 , and R 3 have the meanings given above, and X is a suitable halogen or leaving group. The invention is also directed to intermediate aminoalkylpyrrolidine compounds and pharmaceutically acceptable salts thereof which are useful in the synthesis of compounds of Formula I. Such intermediates are represented by Formula II: wherein 1, n, R , and R are defined as above, and may be prepared according to the general method shown above. The aminoalkylpyrrolidine intermediates used therein may be prepared by the following general method: In the first step (Step A) of this method, a hydroxyalkylpyrrolidine is N-protected with protecting group "P" using conventional techniques. The hydroxy moiety is converted in Step B into a leaving group. Suitable leaving groups include tosylate, mesylate, triflate, halo, and the like. The conversion o the hydroxyl moiety into these suitable leaving groups may be conducted using conventional procedures. The leaving group may be displaced in Step C using sodium cyanide, or another suitable a nitrogen- containing nucleophilic reagent to provide a cyanoalkylpyrrolidine. Reduction ofthe cyano moiety provides the aminoalkylpyrrolidine useful in the method of this invention. Preferably, the protecting group is selected such that during Step D, the protecting group is converted to a suitable R 1 group. Alternatively, R 1 may be directly introduced in Step A or may be introduced during Step D (wherein Step D may comprise two or more steps to affect removal ofthe protecting group, introduction of R 1 and reduction ofthe cyano moiety). Alternatively, compounds and intermediates having varying spacer lengths (n is 1 or 2) may be prepared by the following general method: wherein s is 0 or 1, R 2' and R 3' represent -(CH 2 )-R 2 and -(CH 2 )-R 3 , respectively, R 1 is defined as above or is a precursor or protecting group that can be converted to a lower alkyl group during reaction with a reducing agent. In preferred embodiments of this invention, the intermediate compounds, or a pharmaceutically acceptable salt thereof, possess a structure that may be represented by Formula Il-a: wherein R 2 is defined as above. In especially preferred embodiments, the intermediates compounds, or a pharmaceutically acceptable salt thereof, have Formula Il-b: wherein R 2 is defined as above. Exemplary compounds ofthe invention include: and the pharmaceutically acceptable salts, solvates, active metabolites, or prodrugs thereof. Particularly preferred compounds of this invention include: and the pharmaceutically acceptable salts, solvates, active metabolites, or prodrugs thereof. Exemplary intermediate compounds useful in the preparation ofthe compounds of this invention include: and pharmaceutically acceptable salts thereof. Particularly preferred intermediate compounds useful in the preparation ofthe compounds of this invention include: and pharmaceutically acceptable salts thereof. The compounds ofthe invention interact with 5-HT receptors and show selectivity for 5-HT receptors. The 5-HT receptor binding properties ofthe compounds are identified by competitive radioligand binding assays wherein membranes prepared from transfected cells expressing the 5-HT receptor subtype of interest. "Binding constants" refers herein to Kj values measured by inhibition ofthe binding of radiolabelled ligands that are selective for the 5-HT receptor type being studied. For 5- HT 7 receptors, Kj values are determined by measuring the inhibition of 5- carboxamidotryptamine (5-CT) binding, wherein 5-HT receptors were incubated with the radiolabelled high affinity ligand, 5-carboxamidotryptamine ([ 3 H]5-CT), in the presence and absence ofthe compounds ofthe invention, at varying concentrations. The compounds ofthe invention have high binding affinity for serotonin receptors as measured by dissociation constant Kj. The compounds ofthe present invention preferably show 5-HT 7 receptor binding characterized by Kj values less than about 100 nM, more preferably by Kj values less than about 10 nM, and most preferably by Kj values less than about 1 nM. "Selectivity" for receptor type, in the context of this invention, refers to the ratio of binding constants for the two receptor types being compared. For example, if a hypothetical ligand shows Kj of 100 nM for 5-HT receptors and 0.5 nM for 5-HT 7 receptors, its selectivity for 5-HT 7 over 5-HT 4 receptors is 200-fold. The compounds ofthe present invention preferably show selectivity for 5- HT 7 receptors over other serotonin receptor subtypes of greater than about 100. The compounds ofthe present invention also preferably show selectivity for 5-HT receptors over other receptor types, such as dopamine D2, of greater than about 100. The compounds ofthe invention interact with 5-HT receptors and act as antagonists at that receptor. The agonist or antagonist properties ofthe compounds were measured by the ability ofthe compounds to increase basal or to inhibit 5-HT-stimulated c-AMP formation in transfected cells expressing 5-HT 7 receptors. The biological activity ofthe inventive compounds is determined by assays that have been devised to serve as animal models for various human medical conditions. Many such assays are known to skilled practitioners. Examples of such assays include, e.g.: • the prokinetic assay, which is an in vivo method of determining the extent the test compound affects the rate of gastric emptying of a test meal in rats; • the anxiolytic behavior assay, which measures the extent to which the test compound can ameliorate ofthe symptoms of natural anxiety in mice when exposed to a novel, brightly lighted environment; • the withdrawal anxiety assay, which measures the extent to which the test compound can ameliorate ofthe symptoms in mice caused by withdrawal from addictive substances by measuring the extent the drug affects the anxiety that occurs in mice after chronically treating with an addictive substance and then abruptly ceasing the treatments; • the cognitive enhancement assay, which measures the extent the test compound can alleviate the cognitive deficit induced in rats by administration of atropine to rats. These assays are described in U.S. Patent No. 5,763,468, the disclosure of which is hereby incorporated herein by reference. The invention encompasses pharmaceutical compositions comprising compounds of Formula I, or a pharmaceutically acceptable salt, solvate, active metabolite, or prodrug thereof, and treatment of a patient in need thereof with a pharmaceutical composition comprising an effective amount of a Formula I compound, or a pharmaceutically acceptable salt, solvate, active metabolite, or prodrug thereof. As 5-HT receptor ligands, the compounds ofthe invention are useful