Title of Invention	BENZOFURAN DERIVATIVES
Abstract	The present invention relates to an isobenzofuran having the general Formula I wherein the subsituent are as herein described.

Full Text

The present invention relates to novel benzofuran derivatives potently binding to Ae 5-HT,A rec^tor, pharmaceutical compositions containing tiiese compounds and tiie use thereof for the treatment of certain psychiatric and neurological disorders. Many of flie compounds of the invention are also potent serotonin reuptake inhibitors and are considered to be particnilarly useful for the treatment of depression. Bacbground Art Clinical studies of known S-HT,A partial agonists such as e.g. buspirone, ips^inme and gepirone have shown that S-HT,^ partial agonists are useful in the treatment of anxiety disoiders such as generalised anxiety disorder, panic disor^r, and obsessive compulsive disorder (Glitz, D. A., Pohl, R., Drugs 1991,41,1 l).^Preclimcal studies indicate that full agonists also are useful in the treatment of the above mcntifmed anxiety related disorders (ScAappet, Human PsychophantL, 1991, (5, S53), There is also evidence, both clinical and preclinical, in support of a beneficial e£fect of 5-HT,A partial agonists in the treatment of depression as well as inqiulse control disorders and alcohol abuse (van Hest, Psychopharm., 1992, 707,474; Schipper et al. Human Psychopharm., 1991, (5, S53; Cervo et al, Eur. J. Pharm,, 1988,158, 53; Oitz. D. A., Pohl» R., Drugs 1991,41, U; Grof et al., InL Oin. Psychopharmacol 1993, 8,167-172; Ansseau et al.. Human Psychopharmacol 1993. S, 279-283). S-HT,A ^onists and partial ^onists inhibit isolation-induced aggression in male mice indicating, that these compounds are useful in the treatment of aggression (Sancfate et al, Psychopharmacology, 1993,110, 53-59). Furthermore, S-Err,^ agonists have berai reported to show activity in animal models predictive for antipsychotic effects (Wadenberg and Ahlouus, J. Neural. Transm., 1991, S3,43; Ahlenius, P/iflrraaco/. &ToxicoL, 1989, 54,3; Lowe etaL, J. Mat Chem., 1991, 34, 1S60; New et al., J. Med. Chem., 1989, 32, 1 ] 47; and Martin et al., J. Med. Chem., 19S9,32,1052) and may therefore be useful in the treatment of psychotic disorders such as schizophrenia. Recent studies also indicate that 5-HTIA receptors are in^Kntant in the serotonergic modulation of haioperidol-induced catalepsy (Ificks, Life Science 1990,47, 1609) suggesting that S-HTi^ agonists are useful in the treatment of the side rfFects induced by conventional antipsychotic agents such as e.g. haloperidol. 5-HT,A agonists have shown neuroprotective properties in rodent models of focal and global cerebral ischaemia and may, therefore, be useful in the treatment of ischaemic disease states (Prehn, Eur. J. Pharm. 1991,203,213). Phannacologicai studies have been presented which indicate that 5-HT,A antagonists are useful in the treatmait of senile dementia (Bowen et al.. Trends Neur. Sci. 1992,15, 84). An overview of 5-HT,A antagonists and proposed potential ther^Kutic targets for these antagonists based i^on preclinical and clinical data are presented by Schechter et al.. Serotonin, 1997, Vol.2, Issue 7. It is stated that 5-HTIA antagonists may be useful in the treatment of schizophrenia, dementia associated vntii Alzheimer's disease, and in combination with SSRI antidq)ressants also to be useful in the treatment of (tepression. Both in animal models and in cUnical trials it has been shown that 5-HT,A agonists exert antihypertensive effects via a central mechanism (Saxena and Villalon, Trends Pharm. Set. 1990,1 J, 95; Gillis et al,J. Pharm. Exp. Ther. 1989,248, 851). 5-HT,^ ligands may, therefore, be beaeficial in the treatment of cardiovascular disorders. 5-HT reuptake inhibitors are well known antidepressant drugs and useful for Ibe treatment of panic disorders and social phobia. The effect of combined administration of a compound that inhibits serotonin rei^take and a 5-HT, A receptor antagonist has been evaluated in several studies (Innis, K-B. et al.^ Eur. J. Pharmacol, 1987,143. p 195-204 and Gartside, S.E., Br. J. Pharmacol. 1995,115. p 1064-1070, Biier, P. et al. Trends Pharmacol Sci. 1994,15, 220). In tiiese stiKiies it was found that 5>HT,A receptor antagonists would abolish the initial brake on 5-HT I neurotransmission induced by the serotonin reuptake inhibitors and thus produce an immediate boost of 5-HT transmission and a more rapid onset of therapeutic action. Several patent applications have been filed which cover the use of a combination of a 5-HT,A antagonist and a serotonin reuptake inhibitor for the treatment of depression (see EP-A2-687 472 and EP-A2-714 663). Accordingly, agents acting on the 5-HT,A receptor, both agonists and ant^onists, are believed to be of potential use in the therapy of psychiatric and neurological disorders and thus being highly desired. Furthermore, antagonists at the same time having potent serotonin reuptake inhibition activity may be useful for the treatment of depression. Sommary of the Invention It has now been found that compounds of a certain class of benzofiiran derivatives bind to the 5-HT,A receptor with high affinities. Furthermore, it has been found that many of these compoimds have potent serotonin reuptake inhibition activity. J or R" and R^ together fonn a fused 5- or 6-nieinbered ring optionally containing further h^eroatoms; s Thus in a preferred anbodiment of the invention A is a groi^ of formula (1) and R* is methyl, ethyl, propyl, prDp-2-en-l-yl, 2-furyhnethyl, or 2-phOTOxyethyl; q = 0; or A is a group of fonnula (1) and Z is O and the other substituents are as defined above. In a fbrther embodiment of the invention, B is a groop of icnmula (II), preferably a alkoxysubstituted phenyl, a benzodioxan