Background of Invention Pharmaceuticals which enhance serotonergic neurotransmission are useful for the treatment of many psychiatric disorders, including depression and anxiety. The first generation of non-selective serotonin-affection drugs operated through a variety of physiological functions which endowed them with several side effect liabilities. The more currently prescribed drugs, the selective serotonin reuptake inhibitors (SSRIs), act predominately by inhibiting 5-HT, which is released at the synapses, from being actively removed from the synaptic cleft via a presynaptic serotonin transport carrier (5-HT-T).

The present invention relates to a new class of molecules which have the ability to act at the 5-HT transporter. Such compounds are therefore potentially useful for the treatment of depression as well as other serotonin disorders.

Some of the present molecules have a second activity as partial agonists/inhibitors of the serotonin 1A receptor (5-HT1A). Since SSRis require several weeks before a full therapeutic effect is seen, their mechanism of action can't solely be explained by the inhibition of 5-HT-T. It is believed that this delayed effect is due to the involvement of 5-HT1A autoreceptors. It has been previously suggested (Artigas et a/. TiPs, 1993,14,262) that the efficacy of reuptake inhibitors may be attenuated by the activation of 5-HT1A receptors which results in the reduced firing rate of 5-HT neurons. Repeated

SSRI administration, causing desensitization of 5-HT1A receptors, is postulated to be required before the antidepressant effect of these compounds is seen. Support for desensitization of 5-HT1A in humans is shown by an obsessive-compulsive disorder (OCD) study (Lesch et al.

Psychopharm. 1991,105,415), where patients given repeated treatment with SSRts developed tolerance to the hypothermic response induced by the administration of the 5-HT1A antagonist ipsapirone. Thus a dual SSRI/5-HT1A antagonists should provide antidepressant activity with a rapid onset of action. Studies using a combination of an SSRI (fluoxetine) and a 5-HT1A antagonists (pindolol) appear to support this hypothesis (Artigas et al. Arch.

Gen. Psychiat. 1994,51,248 and Perez et al. Arch. Gen. Psychiat 1999,56, 375).

Aryloxyalkyl amines have previously been shown to effect 5-HT- reuptake. US Patent No. 5,614,523 (Audia et al.) discloses a series of indoloxyethylpiperazines which affect the 5-HT1A and 5-HT-T receptors. US Patent No. 5,627,196 (Audia et al.) discloses a series of indoloxyethyltetrahydropyridines and indolyoxyethylpiperidinols which affect the 5-HT1A and 5-HT-T receptors. US Patent No. 5,741,789 (Hibschman et a/.) teaches a series of quinolinoxyethylpiperidines which affect the 5-HT1A and 5-HT-T receptors. US Patent No. 5,789,402 (Audia et a/.) discloses a series of indoloxyethylpiperidines which affect the 5-HT1A and 5-HT-T receptors. The current invention differs from the these patents in that the 8- azabicyclo [3.2.1octane and 8-azabicyclo [3.2.1] oct-2-ene ring structures are used instead of the corresponding piperidines/tetrahydropyridines 8-Azabicyclo [3.2.1] octanes and 8-azabicyclo [3.2.1] oct-2-enes have previously been shown to effect 5-HT-T reuptake. WO 9713770 (Moldt et al.) teaches a series of phenyl tropenes which affect the 5-HT-T receptor. WO 9716451 (Scheel-Krügger et a/.) discloses a series of fused tropane derivatives which act as neurotransmitter reuptake inhibitors. WO 9965492 (Audia et a/.) provides a series of aryl tropenes/tropanes that affect the 5-HT- T receptor in. The current invention differs from these references in that an

aryloxy alkyl chain has been attached to the aryl 8-azabicyclo [3.2.1] octane and aryl 8-azabicyclo [3.2.1] oct-2-ene structures.

Summary of the Invention The present invention comprises compounds represented by the formula I : wherein: A is optionally present and is a residue which combines with the carbon atoms to which it is attached to complete a cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrrolyl, imidazolyl, pyridinyl, pyridazynyl, dioxinyl or pyrimidinyl group; X is NH, O orS ; n is an integer from 0 to 3; Ar1 is phenyl or pyridyl substituted with 0-2 substituents selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, halo, cyano, nitro, trifluoromethyl, difluoromethyl, hydroxyl, and trifluoromethoxy groups and combinations thereof; Ar2 is indolyl, benzimidazolyl, phenyl, naphthyl, anthracenyl, phenanthrenyl, benzyl, benzofuryl, or benzothienyl, substituted with 0-2 Ci-C3 alkyl, C1-C3 alkoxy, halo, cyano, nitro, trifluoromethyl, difluoromethyl, hydroxyl, or trifluoromethoxy groups and combinations thereof; the dashed line represents an optional double bond;

and all crystalline forms and pharmaceutical acceptable salts thereof.

The present invention further comprises a pharmaceutical composition which comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier.

The present invention also comprises methods of making and using the compounds and formulations of this invention, which methods are described in further detail below.

Detailed Description In a preferred embodiment, A is present. More preferably, A is a residue which combines with the carbon atoms to which it is attached to complete a cyclopentyl, cyclohexyl, pyrrolyl, or pyridinyl, group. Still more preferably, A is a residue which combines with the carbon atoms to which it is attached to complete a pyrrolyl or pyridinyl group.

In a further preferred embodiment, X is NH or 0.

In a still further preferred embodiment, n is 1 or 2. More preferably, n is 1.

In yet another preferred embodiment, Ar1 is a phenyl group. More preferably, Ar1 is a phenyl group substituted with 0-2 substituents selected from the group consisting of C1-C3 alkyl, Cl-C3 alkoxy, halo, cyano, trifluoromethyl, hydroxyl, and trifluoromethoxy groups and combinations thereof. Most preferably, Ar1 is a phenyl group substituted with 0-2 substituents selected from the group consisting of C1-C3 alkoxy, halo, trifluoromethyl, trifluoromethoxy, and combinations thereof.

In a still further preferred embodiment, Ar2 is indolyl, phenyl, naphthyl, benzofuryl, or benzothienyl. More preferably, Ar2 is indolyl, naphthyl, benzofuryl, or benzothienyl.

In yet another preferred embodiment, Ar2 is substituted with 0-2 substituents selected from the group consisting of C1-C3 alkoxy, halo, cyano, nitro, trifluoromethyl, difluoromethyl, hydroxyl, or trifluoromethoxy, and combinations thereof. More preferably, Ar2 is substituted with 0-2

substituents selected from the group consisting of halo, cyano, trifluoromethyl, difluoromethyl, hydroxyl, or trifluoromethoxy and combinations thereof.

In yet another preferred embodiment the optional double bond is present.

A preferred aspect of this invention comprises compounds of formula I wherein: A is a residue which combines with the carbon atoms to which it is attached to complete a cyclopentyl, cyclohexyl, pyrrolyl, or pyridinyl, group X is an NH, O or S moiety n is 1-2; Ar1 is a phenyl group substituted with 0-2 substituents selected from C1-C3 alkyl, Cl-C3 alkoxy, halo, cyano, trifluoromethyl, hydroxyl, and trifluoromethoxy groups and combinations thereof; Ar2 is indolyl, phenyl, naphthyl, benzofuryl, or benzothienyl, substituted with 0-2 C1-C3 alkoxy, halo, cyano, nitro, trifluoromethyl, difluoromethyl, hydroxyl, or trifluoromethoxy groups; and all crystalline forms and pharmaceutical acceptable salts thereof.

More preferred compounds of this invention are compounds of formula I wherein: A is a residue which combines with the carbon atoms to which it is attached to complete a pyrrolyl, or pyridinyl, group X is an NH, or O moiety n is1 ; Ar1 is phenyl substituted with 0-2 groups selected from C1-C3 alkoxy, halo, trifluoromethyl, trifluoromethoxy, and combinations thereof;

Ar2 is indolyl, naphthyl, benzofuryf, or benzothienyl, substituted with 0-2 halo, cyano, trifluoromethyl, difluoromethyl, hydroxyl, or trifluoromethoxy groups; and all crystalline forms and pharmaceutically acceptable salts thereof.

In this specification, the term alkyl, whether used alone or as part of another group, includes straight and branched chain alkyl groups containing from 1 to 3 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, are encompassed by the term alkyl. The alkyl group may be substituted or unsubstituted. The aforementioned number of carbon atoms in the alkyl group refers to carbon backbone and does not include carbon atoms of substituents, such as alkoxy substitutions and the like.

Alkoxy, whether used alone or as part of another group include straight and branched chain alkoxy groups containing from 1 to 3 carbon atoms. For example, methoxy, ethoxy, propoxy, isopropoxy, are encompassed by the term alkoxy. The alkoxy group may be substituted or unsubstituted. The aforementioned number of carbon atoms in the alkoxy group does not include carbon atoms of substituents, such as alkyl substitutions and the like.

Halogen or halo as used herein means chlorine, bromine, iodine and fluorine.

Examples of A are pyrrolyl, pyridyl, dioxinyl, cycicopentyl.

Examples of X are 0, NH and S.

Examples of n are 1 and 2.

Examples of Ar1 are methoxyphenyl, phenyl, chlorophenyl and trifluormethylphenyl.

Examples of Ar2 are naphthyl, indolyl, methoxynaphthyl, and dichlorophenyl.

In some examples the double bond is present. In other examples the double bond is absent.