for treating conditions which can be ameliorated by interaction with 5-HT 7 receptors. Such conditions include sleep disorders, depression, pain, and schizophrenia. A Aprodrug" is intended to mean a compound that is converted under physiological conditions or by solvolysis or metabolically to a specified compound that is pharmaceutically active. A "pharmaceutically active metabolite" is intended to mean a pharmacologically active compound produced through metabolism in the body ofa specified compound. Prodrugs and active metabolites of compounds of Formulas I-V may be determined using techniques known in the art, for example, through metabolic studies. See, e.g., ADesign of Prodrugs,® (Bundgaard, ed.), 1985, Elsevier Publishers BN., Amsterdam, The Netherlands. A "pharmaceutically acceptable salt" is intended to mean a salt that retains the biological effectiveness ofthe free acids and bases ofa specified compound and that is not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfϊtes, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-l,4-dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycollates, tartrates, methane-sulfonates, propanesulfonates, naphthalene- 1 -sulfonates, naphthalene-2-sulfonates, and mandelates. A "solvate" is intended to mean a pharmaceutically acceptable solvate form ofa specified compound that retains the biological effectiveness of such compound. Examples of solvates include compounds of the invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine. In the case of compounds, salts, or solvates that are solids, it is understood by those skilled in the art that the inventive compounds, salts, and solvates may exist in different crystal forms, all of which are intended to be within the scope ofthe present invention and specified formulas. Administration ofthe compounds ofthe invention and their pharmaceutically acceptable prodrugs, salts, active metabolites, and solvates may be performed according to any ofthe accepted modes of administration available to those skilled in the art. Illustrative examples of suitable modes of administration include oral, systemic (e.g., transdermal, intranasal, or by suppository), parenteral (e.g., intramuscular, intravenous, or subcutaneous), topical, transdermal and rectal. An inventive compound or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof may be administered as a pharmaceutical composition in any pharmaceutical form recognizable to the skilled artisan as being suitable. Suitable pharmaceutical forms include solid, semisolid, liquid, or lyophilized formulations, such as tablets, powders, capsules, suppositories, suspensions, liposomes, and aerosols. Pharmaceutical compositions ofthe invention may also include suitable excipients, diluents, vehicles, and carriers, as well as other pharmaceutically active agents, depending upon the intended use or mode of administration. Acceptable methods of preparing suitable pharmaceutical forms ofthe pharmaceutical compositions are known or may be routinely determined by those skilled in the art. For example, pharmaceutical preparations may be prepared following conventional techniques ofthe pharmaceutical chemist involving steps such as mixing, granulating, and compressing when necessary for tablet forms, or mixing, filling, and dissolving the ingredients as appropriate, to give the desired products for oral, parenteral, topical, intravaginal, intranasal, intrabronchial, intraocular, intraaural, and/or rectal administration. Solid or liquid pharmaceutically acceptable carriers, diluents, vehicles, or excipients may be employed in the pharmaceutical compositions. Illustrative solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, pectin, acacia, magnesium stearate, and stearic acid. Illustrative liquid carriers include syrup, peanut oil, olive oil, saline solution, and water. The carrier or diluent may include a suitable prolonged-release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. When a liquid carrier is used, the preparation may be in the form ofa syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid (e.g., solution), or a nonaqueous or aqueous liquid suspension. The compounds (active ingredients) may be formulated into solid oral dosage forms which may contain, but are not limited to, the following inactive ingredients: diluents (i.e., lactose, corn starch, microcrystalline cellulose), binders (i.e., povidone, hydroxypropyl methylcellulose), disintegrants (i.e., crospovidone, croscarmellose sodium), lubricants (i.e., magnesium stearate, stearic acid), and colorants (FD&C lakes or dyes). Alternatively, the compounds may be formulated into other oral dosage forms including liquids, suspensions, emulsions, or soft gelatin capsules, with each dosage form having a unique set of ingredients. A dose ofthe pharmaceutical composition contains at least a therapeutically 5 effective amount ofthe active compound or agent (i.e., an inventive compound or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof), and preferably is made up of one or more pharmaceutical dosage units. The selected dose may be administered to a mammal, for example, a human patient, in need of treatment mediated by inhibition of serotonin agonist activity, by any known or suitable method of o administering the dose, including topically, for example, as an ointment or cream; orally; rectally, for example, as a suppository; parenterally by injection; or continuously by intravaginal, intranasal, intrabronchial, intraaural, or intraocular infusion. A "therapeutically effective amount" is intended to mean the amount of an inventive compound that, when administered to a mammal in need thereof, is sufficient to effect s treatment for disease conditions alleviated by the inhibition ofthe action of serotonin at the 5-HT receptor. The amount ofa given compound ofthe invention that will be therapeutically effective will vary depending upon factors such as the particular compound, the disease condition and the severity thereof, the age and health ofthe subject in need of treatment, which may be routinely determined by skilled artisans. o The Examples that follow are intended as illustrations of certain preferred embodiments ofthe invention, and no limitation ofthe invention is implied. It is considered within the skill of one in the art to recognize that the chemical reactions described herein are generally applicable to prepare other compounds encompassed within the scope ofthe invention, or that such compounds may be prepared by 5 appropriate modification of these illustrated reactions or use of analogous or other conventional synthetic methods known in the art, without undue experimentation (e.g., by use of appropriate blocking or protecting groups, by substituting other conventional reagents, or by routine modifications of reaction conditions). Although certain protecting groups are exemplified in the syntheses described below, it is understood that other o suitable protecting groups may be used, depending on the functionality present in the desired compound and intermediates required for the preparation thereof, and depending on the particular synthesis method employed In each ofthe synthetic procedures described herein, unless otherwise indicated, the starting materials are known, available, or may be readily prepared from known starting materials, all temperatures are set forth in degrees Celsius, and all parts and percentages are by weight. Reagents were purchased from commercial suppliers, such as Aldrich Chemical Company or Lancaster Synthesis Ltd. Reagents and solvents were commercial grades and were used as supplied. 