grovp or a l^-med^lenedioxyfoenzsoe groi^ and the oth^ substituents are as defined above. In a fiirther embodiment of the invojtjon, B is a groi^ of fomiula (III), preferably a 3-indolyi groiq) and the other substituents are as defined above. In a further embodimrait of the invention, B is a group of fonniila (HI), pr^erabiy a 3-indolyl group and the substituents R* and R' are preferably selected fitnn hydrogen, methyl, fluoro, chloro, bromo, iodo, /-butyl or i-prc^yl in the 5-position; or fhioro, chloro or carboxy in the 7-position; or by 5,7-difluoro, 4-fluoFO-7-methyl or 4-<:iiloro-7-meihyl or the two substituents together form a pyridyl ring fiised to die> In a fiirthCT embodiment of the invention, B is a grDiq> of fimnula (IV) and the other substituents are as defined above. AT is preferably phenyl or phenyl substituted wife halogeo or CFj, most preferably substituted with F or CI in the 4-position or CI or CF, in the 3-position. R' is preferably H, CN or F in the 5-position of the isobrnzofiiran groi^. R' and R^ are preferably selected Smm hydrogen or methyl. n is prefaably 2,3 or 4. m is preferably 0. In a preferred embodiment of the invention n == 2,3 or 4; R^ and R^ are bofli hydrog^; R' is H, CN or F in die 5-position of the isobenzofiiran groiqi; and AT is pboiyl which may be substituted with F or CI in the 4-position or with CI or CF, in die 3-position and the other substituents are as defined above. In another preferred embodunent of the invention, A is a group of fonnula (1); q = 0; R* is methyl; D is propylene; m = 0; and B is a l,4-ben2odioxan groiq> of Formula (II) attached in the 5-position and the otha- substituenls are as defined above. In another preferred embodiment of the invention, A is a group of fonnula (1); R* is CHj or prop-2-en-l-yl; n = 3; D is ethylene or propylene; and B is a phenyl group wherein at least one substituent is OMe and the other substituents are as defined above. In a further embodiment of the inveaition, A is a group of formula (1); q is 0; R* is methyl, ethyl, propyl, 2-propen-I-yI, 2-furyimethyI or 2-phenoxyethyi; D is ethylene, propylene or butylene; m = 0; and B is a 3-indolyl group of Formula (IH) and the other substituents are as defined above. In another preferred embodiment of the invention, A is a group of formula (2) or (3); n = 3; m = 0; and B is an 4- or 5-indolyl-group of Fonnula (TV) wherein R'" is hydrogen; R' is CN in the 5-position of the isoboizofuran and Ar is 4-Fluorophenyl and the other substituents are as defined above. The invention also relates to a pharmaceutical composition comprising a confound of fonnula (I) or a phannaceutically acceptable salt fliereof and at least one phannaceuticaJly acceptable earner or diluent. In a finlher embodiment, the invention relate to the use of a compound of fOTmula (I) or a phannaceutically acceptable acid addition salt thereof for the prq>aration of a medicament for the treatment of a disorder or disease responsive to the effect ofS-KT,,^ receptors. In particular, the invention relies to the use of a compound according to the invention or a phannaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of depression, psychosis, anxiety disorders, panic disordo', obsessive compulsive disorder, impulse control disorder, alcohol abuse, agression, ischacmia, senile dementia, cardiovascular disorders or social phobia. In still another embodiment, the presrait invention relates to a method for the treatment of a disorder or disease of hving animal body, including a human, which is respan^ve to the effect of 5-HT,A receptors comprising administering to such a living animal bodty, incixiding a human, a thCTqieutically effective amount of a compound of formula (I) OT a pharmaceutically acceptable acid addition salt thereof. The compounds of the invention have hi^ affinity for the S-HTiAiecqrtor. Accordingly, the compounds of the invention are considered usefiil for the treatment of depression, psychosis, anxiety disord^s, such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder, impulse control disorder, alcohol abuse, aggr^sion, ischaemia, senile dementia, cardiovascular disorders and social phobia. Due to their combined antagonism of 5-HT,A receptors and serotonin reuptake inhibiting ejfect, many of the compounds of the invention are considered particularly useful as &st onset of action medicaments for the treatment of depression. The compounds may also be useful for the treatment of depression in patients who are resistant to treatment with currently available antidqiressants. Detailed Description of the InvmtioB Some of the compounds of general Formula I may exist as optical isomers thereof and such optical isomers are also embraced by the invention. The term C,^ alkyl refers to a branched or mibranched alkyl group having &om one to six caibon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and 2-methyM-fffopyl. Similarly, Cj^ alkenyl and Cj^ all^Tiyl, respectively, designate such groups having frran two to six caibon atoms, inclusive. flalogen means fluoro, chlora, bromo, or iodo. The tenn Cj^ cycloalkyl designates a monocyclic or bicyclic caibocycle having three to eight C-atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The tenns C,.6 alkoxy, C,^ alkylthio, C,^ alkylsulfonyl, designate such groups in which the aikyl group is C,^ alkyl as defined above. Acyl means -CO-alkyl wherein the alkyl group is C,^ alkyl as defined above. Ci^alkyiamino means -NH-alkyI, and C^.,; dialkylamino means -N-(aIkyl)2 where the alkyl group is C^^ aikyl as defined above. Acylamino means -NH-^yl wherein acyl is as defined above. Cj^ alkoxycarbonylamino means alkyl-O-CO-NH- wherein the alkyl group is C,^ alkyl as defined above. C,^ alkylaminocarbonyiamino means alkyl-NH-CO-NH- wherein the