Highly preferred compounds of the present invention include : 4- [2- (3-Naphthalen-2-yl-8-aza-bicyclo [3.2.1] oct-2-en-8-yl)-ethoxy]-1 H-indole or a pharmaceutical acceptable salt thereof;

3- {8- [2- (l H-1 ndol-4-yloxy) ethyl]-8-azabicyclo [3.2.1] oct-2-en-3-yi}-1 H-indole or a pharmaceutical acceptable salt thereof; 2-[3-(1H-indol-3-yl)-8-azabicyclo[3. 2.1] oct-2-en-8-yl] ethyl 5-quinolinyl ether or a pharmaceutically acceptable salt thereof; 8- [2- (2, 3-Dihydro-benzo [1,4] dioxin-5-yloxy)-ethyl]-3-naphthalen-2-yl-8-aza- bicyclo [3.2.1] oct-2-ene or a pharmaceutical acceptable salt thereof; 6-methoxy-N- {2- [3- (2-naphthyl)-8-azabicyclo [3.2.1] oct-2-en-8-yl] ethyl}-8- quinolinamine or a pharmaceutical acceptable salt thereof; 6-Chloro-N- {2- [3- (2-naphthyl)-8-azabicyclo [3.2.1] oct-2-en-8-yl] ethyl}-8- quinolinamine or a pharmaceutically acceptable salt thereof; N- {2- [3- (2-naphthyl)-8-azabicyclo [3.2.1] oct-2-en-8-yl] ethyl}-8-quinolinamine or a pharmaceutically acceptable salt thereof; 6-Methoxy-8- [2- (3-naphthalen-2-yl-8-azabicyclo [3.2.1] oct-2-en-8-yl)-ethoxy]- quinoline or a pharmaceutical acceptable salt thereof; 8- [2- (Indan-4-yloxy)-ethyl]-3-naphthalen-2-yl-8-azabicyclo [3. 2.1] oct-2-ene or a pharmaceutically acceptable salt thereof; 4- {2- [3- (6-Methoxy-naphthalen-2-yl)-8-aza-bicyclo [3.2.1] oct-2-en-8-yl]- ethoxy}-1 H-indole or a pharmaceutical acceptable salt thereof; 3-Naphthalen-2-yl-8- [2- (3-trifluoromethyl-phenoxy)-ethyl]-8-aza- bicyclo [3.2.1] oct-2-ene or a pharmaceutically acceptable salt thereof; 4- [2- (3-Naphthalen-2-yl-8-aza-bicyclo [3.2.1] oct-8-yl)-ethoxy]-1 H-indole or a pharmaceutical acceptable salt thereof; 4-{2-[3-(3,4-Dichloro-phenyl)-8-aza-bicyclo [3.2.1] oct-2-en-8-yl]-ethoxy}-1 H- indole or a pharmaceutical acceptable salt thereof; 3- {8- [3- (1 H-indol-4-yloxy) propyl]-8-azabicyclo [3. 2.1] oct-2-en-3-yl}-1 H-indole or a pharmaceutical acceptable salt thereof; 4- [3- (3-Naphthalen-2-yl-8-aza-bicyclo [3.2.1] oct-2-en-8-yl)-propoxy]-1 H-indole or a pharmaceutically acceptable salt thereof; 4- {3- [3- (3, 4-Dichlorophenyl)-8-azabicyclo [3.2.1] oct-2-en-8-yl] propoxy-1 H- indole or a pharmaceutical acceptable salt thereof;

8- {2- [3- (2-Naphthyl)-8-azabicyclo [3.2.1] oct-8-yl] ethoxy} quinoline or a pharmaceutically acceptable salt thereof; and, 8- ( {2- [3- (2-naphthyl)-8-azabicyclo [3. 2.1] oct-8-yl] ethyl} sulfanyl) quinoline or a pharmaceutically acceptable salt thereof.

It is understood that the definition of the compounds of formula 1, when Ar contains asymmetric carbons, encompasses all possible stereoisomers and mixtures thereof which possess the activity discussed below. In particular, it encompasses racemic modifications and any optical isomers which possess the indicated activity. Optical isomers may be obtained in pure form by standard separation techniques known in the art.

Pharmaceutical acceptable salts are those derived from organic and inorganic acids such as: lactic, citric, acetic, tartaric, succinic, maleic, malonic, oxalic, fumaric, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and the like. Where Ar contain a carboxyl group, salts of the compounds of this invention may be formed with bases such as alkali metals (Na, K, Li) or the alkaline earth metals (Ca or Mg), and the like.

The compounds of formula I have been found to have affinity for the 5- HT reuptake transporter. They are therefore useful in the treatment of diseases affected by disorders of the serotonin affected neurological systems, such as depression and anxiety.

The present invention further provides a pharmaceutical composition which comprises a compound of this invention in combination or association with a pharmaceutically acceptable carrier. The compositions are preferably adapted for oral or subcutaneous administration. However, they may be adapted for other modes of administration.

The compounds of this invention may be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid

which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Any of the solid carriers known to those skilled in the art may be used with the compounds of this invention. Particularly suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, low melting waxes and ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs of the compounds of this invention. The compounds of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. Suitable examples of liquid carriers for oral and parenteral administration include water, alcohols (including monohydric alcohols and polyhydric alcohols, e. g., glycols) and their derivatives and oils (e. g., fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration may be either liquid or solid composition form.

In order to obtain consistency of administration, it is preferred that a composition of the invention is in the form of a unit dose. Suitable unit dose forms include tablets, capsules and powders in sachets or vials. Such unit dose forms may contain from 0. 1 to 100 mg of a compound of the invention and preferably from 2 to 50 mg. Still further preferred unit dosage forms

contain 5 to 25 mg of a compound of the present invention. The compounds of the present invention can be administered orally at a dose range of about 0.01 to 100 mg/kg or preferably at a dose range of 0.1 to 10 mg/kg. Such compositions typically may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.

The compositions of the invention may be formulated with conventional excipients, such as a filler, a disintegrating agent, a binder, a lubricant, a flavoring agent, and the like. They are formulated in a conventional manner, for example, in a manner similar to those used for known antihypertensive agents, diuretics and p-biocking agents.

The compounds of formula I may be synthesized as described hereinbelow. In particular this invention provides a process for the preparation of a compound of formula I as defined herein comprising one of the following : a) reacting a compound of formula wherein A, Ar1, X and n are as defined herein, and Z is a leaving group e. g. halogen, with a compound of the formula: wherein Ar2 and the dashed line are as defined herein; or b) reacting a compound of the formula

wherein A, Ar1, and X are as defined herein with a compound of the formula wherein Ar2 and the dashed line are as defined herein and Z is a leaving group, e. g. halogen, in the presence of a base; or c) converting a basic compound of formula (I) to a pharmaceutical acceptable acid addition salt thereof; or d) resolving an isomeric mixture of compounds of formula (I) to isolate a specific isomer of formula (I) or a pharmaceutical acceptable acid addition salt thereof.

In any of the reactions described above reactive sites/groups may be protected during the reaction and removed thereafter.

In one aspect of the present invention, compounds of formula I where X = NH, O or S and A = pyrrole may be prepared by reacting the corresponding Ar2-8-azabicyclo [3.2.1]-octane or-octene compound with the corresponding pyrrolyl-Ar1-X-(CH2)n-CH2-halide in the presence of an appropriate solvent and base, as exemplified in Schema 1. Thus a compound of formula III may be reacted with a compound of formula IV in the presence of an appropriate solvent such as DMSO, DMF, EtOH, or MeOH and in the presence of a base such as K2CO3, Et3N, or i-Pr2NEt at 80°C to give a compound of formula 11, where Y is H or 1-2 substituents as defined for Ar1 Scheme

Naphthyl-8-azabicyclo [3.2.1] octenes/naphthyl-8-azabicyclo [3.2.1]- octanes of formula))) may prepared according to Scheme II. Thus bromonaphthalene (formula V) and other bromoarenes may be lithiated by reaction with n-BuLi, s-BuLi or t-BuLi in an etherial solvent such THF, DME or Et20, followed by addition of N-Boc-tropinone to give tropinol (formula VI).

Treatment of tropinol with TFA or other acids in a solvent such as CH2CI2, CHCI3 or CI (CH2) 2CI causes deprotection of the Boc group as well as elimination of H20 to give naphthyl-8-azabicyclo [3.2.1] octene (formula Vil). In addition to Boc, other nitrogen protecting groups useful for these reactions are well known by the skilled artisan (for example, see Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Edition, Wiley Interscience, New York, 1999) and may be used in the practice of this invention. Reduction of naphthyl-8-azabicyclo [3. 2.1] octene (formula VII) to the corresponding saturated naphthyl-8-azabicyclo [3.211] octane (formula Vlla) can be accomplished via hydrogenation conditions using a precious metal catalyst such as palladium on carbon in an appropriate solvent such as EtOH, EtOAc or MeOH.

Scheme II TFA,CH2C12, [H7, Pd/C, Naphthyl-8-azabicyclo [3 2130ctane 23 °C HN EtOH, 23 °C Nlla)

(Vil) Compounds of formula IV may be prepared according to Scheme Ill.

Thus, thio, amino and oxyindoles are reacted with 2-chloromethanol, 2- chloroethanol, 2-chloro-n-propanol or 2-chloro-n-butanol in the presence of diethyl-or diisopropylazodicarboxylate, and triphenylphosphine, in a suitable solvent such as THF, CH2CI2 or MeCN to produce IV according to the procedure of Mitsunobu in Synthesis 1981,1; recent review: Hughs, Org.