1H-NMR (300 MHz) spectra were measured in CDCI 3 solutions unless otherwise indicated and were determined on a Bruker DRX-300 instrument using XWIN NMR Version 1.2 operating software. Chemical shifts are reported in parts per million (ppm) downfield from tetramethylsilane as the internal standard, and coupling constants are given in Hertz. The following abbreviations are used for spin multiplicity: br = broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and cm = complex multiplet. Infrared (IR) spectra were recorded on a Perkin-Elmer 1600 series FTIR spectrometer and are reported in wavenumbers (cm " ). Elemental analyses were performed by Atlantic Microlab, Inc., Norcross, GA. High-resolution mass spectra (HRMS) were performed by Scripps Mass Spectra Laboratory, La Jolla, CA. Melting points (mp) were determined on a Mel-Temp II apparatus and are uncorrected. Unless otherwise indicated, the reactions set forth below were carried out under a positive pressure with a balloon of nitrogen (N 2 ) or argon (Ar) at ambient temperature in anhydrous solvents, and the reaction flasks were fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was heat-dried. Analytical thin-layer chromatography (TLC) was performed on glass- backed silica gel 60 F 254 plates (Analtech, 0.25 mm) and eluted with the appropriate solvent ratios (v/v), which are denoted where appropriate. The reactions were assayed by TLC and terminated as judged by the consumption of starting material. The tip plates were visualized using an ultraviolet (UV) lamp. Visualization can also be accomplished using stains such as potassium permanganate, ninhydrin, ammonium molybdate, iodine (I 2 ) chamber, or j?-anisaldehyde spray reagent or phpsphomolybdic acid reagent (Aldrich Chemical, 20 wt% in ethanol) activated with heat. Recovery ofthe desired compounds from the reaction mixtures described herein was typically accomplished by doubling the reaction volume with the reaction solvent or extraction solvent and washing with the indicated aqueous solutions using 25% by volume ofthe extraction volume (unless otherwise indicated). Product solutions were dried over anhydrous Na SO prior to filtration and evaporation ofthe solvents was conducted under reduced pressure on a rotary evaporator. Purification of products and intermediates was conducted by flash column chromatography using silica gel 60 (Merck Art 9385). (Still et al., J. Org. Chem.43:2923 (1978)) was done using silica gel 60 (Merck Art 9385):crude material ratio of about 20:1 to 50:1 (unless otherwise indicated). EXAMPLE 1 (S)-2-Aminoethyl-l-methylpyrrolidine was prepared according to the following reaction scheme: 1-1 1-2 1-3 1-4 1-5 (S)-N-Boc-2-hydroxymethylpyrrolidine (1-2): , t-Butoxycarboxylic anhydride (23.3 g, 107 mmol) was added to a solution of 5.40 g of (S)-2-hydroxymethylpyrrolidine (1-1, 53.4 mmol) in 100 mL of 1.5 N aqueous sodium hydroxide (NaOH). After stirring for 1 hour, the reaction was extracted twice with ethylacetate (EtOAc). The EtOAc phases were combined, dried with magnesium sulfate (MgSO 4 ), filtered and concentrated under reduced pressure. The residue was purified on a silica gel column using hexane/EtOAc (3:1), followed by (1:1) to provide 10.72 g ofthe title product. 1H NMR(CDC1 3 , ppm): 1.48 (s, 9H); 1.53 (m, 1H); 1.7-1.9 (m, 4H); 2.0 (m, 1H); 3.30 (m, 1H); 3.45 (m, 1H); 3.60 (m, 2H); 3.95 (brd, 1H); 4.80 (brd, 1H). MS: 202 (MAl). (S)-Mesylate of N-Boc-2-hydroxymethylpyrrolidine (1-3): Mesyl chloride (4.8 mL, 61.5 mmol) was added slowly with stirring, at 0°C, to a solution of 10.3 g of N-Boc- 2-hydroxymethylpyrrolidine (51.2 mmol) and triethylamine (7.76 g, 76.8 mmol) in 150 mL tetrahydrofuran (THF). After 40 minutes, the reaction mixture was filtered to remove solid formed, and the solvent was concentrated under reduced pressure. The residue was purified on a silica gel column, using hexane/EtOAc (1:1), to provide 14.25 g (99.7%) ofthe title product. 1H NMR (CDC1 3 , ppm): 1.50 (s, 9H); 1.8 - 2.2 (m, 5H); 3.03 (s, 3H); 3.37 (brd, 2H); 4.05 (brd, 1H); 4.30 (brd, 1H). (S)-N-Boc-2-cyanomethylpyrrolidine (1-4): The mesylate salt of N-Boc-2- hydroxymethylpyrrolidine (12.0 g, 43.0 mmol) and NaCN (6.32 g) were mixed in 50 mL of DMSO and stirred at 55°C for 20 hours. After cooling to room temperature, 200 mL of EtOAc was added and the mixture was washed successively with 10% aq. potassium carbonate (K 2 CO 3j lx) and brine (2x), dried with MgSO and filtered. The resulting solution was concentrated under reduced pressure. The residue was purified on a silica gel using hexane/EtOAc (1 : 1) to provide 8.2 g (91.1%) of the title product. 1H NMR (CDCls, ppm): 1.43 (s, 9H); 1.75-2.05 (m, 3H); 2.13 (brd, 1H); 2.45 - 2.90 (m, 2H); 3.40 (m, 2H); 3.95 (brd, 1H). MS: 211 (MA-l). (S)-2-Aminoethyl-l-methylpyrrolidine (1-5): Lithium aluminum hydride (201 mL of 1.0 M solution in THF) was added slowly to a solution of N-Boc-2- • cyanomethylpyrrolidme (14.1 g, 31.0 mmol) in 500 mL of diethyl ether. After stirring at room temperature for 10 min., the reaction mixture was heated to reflux for 18 hours, cooled in ice bath, and quenched with 25% NaOH aqueous solution. The resulting mixture was filtered, and the solid was washed thoroughly with ether. The filtrate and combined washings were dried with sodium sulfate (Na 2 SO 4 ), filtered, and concentrated under reduced pressure to provide 6.63 g (77.2%) ofthe title product. 