alkyl group is C,^ alkyl as defined above. C;.,; dialkylaminocarbonyiamino means (alkylVN-CO-NH- wherein the alkyl grovp is C,^ alkyl as defined above. Exemplaiy of organic acid addition salts according to the inventioa are those with maleic, fimiaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of inorganic acid addition salts according to the invention are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids. The acid addition salts of the invention are preferably pharmaceutically acceptable salts fonned with non-toxic acids. Furthermore, the compounds of ttiis invention may exist in unsolvated as well as in solvatMi forms with pbarmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of ttiis invention. Some of the compounds of the present invention contain chiral centres and such compounds exist in the form of isomers (e.g. enantiomKs). The invention includes all such isomCTS and any mixtures thereof including racemic mixtures. Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another metiiod for resolving racemates into the optical antipodes is based i^on chromatogr^hy on an optically active matrix. Racemic compotmds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional ciystallisatirai of d- or 1- (tartrates, mandelates, or camphotsulphonate) salts for example. The compounds of the present invention may also be resolved by the formation of diastereomeric derivatives. Additional methods for the resolution of optical isomers, known to tbi^e skilled in the art, may be used. Such methods include tiwse discussed by J. Jaques, A. Collet, and S. Wilen in "Enantiomors, Racemates, and Resolutions", John Wiley and Sons, New Yodc (1981). Optically active compounds can also be prepared from optically active starting materials. The compounds of the invention can be prepared by one of the following methods comprismg: a) alkylating an amine of formula The alkylations according to Meduids a and b are generally performed by boiling die reactants under reflux or by heatii^ &em at a fixed temperature in a suitable solvent such as acetone, methyl isobutyl ketone, tetrahydrofuran, dioxane, ethanol, 2-propanDl, ethyl acetate, N,N-dimethyifonnamide, dimethyl sulfoxide or I-methyI-2-pyiToIidinone in the presence o^^a^iase su^ as ttiethylamine or potassium caibonate. Amines of fonnula V are prepared by means of danediylation according to the method described by Bigler et al, Eur. J. Med. Chem. Chim. Tber, 1977, 12, 289-295, or by the methods outlined in examples 14 and 15. The starting materials used in example 14 were prepared as described in example 9 or fiom readily available compounds by standard methods. The enantiomers of l-[3-(dimethylamino)i»ropyl]-l-(4-fluorophenyl>-l,3-dihydTOisobenzofuran-5~ carbonitrile used as starting material for the demethylation are prepared as described in EP patent No. 347066. The alkylating agents of fomiula G-(D)r(Z),-(CH3)„-B are commercially available, prepared by methods obvioas to flie chemist skilled in the art or prepared as exemplified in Exanq)les 5-8. Ethyl l,4-benzodioxan-5-carboxylate used as staiting material in Example 5 is prepared by m^bods obvious to the ciKsnist sidUed in the art from the corresponding carboxylic acid prg)ared according to literature (Fnson et al., J. Org. Chran., 1948, 13, 4S9). Alkylating agents of formula VT are prepared from the corresponding dimethylamine (Fonnula VI: G = N(Me)i) as exemplified in example 9. The secondary amines of formula H-A-(CH2)„-B are commercially available, prepared by methods obvious to the chemist skilled in the art or prepared according to literature procedures. l-(2-m^boxyphenyl)piperazine is prepared according to Pollard et al., J- Org. Chem., 1958, 23, 1333. [2-(2-Methoxyphenoxy)ethyl]methylamine and [2-{3-mediDxyphenoxy)ethyl]-methylamine are prepared as exemplified in £xanq>les 7 and 10 using commercially available 2-metboxypbaioxyacetic acid and 3-methoxyphaH3xyacctic acid, respectively, as starting materials. The reductive aDcylations according to m^hod c and d are performed according to standard literature mettiods using MaCNBH,, NaBH, or NaBH(OAc)] as reducmg agrait in a suitable solvent. The reductions according to Methods e and f are gaierally performed by use of LiAIH^, AlH] or diborane in an inert solvent such as tetrahydrofuran, dioxane, or diethyl ether at room tenq>erature or at a slightly elevated tempeaature. The release of final products by means of Hofinann elimination in Method g is generally perjbrm^ by the use of an organic base such as triefliylamine or diisopropyleOiylamine in an aprotic organic solvent such as dichlorcnn^han^ toluene or N,N-dimetbyIfoimamide. The polymer of formula Xn is prepared in a syn&esis seqtieoce as «cei]:q>lified in Example 4 and described in the following. The starting acryl ester resin (CH3CH0(O)OR') is prepared according to literature procedures (Biown et aL, J. Am. Chem. Soc., 1997, 119, 3288-95) by acylation of commercially available hydroxy substituted resins such as cross linked hydroxymethylpol^tyrene or Wang resin with acryloyl chloride. Secondary amines of formula H2N-D-Z-(CH3)„-6 are introduced by Michael addition in an organic solvent such as N^-dimethylformamide at ambient temperature. The secondary amines used are either commercially available, prepared by methods obvious to the chemist skilled in the art or prepared according to literature procedures. 3-(2-Medioxyphenyl)propyiamine is prepared according to Leeson et al., I Med. Chem. 1988, 31, 37-54, 3-(3-methoxyphenyl)propylamine according to Meise et al. Lidji^ Ann. Chem., 1987, 639-42, 3-(2-methoxyphenoxy)propylamine according to Augsein et al., J. Med. Chem., 1965, 8, 356-67, 3-(3-methoxyphenoxy)propyIamine according to Bnemner et al., Aust. J. Chem. 1984, 37,129-41, 2-benzyloxyethylamine according to Harder et al. Chem. Ber. 1964, 97. 