React. 1992,42,337. Similar thio, amino and oxy-heterocyclic compounds may be prepared similarly.

Scheme III Compounds of formula I where X = NH, O or S, Ar1 is phenyl and A = pyridinyl (NH, O and S substituents are in the 8-position of the quinoline) require a different preparation route due to the position of the quinoline nitrogen. Compounds of formula 1, where X = NH, Ar1 is phenyl and A = pyridinyl may be prepared by reacting the corresponding 8-haloquinoline with the corresponding Ar2-8-azabicyclo [3. 2.1] oct (a/e) ne-CH2- (CH2) n-NH2 compound in the presence of NaOt-Bu and a suitable catalyst, as exemplified

in Scheme IV. Thus, compounds of formula IX are reacted with compounds of formula X, catalytic Pd2dba3 or Pd (OAc) 2, catalytic BINAP or other suitable phosphine ligands known to a skilled artisan, in the presence of NaOt-Bu, in PhMe or THF at 80 °C to give compounds of type Vil in accordance with the procedure described by Buchwald in Angew. Chem., Int. Ed. Engl. 1995,34, 1348.

Scheme IV

n = 0-3 (VIII) Compounds of formula IX may be prepared according to Scheme V.

Alkylation of the secondary amine in a compound of formula Vil or formula Vlla with 2- (N-Boc amino) ethyl chloride (prepared according to the procedure of Tanaka (Chem. Pharm. Bull. 1988,36,3125) in the presence of Et3N in a solvent such as CH2CI2 or DMF gives the N-Boc ethylamin derivative of formula Xi. Removal of the Boc group is accomplished by treatment with TFA in a solvent such as CH2CI2 to give naphthyl-8- azabicyclo [3.2.1] octene/naphthyl-8-azabicyclo [3.2.1] octane of formula IX.

Scheme V

(Xl) (IX) In the case where the bromoarene is a 3-bromoindole, 3-indolyltropene (formula IX) may be synthesized according to Scheme V !. Thus 3-Br-N-TBS-

indole (formula XII), prepared according to the procedure of Bosch in J. Org.

Chem. 1994,59,10, is lithiated using an alkyl lithium such as t-BuLi and then reacted with N-Boc-tropinone to give tropinol (formula XIII). Deprotection of both the TBS groups and elimination of H20 occurs with TFA or other acids to give 3-indole-8-azabicyclo [3.2.1] octene XIV. Reduction using hydrogen gas, a precious metal catalyst such as palladium on carbon in a suitable solvent such as EtOH, MeOH, or EtOAc gives indole-8-azabicyclo [3.2.1] octane XIVa.

Scheme VI TBS H N N Br HO 1. t-BuLi, THF,-78°C TFA, CH2CI2 N 2. 0 THF,-78 to BocN HN H2, Pd/C TBS 23 °C EfOH, (XIII) (Xll) 23 °C (XI) Indoletropane (XIVa)

8-Bromoquinolines, such as a compound according to formula X, may be synthesized as shown in Scheme VII. 2-Nitroanilines of formula XV may be converted to their corresponding nitroquinolines (formula XVI) via a Skraup reaction using glycerol, 3-NO2PhSO3Na in hot concentrated H2SO4 according to Palmer in J. Chem. Soc. 1962,3645, reduction of the nitroquinoline to the corresponding quinolineamine (formula XVII) may be accomplished using H2, a precious metal catalyst such as Pd on carbon in a solvent such as EtOAc or EtOH or iron, NH4CI and H20 in an alcoholic solvent. Diazotization of the compound of formula XVII using NaN02 in HBr, followed by heating in the presence of CuBr and additional HBr at an elevated temperature produces the 8-bromoquinoline of formula X.

Scheme Vil OH H2, Pd/C EtOH, THF, 23 °C I. NaNO2, HBr, 0 °C NH2 > YNW Fe, NH4CI tNJ 2. CuBr, HBr, 75 °C NO 3 NO EtOH, HO, reflux NH 02N H2SO4, H2O, reflux (XVI) (XVII)

Compounds of formula I where X = O, and A-Ar1 form an 8-quinolinyl may be prepared by reacting the corresponding 8-hydroxyquinoline with the corresponding Ar2-8-azabicyclo [3.2.1] oct (a/e) ne-CH2- (CH2) n-halide compound in the presence of NaH, as exemplified in the following Scheme VIII. Thus a compound of formula XIX is reacted with compound of formula XX, a NaH dispersion in mineral oil, in an appropriate solvent such as DMSO or DMF at 80 °C to produce the compound of formula XVIII.

Scheme VIII

Naphthyl-8-azabicyclo [3.2.1] octene/naphthyl-8-azabicyclo [3.2.1] octane (formula XIX) may be prepared according to Scheme IX. Thus naphthyl-8- azabicyclo [3.2.1] octenes/naphthyl-8-azabicyclo [3.2.1] octanes of formulae VII and Vlla are reacted with 2-bromoethanol in the presence of K2CO3 at 80 °C in an appropriate solvent such as DMF, DMSO or EtOH to produce the compound of formula XXII. Conversion to the corresponding chloride (formula XIX) may be accomplished using MsCl, a tertiary amine base such as Et3N or i-Pr2NEt in a solvent such as CH2CI2, CI (CH2) 2CI or DMF.

Scheme IX

The sequence in Scheme VI may also be applied to indoles of formulae XIV and XIVa to synthesize the corresponding indoles of formula XIXor formula XVII.

Compounds of formula I where X = S may be prepared by reacting the corresponding 8-thioquinoline with the corresponding Ar2-8-azabicyclo [3.2.1] oct (a/e) ne-CH2- n-halide compound in the presence of NaH, as exemplified in the following Scheme X. Thus a compound of formula XIX may be reacted with a compound of formula XXIII in a suitable solvent such as DMSO, DMF, MeCN or EtOH at an elevated temperature such as 50 °C to produce a compound of formula XXII. The synthesis of compounds of formula XIX is illustrated in Scheme IX, above.

Scheme X The synthesis of compounds of formula XXIII is shown in Scheme Xi, in which a compound of formula X is reacted with an alkyllithium such as n- BuLi, s-BuLi or t BuLi in an etherial solvent such THF or Et20, allowed to stir

for 0 to 60 minutes and then quenched with a slurry of S8 in benzene or toluene according to the procedure of Bergman et al. Isr J Chem 1969,7, 477.

Scheme XI

The present invention further provides a compound of the invention for use as an active therapeutic substance. Compounds of formula I are of particular use in the treatment of diseases affected by disorders of the serotonin.

The present invention further provides a method of treating depression and anxiety in mammals including man, which comprises administering to the afflicted mammal an effective amount of a compound or a pharmaceutical composition of the invention.

The following examples are presented to illustrate certain embodiments of the present invention, but should not be construed as limiting the scope of this invention.

EXAMPLE 1 4-2- (3-Naphthalen-2-vl-8-aza-bicvclor3.2.1 loct-2-en-8-vl)-ethoxvl-1 H- indole Step 1 4-(2-Chloro-ethoxy)-1H-indole

To 2.0 g (1.5 mmol) 4-hydroxyindole in 50 mL THF at 0 °C is added 6.3 g (24 mmol) Ph3P, 1.51 mL (1.81 g, 22.53 mmol) 2-chloroethanol and 3.78 mL (4.19 g, 24.03 mmol) diethylazodicarboxylate. After stirring at 23 °C for 20 h, the dark reaction mixture is evaporated to a black oil. Diethyl ether (30 mL) is added, the dark solution stirred on a magnetic stir plate, and 200 mL hexanes is added (to precipitate Ph3PO). After stirring at 23 °C for 30 min, the mixture is filtered and the filtrate evaporated to a light yellow oil. Flash chromatography on Si02 gel, eluting with hexanes/EtOAc (8/1 to 4/1), gives 1.13 g (5.78 mmol, a 39% yield) of the title compound as an off-white solid.

MS (ES) m/z 196 (MH) +.

Step 2 3-Hydroxy-3-naphthalen-2-yl-8-aza-bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester

To a-78 °C solution of 6.20 g (29.9 mmol) 2-bromonaphthalene and 125 mL THF is added 12 mL of 2.5 M n-BuLi/hexanes. After stirring at-78 °C for 30 mins a solution of 6.40 g (28.4 mmol) 3-oxo-8-aza-bicyclo [3.2.1] octane- 8-carboxylic acid tert-butyl ester and 14 mL THF is added dropwise. The reaction is allowed to proceed at-78 °C for 30 mins and then warmed to 23 °C over 6 h. After quenching with 100 mL 1N NaOH and extraction with 3 x 100 mL of EtOAc, the combined organics are washed with 1 x 100 mL H20,1 x 100 mL brine, dried over MgS04, filtered, and the volatiles removed. Flash chromatography in Si02 gel, eluting with hexanes/EtOAc (4/1 to 1/1) gives 7.00 g (19.8 mmol, a 66% yield) of the title compound as a white solid. MS (ES) m/z 354 (M++H, 100).