1H NMR (CDC1 3 , ppm): 1.40 (s, 2H); 1.50 - 2.15 (m, 8H); 2.28 (s, 3H); 2J0 (m, 2H); 3.00 (m, 1H). MS: 129 (MM). The (R)-enantiomer of intermediate 1-5 was made by the same procedure using the (R)-enantiomer of 1-1 as starting material. Racemic intermediate 1-5 is commercially available. EXAMPLE 2 (S)-Di-(3-hydroxybenzyl)-2-aminoethyl-N-methylpyrroIidine was prepared according to the following reaction scheme: 3-hydroxybenzaldehyde NaBH CN Sodium cyanoborohydride (5.0 g, 79.6 mmol), admixed with a few droplets of trifluoroacetic acid (TFA), was slowly added to a solution of (S)-2-aminoethyl-l- methylpyrrolidine (1.28 g, 10 mmol) and 3-hydroxybenzaldehyde (4.9 g, 40 mmol) in 30 mL of methanol. The resulting mixture was stirred for 48 hours, quenched with 2N HCI, and concentrated under reduced pressure. The residue was dissolved in MeOH , filtered and the resulting clear solution concentrated under reduced pressure. The residue was purified on a silica gel column using MeOH/CH 2 Cl 2 (5:95 first, then changed to 15:85) to provide 3.04 g ofthe title compound. The compound was further purified using reverse phase HPLC using a C- 18 column. J H NMR (CD 3 OD): δ 1.34-2.21 (m, 7H), δ 2.62-2.82 (m, 2H), δ 2.84 (s, 3H), δ 3.10-3.27 (m, 1H), δ 3.48-3.85 (m, 4H), δ 4.12-4.32 (m, 1H), δ 6J0-7.06 (m, 6H), δ 7.15-7.45 (m, 2H). MS (APCI): 341.3 (M+l). The compounds of Examples 3 to 12 were prepared according to the general procedure of Example 2, using the specified aldehydes. EXAMPLE 3 The following compound was prepared from racemic 2-aminoethyl-l- methylpyrrolidine and 3-hydroxybenzaldehyde: 1H NMR (DMSO-d 6 ): δ 1.97 (brd, 2H), δ 2J4 (d, 3H), δ 2.98 (brd, 3H), δ 3.52 (brd, 6H), δ 4.22 (brd, 4H), δ 6.87 (d, 2H), δ 7.06 (m, 4H), δ 7.25 (t, 2H), δ 9J5 (brd, IH), δ 10.89 (brd, IH). MS (APCI): 341.3 (M+l). EXAMPLE 4 The following compound was prepared from racemic 2-aminoethyl-l- methylpyrrolidine and p-tolualdehyde: ! H NMR (CDC1 3 ): δ 1.21-1.44 (m, 2H), δ 1.52-1.76 (m, 3H), δ 1.85-2.15 (m, 3H), δ 2,29 (s, 3H), δ 2.35 (s, 6H), δ 2.30-2.60 (m, 2H), δ 3.05 (t, IH), δ 3.44 (d, 2H), δ 3.65 (d, 2H), δ 7.08 (m, 4H), δ 7.23 (m, 4H). MS (APCI): 337.2 (M+l). EXAMPLE 5 The following compound was prepared from racemic 2-aminoethyl-l- methylpyrrolidine and 4-chlorobenzaldehyde: 5 1H NMR (CDC1 3 ): δ 1.24-1.60 (m, 2H), δ 1.64-1.87 (m, 3H), δ 1.92-2.06 (m, IH), δ 2.14-2.32 (m, 2H), δ 2.35 (s, 3H), δ 2.43 (t, 2H), δ 3.19 (t, IH), δ 3.37 (d, 2H), δ 3.60 (d, 2H), δ 7.26 (m, 8H). MS (APCI): 377 (M+l). EXAMPLE 6 l o The following compound was prepared from (R)-2-aminoethyl- 1 - methylpyrrolidine and p-tolualdehyde: 1H NMR (CDC1 3 ): δ 1.21-1.48 (m, 2H), δ 1.54-1.83 (m, 2H), δ 1.87-2.24 (m, 4H), δ 2.26 s (s, 3H), δ 2.32 (s, 6H), δ 2.36-2.53 (m, 2H), δ 3.05 (t, IH), δ 3.43 (d, 2H), δ 3.60 (d, 2H), δ 7.10 (m, 4H), δ 7.22 (m, 4H). MS (GC): 337 (M+l). EXAMPLE 7 The following compound was prepared from (S)-2-aminoethyl-l- o methylpyrrolidine and p-tolualdehyde: 1H NMR (CDC1 3 ): δ 1.21-1.48 (m, 2H), δ 1.54-1.83 (m, 2H), δ 1.87-2.24 (m, 4H), δ 2.26 (s, 3H), δ 2.32 (s, 6H), δ 2.36-2.53 ( , 2H), δ 3.05 (t, IH), δ 3.43 (d, 2H), δ 3.60 (d, 2H), δ 7.10 (m, 4H), δ 7.22 (m, 4H). MS (GC): 337 (M+l). EXAMPLE 8 The following compound was prepared from racemic 2-aminoethyl-l- methylpyrrolidine and phenylacetaldehyde: 1H NMR (CDCI3): δ 1.31-1.58 (m, 2H), δ 1.60-1.87 (m, 2H), δ 1.87-2.24 (m, 4H), δ 2.29 (s, 3H), δ 2.60 (t, 2H), δ 2.68-2.91 (m, 6H), δ 3.06 (t, IH), δ 7.08-7.42 (m, 10H). MS (APCI): 337.8 (M+l). EXAMPLE 9 The following compound was prepared from (S) 2-aminoethyl-l- methylpyrrolidine and 3-(chloromethyl)benzamide): (S)-2-Aminomethyl-l -methylpyrrolidine (0.20 g, 1.6 mmol) and 3- (chloromethyl)benzamide (0J5 g, 4.4 mmol) were mixed in 15 mL MeOH and stirred overnight. The reaction mixture was subjected to HPLC to provide purified compound 9. 1H NMR (CD 3 OD): δ 1.62 (m, IH), δ 1.95-2.30 (m, 4H), δ 2.63 (m, IH), δ 2.91 (s, 3H), δ 3.08-3.45 (m, 4H), δ 3.60-3.81 (m, IH), δ 4.40-4.66 (m, 4H), δ 7.41-8.10 (m, 8H). MS (LC-MS): 395.5 (M+l). EXAMPLE 10 The following compound was prepared from (R)-2-aminoethyl-l- methylpyrrolidine and 3-hydroxybenzaldehyde: 1H NMR (DMSO-d 6 ): δ 1.10-2.30 (m, 6H), δ 2.61 (s, 3H), δ 2J6-3.50 (m, 5H), δ 3.94- 4.29 (m, 4H), δ 6.70-7.30 (m, 8H), δ 11.10 (d, 2H). MS (APCI): 341.12 (M+l). EXAMPLE 11 The following compound was prepared from (S)-2-aminoethyl-l- methylpyrrolidiήe and 3,5-dimethyl-4-hydroxybenzaldehyde: 1H NMR (CDC1 3 ): δ 1.43-1.62 (m, IH), δ 1.87-2.12 (m, 4H), δ 2.15 (s, 12H), δ 2.25-2.40 (m, IH), δ 2.82 (s, 3H), δ 2.95-3.20 (m, 4H), δ 3.55-3.66 (m, IH), δ 4.02-4.26 (m, 4H), δ 6.93-7.07 (m, 4H). MS (APCI): 397.3 (M+l). EXAMPLE 12 The following compound was prepared from racemic 2-aminoethyl-l- methylpyrrolidine and benzaldehyde: 1H NMR (CDCI3): δ 1.19-1.44 (m, 2H), δ 1.55-1.79 (m, 2H), δ 1.86-2.17 (m, 4H), δ 2.26 (s, 3H), δ 2.43-2.55 (m, 2H), δ 3.05 (m, IH), δ 3.44 (d, 2H), δ 3.66 (d, 2H), δ 7.16-7.47 (m, 1 OH). MS (GC-EI): 309 (M+l). EXAMPLE 13 (S)-(3-Hyckoxybenzyl)-2-aminoethyl-N-methylpyrrolidine was prepared according to the following: (S)-2-Aminoethyl- 1 -methylpyrrolidine (1.28 g, 10 mmol) and 3- hydroxybenzaldehyde (1.22 g, 10 mmol) were dissolved in 25 mL of MeOH, and the resulting solution was stirred overnight. After the reaction mixture was cooled in an ice bath, sodium borohydride (NaBH*, 0.76 g) was added slowly in aliquots. The reaction mixture was stirred for 15 minutes while chilled, and for another 1.5 hours at room temperature. The reaction mixture was cooled down in an ice bath, quenched slowly with TFA, and the solvent was concentrated under reduced pressure. The residue was purified on a silica gel column using EtOAc/MeOH (2:1). The product obtained was converted to the hydrochloride salt, providing 2.7 g (88%) . 1H NMR (2HC1 salt in DMSO, ppm): 1.60 (m, lH); 1.90 (m, 2H): 2.10 (m, IH); 2.25 (m, IH); 2.40 (m, IH); 2.74 (d, 3 H); 3.00 (m, 3H); 3.38 (m, IH) 3.50 (m, 1H0; 4.00 (m, 2H); 6.83 (m, IH); 7.00 (m, 2H); 7.19 (t, IH); 9.70 (brd, 2H) 11.2 (bred, IH). MS (APCI): 235 (MAl). The intermediate compounds of Examples 14 to 18 were prepared according to the general procedure of Example 13 using the specified aldehydes. EXAMPLE 14 The following intermediate compound was prepared from 2-aminoethyl-l- methylpyrrolidine and benzaldehyde: 1H NMR (CDC1 3 ): δ 1.44-1.52 (m, 2H), δ 1.53-1.80 (m, 3H), δ 1.85-1.95 (m, 2H), δ 2.04-2.15 (m, 2H), δ 2.30 (s, 3H), δ 2.61-2.64 (m, IH), δ 2.64-2.74 (m, IH), δ 3.05 (t, IH), δ 3.80 (m, 2H), δ 7.26 (d, IH), δ 7.32 (m, 4H). MS (APCI): 219.2 (M+l). EXAMPLE 15 The following intermediate compound was prepared from 2-aminoethyl- 1- methylpyrrolidine and 2-naphthaldehyde: 1H NMR (CDC1 3 ): δ 1.38-1.61 (m, 2H), δ 1.63-1.83 (m, 2H), δ 1.84-2.03 (m, 2H), δ 2.05-2.23 (m, 2H), δ 2.32 (s, 3H), δ 2.60-2.84 (m, 2H), δ 3.05 (t, IH), δ 3.95 (s, 2H), δ 7.36 - 7.60 (m, 3H), δ 7.95 (m, 4H). MS (FAB): 269.4 (M+l). EXAMPLE 16 The following intermediate compound was prepared from 2-aminoethyl- 1 - methylpyrrolidine and 4-chlorobenzaldehyde: 1H NMR (CDCI3): δ 1.36-1.61 (m, 2H), δ 1.62 - 2.00 (m, 4H), δ 2.01-2.20 (m, 2H), δ 2.29 (s, 3H), δ 