510-19, 2-{l/^-indolyl-3-yl)ethyIamine according to Nenitzescu et al., Chem. Her., 1958, 91, U41-45 and 3-(lii/-indolyl-3-yl)propylaniineaccordingto Jackson etal., J. Am. Chem. Sec., 1930, 52, 5029. The second diversifying group is introduced by means of alkylation with an agent of fonnula VI by boiling the reactants under reflux or by beating them at a fixed temperature in a suitable solvent such as tetrahydrofuran, dioxane, ethanol, 2-propanol, ethyl acetate, N,N-dimethylformamide, dimefliy) sulfoxide or l-meaiyl-2-pyrrolidinone in the presence of a soluble base such as diisopropylethyiamine or triethylaniine, or by means of reductive alkylation with an aldehyde of formula DC using standard solid phase synthesis Uterature methods using NaCNBH^, NaBH4 or NaBH(OAc)j as reducing agent in a suitable solvent The third diversifying group was introduced by means of quartemisation using an alkylating agent of formula R'-G in an organic solvent such as tetrabydroiuran, dioxane, ethanol, 2-propanol, ethyl acetate, NJ^-dimethylfonnainide, dime&yl sulfoxide or l-methyl-2-pyrTolidinone at ambient temperature giving resins of formula XH. The indole formation according to method h is performed by the reaction of acetals of formula XIII with aryl hydrazines of formula XTV resulting in the corresponding hydrazones, which subsequently are converted into indoles by means of the Fisdier indole synthesis. The synthesis sequence is preferably performed as a one-pot procedure using a Lewis acid catalysts, preferably zinc chloride or boron fluoride, or protic acids, preferably sulfuric acid or phosphoric acid, in a suitable solvent such as acetic acid or ethanol at an elevated temperature, Acetals of fonnula XIH are prepared by alkylation of secondary amines of formula V with acetals of formula XV Melting points were detennined on a BQcfai SMP-20 ^^aratus and are uncoiTected. Mass spectra were obtained on a Quattro MS-MS system &om VG Biotedi, Fisons Instruments. The MS-MS system was coimected to an HP 1050 moAiIar HPLC syston. A volume of 20-50 ^1 of the sample (10 ttg/ral) dissolved in a mixture of 1% ac^c acid in acetonitrilAvatCT 1:1 was introduced via the autosampler at a flow of 30 ^1/min into the Electrospray Source. Spectra were obtained at two standard set& of opoating conditions. Analytical LC-MS data were obtained on a PE Sciex API 150EX instrument equipped with lonSpray source and Shimadzu LC-8A/SLC-10A LC system. The LC conditions (50 X 4.6 mm YMC ODS-A with 5 fim particle size) were linear gradient elution with water/acetonitrile/trifluoroacetic acid (90:10:0.05) to water/acetonitrile/trifiuoroacetic acid (10:90:0.03) in 7 min at 2 mL/min. Purity was determined by integration of the UV trace (254 nm). The retention times R, are expressed in minutes. One set to obtain molecular weight information (MH+) (21 eV) and the other set to induce fiagmentation patterns (70 eV). The backgroimd was subtracted. The relative intensities of the ions are obtained from the fragmentation pattern. When no intensity is indicated for the Molecular Ion (MH+), this ion was only present under the first set of operating conditions. Preparative LC-MS-separation was performed on the same instrument. The LC conditions (50 X 20 mm YMC ODS-A with 5 yun particle size) were linear gradient elution with water/acetonitrile/triQuoroacelic acid (80:20:0.05) to water/acetonitrile/trifluoroac^c acid (10:90:0.03) in 7 min at 22.7 mUmin. Fraction collection was performed by spHt-flow MS detection. 'H NMR spectra were recorded at 500.13 MHz on a Bniker Avance DRX500 instrument or at 250.13 MHz on a Bruker AC 250 instrument Deuterated chloroform (99.8%D) or dimethyl sulfoxide (99.9%D) were used as solvents. TMS was used as internal reference standard. Chemical shift valuK are expressed in ppm-values. The following abbreviations are used for multiplicity of NMR signals: s=singlet, d=doubief, ^=triplet, cpquartet, qui=quintet, h=heptet, dd=double doublet, dt=double triplet, dq=double quartet, tt=triplet of triplets, m=multiplet NMR signals coiresponding to acidic protons are gaierally omiOed. Content of water in crystalline confounds was determmed by Karl Fischer titration. Standard woiioq) pnoceiures nsfer to extraction with die indicated organic solvent fiom proper aqueous solutions, drying of combined organic extracts (anhydrous MgS04 or Na2S04), filtering and evaporation of the solvent in vacuo. For colunm chromatography silica gel of type iCieselgel 60,230-400 mesh ASTM was used. Example 1 (+)_l.[3-[[4_(l,4-Ben2odioxan-5-yl)butyl]methylanmio]pTopyl]-l-(4-fluorophenyl)-l,3-dihydroisobenzofiiran-5-caibonitrile(la). Amixtureof 5-{4-bromobutyl)-^,4~ benzodioxane (1.5 g, 5.5 mmoi), (+)-I-[3-(methylamino)propyI]-l-(4-fluorophenyl)-l,3-dihydroisobenzofuran-5-carbonitrile (2.2. g, 5.5 iranol), potassimn carbonate (3.0 g, 22 mmoi), and methyl isobutyl ketone (150 mL) was boiled under reflux for 16 h. After cooling to room temperature the organic phase was washed with water (150 mL), the solvents ev^wrated in vacuo and the remaining oil puiiSed by column chromatogr^hy {ethyl acetate/heptane/triethylamine 75:20:5) affording 2.0 g (73%) of the title compound as an oil: [aj^o + 8.93" (c 0.5; CHjOH). 'H NMR (CDClj) 3 1.25-1.35 (m. IH). 1.40-1.60 (m. 5H). 2.05-2.30 (m, 9H). 2.55 (t, 2H), 4.20-4.30 (m, 4H), 5.10-5.20 (m, 2H), 6.65-6.75 (m, 3H), 7.00 (t, 2H), 7.35 (d,lH), 7.40 (dd, 2H), 7.50 (s, IH), 7.60 (d, IH); MS m/z 501 (MH+, 100), 262 (27), 149 (77), 109 (52). The following compounds were prepared analogously: (+>l-[3-[[3-(l,4-Ben2odioxan-5-yI^)ropyl]methylanuno]propyl]-l-(4-fluorophenyl)-13-dihydroisobenzofuran-5-carbomtriie oxalate (lb): mp 114-16°C (rthyl acetate);[a]^p -*■ 8.96° (c 1.0; CH3OH); 'HNMR (DMSCW5) 5 1.35-1.45 (m, IH),1.45-1.55 (m. IH), 1.80 (m. 2H), 2.20-2.30 (m, 2H), 2.45-2.55 (m, 2H), 2.60 (s, 3H), 2.90 (m, 2H), 2.95 (m, 2H), 4.20-4.30 (m, 4H), 5.20 (m, 2H), 6.65-6.75 (m, 3H), 7.10-7.20 (m, 2H), 7.55-7.60 (m, 2H), 7.70-7.80 (m, IH), 7.80-7.95 (m, 2H); MS m/z 488 (MH+, 100). 