Step 3 3-Naphthalen-2-yl-8-aza-bicyclo [3.2.1] oct-2-ene 3-Hydroxy-3-naphthalen-2-yl-8-aza-bicyclo [3.2.1] octane- 8-carboxylic acid tert-butyl ester (6.80 g, 19.3 mmol) and 10 mL TFA are stirred at 23°C in 80 mL of CH2Cf2 for 2.5 h. The volatiles are removed and the residue partitioned between 100 mL of saturated NaHC03 and 100 mL EtOAc. The aqueous layer is extracted with 2 x 50 mL EtOAc, and the combined organics are washed with 3 x 50 mL H20, 1 x 50 mL brine, dried over MgS04, filtered, and stripped to give 4.50 g (19.1 mmol, a 100% yield) of the title compound as a white solid. MS (ES) m/z (relative intensity): 236 (M++H, 100).

Step 4 <BR> <BR> 4- [2- (3-Naphthalen-2-yl-8-aza-bicyclo [3. 2. 1] oct-2-en-8-yl)-ethoxy]-1 H- indole

4- (2-Chloro-ethoxy)-1 H-indole (170 mg, 0.87 mmol), 469 mg (1.74 mmol) of 3-naphthalen-2-yl-8-aza-bicyclo [3.2.1] oct-2-ene and 10 mL of DMSO are heated at 100 °C for 24 h. After cooling to 23 °C, the orange reaction mixture is poured into 100 mL H20. Extraction with CH2CI2 (2 x 50 mL), combining the organic layers and washing with H20 (4 x 50 mL), brine (1 x 50 mL), drying over MgS04, and evaporation gives an orange oil. Flash chromatography on Si02 gel, eluting with CHCWMeOH (40/1 to 10/1), gives 216 mg (0.59 mmol, a 63% yield) of the title compound as an off-white solid.

The corresponding oxalate salt is prepared by combining the title compound with 1 equiv. of oxalic acid in EtOH. A white solid precipitates.

Recrystallization from EtOH/Et2O gives the oxalate salt of the title compound as an off-white solid. mp: 212-215 °C ; MS (ES) m/z 395 (MH) +.

EXAMPLE 2 3-f8-2- (1 H-Indol-4-vloxv) ethvll-8-azabicvclof3. 2. 1]oct-2-en-3-yl}-1H-indole Step 1 tert-Butyl-3-{1-[tert-butyl(dimethyl)silyl]-1H-indol-3-yl}-3 -hydroxy-8- azabicyclo [3. 2.1] octane-8-carboxylate

To 4.8 g (15.5 mmol) 3-bromo-1-(tert-butyl-dimethyl-silanyl)-1H-indole in 60 mL THF at-78 °C is added 19.1 mL (32.5 mmol) of a 1.7M solution of t- BuLi/pentane in drops over 10 min. After stirring at-78 °C for 30 min, 3.48 g (15.5 mmol) 3-oxo-8-aza-bicyclo [3.2.1] octane-8-carboxylic acid ter-butyl ester in 20 mL THF is added via a cannula over 5 min. After stirring at 23 °C for 3 h, the reaction mixture is poured into sat. aqueous NaHC03, and extracted with 2 x 50 mL EtOAc. The combined organics are washed with 1 x 100 mL H20, 1 x 100 mL brine, dried over MgS04, filtered and evaporated to an orange oil. Flash chromatography on Si02 gel, eluting with CH2CI2/EtOAc (80/1 to 20/1), gives 3.74 g (8.2 mmol, a 53% yield) of the title compound as an off-white wax. MS (ES) m/z 457 (MH) +.

Step 2 3- (8-Aza-bicyclo [3. 2.1] oct-2-en-3-yl)-1H-indole To 1.25 g (2.74 mmol) tert-butyl-3- {1- [tert-butyl (dimethyl) silyl]-1H-indol- 3-yl}-3-hydroxy-8-azabicyclo [3.2.1] octane-8-carboxylate in 25 mL CH2CI2 is added 6 mL of TFA. After stirring at 23 °C for 45 min, the reaction mixture is poured into sat. aqueous NaHC03 (300 mL) and extracted with 3 x 50 mL CH2CI2. The combined organics are washed with 1 x 100 mL H20,1 x 100 mL of brine, dried over Na2SO4, filtered and evaporated to give 603 mg (2.24

mmol, an 82% yield) of the title compound as a yellow/orange oil. MS (ES) m/z 269 (MH)+.

Step 3 3-{8-[2-(1H-Indol-4-yloxy)ethyl]-8-azabicyclo[3. 2.1] oct-2-en-3-yl}-1 H-indole

To 200 mg (0.89 mmol) 3- (8-aza-bicyclo [3.2.1] oct-2-en-3-yl)-1H-indole, 174 mg (0.89 mmol) 4-(2-chloroethoxy)-1H-indole and 10 mL MeCN is added 246 mg (1.78 mmol) K2CO3. After heating at 80 °C for 12 h, the reaction mixture is cooled to 23 °C, filtered through celite and evaporated to a light yellow oil. Flash chromatography on SiO2 gel, eluting with CHCI3/MeOH (20/1 to 10/1), gives 208 mg (0.54 mmol, a 61% yield) of the title compound as an off-white solid. The corresponding oxalate salt is prepared by combining the title compound with 1 equivalent of oxalic acid in EtOH/Et20. The oxalate salt of the title compound precipitates as an off-white solid. Recrystallization from EtOH/Et2O gives the oxalate salt of the title compound as an off-white solid. mp: 135-138 °C ; MS (ES) m/z 384 (MH) +.

EXAMPLE 3 2-[3-(1H-Indol-3-yl)-8-azabicyclo[3. 2.11oct-2-en-8-vllethvl 5-auinolinvl ether Step 1

5- (2-Chloro-ethoxy)-quinoline

The title compound is prepared according to the procedure for Example 1, Step 1 except that 5-hydroxyquinoline is used in place of 4-hydroxyindole.

Yield : 41 %; MS (ES) m/z 208 (MH) +.

Step 2 2- [3- (1 H-Indol-3-yl)-8-azabicyclo [3. 2.1] oct-2-en-8-yl] ethyl 5-quinolinyl ether

The title compound is prepared according to the procedure of Example 2, Step 3 except that 5- (2-chloro-ethoxy)-quinoline is used in place of 4- (2- chloro-ethoxy)-1H-indole. Yield : 59%. The corresponding oxalate salt is prepared by combining the title compound with 1 equiv. of oxalic acid in EtOH/Et2O. The oxalate salt of the title compound precipitates as an off-white solid. Recrystallization from EtOH/Et20 gives the oxalate salt of the title compound as an off-white solid. mp: 91-93 °C (dec.); MS (ES) m/z 396 (MH) +.

EXAMPLE 4 <BR> 8-r2- (2, 3-Dihvdro-benzorl, 4ldioxin-5-vloxv)-ethvll-3-naphthalen-2-vl-8-aza- bicvclor3.2.11oct-2-ene Step 1 5-(2-Chloro-ethoxy)-2, 3-dihydro-benzo [1,4] dioxine

The title compound is prepared according to the procedure for Example 1, Step 1 except that 8-hydroxybenzodioxane is used instead of 4- hydroxyindole. Yield : 41 % ; MS (Cl) m/z 215 (MH)+.

Step 2 8- [2- (2, 3-Dihydro-benzo [1, 4] dioxin-5-yloxy)-ethyl]-3-naphthalen-2-yl-8-aza- bicyclo [3. 2.1] oct-2-ene The title compound is prepared according to the procedure of Example 2, Step 3 except that 5-(2-chloro-ethoxy)-2, 3-dihydro-benzo [1,4] dioxine is used in place of 4-(2-chloro-ethoxy)-1H-indole. Yield : 70%. The corresponding oxalate salt is prepared by combining the title compound with 1 equivalent of oxalic acid in EtOH. The oxalate salt of the title compound precipitates as an off-white solid. mp: 151-153°C (dec.); MS (ES) m/z 414 (MH)+.

EXAMPLE 5 6-Methoxv-N-f2-r3- (2-naphthvl)-8-azabicvclor3.2.1 loct-2-en-8-vllethvIT-8- quinolinamine Step 1 tert-Butyl 2- [3- (2-naphthyl)-8-azabicyclo [3.2.1] oct-2-en-8- yl]ethylcarbamate

3-Naphthalen-2-yl-8-aza-bicyclo [3.2.1] oct-2-ene (1.0 g, 4.25 mmol), 0.84 g (4.68 mmol) tert-butyl 2-chloroethylcarbamate, and 1.80g (12.8 mmol) K2CO3 are stirred at 80 C in 8 mL DMF for 10 h. The reaction mixture is poured into 100 mL H20 and extracted with 3 x 50 mL EtOAc. The combined organics are washed with 3 x 100 mL H2O, 1 x 100 mL brine, dried over MgS04, filtered, and the volatiles are evaporated. Flash chromatography of the crude product on Si02 gel (gradient of EtOAc to EtOAc: 2M NH3 in MeOH 10: 1) gives 0.96 g (2.54 mmol, a 60% yield) of the title compound as a yellow solid. mp: 105 C; MS (ES) m/z 379 (MH) +.

Step 2 2- [3- (2-Naphthyl)-8-azabicyclo [3.2.1] oct-2-en-8-yl] ethylamine

tert-Butyl 2- [3- (2-naphthyl)-8-azabicyclo [3.2.1] oct-2-en-8- yl] ethylcarbamate (0.50 g, 1.30 mmol) and 1 mL trifluoroacetic acid are stirred at 23 C in 20 mL CH2CI2 for 2 h. The volatiles are evaporated, and the residue is partitioned between 50 mL of saturated aqueous NaHC03 and 50 mL EtOAc. The aqueous layer is extracted with 2 x 25 mL EtOAc, and the combined organics are washed with 3 x 50 mL H20, 1 x 50 mL brine, dried over MgS04, filtered, and evaporated to give 0.22g (0.79 mmol, a 60% yield) of the title compound as an orange solid. mp: 62-65 C; MS (ES) m/z 279 (MH) +.