2.53-2.79 (m, 2H), δ 3.08 (t, IH), δ 3.75 (s, 2H), δ 7.17-7.41 (M, 4H). MS (FAB): 253.2 (M+l). EXAMPLE 17 The following intermediate compound was prepared from 2-aminoethyl- 1- methylpyrrolidine and p-tolualdehyde: 1H NMR (CDCI3): δ 1.35-1.52 (m, 2H), δ 1.56-1.80 (m, 2H), δ 1.84-1.99 (m, 4H), δ 2.00-2.16 (m, 2H), δ 2.30 (s, 3H), δ 2.34 (s, 3H), δ 2.56 - 2.79 (m, 2H), δ 3.04 (t, IH), δ 3.75 (s, 2H), δ 7.07-7.24 (dd, 4H). MS (GC): 232 (M). EXAMPLE 18 The following intermediate compound was prepared from 2-aminoethyl- 1- methylpyrrolidine and 2-quinolinecarboxaldehyde: 1H NMR (CDC1 3 ): δ 1.42-1.87 (m, 4H), δ 1.88-2.05 (m, 2H), δ 2.06-2.24 (m, 2H), δ 2.34 (s, 3H), δ 2.66-2.89 (s, 2H), δ 3.07 (t, IH), 64.11 (s, 2H), δ 7.42 - 7.56 (m, 2H), δ 7.67 (t, IH), δ 7.80 (d, IH), δ 8.02-8.21 (m, 2H). MS (APCI): 270.3 (M+l). EXAMPLE 19 (S)-(3 -Hydroxybenzyl)(4-chlorobenzyl)-2-aminoethy 1-N-methy lpyrrolidine was prepared as follows: To a stirred solution of S-2-(3-hydroxybenzyl)aminoethyl-l-methylpyrrolidine (0.31 g, 1.0 mmol) and p-chlorobenzaldehyde (0.28 g, 2.0 mmol) in 8 mL of MeOH, was added a sodium cyanoborohydride (0.28 g, 4.46 mmol), followed by a droplet of TFA. The resulting mixture was stirred for 24 hours at 55°C, followed by addition of 2N HCI. The mixture was concentrated under reduced pressure and the resulting residue was dissolved in aqueous HCI. The aqueous solution was extracted with EtOAc and concentrated under reduced pressure. The residue was subjected to purification by reverse phase HPLC ( g, reverse phase column) to provide the title compound (106 mg, 30%). 1HNMR (CD3OD): δ 1.51 - 1.73 (m, IH), δ 1.92 - 2.29 (m, 4H), δ 2.36 - 2.58 (m, IH), δ 2.92 (s, 3H), δ 3.06-3.29 (m, 4H), δ 3.66-3.83 (m, IH), δ 4.27-4.55 (m, 4H), δ 6.86-7.04 (m, 3H), δ 7.27-7.40 (m, IH), δ 7.50-7.64 (M, 4H). MS (APCI):359.8 (M+l). The compounds of Examples 20 to 53 were prepared according to the general procedure of Example 19, or by straightforward modification thereof, using the intermediate 2-aminoethyl-N-methylpyrrolidines of Examples 13 to 18, or related pyrrolidine intermediates prepared by straightforward modification ofthe general procedure of Example 13, and commercially available aldehydes. EXAMPLE 20 1H NMR (CD 3 OD): δ 1.46 - 1.72 (m, IH), δ 1.90-2.29 (m, 4H), δ 2.31 - 2.50 (m, IH), δ 2.87 (s, 3H), δ 3.01 - 3.31 (m, 4H), δ 3.60 - 3.78 (m, IH), δ 4.30 (s, 4H), δ 6.76 - 7.03 (m, 5H), δ 7.22 - 7.44 (m, 3H). MS (APCI): 341.4 (M+l). EXAMPLE 21 1H NMR (CD 3 OD): δ 1.54 (m, IH), δ 1.90 - 2.22 (m, 4H), δ 2.39 (m, IH), δ 2.83 (s, IH), δ 2.97 - 3.39 (m, 4H), δ 3.59 (m, IH), δ 3.82 (s, 3H), δ 4.05 - 4.64 (m, 4H), δ 6J3 - 7.01 (m, 2H), δ 7.13 (s, IH), δ 7.35 - 7.64 (m, 4H). MS (APCI): 389.2 (M+l). EXAMPLE 22 1H NMR (CDC1 3 ): δ 0.76 - 1.00 (m, IH), 6 1.18 - 1.47 (m, 3H), 5 1.55 - 2.11 (m, 4H), δ 2.25 - 2.89 (m, 9H), δ 3.30 - 3.56 (m, 2H), δ 3.59 - 3.77 (m, IH), δ 4.60 (m, IH), δ 7.00 - 7.49 (m, 9H). MS (APCI): 323.1 (M+l). EXAMPLE 23 1H NMR (CDCI3): δ 0.74 - 1.42 (m, 4H), δ 1.45 - 1.76 (m, 2H), δ 1.80 - 2.14 (m, 2H), δ 2.14 - 3.83 (m, 5H), δ 3.33 - 4.02 (m, 4H), δ 4.95 (m, IH), δ 7.08 - 7.40 (m, 8H). MS (APCI): 378 (M+l). EXAMPLE 24 J H NMR (CDCI3): δ 0.94 - 1.72 (m, 6H), δ 1.74 - 2.05 (m, 2H), δ 2.13 - 2.57 (m, 14H), δ 3.56 - 3.70 (m, 2H), δ 3.33 - 3.47 (m, 2H), δ 5.21 - 5.63 (m, IH), δ 6.89 - 7.41 (m, 8H). MS (APCI): 337.1 (M+l). EXAMPLE 25 1H NMR (CDC1 3 ): 60.99 - 2.05 (m, 6H), δ 2.11 - 2.63 (m, 7H), δ 3.21 - 4.24 (m, 5H), δ 7.10 - 8.19 (m, 12H). MS (APCI): 359.1 (M+l). EXAMPLE 26 1H NMR (CDCI3): δ 0.92 - 2.08 (m, 6H), δ 2.27 - 2.54 (m, 7H), δ 3.31 - 3.48 (m, 2H), δ 3.57 - 3.71 (m, 2H), δ 6.99 (t, 2H), δ 7.29 (m, 7H). MS (APCI): 327.1 (M+l). EXAMPLE 27 1H NMR (CDCI3): δ 0.98 - 1J3 (m, 4H), δ 1.85 - 2.11 ( , 2H), δ 2.19 - 3.02 (m, 10H), δ 3.14 - 4.29 (m, 5H), δ.04 - 7.41 (m, 9H). MS (APCI): 355.1 (M+l). EXAMPLE 28 1H NMR (CDC1 3 ): δ 0.95 - 1.43 (m, 4H), δ 1.44 - 2.10 (m, 6H), δ 2.21 - 2.70 (m, 8H), δ 3.21 - 3.36 (m, IH), δ 3.37 - 3.50 (m, 2H), δ 3.57 - 3.72 (m, 2H), δ 7.04 - 7.50 (m, 9H). MS (APCI): 337.1 (M+l). EXAMPLE 29 1H NMR (CDCI3): δ 0.92 - 1.98 (m, 6H), δ 2.21 - 3.10 (m, 7H), δ 3.30 - 4.13 (m, 5H), δ 6.68 - 7.45 (m, 9H). MS (APCI): 325.2 (M+l). EXAMPLE 30 1H NMR (CDCI3): δ 0.89 - 2.12 (m, 9H), δ 2.22 - 2.56 (m, 7H), δ 3.27 (t, IH), δ 3.40 3.56 (m, 2H), δ 3.81 - 3.60 (m, 2H), δ 6.96 - 7.45 (m, 9H). MS (APCI): 323.2 (M+l). EXAMPLE 31 1H NMR (DMSO-de): δ 1.16 (m, IH), 6 1.64 (m, 2H), δ 1.95 (m, IH), δ 2.26 (s, 5H), δ 2.48 (d, 2H), 62.75 (m, 2H), δ 3.25 (m, IH), δ 3.67 (s, 9H), δ 3.96 - 4.32 (m, 4H), δ 6.67 - 7.52 (m, 9H). MS (APCI): 365.2 (M+l). EXAMPLE 32 1H NMR (DMSO-d 6 ): δ 0.80 - 2.13 (m, 8H), 2.40 (s, 3H), δ 2.58 (m, 2H), δ 2.61 (s, 6H), δ 2.90 (m, IH), δ 3.36 - 3.81 (m, 4H), δ 4.67 (s, IH), δ 7.17 - 8.49 (m, 9H). MS (APCI): 351.2 (M+l). EXAMPLE 33 1H NMR (CDCI3): δ 0J4 - 2.33 (m, 8H), δ 2.41 (s, 3H), δ 2.48 - 2.78 (m, 2H), δ 3.34 3.70 (m, 4H), δ 3.60 - 3.80 (m, IH), δ 3.82 - 4.00 (s, 3H), δ 6.70 - 7.50 (m, 9H). MS (APCI): 339.1 (M+l). EXAMPLE 34 1H NMR (DMSO-de): δ 1.77 - 2.42 (m, 6H), δ 2.72 (s, 3H), δ 2.86 - 3.18 (m, 4H), δ 3.23 (m, IH), δ 4.15 - 4.70 (m, 4H), δ 6.81 - 8.35 (m, 11 H), δ 9.86 (s, IH). MS (APCI): 375.5 (M+l). EXAMPLE 35 1H NMR (DMSO-de): δ 1.39 - 1.58 (m, IH), δ 1.80 - 2.05 (m, 4H), δ 2.06 - 2.32 (m, 7H), δ 2.75 (s, 3H), δ 2.84 - 3.10 (m, 4H), δ 3.16 - 3.35 (m, IH), δ 4.00 - 4.35 (m, 4H), δ 6.81 - 6.92 (m, IH), δ 7.01 - 7.14 (m, 2H), δ 7.18 - 7.30 (m, IH), δ 7.36 (s, IH), δ 7.55 (s, IH). MS (APCI): 369.8 (M+l). 1H NMR (DMSO-d 6 ): δ 1.34 - 2.60 (m, 6H), δ 2.77 (s, 3H), δ 2.84 - 3.10 (m, 4H), δ 3.15 (m, IH), δ 3.80 (s, 3H), δ 4.08 - 4.40 (m, 4H), δ 6.82 - 6.93 (m, IH), δ 6.93 - 7.12 (m, 4H), δ 7.18 - 7.32 (m, 2H), δ 7.39 (s, IH), δ 7.55 (s, IH), δ 7.61 - 7.74 (m, 2H). MS (LC- MS): 355.4 (M+l). EXAMPLE 37 1HNMR (DMSO-d 6 ): δ 1.34 - 1.55 (m, 10H), δ 1.77 - 2.15 (m, 4H), δ 2.30 - 2.52 (m, IH), δ 2.77 (s, 3H), δ 2.93 - 3.31 (m, 4H), δ 3.63 (m,lH), δ 4.08 - 4.53 (m, 4H), δ 6J9 ■ 7.02 (m, 3H), δ 7.20 - 7.35 (m, IH), δ 7.41 - 7.61 (m, 4H), δ 10.36 (s, IH). MS (APCI): 381.6 (M+l). EXAMPLE 38 1H NMR (CD3OD): δ 1.60 - 1.83 (m, IH), δ 1.94 - 2.01 (m, 3H), δ 2.03 - 2.44 (m, IH), δ 2.45 - 2.65 (m, IH), δ 2.95 (s, 3H), δ 3.04 - 3.23 (m, 2H), δ 3.25 - 3.53 (m, 6H), δ 3.65 - 3.84 (m, IH), δ 4.40 - 4.67 (m, 2H), δ 7.24 - 7.43 (m, 3H), δ 7.51 - 7.72 (m, 4H). MS (APCI): 357.8 (M+l). EXAMPLE 39 1HNMR (CD 3 OD): δ 1.58 - 1.81 (m, IH), δ 1.92 - 2.36 (m, 4H), δ 2.41 - 2.68 (m, IH), δ 2.92 (s, 3H), δ 3.07 - 3.52 (m, 6H), δ 3.61 - 3.84 (m, IH), δ 4.28 - 4.50 (m, 4H), δ 6.72 - 7.04 (m, 2H), δ 7.34 - 7.66 (m, 5H). MS (APCI): 393.9 (M+l). EXAMPLE 40 1H NMR (CD3OD): δ 1.53 - 1.77 (m, IH), δ 1.94 - 2.31 (m, 4H), δ 2.39 - 2.62 (m, 4H), δ 2.94 (s, 