262 (33), 149 (52), 109 (55). l-[3-[[2-(l,4-Benzodioxan-5-yI)e1hyl]methylamino]propyl3-l-(4-fluorophenyl)-l,3-dihydix)isobcn2ofuran-5-caibonitiile oxalate (Ic): mp 118-20T (ethyl acetate); 'H NMR (DMSO-d^) S 1.40-1.70 (m, 2H). 2.25 (t, 2H), 2.70 (s, 3H). 2.75-2.90 (m, 2H), 2.90-3.15 (m, 4H), 4.15-4.30 (m, 4H). 5.20 (m. 2HX 6.65-6.80 (m, 3H). 7.20 (t, 2H), 7.60 (dd, 2H), 7.70-7.85 (m, 3H); MS m/z 473 (MH+, 64), 323 (13), 262 (24X 163 (100). 109 (25). l-[3-[[l,4-Benzodioxan-5-ylmethyl]methylainino]propyl}-l-(4-fliiorophaiyl)-l,3-dihydrDisobenzofuran-5-caibonitiile oxalate (Id): mp 160-62 °C (acetonc/methanol); 'H NMR PMSO-J5) 6 1.40-1.70 (m, 2H), 2.25 (t, 2H), 2.60 (s, 3H), 2.90 (t, 2H), 4.00 (s, 2H), 4.20-4.30 (m, 4H), 5.20 (m, 2H), 6.80-7.00 (m, 3H). 7.15 (t, 2H), 7.50-7.65 (dd, 2H), 7.70-7.85 (m, 3H); MS m/z 459 (MH+, 7), 109 (100). Example 2 l-(4-FluorophenyI>l-[3-[4-(2-methoxyphenyl)piperazmyl]propyl]-13-dihydroisobenzofuraii-5-carbomtrile (2a). A mixture of l-(3-chloropropyl)-l-(4-fluo^ophe^yl)-l,3-dihydroisofaen2oiuran-5-ca^bomtrile (2.5 g, 7.9 mmol), I-{2-methoxyphenyI)piperazme (2.0 g, 10.4 mmol), potassium carbonate (3 g, 22 mmol) and methyl isobutyl ketone (200 mL) was boiled under reflux for 16 h. Aftar cooling to room ten^ierature the organic phase was washed with water (200 mL), the solvents were ev^orated in vacuo and the remaining oil purified by column chromatogr^hy (ethyl acetate/hq>tane/triethylamine 75:20:5). The tide compound crystallised fit)m diethyl ether 1.5 g (40 %): mp 147-49 "C; 'H NMR (DMSO-rf(j) 6 1.30-1.65 (m, 2H). 2.10-2.30 (m, 2H), 2.40 (t, 2H), 2.50-2.70 (m, 4H), 2.90-3.20 (m, 4H), 3.85 (s. 3H), 5.20 (m, 2H). 6.70-7.10 (m, 6H), 7.30-7.55 (m, 4H). 7.60 (d, IH); MS m/z, 472 (MH+, 100), 262 (14), 109 (19). The following compounds were prepared analogously: l-(4-FluorophenyI)-l-[3-[[2-(2-methoxypfaaaoxy)ethyl3methylamino}prc^yl3-l3-dihydroisobenzofuran-5-carbonitrile (2b): (oil) 'H NMR (CDQ,) 5 1.30-1.40 (m, IH), 1.40-1.55 (m, IH), 2.1O-2.20 (m, 2H), 2.25 (s, 3H), 2.40-2.45 (t, 2H), 2.70-2.80 (m, 2H), 3.70 (s. 3H), 4.05 (t, 2H), 5.15 (m, 2H). 6.85-7.00 (m, 6H), 7.30-7.45 (m, 3H). 7.50 (s, IH), 7.55 (d, IH). 1 -(4-Fluorophenyl)-1 -[3-[[2-(3-metiioxyphenoxy)ethyI]methyiamino]propyl]-l 3-dihydroisobenzoiiiran-S-caibomtrile (2c): (oil) 'H NMR (CDClj) 5 1.30-1.40 (m, IH), 1.40-1.55 (m, IH), 2.10-2.20 (m, 2H), 105 (s, 3H), 2.40 (t, 2H), 2.70-2.75 (m, 2H), 3.70 (s, 3H), 4.00 (t, 2H), 5.15 (m, 2H), 6.40-6.55 (m. 3H), 7.00 (t, 2H), 7.20 (t, IH), 7.35 (d, IH), 7.40 (dd, 2H), 7.50 (s, IH), 7.55 (d. IH). (5)-l-[3-[[4-(I//-Indol-3-yl)butyl]methylamino]propyl]-l-(4-fiuon^henyl)-13-dihydro-isobenzofuran-S-carbonitile (2d): LC/MS (m/z) 482 (MH*), Rt = 4.24, purity: 84 %. l-[3-[[4-(I//-Indol-3-yl)butyl]metiiylamino]propyl]-I-ph«iyI-l,3-dihydioisobenzofuran (2e): LC/MS (m/z) 439 (MIT), Rt = 4.33, purity: 77 %. (Sy 1 -[3-[[3-( lif-Indol-3-yl)propyi]methylanuno]propyI]-1 -(4-fluorophenyl>l 3-dihydroisobenzoforan-5-carbomtiile (2f): LCMS (m/z) 468 (MET). Rt = 4.11, purity: >99 %. l-[3-[[3-(lH-Imiol-3-yl)propyl3methylamino]propyI]-l-pheny!-13-dihydroisoben2ofiiran (2g): LC/MS (m/z) 425 (MfT). Rt = 4.15, purity: >99 %. 5-[3-[[3-{l-PhenyH,3-dihydroisobenzofuran-l-yI)propyl3metfayIamino]propyl3-l,4-benzodioxaae (2h): LC/MS (m/z) 444 (MIT), Rt = 4.12. purity: 97 %. 5-[3-[[3-[l-(3-Chlorophenyl)-U3H3ihydroisobenzofiiran-l-yI]propyI}methylamino]propyI]-1,4-benzodioxane (2i): LC/MS (m/z) 478 (MH*), Rt = 4.45, purity: 93 %. 5-[3-[[3-[l-(4-nuorophenyI)-13-dihydroisobenzofiiran-l-yl]propyl]mefeylamino]propyl]-1,4-benzodioxane (2j): LC/MS (m/z) 462 (MET), Rt = 4.21. purity: 93 %. 5-[3-[[3-[l-(3-Trifluoromethylphrayl)-13-dihydroisobenzoftiran-l-yl]propyl]methylamino]propyl]-1.4-benzodioxane (2k): LC/MS (m/z) 512 (MH*), Rt= 4.59, purity: 90 %. l-[3-[[3-(1.4-Benzodioxan-5-yl)propyI3methylamino]propyl]-l-(4-chioropheny!)-l,3-dihydroisobenzoiuran-5-carbomtrile (21): LC/MS (m/z) 503 (MH*), Rt = 4.59, purity: >99 %. l-[3-[4-(l/f-Indol-4-yl)pg)eraziny!]propyl]-l-(4-fluorophaiyI)-13-dihydroisobenzofiiran-5-carbonitrile (2m): LC/MS (m/z) 481 (MH*), Rt = 5.61, purity: 97 %. l-[3-[4- l-[3-[4-(6-chioro-lfl'-Indo!-3-yl)pip«idinyi]propyll-l-(4-fluon^h«iyI)-13-dihydroisobenzofiiran-5-carbomtrile (2o): LC/MS (m/z) 514 (MH*). Rt = 6.38, purity: 96 %. Example 3 5-[3-[[3-[-S-Fluoro-l- dissolved in dichloromethane (30 mL). The resulting solution was added to a solution [3-[-5-fluoro-l-(4-fluorDphenyi)-l,3-dihydroisobenzofuran-l-yl}pn^yl]methyiamine (3.0 g, 10 nimol) and triethylamine (10 mL) in dichloromethane (100 mL). After stimng for 16 h the volatile solvents wrare ev^orated in vacuo and the remaining oil was purified by column chromatogr^hy (ethyl acetate/heptane 75:25) affording 1.4 g of crude amide which was used without fiirther purification. To a solution of the amide (1.4 g, 2.8 nunc!) in tetrahydrofiiran (200 mL) was added lithium aluminum hydride (1.0 g, 2.6 mmol). Alter boiling of the resulting mixture under reflux for 3 h, the reaction mixture was cooled to 0 "C and carefully treated with water (1 mL) and 4 H aqueous sodium hydroxide (1 mL). The resulting mixture was filtered and dried (Na^SOJ. Evaporation of the volatile solvraits afforded tiie title compound as an oil which was precipitated as its oxalate in acetone 0.9 g (19%): mp 131-33 "C; 'H NMR (DMSO-rfg) 5 1.35-1.45 (m, IH). 1.45-1.55 (m, IH), 1.75-1.80 (m, 2H). 2.10-2.25 (m, 2H), 2.50-2.55 (m, 2H), 2.60 { s. 3H), 2.90 (t, 2H). 