Step 3 6-Methoxy-8-nitroquinoline 4-Methoxy-2-nitroaniline (20.0 g, 119 mmol), 34.0 g (369 mmol) glycerol, 24.0 g (107 mmol) 3-nitrobenzensulfonic acid sodium salt, 25 mL H20

and 34 mL H2S04 are refluxed for 12 h. The reaction mixture is cooled to 45 °C, poured into 1 L of cold H20 and vigorously stirred with 500 mL of CH2CI2 for 30 min. The resulting bi-phasic solution is filtered through celite, and the aqueous layer is extracted with 3 x 300 mL CH2CI2. The combined organics are washed with 1 x 400 mL H20, 1 x 400 mL brine, dried over MgS04, filtered, and the volatiles are evaporated. Flash chromatography of the crude product on Si02 gel, eluting with hexanes/EtOAc (4/1), gives 10.0 g (49.0 mmol, a 42% yield) of the title compound as a tan solid. MS (ES) m/z 205 (MH) .

Step 4 6-Methoxy-quinolin-8-ylamine

A mixture of 9.20 g (45.1 mmol) 6-methoxy-8-nitroquinoline, 1.8 g of 10% Pd/C and 150 mL THF is placed under40 psi of H2 and shaken in a Parr reactor at 23 °C for 4 h. The Pd/C is removed via filtration through celite, and the solvent evaporated. Flash chromatography on Si02 gel, eluting with hexanes/EtOAc (1/1 to 1/3), gives 7.40 g (42.5 mmol, a 95% yield) of the title compound as an off-white solid. MS (ES) m/z 175 (MH) +.

Step 5 8-Bromo-6-methoxyquinoline To 5.05g (29. Ommol) 6-methoxy-quinolin-8-yl-amine in 25 mL of 48% HBr at 0 °C is added a solution of 2.60 g (37.7 mmol) and 20 mL H20. After stirring at 0 °C for 15 min, the resulting mixture is added dropwise to a 75 °C

solution of 5.0 g (34.8 mmol) CuBr and 60 mL of 48% HBr. After 5.5 h, the reaction mixture is neutralized with 150 mL of ice cold 5N NaOH, the resulting mixture is stirred with 300 mL EtOAc and filtered through a pad of celite. This mixture is extracted 2 x 100 mL EtOAc, and the combined organics are washed with 1 x 200 mL H20, 1 x 200 mL brine, dried over Na2SO4, filtered, and the volatiles are evaporated. Flash chromatography on Si02 gel, eluting with hexanes/EtOAc (4/1 to 1/1), gives 4.23g (17.8 mmol, a 61% yield) of the title compound as a brown oil. MS (ES) m/z 239 (MH) +.

Step 6 6-Methoxy-N-2- [3- (2-naphthyl)-8-azabicycto [3.2. 1]oct-2-en-8-yl]ethyl}-8- quinolinamine A mixture of 0.17 g, (0.61 mmol) 2- [3- (2-naphthyl)-8- azabicyclo [3.2.1] oct-2-en-8-yl] ethylamine, 0.13 g (0.55 mmol) 8-bromo-6- methoxyquinoline, 30 mg (0.03 mmol) Pd2 (dba) 3, 20 mg (0.08 mmol) 2- (di-t- butylphosphino) biphenyl and 10 mL PhMe is stirred at 23 °C for 16 h. The reaction mixture is poured into 100 mL of H20 and extracted 3 x 50 mL EtOAc.

The combined organics are washed with 1 x 100 mL H2O, 1 x 100 mL brine, dried over MgS04, filtered, and the volatiles are evaporated. The crude product is subjected to flash chromatography on Si02, eluting with EtOAc to EtOAc/2M NH3 in MeOH (40/1), to give the title compound as an off-white solid. This solid is dissolved in 4 mL of absolute EtOH and treated with 0.01 g (0.14 mmol) (CO2H) 2 to give 0.07 g (0.13 mmol, a 23% yield) of the oxalate salt of the title compound as a dark green solid : mp: 179-182 C; MS (ES) m/z 436 (MH)+.

EXAMPLE 6 6-Chloro-N-{2-[3-(2-naphthyl)-8-azabicyclo[3. 2. lloct-2-en-8-vllethyll-8- quinolinamine

Step 1<BR> <BR> 6-Chloro-8-nitroquinoline

6-Chloro-8-nitroquinoline is made by the method described for Example 5, Step 3, where 4-chloro-2-nitroaniline is used in place of 4-methoxy-2- nitroaniline. Yield : 42% of tan needles ; mp: 149-155 °C ; MS (ES) m/z 209 (MH) +.

Step 2 6-Chloro-quinolin-8-ylamine

To a solution of 6.30 g (30.3 mmol) 6-chloro-8-nitroquinoline, 14.7 g (272 mmol) NH4CI, 120 mL H20 and 250 mL EtOH is added 5.0 g (90.6 mmol) Fe powder, and the resulting mixture is refluxed for 2.5 h. The volatiles are evaporated, and the residue is stirred in mixture of 200 mL CH2CI2 and 300 mL water for 30 min. The resulting bi-phasic solution is filtered through celite, the layers are separated, and the aqueous layer is extracted 2 x 100 mL CH2Cl2.

The combined organics are washed with 1 x 100 mL H2O, 1 x 100 mL brine, dried over MgS04, filtered, and the volatiles are evaporated. Flash chromatography on Si02, eluting with hexanes/EtOAC (10/1 to 4/1), gives 2.80 g (15.7 mmol, a 52% yield) of the title compound as a tan solid. mp: 70-73 °C ; MS (ES) m/z179 (MH) +.

Step 3 8-Bromo-6-chloroquinoline 8-Bromo-6-chloroquinoline is synthesized by the method described for Example 5, Step 5, where 6-chloro-quinolin-8-ylamine is used in place of 6- methoxy-quinolin-8-yl-amine. Yield : 77% yield of a tan solid. MS (ES) m/z 243 (MH) +.

Step 4 <BR> <BR> 6-Chloro-N-{2-13-(2-naphthyl)-8-azabicyclol3.2.1] oct-2-en-8-yl] ethyl}-8-<BR> <BR> <BR> <BR> <BR> <BR> quinolinamine 6-Chloro-N- {2- [3- (2-naphthyl)-8-azabicyclo [3.2.1] oct-2-en-8-yl] ethyl}-8- quinolinamine is synthesized by the method described for Example 5, Step 6, where 8-bromo-6-chloroquinoline is used in place of 8-bromo-6- methoxyquinoline and BINAP is used in place of 2-(di-t- butylphosphino) biphenyl. The oxalate salt of the title compound, a tan solid prepared in 60% yield, is prepared as in Example 5, Step 6. mp: 205-206 °C ; MS (ES) m/z 441 (MH)+.

EXAMPLE 7 N-{2-[3-(2-Naphthyl)-8-azabicyclo[3.2.1]oct-2-en-8-yl]ethyl} -8- quinolinamine

N- {2- [3- (2-Naphthyl)-8-azabicyclo [3.2.1] oct-2-en-8-yl] ethyl}-8-quinolin- amine is prepared by the method described for Example 5, Step 6, where 8- bromo-6-chloroquinoline is used in place of 8-bromo-6-methoxyquinoline and BINAP is used in place of 2- (di-t-butylphosphino) biphenyl. The oxalate of the title compound, a yellow solid prepared in 49% yield, is synthesized as in Example 5, Step 6. mp: 199-200 C; MS (ES) m/z 406 (MH) +.

EXAMPLE 8 6-Methoxy-8-[2-(3-naphthalen-2-yl-8-azabicyclo[3. 2. 1]oct-2-en-8-yl)- ethoxvl-quinoline

Step 1 2-l3-(2-Naphthyl)-8-azabicyclol321] oct-2-en-8-yl] ethanol

3-Naphthalen-2-yl-8-aza-bicyclo [3.2.1] oct-2-ene (1.00 g, 4.25 mmol), 1.05 g (8. 40 mmol) 2-bromoethanol, 1.70g (12.6 mmol) K2CO3 and 57 mL of DMF are stirred at 80 C for 12 h. The reaction mixture is poured into 300 mL of cold H20 and extracted with 3 x 50 mL of EtOAc. The combined organics

are washed with 3 x 100 mL of H2O, 1 x 100 mL of brine, dried over MgS04, filtered, and the volatiles are evaporated to give 1.08 g (3.87 mmol, a 91% yield) of the title compound as a white solid. mp: 113-114 °C ; MS (ES) m/z 280 (MH) +.