3H), δ 3.06 - 3.31 (m, 4H), δ 3.66 - 3.84 (m, IH), δ 4.32 - 4.55 (m, 4H), δ 7.31 - 7.64 (m, 8H). MS (APCI): 389.6 (M+l). EXAMPLE 41 1H NMR (CD 3 OD): δ 1.29 - 1.53 (m, IH), δ 1.71 - 2.08 (m, 4H), δ 2.15 - 2.38 (m, IH), δ 2.68 (s, 3H), δ 2.87 - 3.16 (m, 4H), δ 3.41 - 3.61 (m, 4H), δ 4.07 - 4.36 (m, 4H), δ 6J9 - 7.00 (m, 3H), δ 7.14 - 7.44 (m, 5H). MS (APCI): 373.4 (M+l). EXAMPLE 42 1H NMR (CDC1 3 ): δ 1.73 - 1.90 (m, IH), δ 1.96 (s, 3H), δ 1.98 - 2.09 (m, 2H), 52.11 - 2.23 (m, IH), δ 2.26 (s, 3H), δ 2.35 - 2.62 (m, 2H), δ 2J6 - 2.94 (m, 4H), δ 2,95 - 3.10 (m, IH), 63.11 - 3.24 (m, IH), δ 3.25 - 3.43 (m, IH), δ 3.77 - 3.94 (m, IH), δ 4.04 - 4.32 (m, 4H), δ 6.46 (s, IH), δ 7.40 - 7.70 (m, 4H). MS (APCI): 361.2 (M+l). EXAMPLE 43 1 H NMR (CDC1 3 ): δ 1.15 - 1.21 (m, IH), δ 1.57 - 1.94 (m, 3H), δ 1.95 - 2.32 (m, 7H), δ 2.36 - 2.63 (m, 2H), δ 2.78 - 2.92 (m, 6H), δ 3.03 - 3.25 (m, IH), δ 3.26 - 3.50 (m, 2H), δ 3.64 - 3.83 (m, IH), δ 4.09 - 4.45 (m, 2H), δ 5.53 - 5.80 (m, 2H), δ 7.33 - 7.64 (m, 4H). MS (APCI): 347.5 (M+l). EXAMPLE 44 1H NMR (CD 3 OD): δ 1.63 - 1.92 (m, IH), δ 2.00 - 2.44 (m, 4H), δ 2.57 - 2.79 (m, IH), δ 2.99 (s, 3H), δ 3.10 - 3.29 (m, IH), δ 3.31 - 3.57 (m, 3H), δ 3.65 - 3.84 (m, IH), δ 4.40 - 4.82 (m, 4H), δ 7.36 - 7.92 (m, 8H). MS (APCI): 377.6 (M+l). EXAMPLE 45 1H NMR (CD3OD): δ 1.54 - 1J8 (m, 4H), δ 2.47 - 2.74 (m, IH), δ 2.95 (s, 3H), δ 3.09 ■ 3.52 (m, 4H), δ 3.60 - 3.82 (m, IH), δ 3.96 (s, 2H), δ 4.42 - 4.73 (m, 4H), δ 7.26 - 8.00 (m, 11H). MS (APCI): 431.5 (M+l). EXAMPLE 46 1H NMR (CD 3 OD): δ 1.26 (d, 6H), δ 1.50 - 1.71 (m, IH), δ 1.92 - 2.28 (m, 4H), 62.37 2.59 (m, IH), 52.90 (s, 3H), δ 3.05 - 3.35 (m, 4H), δ 3.61 - 3.80 (m, IH), δ 4.29 - 4.54 (m, 4H), δ 7.29 - 7.58 (m, 8H). MS (APCI): 385.6 (M+l). EXAMPLE 47 1H NMR (CD 3 OD): δ 1.46 - 1.64 (m, IH), δ 1.85 - 2.19 (m, 4H), δ 2.34 - 2.52 (m, IH), δ 2.83 (s, 3H), δ 2.96 - 3.18(m, 3H), δ 3.19 - 3.26 (m, IH), δ 3.52 - 3.64 (m, IH), δ 4.17 - 4.45 (m, 4H), δ 6.82 - 6.95 (m, IH), δ 7.21 - 7.55 (m, 7H). MS (APCI): 393.5 (M+l). EXAMPLE 48 1HNMR (CD 3 OD): δ 1.41 - 1.59 (m, IH), δ 1.82 - 2.04 (m, 10H), δ 2.28 - 2.45 (m, IH), δ 2.77 (s, 3H), δ 2.93 - 3.10 (m, 3H), δ 3.11 - 3.21(m, IH), δ 3.49 - 3.61 (m, IH), δ 4.07 - 4.39 (m, 4H), δ 6.96 - 7.05 (m, 2H), δ 7.31 - 7.40 (m, 2H), δ 7.41 - 7.52 (m, 2H). MS (APCI): 387.4 (M+l). EXAMPLE 49 1H NMR (CD 3 OD): δ 1.38 - 1.59 (m, IH), δ 1.78 - 2.13 (m, 4H), δ 2.26 - 2.47 (m, IH), δ 2.76 (s, 3H), δ 2.90 - 3.10 (m, 3H), δ 3.11 - 3.26 (m, IH), δ 3.45 - 3.60 (m, IH), δ 4.13 - 4.38 (m, 4H), δ 6.66 - 6.78 (m, 2H), δ 7.23 - 7.38 (m, 4H), δ 7.42 - 7.53 (m, 2H). MS (APCI): 359.4 (M+l). EXAMPLE 50 1H NMR (CD 3 OD): δ 1.40 - 1.61 (m, IH), δ 1.80 - 2.17 (m, 4H), δ 2.31 - 2.52 (m, IH), δ 2.80 (s, 3H), δ 2.94 - 3.15 (m, 3H), δ 3.15 - 3.31 (m, IH), δ 3.57 (m, IH), δ 3.80 (s, 3H), § 4.I6 - 4.46 (m, 4H), δ 6.66 - 6.83 (m, IH), δ 6.87 - 7.01 (m, IH), δ 7.10 - 7.21 (m, IH), δ 7.30 - 7.45 (m, 2H), δ 7.52 (t, 2H). MS (APCI): 389.4 (m+l). EXAMPLE 51 1H NMR (CD3OD): δ 1.41 - 1.65 (m, IH), δ 1.79 - 2.19 (m, 4H), δ 2.30 - 2.52 (m, IH), δ 2.75 (s, 3H), δ 2.89 - 3.26 (m, 4H), δ 3.44 - 3.68 (m, IH), δ 4.19 - 4.46 (m, 4H), δ 7.05 (d, IH), δ 7.27 - 7.60 (m, 4H), δ 7.63 (d, IH), δ 8.10 (s, IH). MS (APCI): 404.1 (M+l). 1H NMR (CDCI3): δ 1.54 - 1.75 (m, IH), δ 1.88 - 2.26 (m, 2H), δ 2.31 - 2.66 (m, 4H), δ 2.86 (s, 3H), δ 3.07 (br d, IH), δ 3.20 - 3.46 (m, 3H), δ 3.63 (br d, IH), δ 4.45 (s, 2H), δ 7.36 - 7.70 (m, 6H), δ 7.74 - 7.96 (m, 2H). MS (APCI): 413.1 (M+l). EXAMPLE 53 'HNMR CDaOD): δ 1.17 (dd, 3H), δ 1.35 - 1.74 (m, IH), δ 1.80 - 2.50 (m, 5H), δ 2.69 (s, IH), δ 2J8 (s, 2H), δ 2.84 - 3.05 (m, 2H), 63.07 - 3.22 (m, 2H), δ 3.25 - 3.64 (m, 3H), δ 4.18 - 4.43 (m, 2H), δ 7.07 - 7.52 (m, 5H), δ 7.32 - 7.53 (m, 4H). MS (APCI): 371.7 (M+l). EXAMPLE 54 (S)-Di-(4-methylbenzyl)aminoethyl-N-ethylpyrrolidine may be prepared as follows: 5 M 1-7 1-6 (S)-N-Acetyl-2-cyanomethylpyrrolidine (I-7): N-Boc-2-cyanomethyl-pyrrolidine 1-4 (2.10 g) was dissolved in 20 mL ofa solution of TFA in CH 2 C1 2 (vol. 1:1) and stirred for 15 minutes. The solvent was concentrated under reduced pressure. The residue was l o dissolved in 20 mL of THF, treated with 4 mL of triethylamine (Et3 ) and 2 mL of acetic anhydride, and stirred overnight. The resulting mixture was quenched with water and extracted with ethyl acetate. The ethyl acetate phase was dried with Na 2 SO , filtered and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and filtered through silica gel, which was then washed with more ethyl acetate to provide is 1.26 g of the title compound. Confirmation of the identity of the title compounds was confirmed by GC MS and LC/MS. (S)-2-Aminoethyl-l-ethylpyrrolidine (1-8): Lithium aluminum hydride (30 mL of a 1M solution in THF) was added dropwise to a 0°C solution of N-acetyl-2- cyanomethylpyrrolidine 1-7 (14.1 g, 31.0 mmol) in 35 mL of diethyl ether. After stirring 20 at room temperature for 5 hours, the reaction mixture was heated to reflux for 5 hours, cooled in an ice bath, and quenched with 25% NaOH aqueous solution. The solid formed was filtered and thoroughly washed with THF. The filtrate was dried with Na 2 SO , filtered and concentrated under reduced pressure to provide 0.65 g ofthe title compound. It is considered within the ordinary skill of one in the art to prepare other N- substituted analogs of compound 1-8 by straightforward modification ofthe above method (e.g., using different acylating agents). (S)-Di-(4-methylbenzyl)aminoethyl-N-ethylpyrrolidine: Sodium cyanoborohydride (0J5 g, 11.9 mmol) was slowly added to a stirred solution of (S) 2- aminoethyl-N-ethylpyrrolidine (0.21 g, 1.5 mmol) and 4-methylbenzaldehyde (0J2 g, 6.0 mmol) in 10 mL of MeOH. The mixture was stirred for 4 hours at room temperature and 4 hours at 50°C, quenched with 2 N HCI, and the solvent was concentrated under reduced pressure. The residue was dissolved in MeOH and filtered, concentrated (223 mg), and purified by HPLC. 1 HNMR (CDC1 3 ): δ 0.92 - 1.11 (m, 2H), δ 1.26 - 1.71 (m, 4H), δ 1.82 - 2.20 (m, 4H), δ 2.24 (s, 6H), δ 2.31 - 2.52 (m, 3H), δ 2J1 - 2.85 (m, IH), δ 3.07 (m, IH), δ 3.30 (d, 2H), δ 3.54 (d, 2H), δ 6.97 - 7.26 (m, 8H). MS (APCI): 351.4 (M+l). Other symmetric compounds encompassed within the scope of this invention may be prepared using Compound 1-8, or using other N-substituted analogs of compound 1-8, and commercially available or readily available aldehydes by the methods described in Example 1. Asymmetrically substituted compounds encompassed within the scope of this invention may be prepared using Compound 1-8, or using other N-substituted analogs of compound 1-8, and commercially available or readily available aldehydes by the methods of Examples 13 and 19. EXAMPLE 55 (S)-Di-(benzyl)-2-aminomethyl-N-methylpyrrolidine may be prepared according to the following: (S)-Di-(benzyl)-2-aminocarbonyl-N-methylpyrrolidine (I- 10): To a solution of N-Boc-2-proline (1-9, 2.15 g, 10 mmol) and dibenzylamine (2.17 g, 11 mmol) in 20 mL of THF, was added 1,1-carbonyldiimidazole (CDI; 1.94 g, 12 mmol), and the reaiction mixture was stirred for 48 hours. After solvent evaporation, the residue was purified on a silica gel column, using hexane/EtOAc (4:1) first, then 2:1, to provide 3.20 g ofthe title compound (I- 10). (S)-Di-(benzyl)-2-aminomethyl-N-methylpyrrolidine (D-l): Intermediate 1-10 (3.2 g) was dissolved in 50 mL of dry ether, and 50 mL of 1.0 M lithium aluminum hydride solution in THF was added slowly at room temperature, followed by reflux for 14 hours under N 2 atmosphere. The reaction cooled in an ice bath and quenched with 25% aqueous NaOH. The solid formed was filtered out and washed with THF thoroughly. The filtrate was dried with Na 2 SO and solvent was concentrated under reduced pressure. The residue was purified on a silica gel column, using chloroform/MeOH (95:5), to provide 0.81 g ofthe title compound, for a two-step yield of 28%. 1 HNMR (CDC1 3 ): δ 1.32 - 1.56 (m, IH), δ 1.58 - 1.76 (m, 2H), δ 1.92 - 2.05 (m, IH), 52.08 (q, IH), δ 2.32 (s, 3H), δ 2.32 - 2.47 (m, 2H), δ 2.60 (dd, IH), δ 2.99 (m, IH), δ 3.43 (d, 2H), δ 3.69 (d, 2H), δ 7.08 - 7.56 (m, 10H). MS (APCI): 295.1 (M+l). BIOCHEMICAL AND BIOLOGICAL ASSAYS Cells and Membrane Preparation: HEK 293 cells stably expressing human 5- HT B (h5-HT 7 b) receptors were grown in Dulbecco's Modified Eagle's Medium (DMEM; Gibco) without sodium pyruvate and containing 4.5 g/L glucose, L- glutamine/penicillin-streptomycin (Gemini), 10% fetal bovine serum and 250 mg 1 ofthe antibiotic, G418 (Geneticin) as previously described (Jasper, J.R., Kosaka, A., To, Z.P., Chang, D.J. and Eglen, R.M. (1997) Cloning, expression and pharmacology ofa truncated splice variant ofthe human 5-ht receptor (h5-ht b ). Br. J. Pharmacol. 122(1): 126-132.). Cell pellets were homogenized in approximately 50 mL of homogenization buffer (buffer A) containing: 50 mM Tris (pH 7.4), 2 mM EGTA, 0.32 M sucrose, 10 μM PMSF, 1 μg/mL leupeptin, 5 μg/mL Pepstatin A, and 5 μg/mL aprotinin using an UltraTurax homogenizer (Tekmar Company, Cincinnati, OH) at 80% maximum setting three times for 10 sec. Cell pellets were centrifuged at 4°C at 1,500 x g for 10 min in a Beckman GS-6R centrifuge. Pellets were resuspended in buffer A, homogenized and centrifuged as described above. Pooled supernatants were transferred to centrifuge bottles and centrifuged at 4°C at 20,000 x g for 30 min in a Beckman J2-HS centrifuge. Cell pellets were resuspended in buffer A and were centrifuged at 4°C at 20,000 x g for 30 min. Cell pellets were resuspended in buffer A and stored at -70°C in aliquots of 2.5 mg/mL total membrane protein. Total membrane protein was assessed utilizing a BCA kit (Pierce; Rockford, IL). Membranes containing human 5-HTι a or 5- HT 2a receptors expressed in CHO Kl cells were prepared as described above. Membranes bearing human D 2 s dopamine (hD 2 s-DA) receptors expressed in A9 L cells and human 5-HTβ (h5-HT 6 ) receptors expressed in HEK-293 cells were purchased from Receptor Biology, Inc. (Beltsville, Maryland) and were utilized according to the suggested guidelines provided by the manufacturer. Radioligand Binding Assays: For 5-HT 7 saturation binding experiments, HEK- 293 cell membranes expressing h5-HT receptors (5-10 μg membrane protein/well) were incubated in duplicate with [ 3 H]5-CT (approximately 0.2 nM) in binding assay buffer containing: 50 mM HEPES (pH 7.4), 0.5 mM EDTA, 10 mM MgCl 2 , 10 μM pargyline to inhibit monoamine oxidase activity, and 0.1% sodium ascorbate, in a final volume of 200 μL in 96-well polypropylene plates for 2 hours at 37°C. Nonspecific binding was determined by incubating membranes with 1 μM 5-HT. All radioligand binding assays were stopped by rapid filtration onto 96-well GF/C filter plates (Packard) soaked in 0.1% polyethylenimine. Filters were washed three times with ice-cold phosphate-buffered saline (PBS) wash buffer containing 50 mM NaPO 4 (pH 7.4), 0.9% NaCl, 2 mM MgCl 2 and 0.02% NaN 3 . The filters were then counted using liquid scintillation in a Packard Topcount scintillation counter. Competition binding to the other receptor types was assayed in a similar fashion, under conditions summarized in Table 1 below. + RT = room temperature ++ Buffer compositions: A: 50 mM HEPES (pH 7.4), 0.5 mM EDTA, 10 mM MgCl 2 , 10 μM pargyline, 0.1% sodium ascorbate. B: 50 mM Tris (pH 7.4), 0.1% sodium ascorbate C: 50 mM Tris (pH 7.4), 10 mM MgCl 2 , 0.5 mM EDTA D: 50 mM Tris (pH 7.4), 10 mM MgCl 2 , 0.1 % sodium ascorbate E: 50 mM Tris (pH 7.4), 5 mM MgCl 2 , 1 mM EDTA, 0.1% sodium ascorbate Cyclic AMP Determination: The ability of various compounds to increase basal or to inhibit 5HT-stimuIated cAMP formation in HEK-293 cells expressing h5-HT 7b receptors was assessed utilizing adenylyl cyclase flashplates custom synthesized by New England Nuclear (NEN). Cells (approximately 50,000 cells/well) were incubated with compounds in a total volume of 100 μl on 96-well adenylyl cyclase flashplates (NEN) for 20 minutes at room temperature with compounds to assess for agonist activity. To assess for antagonist activity, cells were incubated for 1 hr at room temperature with test compounds and then were stimulated for 20 min with 5-HT (10 nM). 100 μl of detection mix containing I-cAMP was added to quench reactions according to the manufacturer's instructions. Plates were counted on a Packard TopCount after approximately two hours. Control dose-response curves to 5-HT were generated for each plate. Cyclic AMP levels were determined from standard curves generated to non- radioactive cAMP standards (10 nM-1 μM). By this method, all ofthe Formula I compounds acted as antagonists at 5-HT 7 receptors. Data Analysis: Radioligand binding experiments were analyzed with Prism™ (GraphPad, San Diego, CA), a computer graphics and statistics program. IC 50 values and Hill slopes for compounds were generated by nonlinear regression using Prism™. Values for Kj were calculated from IC 50 values by the Cheng and Prussof equation (Cheng, Y. and Prusoff, W.H., (1973), "Relationship between the inhibition constant (Kj) and the concentration of inhibitor which causes 50 per cent inhibition (I 50 ) of an enzymatic reaction." Biochemical Pharmacol.22:3099-3108). Biochemical ActivityThe Formula I compounds were assayed for binding activity vs. 5-HTι, 5-HI2A, 5-HT 6 , and 5-HT receptor subtypes, as well as dopamine D 2 receptors. Data are summarized in Table 2 below, where entries are blank in cases where the