2.95 (t, 2H), 4.20^.25 (m, 4H), 5.10 (m, 2H), 6.65-6.75 (m, 3H), 7.10-7.15 (m, 4H), 7.45-7.60 (m, 3H); MS m/z, 480 (MH+, 100), 225 (34), 109 (51). Example 4 l-[3-[[2-(li/-Indol-3-yl)ethyl]nietiiylanunolpropyl]-l-(4-fluoTophettyl)-l,3-dihydroisobenzofiiran-5-carbonitrile (4a). To a suspension of acryl esta- Wang resin (CH3CHC(0)0R', HOR' * Wang resm) (loading 1.0 mmol/g) (300 mg, 0.30 mmol) (prepared from Wang resin (Loadmg 1.09 mmol/g, 200-400 mesh, 1 % divinylbenzaie) in analogy with the procedure described for the preparation of acryl esto* hydroxymediyl polystyrene by Brown et aL. J. Am. Chem. Soc., 1997,119,3288-95) in N,N-dimefliylformamide (1.5 mL) was added a solution of 2-(lf/-ind3lyl-3-yl)etiiylamine (96 mg, 0.60 nmioi) in N,N-dimethylfbrmamide (1.5 mL). After stirring of the resulting suspension at room tenq>eiature for 16 h, the resin was filtered off and subsequently washed with 0.3 M diisopropyicthylamine in N,N-dimethyIfoimamide (3 X 2.5 mL), methanol (2 X 2.5 mL) and dichloromethane (2 X 2.5 mL). To a suqaension of the resulting r«in in acetonitrile (1.5 mL) was added a solution of l- (473 mg, 1.5 mmol) in acetomtrile (1.5 mL) and diisopropylethylamine (280 mL, 1.6 mmoi). After beating of the resulting mixture at 75 "C under stirring for 16 h, the resin was filtered off. The resin was subsequently washed with acetomtrile (3 X 2.5 mL), methanol (3 X 2.5 mL), and dichloromethane (3 X 2.5 mL). The resin was suspended in NJ^-dimethylfonnamide and diisopropylethylamine (2S0 mL, 1.6 mmoi) and acetic anhydride (140 mL, 1.5 mmoi) was added. After stirring of the resulting mixture for 16 h the r^in was filtered off and washed with NJ^-dimethylfonnamide (3 X 2.5 mL), methanol (3 X 2.5 mL), and dichloromethane (3 X 2.5 mLX The intermediate resin was suspended in N,N-dimethylfoimainide (2 mL) and a solution of iodomethan (187 mL, 3.0 mmol) in NJ^-dimethylformamide was added. After stirring of the resulting mixture for 16 h at room temperature, the resin was filtered off and washed with NJ 1 -(4-Fluoropheny 1>-1 -[3-[t2-(3-methoxyphenyl)ethyllmethylamino)propyl]-l 3-dihydroisobenzofiiran-S-carbonitrile (4b): LC/MS (m/z) 445 (MIT). R,= 8.58 , purity: 88% l-(4-Fluoropbaiyl)-l-[3-[t2-(3-methoxyphenyI)ethyI](prop-2-en-l-yl)anmio]propyl]-13-dihydroisobenzofiffan-5-carbonitrile (4c): 'H^fMR (CDQa) 6 1.30-1.60 (m, 2H), 2.00-2.20 (m. 2H), 2.40-2.55 (m, 2H), 2.55-2.70 (m, 4H), 3.00-3.15 (broad s, 2 H), 3.80 (s, 3H), 5.05- 5.20 (m, 4H), 5.75-5.85 (m. IH), 6.65-6.80 (m, 3H). 7.00 (t, 2H). 7.20 (t, IH), 7.30 (d, IH), 7.40 (m, 2H), 7.50 (s, IH), 7.60 {d, IH); LC/MS (m/z) 471 (MH*), R,= 8.85 , purity: 91% H4-FIuo^DphalyI)-l-[3-t[3-(2-mcthoxyphe^yi)p^opyI](>^op-2■^!D-l-yl)aInilK>3pn^ dihydroisobeii2ofuran-5-carbonitriie (4k): LC/MS (m/z) 485 (MS*\ R,= 6.77 , purity >99% l-[3-E[3-(lH-Indol-3-yl)propyl]methylainmojpropyl]-l-{4-fluorophenyI)-13-dibydroisobenzoiuran-5-carbonitriJe (4sy. LCMS (mJz) 468 (MfT), R,= 6.28, pmity:80% boiled unda- reflux for 16 h. After evaporation of the solvents in vacuo, wato- (200 mL) was added and die resulting slurry was extracted with diethyl ether (2 X 200 mL). The collected oi^anic phases were washed with brine, dried (NasSO^) and the solvents were evaporated in vacuo affording 4.0 g (43%) of the title compourwl as an oil: 'HNMR (CDCI3) 5 3.65 (s, 2H), 4.15-4.30 (m, 4H), 6.70-6.BS (m, 3H). Example 7 5-(2-bromoethyl)-l,4-benzDdioxan(7a), To a solution of2-(l,4-benzodioxaD-5-yI)acetic acid (6) (4.0 g, 21 mmol) in tetrahydrofuran (200 mL) was added lithium alumimun hydride (1.0 g, 26 mmol). After boiling under reflux for 2 h the reaction mixture was cooled to 0 "C and carefully treated with water (1 mL) and 4 N aqueous sodium hydroxide (1 mL). The resulting mixture was filtered and dried (NajSO^). Evaporation of tiie solvents a£fOFded crude intermediate alcohol (3.9 g, 21 mmol) as an oil which was used without fiirther purification. To a solution of the intermediate alcohol and tetrabromomethane (8.8 g, 27 mmol) in acetonitrile (120 mL) was added triphenylpho^hine (6.3 g, 24.9 mmol) in small portions at 0 °C. After reaction for fiirther 15 minutes at 0 "C the solvents were evaporated in vacuo and the remaining oil was purified by column cfaromatogre^fay (ethyl acetate/heptane 66:34) affording 5.5 g (99%) of the title compound as an oil: 'H NMR (CDCI3) 5 3.15 (t, 2H), 3.55 (t, 2H). 4.20-4.35 (m. 4H). 6.65-6.85 (ro, 3H). The following compounds were prepared analogously: 5-(3-BromopropyI)-l,4-benzodioxan (7b): (oil) 'H NMR {CDCI3) 5 2.15 (qui. 2H), 2.75 (t, 2H), 3.40 (t, 2H), 4.20-4.30 (m, 4H), 6.65-6.75 (m, 3H). 5-(4-Biomobutyl)-l,4-benzodioxan (7c): (oil) 'H NMR (CDCI3) 5 1.70-1.80 (qiii, 2H), 1.85-1.90 (qui, 2H), 2.60 (t, 2H). 3.40 (t, 2H), 4.25 (m, 4H), 6.65-6.75 (m, 3H). l-(2-Bromoethoxy)-2-methoxybenzene (7d): (oil) 'H NMR (CDQj) 5 3.65 (t, 2H), 3.85 (s, 3H), 4.30 (t, 2H), 6.80-7.05 (m, 4H). l-(2-BTomoethoxy>-3-methoxybenzene (7e): (oil) 'H NMR (CDQj) 5 3.60 (t, 2H), 3,80 (s, 3H), 4.25 (t, 2H), 6.45-6.55 (m, 3H), 7.15 (t, IH). Example 8 4-(l,4-Benzodioxan-5-yI)butanoic acid (8a). Neat 5-(4-bromoethyI)-l,4-benzodioxaii (7c) (18.0 g, 74 mmol) was added to a mixture of diethyl malonate (12 g, 75 mmol), potassium lert-butoxide (8.4 g, 75 mmol), toluene (250 mL) and dimethyl sulfoxide (50 mL) at room temperature. The resulting mixhire was heated at 50 °C for 3 h, cooled to room temperature and water was added. After the slurry was acidified with concentrated hydrochloric acid the phases were separated. The organic phase was dried (NajS04) and the solvents evaporated in vacuo. The remaining oil was dissolved in ethanol (200 nxL) and 9 N aqueous sodium hydroxide. After boiling of the resulting mixture under reflux for 15 minutes the solution was stirred at room temparature