Step 2 8- (2-Chloroethyl)-3- (2-naphthyl)-8-azabicyclo [3.2.1] oct-2-ene 2- [3- (2-Naphthyl)-8-azabicyclo [3.2.1] oct-2-en-8-yl] ethanol (0.95 g, 3.40 mmol), 0.42 g (3.70 mmol) MsCI, 0.71 mL (515 mg, 5.10 mmol) Et3N and 20 mL CH2CI2 are stirred at 23 C in for 12 h. The reaction mixture is poured into 200 mL of H20 and extracted with 3 x 50 mL CH2CI2. The combined organics are washed with H20 (3 x 100 mL,) brine (1 x 100 mL), dried over MgS04, filtered, and the volatiles are evaporated. Flash chromatography on Si02 gel, eluting with EtOAc/MeOH (20/1 to 10/1), gives 0.50 g (1.68 mmol, a 50% yield) of the title compound as a tan solid. mp: 122-123 °C ; MS (ES) m/z 298 (MH) +.

Step 3 6,8-Dimethoxyquinoline 2,4-Dimethoxyaniline (20.0 g, 131 mmol), 8. 70 mL (7.30 g, 131 mmol) acrolein and 500 mL 1N HCI are refluxed for 30 min. The reaction mixture is cooled to 23 °C, poured into 200 mL of vigorously stirring EtOAc, and neutralized with 10N NaOH. The resulting bi-phasic solution is stirred for 30 min and filtered through celite. The layers are separated, and the aqueous layer is extracted with 3 x 300 mL EtOAc. The combined organics are washed with 1 x 400 mL H20, 1 x 400 mL brine, dried over MgS04, filtered, and the

volatiles are evaporated. Flash chromatography on Si02, eluting with 4/1 EtOAc/hexanes containing 10% MeOH, gives 6.40 g (33.8 mmol, a 26% yield) of the title compound as an off-white solid. MS (ES) m/z 190 (MH) +.

Step 4 6-Methoxyquinolin-8-ol

To a-25 °C solution of 3.0 g (15.9 mmol) 6,8-dimethoxyquinoline and 160 mL CH2CI2 is added 16 mL (15.9 mmol) of 1M BBr3 in CH2CI2. After stirring for 2 h at-25 °C, the reaction mixture is quenched with 300 mL of H2O, the layers separated in a separatory funnel, and the aqueous extracted with CH2CI2 (2 x 100 mL). The combined organics are washed with 1 x 100 mL H2O, 1 x 100 mL brine, dried over MgS04, filtered, and the volatiles are evaporated. Flash chromatography on Si02, eluting with 3/1 EtOAc/hexanes containing 10% MeOH, gives 0.96 g (5.48 mmol, a 34% yield) of the title compound as an tan solid. MS (ES) m/z 176 (MH) +.

Step 5 6-Methoxy-8-E2-(3-naphthalen-2-yl-8-azabicyclot3. 2.1] oct-2-en-8-yl)- ethoxy]-quinoline

8-(2-Chloroethyl)-3-(2-naphthyl)-8-azabicyclo[3. 2.1] oct-2-ene (0.50 g, 1.70 mmol), 0.39g (2.20 mmol) 6-methoxyquinolin-8-ol, 0.08 g (2.00 mmol) NaH (60% dispersion in mineral oil) and 3 mL DMSO are stirred at 50 C for 16 h. The reaction mixture is poured into 100 mL of H20 and extracted with 3 x 50 mL EtOAc. The combined organics are washed with 3 x 100 mL H2O, 1 x 100 mL brine, dried over MgS04, filtered, and the volatiles are evaporated.

The crude product is subjected to flash chromatography on Si02 gel, eluting with EtOAc and then 40/1 EtOAc/2M NH3 in MeOH, to produce an off-white solid. This solid is treated with 0.06 g (0.67 mmol) (C02H) 2 in 4 mL of absolute EtOH to give 0.33 g (0.13 mmol, a 38% yield) of the oxalate salt of the title compound as a white solid.. mp: 100-103 °C ; MS (ES) m/z 437 (MH) +.

EXAMPLE 9 8-r2- (Indan-4-vloxv)-ethvll-3-naphthalen-2-vl-8-azabicvclor3. 2. lloct-2-ene Step 1 4- (2-Chtoroethoxy)-indan 4- (2-Chloroethoxy)-indan is made by the method described for Example 1, Step 1, where 4-indanol is used in place of 4- (2-chloro-ethoxy)-1H-indole Yield : 53% yield of a pale yellow oil. MS (ES) m/z 197 (MH) +.

Step 2 8- [2- (Indan-4-yloxy)-ethyl]-3-naphthalen-2-yl-8-azabicyclo [3.2.1] oct-2-ene The title compound is prepared according to the procedure of Example 1, Step 4, except that 4- (2-chloroethoxy)-indan is used in place of 4- (2-chloro- ethoxy)-1H-indole. The oxalate salt of the title compound is prepared by treating the title compound with 1 equivalent of oxalic acid in EtOH. Yield : 37% yield of a white solid. mp: 172-174 °C ; MS (ES) m/z 396 (MH) +.

EXAMPLE 10<BR> <BR> 4-{2-[3-(6-Methoxy-naphthalen-2-yl)-8-aza-bicyclo[3.2.1]oct- 2-en-8-yl]#<BR> <BR> ethoxv}-1 H-indole

Step 1 3-Hydroxy-3- (6-methoxy-naphthalen-2-yl)-8-aza-bicyclo [3. 2.1] octane-8- carboxylic acid ter-butyl ester The title compound is prepared according to the procedure of Example 1, Step 2, except that 2-bromo-6-methoxy-naphthalene is used in place of 2- bromonaphthalene. Yield : 43%; MS (ES) milz 384 (MH) +.

Step 2 3-(6-Methoxy-naphthalen-2-yl)-8-aza-bicyclo[3. 2.1] oct-2-ene The title compound is prepared according to the procedure of Example 1, Step 3, except that 3-hydroxy-3-(6-methoxy-naphthalen-2-yl)8-aza- bicyclo [3.2.1] octane-8-carboxylic acid tert-butyl ester is used in place of 3- hydroxy-3-naphthalen-2-yl-8-aza-bicyclo [3.2.1] octane-8-carboxylic acid tert- butyl ester. Yield 85% ; mp: 138 °C ; MS (ES) m/z 266 (MH) +.

Step 3 4-{2-[3-(6-Methoxy-naphthalen-2-yl)-8-aza-bicyclo[3. 2.1] oct-2-en-8-yl]- ethoxy}-1H-indole

The title compound is prepared according to the procedure of Example 1, Step 4 except that 3-(6-methoxy-naphthalen-2-yl)-8-aza-bicyclo [3.2.1] oct-2- ene is used in place of 3-naphthalen-2-yl-8-aza-bicyclo [3.2.1] oct-2-ene. Yield : 44%. The oxalate salt of the title compound is prepared by treating the title compound with 1 equiv. of oxalic acid in EtOH/Et20. mp : 130-132 °C (dec.); MS (ES) m/z 425 (MH) +. <BR> <BR> <P> EXAMPLE 11<BR> 3-Naphthalen-2-vl-8-r2- (3-trifluoromethvl-phenoxv)-ethvll-8-aza- bicyclo[3.2.1]oct-2-ene Step 1 1-(2-Chloro-ethoxy)-3-trifluoromethyl-benzene The title compound is prepared according to the procedure of Example 1, Step 1, except that 3-trifluoromethylphenol is used in place of 4- hydroxyindole. Yield : 99%; MS (Cl) m/z 225 (MH) +.

Step 2<BR> <BR> 3-Naphthalen-2-yl-8- [2- (3-trifluoromethyl-phenoxy)-ethyl]-8-aza- bicyclo [3. 2.1] oct-2-ene

The title compound is prepared according to the procedure of Example 1, Step 4 except that 1- (2-chloro-ethoxy)-3-trifluoromethyl-benzene is used in place 4- (2-chloro-ethoxy)-1H-indole. Yield : 33%. The oxalate salt of the title compound is prepared by treating the title compound with 1 equiv. of oxalic acid in EtOH. mp: 128-130 °C (dec.); MS (ES) m/z 424 (MH) +.

EXAMPLE 12 4-f2- (3-Naphthalen-2-vl-8-aza-bicvclof3. 2. 1]oct-8-yl)-ethoxy]-1H-indole Step 1 3- (2-Naphthyl)-8-azabicyclo [3. 2.1] octane To 313 mg (1.33 mmol) 3-naphthalen-2-yl-8-aza-bicyclo [3.2.1] oct-2-ene in 10 mL EtOAc is added 100 mg of 10% Pd/C. This mixture is placed under 40 psi of H2 and shaken in a Parr hydrogenator for 47 h. The resulting mixture is then filtered through celite and evaporated to give 197 mg (0.83 mmol, a 62% yield) of the title compound as a white solid. mp: 189-194 °C ; MS (ES) m/z 238 (MH) +.

Step 2 4- [2- (3-Naphthalen-2-yl-8-aza-bicyclo [3. 2.1] yl)-ethoxyl"1H-indole

The title compound is prepared according to the procedure of Example 1, Step 4 except that 3- (2-naphthyl)-8-azabicyclo [3.2.1] octane is used in place of 3-naphthalen-2-yl-8-aza-bicyclo [3.2.1] oct-2-ene. Yield: 36%. The corresponding oxalate salt is prepared by treating the title compound with 1 equiv. of oxalic acid in EtOH. mp: 119-120 °C (dec.); MS (ES) m/z 397 (MH) +.