particular assay was not performed. Biological Activity: The biological activity ofthe inventive compounds is determined by assays that have been devised to serve as animal models for various human medical conditions. Many such assays are known to skilled practitioners. Useful assays include: the prokinetic assay, which is an in vivo method of determining the extent the test compound affects the rate of gastric emptying of a test meal in rats; the anxiolytic behavior assay, which measures the extent to which the test compound can ameliorate the symptoms of natural anxiety in mice when exposed to a novel, brightly lighted environment; the withdrawal anxiety assay, which measures the extent to which the test compound can ameliorate the symptoms in mice caused by withdrawal from addictive substances by measuring the extent the drug affects the anxiety that occurs in mice after chronically treating with an addictive substance and then abruptly ceasing the treatments; and the cognitive enhancement assay, which measures the extent the test compound can alleviate the cognitive deficit induced in rats by administration of atropine to the rats. These assays are described in U.S. Patent No. 5,763,468, the disclosure of which is hereby incorporated herein by reference. While the invention has been described in terms of preferred embodiments and specific examples, those skilled in the art will recognize through routine experimentation that various changes and modifications can be made without departing from the spirit and scope ofthe invention. Thus, the invention should be understood as not being limited by the foregoing detailed description, but as being defined by the appended claims and their equivalents.

Claims: WE CLAIM: 1. A compound of formula: where: 1, m, and n are independently 1 or 2; R 1 is lower alkyl; R 2 and R 3 are independently selected from substituted or unsubstituted aryl, heteroaryl, arylalkyl, heteroarylalkyl, and cycloalkenyl, provided that when R 1 is ethyl and 1, m and n are 1, R 2 and R 3 are not both unsubstituted phenyl; and pharmaceutically acceptable salts, solvates, active metabolites, or prodrugs thereof. 2. The compound according to claim 1 , wherein 1 and m are 1. 3. The compound according to claim 1, wherein n is 2. 4. The compound according to claim 1, wherein R 1 is selected from methyl or ethyl. 5. The compound according to claim 1, wherein R 2 and R 3 are independently selected from substituted or unsubstituted benzyl, methyldibenzylfiiranyl, cyclohexenyl, fluorenyl, phenyl, naphthyl, furanyl, benzofuranyl and benzothienyl. 6. The compound according to claim 5, wherein said substituted benzyl, methyldibenzylfiiranyl, cyclohexenyl, fluorenyl, phenyl, naphthyl, furanyl, benzofuranyl and benzothienyl is substituted by one or more include lower alkyl, substituted or unsubstituted aryl, arylalkyl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, heteroaryl, halo, hydroxyl, alkoxy, aryloxy, cycloalkoxy, heteroaryloxy, nitro, alkylthio, arylthio and aminocarboxyl. 7. The compound according to claim 1, having formula: 8. The compound according to claim 5, having formula: 9. A compound having the formula: and pharmaceutically acceptable salts, solvates, active metabolites, or prodrugs thereof. 10. The compound according to claim 9 having the formula: 11. A pharmaceutical composition comprising an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, solvate, active metabolite, or prodrug thereof. 12. A pharmaceutical composition comprising an effective amount of a compound according to claim 9, or a pharmaceutically acceptable salt, solvate, active metabolite, or prodrug thereof. 13. A method of preparing a compound of formula: wherein: 1, m, and n are independently 1 or 2; R 1 is lower alkyl; R 2 and R 3 are independently selected from aryl, heteroaryl, arylalkyl, heteroarylalkyl, and cycloalkenyl, each optionally substituted by one or more substituents, provided that when R 1 is ethyl and 1, m and n are all 1, R 2 and R 3 are not both unsubstituted phenyl; comprising the steps of: (a) coupling under reducing conditions a compound of formula: with one equivalent ofa compound of formula R 2 -(CH 2 ) p CHO, wherein p is (1-1), and (b) coupling under reducing conditions the coupled product of step (a) with one equivalent ofa compound of formula R 3 -(CH 2 ) q CHO, wherein q is (m-1). 14. A compound having the formula: where: 1 and n are independently 1 or 2; R 1 is lower alkyl; R 2 is a selected from aryl, heteroaryl, arylalkyl, heteroarylalkyl, and cycloalkenyl, each optionally substituted by one or more substituents. 15. The compound according to claim 13, having formula: 16. The compound according to claim 14, having formula: 17. A compound having the formula: UOf and pharmaceutically acceptable salts, solvates, active metabolites, or prodrugs thereof. 18. A method of treatment of a patient in need thereof comprising administering to said patient a pharmaceutical composition comprising an effective amount ofa compound according to claim 1, or a pharmaceutically acceptable salt, solvate, active metabolite, or prodrug thereof. 19. A method of treatment of pain in a patient in need thereof comprising administering to said patient a pharmaceutical composition comprising an effective amount ofa compound according to claim 1, or a pharmaceutically acceptable salt, solvate, active metabolite, or prodrug thereof. 20. A method of treatment of schizophrenia in a patient in need thereof comprising administering to said patient a pharmaceutical composition comprising an effective amount ofa compound according to claim 1, or a pharmaceutically acceptable salt, solvate, active metabolite, or prodrug thereof. 21. A method of treatment of depression in a patient in need thereof comprising administering to said patient a pharmaceutical composition comprising an effective amount ofa compound according to claim 1, or a pharmaceutically acceptable salt, solvate, active metabolite, or prodrug thereof. 22. A method of treatment of sleep disorders in a patient in need thereof comprising administering to said patient a pharmaceutical composition comprising an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt, solvate, active metabolite, or prodrug thereof.

Inventors: HONG YUFENG, KUKI ATSUO, LUTHIN DAVID ROBERT, PENG ZHENGWEI, RUI YUANJIN, HONG, YUFENG, KUKI, ATSUO, LUTHIN, DAVID ROBERT, PENG, ZHENGWEI, RUI, YUANJIN
Applicants: HONG YUFENG, KUKI ATSUO, LUTHIN DAVID ROBERT, PENG ZHENGWEI, RUI YUANJIN, WARNER LAMBERT CO, HONG, YUFENG, KUKI, ATSUO, LUTHIN, DAVID ROBERT, PENG, ZHENGWEI, RUI, YUANJIN, WARNER-LAMBERT COMPANY
Application year: 2001
Main classification: C07D207
IPC codes: A61K31, A61P25, C07D207, C07D401, C07D405, C07D409