for 1 h. The solvents were evaporated and the remaining oil was diluted in water (200 mL) and extracted with diethyl ether (2 X 100 mL). The aqueous phase was acidified with 4 N hydrochloric acid and extracted with ethyl acetate (2 X 200 mL). Drying of the collected organic phases and ev^wration of the solvraits in vacuo afforded the intermediate dicarboxyHc acid as an oil (5.0 g). The crude oil was diluted in pyridine (10 mL) and the resulting solution was heated at 115 °C for 1 h. Aflor cooling to room temperature, water (50 mL) was added and the aqueous phase was acidified with 4 N hydrochloric acid. The resulting slmry was extracted with diethyl ether (2 X 50 mL) and the collected organic phases were dried (NajSO^). Evaporation of the solvents in vacuo afforded 3.8 g (23%) of the title compound as an oil. The following compoimd was prepared analogously: 3-{l,4-Benzodioxan-5-yl)propionic acid (8b): (oil) 'H NMR (CDClj) 5 2.65 (t, 2H), 2.95 (t, 2H), 4.20-4.30 (m, 4H), 6.65-6.80 (m, 3H). Example 9 l-(3-Chloropropyl)-l-(4-fluorophenyI)-l,3-dihydroisoben2ofuran-5-carbonitrile(9). To a mixture of l-[3-(methyiamino)propyl]-l-(4-fluorophenyl)-l,3-dihydroisobenzofiiran-5-carbonitrile (43 g, 138 mmol), potassium carbonate (30 g, 217 mmol), and ethanol (400 mL) was added ethyl bromoacetate (20 mL, 1 SO mmol) at room temperature and the resulting mixture was boiled under reflux for 90 minutes. After cooling to room temperature water (800 mL) and ethyl acetate (500 mL) was added and the phases were separated. The organic phase was washed with brine, dried (Na2S04) and tiie solvents evaporated in vacuo. The remaining oil (36 g, 101 mmol) was added slowly to a mixture of ethyl chlorofonnate (50 mL, 523 mmol), potassium carbonate (36 g, 260) and toluene (300 mL) at 90 °C. After boiling of the resulting mixture under reflux for 1 h and cooling to room temperature, the solvents were evaporated in vacuo. The remaining oil was purified by column chromatognq>hy (ethyl acetate/heptane 1:3) giving 15 g (34%) of the title compound as an oil: 'HNMR (CDOj) 5 1.60-1.90 (m, 2H), 2 JO-2.45 (m, 2H), 3.45-3.55 (m, 2H), 5.20 (m, 2H), 6.95-7.10 (t, 2H), 7.40-7.55 (m. 4H), 7.60 (d, IH). Example 10 [2-(2-Methoxyphenoxy)ethyl]methylamine (10a). A solution of l-(2-brDmoethoxy)-2-methoxybenzene (7d) (7.7 g, 33 mmol) in a 33% solution of methylamine in ethanol was heated at 80 "C in a sealed tube for 16 h. After cooling to room temperature, the solvents were evaporated in vacuo. A 2 N aqueous solution of sodium hydroxide was added to the remaining oil and the resulting slurry was extracted with ethyl acetate (2 X 250 mL). The collected oi^anic phases were dried (NajSOJ and the solvents evaporated in vacuo giving 5.9 g (98%) of the title compound as an oil: 'H NMR (CDCI3) 5 1.85 (broad s, IH), 2.50 (s, 3H). 3.00 (t. 2H), 3.85 (s, 3H), 4.10 (t, 2H), 6.85-6.95 (m, 4H). The following compound was pr^ared analogously: [2-(3-Methoxyphenoxy)ethyl]methylamine (1(H»): (oil) 'H NMR (CDClj) 5 1.85 (broad s, IH), 2.50 (s, 3H), 2.95 (t, 2H), 3.80 (s, 3H). 4.05 (t, 2H). 6.45-6.55 (m, 3H). 7.15 (t, IH). Example 11 2-(4-Chlorobutyl)-dioxoian-4-yhnethcxymethyl polystyrene (11a). A 2 L roimd bottom flask was charged witti 2,2-dimethyldioxolan-4-ylmethoxymethyl polystyrraie (90 g, 72 mmol, commercially available as (±)-l-(2,3-isopropylidene) glycCToI polystyrene from Calbiochem-Novabiochem, cat. no. 01-64-0291). Toluene (900 mL) followed by p- toluenesulfonic acid mono hydrate (5.0 g, 26 mmol), sodium sulfate (25 g), and readily available 5-chloropentanal (25.5 g, 211 mmol) were added and the mixture heated at reflux for 12 h. The reflux condenser was replaced by a Dean-Start apparatus and the mixture was heated at reflux for an additional 3 h. After cooling of the reaction mixture to 60 °C, the resin was filtered and wadied with toluene (200 mL), tetrahydrofiiran/pyiidine (1:1, 200 mL), tetrahydrofiiran/water/pyridine (10:10:1,200 mL), methanol (200 mL), water (2O0 mL), tetrahydrofuran (200 mL), dichloromethane (200 mL), methanol (3 X 200 mL), and dichlorometiiane (3 X 200 mL). Tlie resin was dried in vacuo (55 "C, 12 h) to yield the title compound 11a (97 g). The following compounds were prepared analogously: 2-(3-Chloropropyl)-dioxolan-4-yImethoxymethyl polystyrene (lib) 2-(5-ChloropentyI)-dioxolan-4-yhBethoxymethyI polystyrene (lie) Example 12 l-[3-[[3-(l/MndDl-3-yl)propyl]methylamino3propyi]-l-(4-fluorophenyJ)-13-dihydroisobenzofuran-S-caibonitrile (4s). 2-(4-Chlorobutyl)-dioxolan-4-ylmethoxymethyl polystyrene (11a) (8.0 g, 6,1 mmol) was suspended in dry N,N-dimefliylfotmamide (90 mL). Sodium iodide (3.38 g, 22.5 mmol) was added followed by diisopropylethylamine (6.30 mL, 36 mmol) and l-[3-(metbylamino)propyl}-l-(4-fluorophenyl)-U3-dihydroisDbaizD&ran-5-caihonitiile (5.56 g, 18 mrool). The reaction mixture was heated at 80 °C under stirring for 12 h. AStex cooling to room tempeiature, the resin was filtered and washed with with NJ^-dimethylformamide (3 X 65 mL), methanol (3 X 60 mL), tetrahydrofiiran (3 X 60 mL), and thrai subsequently with methanol and tetrahydrofiiran (each ^proximately 40 mL, 5 cycles). Finally, the resin was washed with tetrahydrofuran (4 X 40 mL) and dried in vacuo (55 "C, 12 h, 9.5 g). An aliquot of this material (147 mg, 0.112 mmol) and phenylhydrazine hydrochloride (43 mg, 0^97 mmol) were mixed in a reactor tube. A 0.5 M solution of anhydrous zinc chloride in acetic acid (1.5 mL) was added and the reaction tube was sealed. The reaction mixture was stirred for 12 h at 75 "C. After cooling to room temperature, the reaction mixture was filtered and the r^idual resin washed with dimetiiylsulfoxide (1.5 mL). To the confined filtrates was added saturated aqueous sodium bicarbonate solution (1.5 mL). The soiunon