EXAMPLE 13 4-f2-r3- (3, 4-Dichloro-phenvl)-8-aza-bicvclor3. 2. 1]oct-2-en-8-yl]-ethoxy}-1H- indole

Step 1 3- (3, 4-Dichloro-phenyl)-8-methyl-8-aza-bicyclo [3. 2.1] octanol

To 4.0 mL (7.04 g, 31.18 mmol) 4-bromo-1,2-dichloro-benzene in 100 mL THF at-78 °C is added 12.47 mL of a 2.5 M solution of n-BuLi in hexanes in drops over 5 min. After stirring at-78 °C for 45 min, 4.34 g (31.18 mmol) tropinone is added as a solid. The resulting mixture is warmed to 23 °C and stirred for 18 h. After pouring into 2.5 N NaOH, the reaction mixture is extracted with 2 x 100 mL EtOAc, the organics are combined and washed with 1 x 100 mL H20, 1 x 100 mL brine, dried over MgS04, filtered and evaporated to an off-white solid. Flash chromatography on Si02 gel, eluting with

CHCI3/MeOH (20/1 to 5/1), gives 2.58 g (9.02 mmol, a 28% yield) of the title compound as a white solid. mp: 153-154 °C ; MS (ES) m/z 287 (MH) +.

Step 2 3- (3, 4-Dichloro-phenyl)-8-methyl-8-aza-bicyclo [3.2.1] oct-2-ene

To 2.35 g (8.76 mmol) of 3- (3, 4-dichloro-phenyl)-8-methyl-8-aza- bicyclo [3.2.1] octanol in 50 mL of CI (CH2) 2CI is added 1.92 mL (3.13 g, 26.67 mmol) SOCI2. After stirring at 23 C for 17 h, the reaction mixture is poured into 5 N NaOH, extracted with 1 x 100 mL H20,1 x 100 mL brine, dried over MgS04, filtered and extracted to give a brown oil. Flash chromatography on Si02, eluting with CHCI3/MeOH (40/1 to 10/1) gives 1.24 g (4.62 mmol, a 53% yield) of the title compound as an orange oil. MS (ES) m/z 269 (MH) +.

Step 3 3- (3, 4-Dichloro-phenyl)-8-aza-bicyclo [3. 2. 1] oct-2-ene

To 1.08 g (4.03 mmol) 3- (3, 4-dichloro-phenyl)-8-methyl-8-aza- bicyclo [3.2.1] oct-2-ene in 20 mL CI (CH2) 2CI is added 1.31 mL (1.73 g, 12.08 mmol) of 1-chloroethyl chloroformate, and the resulting mixture is heated to reflux for 24 h. Evaporation of all volatiles gives an orange oil which is dissolved in methanol (20 mL) and heated to reflux for 1 h. Evaporation of all volatiles yielded an orange solid which is dissolved in 100 H20 and treated with 50 mL of 2.5 N NaOH. Extraction with 3 x 25 mL CH2CI2, combining the organics and washing with 1 x 50 mL H2O, 1 x 50 mL brine, drying over MgS04, filtering and evaporation a dark orange oil. Flash chromatography on Si02 gel, eluting with EtOAc, then 10/1 EtOAc/2.0M NH3 in MeOH), gives 511 mg (2.01 mmol, a 50% yield) of the title compound as an orange solid. The

oxalate salt of the title compound may be prepared by combining the title compound with 1 equiv. of oxalic acid in EtOH. A white solid precipitates. mp: 185-186 °C. MS (ES) m/z 255 (MH) +.

Step 4 4- (2- [3- (3, 4-Dichloro-phenyl)-8-aza-bicyclo [3. 2.1] oct-2-en-8-yl]-ethoxy}-1 H- indole

The title compound is prepared according to the procedure of Example 1, Step 4 except that 3- (3, 4-dichloro-phenyl)-8-aza-bicyclo [3.2.1] oct-2-ene is used in place of 3-naphthalen-2-yl-8-aza-bicyclo [3.2.1] oct-2-ene. Yield: 44%.

The corresponding oxalate salt is prepared by treating the title compound with 1 equiv. of oxalic acid in EtOH/Et20. mp: 120-123 °C (dec.); MS (ES) m/z 414 (MH) +.

EXAMPLE 14 3-{8-[3-(1H-Indol-4-yloxy)pyopyl]-8-azabicyclo[3. 2. 1]oct-2-en-3-yl}-1H- indole Step 1 4-(3-Chloropropoxy)-1H-indole

The title compound is prepared by the method described for Example 1, Step 1, where 2-chloropropanol is used in place of 2-chloroethanol Yield : 17% yield of a pale colorless wax. MS (ES) m/z210 (MH) +.

Step 2 3-{8-[3-(1H-Indol-4-yloxy)propyl]-8-azabicyclo[3. 2.1] oct-2-en-3-yl}-1 H- indole The title compound is prepared according to the procedure for Example 2, Step 3, except that 4- (3-chloropropoxy)-1H-indole is used in place of 4- (2- chloro-ethoxy)-1H-indole. Yield : 67% of a yellow gum. The corresponding oxalate salt is prepared by treating the title compound with 1 equiv. of oxalic acid in EtOH. mp: 182-184°C, MS (ES) mlz 398 (MH)-'.

EXAMPLE 15 4-[3-(3-Naphthalen-2-yl-8-aza-bicyclo[3. 2. 1]oct-2-en-8-yl)-propoxy]-1H- indole The title compound is prepared according to the procedure of Example 2, Step 3, except that 4-(3-chloropropoxy)-1H-indole is used in place of 4- (2- chloro-ethoxy)-1 H-indole and 3-naphthalen-2-yl-8-aza-bicyclo [3.2.1] oct-2-ene

is used in place of 3- (8-aza-bicyclo [3.2.1] oct-2-en-3-yl)-1H-indole. The corresponding oxalate salt is prepared by treating the title compound with 1 equiv. of oxalic acid in EtOH. Yield : 35% of a white solid. mp: 118-123 °C ; MS (ES) m/z : 409.3 (MH) +.

EXAMPLE 16 4-{3-[3-(3,4-Dichlorophenyl)-8-azabicyclo[3. 2.11oct-2-en-8-vllpropoxv-1 H- indole

The title compound is prepared according to the procedure of Example 2, Step 3, except that 4- (3-chloropropoxy)-1 H-indole is used in place of 4- (2- chloro-ethoxy)-1 H-indole and 3- (3, 4-dichloro-phenyl)-8-aza-bicyclo [3.2.1] oct-2- ene is used in place of 3- (8-aza-bicyclo [3.2.1] oct-2-en-3-yl)-1H-indole. The corresponding oxalate salt is prepared by treating the title compound with 1 equiv. of oxalic acid in EtOH. Yield : 22% of an off-white solid. mp: 150-153 °C ; MS (ES) m/z : 427.2 (MH) +.

EXAMPLE 17 8-{2-[3-(2-Naphthyl)-8-azabicyclo[3.2.1]oct-8-yl]ethoxy}quin oline

Step 1 2- [3- (2-Naphthyl)-8-azabicyclo [3. 2.1] oct-8-yl] ethanol

The title compound is prepared according to Example 8, Step 1, except that 3- (2-naphthyl)-8-azabicyclo [3.2.1] octane is used in place 3-naphthalen-2- yl-8-aza-bicyclo [3.2.1] oct-2-ene. Yield : 70%; mp: 84-88 °C ; MS (ES) m/z : 282 (MH) +.

Step 2 8-(2-Chloroethyl)-3-(2-naphthyl)-8-azabicyclo[3. 2.1] octane

The title compound is prepared according to Example 8 Step 2, except that 2- [3- (2-naphthyl)-8-azabicyclo [3.2.1] oct-8-yl] ethanol is used in place of 2- [3- (2-naphthyl)-8-azabicyclo [3.2.1] oct-2-en-8-yl] ethanol. Yield : 91%; mp: 84- 88 °C ; MS (ES) m/z : 300 (MH) +.

Step 3 8- {2- [3- (2-Naphthyl)-8-azabicyclo [3. 2.1] oct-8-yl] ethoxy} quinoline

The title compound is prepared according to Example 8, Step 5, except 8-hydroxyquinoline is used in place 6-methoxyquinolin-8-ol. The corresponding oxalate salt is prepared by treating the title compound with 1 equiv. oxalic acid in DMF to precipitate a white solid. Yield : 51 % ; mp: 110-113 °C ; MS (ES) m/z : 409 (MH) +.

EXAMPLE 18 8-({2-[3-(2-Naphthyl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}sulf anyl)quinoline

Step 1 8-Quinolinethiol To a-78 °C solution of 2.37 g (11.1 mmol) 8-bromoquinoline in 20 mL diethyl ether (anhyd.) is added 4.4 mL (11 mmol) of n-BuLi (2.5 M in hexanes) in drops over 5 min. After 15 min, a suspension of 710 mg (22.2 mmol) of elemental sulfur in 15 mL benzene (anhyd.) is added in drops over 10 min, and then allowed to warm to 23 °C. After 21 h, the mixture is poured into 200 mL 2 N NaOH, and the aqueous layer is extracted with CH2CI2 (4 x 50 mL).

The combined organics are washed with H2O (1 x 150 mL), brine (2 x 150 mL), dried over MgS04, filtered, and evaporated to an oil. The crude material was purified by flash chromatography on SiO2 gel, using a gradient elution of hexanes/EtOAc (10: 1 to 4: 1 to 1: 1), afforded 317 mg (2.0 mmol, a 20% yield) of the title compound as a tan solid. MS (ES) m/z : 162 (MH) +.

Step 2 8- ( {2- [3- (2-Naphthyt)-8-azabicycto [3. 2. 1] oct-8-yl] ethyl} sulfanyl) quinoline

The title compound was prepared by the procedure described in Example 8, Step 5, except that 8- (2-chloroethyl)-3- (2-naphthyl)-8- azabicyclo [3.2.1] octane was used in place of 8- (2-chloroethyl)-3- (2-naphthyl)- 8-azabicyclo [3.2.1] oct-2-ene, and 8-quinolinethiol was used in place of 6- methoxyquinolin-8-ol. Yield : 36% of a tan solid. The corresponding oxalate salt was prepared by combining the title compound with 1 equiv. of oxalic acid in CH2CI2/MeOH to precipitate a white solid. Yield : 71% ; mp: 200-203 °C ; MS (ES) m/z : 425.

EXAMPLE 19 The 5-HT transporter affinity of compounds illustrated in Examples 1- 18 is established in accordance with standard pharmaceutical accepted test procedures with representative compounds as follows : Rat Brain 3H-Paroxetine Binding Assay (RB 5HT Transporter): This assay is used to determine a compound's affinity of the 5-HT transporter.

The protocol is similar to that used by Cheetham et al.

(Neuropharmacol.. 1993,32,737). Briefly, frontal cortical membranes prepared from male S. D. rats are incubated with 3H-parxetine (0.1 nM) for 60 min. at 25'C. All tubes contain either vehicle, test compound (one to eight concentrations), or a saturating concentration of fluoxetine (10 uM) to define specific binding. All reactions are terminated by the addition of ice cold Tris buffer followed by rapid filtration using a Tom Tech filtration device to separate bound from free 3H-paroxetine. Bound radioactivity is quantitated using a Wallac 1205 Beta Platee counter. Nonlinear regression analysis is used to determine IC50 values which are converted to Ki values using the method of Cheng and Prusoff (Biochem. Pharmacol 1973,22,3099): ! coo ---------------------------------------------- Radioligand concentration/ (1+KD).

Inhibition of 3H-5-HT Uptake by cells Possessing the Human 5-HT Transporter (HC 5HT Transporter) : A human carcinoma cell line (Jar cells) possessing low endogenous levels of the 5-HT-transporter is seeded into 96 well plates and treated with staurosporine at least 18 h prior to assay. [Staurosporine greatly increases the expression of the 5-HT-transporter.] On the day of assay, vehicle, excess of fluoxetine, or test compound is added to various wells on the plate. All wells then receive 3H-5-HT and are incubated at 37°C for 5 min. The wells are then washed with ice cold 50 mM Tris HCI (pH 7.4) buffer and aspirated to remove free 3H-5-HT. 25 pl of 0.25 M NaOH is then added to each well to lyse the cells and 75 pI scintillation cocktail (MicroscintTM 20) added prior to quantitation on a Packard TopCount machine. Tubes with vehicle represent total possible uptake; radioactivity counted in tubes with fluoxetine represent nonspecific binding/uptake and is subtracted from the total possible uptake to give total possible specific uptake. This nonspecific binding (usual low in number) is then subtracted from the counts obtained in wells with various test compounds (or different concentrations of test drug) to give specific uptake in the presence of drug. Specific uptake is then expressed as a % of control values and is analyzed using nonlinear regression analysis (Prizm) to determine IC50 values. If the compound is active at inhibiting 5-HT uptake, its counts will be close to that obtained with fluoxetine.

Results from these two assays are presented below in Table I.

Table I. Rat Brain 3H-Paroxetine Binding Assay (RB 5-HT Transporter) and Inhibition of 3H-5-HT Uptake by cells Possessing the Human 5-HT Transporter (HC 5-HT Transporter) Data for Examples 1-18.

RB 5-HT HC 5-HT Compound n Transporter Transporter K ; (nM) IC50 (nM) Example 1 2 0.20 55.1 Example 2 1 0.94 46.4 Example 3 1 2.27 86.5 Example 4 1 0.17 21.7 Example 5 1 2.67 42.8 Example6 1 7.50 Example 7 1 1.61 Example 8--- Example 9 1 5.00 536 Example 10 1 1.11 58.6 Example 11 1 34.0 191.0 Example 12 1 0.39 35.7 Example 13 1 0.48 42.6 Example 14 1 0.65 Example 15 1 0.14 17.5 Example 16 1 0.65 39.2 Example 17 1 0.13 Example 18 1 0.06 3.5 The 5-HT1A affinity of the compounds of this invention is established in accordance with standard pharmaceutical accepted test procedures with representative compounds as follows :

Cloning of human 5-HTiA Receptor: The PCR cloning of the human 5-HT1A receptor subtype from a human genomic library has been described previously (Chanda et al., 1993). A stable Chinese hamster ovary cell line expressing the human 5-HT1A receptor subtype (h5-HT1A. CHO cells) is employed throughout this study. Cells are maintained in DMEM supplemented with 10% fetal calf serum, non-essential amino acids and penicillin/streptomycin.

Radioligand binding Cells are grown to 95-100% confluency as a monolayer before membranes are harvested for binding studies. Cells are gently scraped from the culture plates, transferred to centrifuge tubes, and washed twice by centrifugation (2000 rpm for 10 min., 4°C) in buffer (50 mM Tris; pH 7.5). The resulting pellets are aliquote and placed at-80 C. On the day of assay, the cells are thawed on ice, and resuspended in buffer. Studies are conducted using [3H] 8-OH-DPAT as the radioligand. The binding assay is performed in 96-well microtiter plates in a final total volume of 250 uL of buffer.

Competition experiments are performed by using 7 concentrations of unlabelled drug and a final ligand concentration of 1.5 nM. Non-specific binding is determined in the presence of 10 uM 5HT. Saturation analysis is conducted by using [3H] 8-OH-DPAT at concentrations ranging from 0.3-30 nM. Following a 30 minute incubation at room temperature, the reaction is terminated by the addition of ice cold buffer and rapid filtration using a M-96 Brandel Cell Harvester (Gaithersburg, MD) through a GF/B filter presoaked for 30 minutes in 0.5% polyethyleneimine.

3H-Paroxetine binding to assess affinity of drugs for the serotonin transporter (HC 5-HT_ Binding Assay : A protocol similar to that used by Cheetham et al. (Neuropharmacol.

1993,32,737) is used to determine the affinity of compounds for the serotonin transporter. Briefly, frontal cortical membranes prepared from male

S. D. rats are incubated with 3H-paroxetine (0.1 nM) for 60 min at 25°C. All tubes contain either vehicle, test compound (one to eight concentrations), or a saturating concentration of fluoxetine (10 p, M) to define specific binding. All reactions are terminated by the addition of ice cold Tris buffer followed by rapid filtration using a Tom Tech filtration device to separate bound from free 3H-paroxetine. Bound radioactivity is quantitated using a Wallac 1205 Beta Plate counter. Nonlinear regression analysis is used to determine IC50 values which are converted to Ki values using the method of Cheng and Prusoff (Biochem. Pharmacol. 1973,22,3099); Ki = IC5o/ ( (Radioligand conc.)/ (1 + KD)).

Assessment of agonism/antagonism at the 5-HT_ receptor using fS1- GTPvS binding to cloned human 5-HT_ receptors : The [35S]-GTPyS binding assay is similar to that used by Lazareno and Birdsall (Br. J. Pharmacol. 1993, 109, 1120). Briefly, 5-HT1A cloned receptor membrane fragments (as used for 5-HT1A receptor binding assays) are stored at-70 °C until needed. When needed, membranes are rapidly thawed, centrifuged at 40,000 x g for 10 minutes and resuspended at 4 °C for 10 minutes in assay buffer (25 mM HEPES, 3 mM MgCl2, 100 mM NaCI, 1 mM EDTA, 10 uM GDP, 500 mM DTT, pH 8.0). These membranes are then incubated for 30 min at 30 °C with [35S] GTPgS (1 nM) in the presence of vehicle, test compound (one to eight concentrations), or excess 8-OH-DPAT to define maximum agonist response. All reactions are terminated by the addition of ice cold Tris buffer followed by rapid filtration using a Tom Techs filtration device to separate bound from free [35S] GTPgS. Agonists produce an increase in the amount of [35S] GTPgS bound whereas antagonists produce no increase in binding. Bound radioactivity is counted and analyzed as above.

Results from these two assays are presented below in Table II.

Table II. 3H-Paroxetine binding to assess affinity of drugs for the serotonin transporter (HC 5-HT1A affinity) and Assessment of aqonism/antaqonism at the 5-HT1A receptor using 35Sl-GTPYS bindina to cloned human 5-HT1A receptors ([35S]GTPgS) Data for Examples 1-X Compound n HC 5-HT1A affinity [3tS] GTPgS Kl (nm) Emax, IC50 (nm) Example 1 2 295.3 25%, 243 nM Example 2 2 111.1 0%, 952 nM Example 3 2 173.0 0% 1169 nM Example 4 2 329.0 Example 18 1 256.0 The foregoing data show that the compounds of this invention have substantial affinity for the 5-HT transporter and are useful in the treatment of diseases affected by disorders of the serotonin-affected neurological systems, such as depression and anxiety, by administration orally, parenterally, or by aspiration to a patient in need thereof.

Many variations of the present invention not illustrated herein will occur to those skilled in the art. The present invention is not limited to the embodiments illustrate and described herein, but encompasses all the subject matter within the scope of the appended claims and equivalents thereof.