was loaaea on a reversed solid phase eixtraction column (C-18, 1 g, Varian Mega Bond Elut®, Chrompack cat no. 22050S), pre-conditioned with methanol (3 mL) and water (3 mL). The column was washed with water (4 mL) and the product was eluted with methanol (4.5 mL). The resulting solution was loaded on an ion exdiange column (SCX, 1 g, Varian Mega Bond Elut®, Chrompack cat no. 220776), pre-conditioned witii ID % solution of acetic, acid in methanol (3 mL) and the column was washed with methanol (4 mL) and acetonitrile (4 mL), followed by elation with 4 N solution of ammonia in methanol (4.5 mL). Evqwration of the volatile solvents afforded the title compound (4s) as a colourless oil (22 mg, 42 %). LC7MS (m/z) 468 (MH*), Rt = 4.30, purity: 83 %. The following compounds were prepared analogously: l-[3-[[2-(5-Methyl-l//-indoI-3-yl)ethyI]methylamino]pit)pyl3-l-(4-fluorophenyl>l,3-dihydToisobenzofuran-5-caibonitrile (12a): LC/MS (m/z) 468 (MH*), Rt = 422, purity: 96 %, l-[3-[[2-(7-Fluoro-li/-indoI-3-yI)ethyI]methyiamino]propyI]-l-(4-fluorophenyI)-l,3-dihydroisobenzofuran-5-cari>omtrile (12b): 'H NMR (CDCI3) 5 1.2-1.4 (m, IH), 1.4-1.55 (m,lH), 2.0-2.25 (m, 2H), 2.25 (s. 3H), 2.39 (t, 2H), 2.60 (t, 2H), 2.86 (t, 2H). 5.05-5.21 (m, 2H), 6.93-7.07 (m, 4H), 7.17-7.3 (m, 2H), 7.3-7.4 (m. 3H), 7.4-7.5 (m, IH), 7.5-7.6 (m, IH); LC/MS (m/z) 472 (MR*), Rt =» 4.12, purity: 86 %. 5-Fluoro-l-[3-[[3-(5-mefliyl-l/r-iDdol-3-yl)propyI]methylammo]propyl]-l-('*-iluorophenyl)-l,3-dihydroisobeiizofiiran (12c): LC/MS (m/z) 475 (MH*), RJ= 4.57, purity: 92%. 5-Fluoro-l-[3-[[3-(7-fluoro-lff-indol-3-yl)propyl]m^ylamino]propyl]-l-(4- fluorophenyl)-1,3-dihydiDisobenzofuran (12d): LC/MS (m/z) 479 (MH*), Rt = 4.47, purity: 94%. I -[3-[[3-(5-Methy 1 -1 iir-indol-3-yl)propyl]methylamino]propyl]-1 -(4-fluorophMiy!)-1,3- dihydroisoben2ofiiran-5-carbonitrile (12e): LC/MS (m/z) 482 (MH*), Rt = 4.54, purity: 80 %. l-[3-[Ethyl[3-(l//-indol-3-yl)propyl]amino]propyl]-H4-fluorophenyl)-13- dihydroisobenzofuran-5-carbonitriIe (12f): LC/MS (m/z) 482 (MH*), Rt = 4 JI, purity: 94 %. l-p-[Ethyl[2I,3-dihydroisobenzofuran-S-carbonitrile (12g): LC/MS (m/z) 482 (MJET), Rt = 438, purity: 89 I-[3-[[3-(5-ChIoro-lH-mdoi-3-yl)propyI]methylaiiiino]propyl] - 5-fluoro -I-{4-fluorophenyl) -1,3-dihydroisobenzofuraii (12ni): LC/MS (m/z) 495 (MPT), Rt = 4.64, dihydroisobenzofi2ian-5-cartK)mtriJe (12ae): LCMS (m/z) 594 (Mit), Rt = 4.60, purity: 82 l-[3-[Ethyl[3-(5-iodo-lff-mdol-3-y])propyl]aniino]propyl3-I-(4-fhK>rqpAeQy^l3-dihydroisobenzoiuran-5-carbomtrile (12af): LC/MS (m/z) 608 (MH*), Rt = 4.72, purity: 71 l-[4-[[2-(5-(2-Propyl)-li/-indo]-3.yI)ethyI]methylammo]butyl]-l.(4-auorophenyl)-13-dihydroisobenzofiiran-5-carboratrile (12ap): LC/MS (m/z) 510 (MH*), Rt = 4.72, purity: 92 %. Example 13 l-[3-[[2-(5-Methyl-l//-indol-3.yl)ethyl](prop-2-en-l-yl)amino]propyl]-l-(4-fluorophenyl>l,3-dihydroisoben20fiiran-5-carbonitrile(13a). 2-(3-Chloropropyl)-l,3-dioxolan-4-ylmethoxymethyl polystyrene (2.0 g, 1.6 nrniol) was suspended in dry N,N-dimethylfonnamide (15 mL). Sodium iodide (0.67 g, 4.5 mmol) was added followed by diisopropylethylamine (1.70 mL, 9,6 mmol) and allyl amine (0.28 g, 4.8 mmol). The reaction mixture was heated at 80 "C under stirring for 12 h. After cooling to room temperature, the resin was filtered and washed with NJ^-dimethylformamide (3 X15 mL), methanol (3X15 mL), tetrahydrofiiran (3X15 mL), and subsequently with methano! and tetrahydrofiiran (each 10 mL, 5 cycles). Finally, the resin was washed with tetrahydrofiiran (4 X 10 mL) and dried in vacuo (55 *C, 12 h). The resin was then suspended in dry N,N-dimethylfonnaimde (20 mL). Sodium iodide (0.60 g, 4.0 mmol) was added followed by diisopropylethylamine (0.48 mL, 2.7 mmol) and l-(3-chloroprc^y!)-l-(4-fluoropheny!)-l,3-dihydroisobenzofiiran-5-caibonitrile (9) (0.79 g, 2.5 mmol). The reaction mixture was stirred for 12 h at 80 "C. After cooling to room temperature, the resin was filtered and washed with with N J^-dimethylformamide (3 X 15 mL), methanol (3 X 15 mL), tetrahydrofiiran (3X15 mL), and then suteequently with methanol and tetrahydrofiiran (each ca. 15 mL, 5 cycles). Finally, the resin was wa^ed with tetrahydrofiiran (4 X 15 mL) and dried in vacuo (55 "C, 12 h, 2.1 g). An aliquot of this material (120 mg, ca. 0.08 mmol) and 4-methyIphenylhydrazme hydrochloride (ca. 40 mg, 0.20 mmol) were mixed in a reactor tube. A 0.5 M solution of anhydrous zinc chloride in acetic acid (1.5 mL) was added and the re^:tion tube was sealed. TTie reaction mixture was stirred for 12 h at 75 "C. After cooling to room temperature, the reaction mixture was filtered and the residual resin washed with dimethylsuJfoxide (1.5 mL). To the combined filtrates was added saturated aqueous sodium bicarbonate solution (1.5 mL). Tlie solution was loaded on a reversed phase column (C-18,1 g, Varian Mega Bond Ehit®, Chrompack cat. no. 22050S), pre¬conditioned with methanol (3 mL) and water (3 mL). The column was washed with water 13-dihydroisobenzofiiran-5-carbomtrile (13h): LC/MS (m/z) 524 (MIT), Rt = 4.78, purity: 96%. l-[3-[[3-(4-Fluoro-7-methyl-lif--indol-3-yI)propyl](prop-2-en-l-yI)anuno]propyl]-l-(4-fluorophenyl)-l,3-dihydroisobenzoftiran.5-carbonitrile(13i): LCMS (m/z) 526 (MIT), Rt = 4.65, purity: 83%. 1 -[3-[[3-( li;f-Pyirolo[3^-A]quiiioIin-3-yI)propyI](2-&rylmethyI)ammo]propyI]-1 -(4- 2.21 (ddd, IH). 2.31 (ddd, IH), 3.16 (td, 2H), 5.12 (dt, IH), 5.21 (dt, IH), 7.02 (t, 2H), 7.41 (d, 2HX 7.43 (d, IH), 7.51 (s, IH), 7.62 (dq, IH) The foliowing compounds were prepared analogously: l-{2-IodoethyI)-]-(4-£]uorophenyl)-l,3-dihydroisobenzofiiran-5-carbonitrile (14b): yellow oil, 'H NMR (CDCU 6 2.4-2.9 (m, 2H), 3.38 (dt, IH), 3.45 (dt, IH), 5.15 (d, IH), 5.21 (d, IH), 7.03 (t, 2H), 7.35-7.48 (m, 3H), 7.52 (s, IH). 7.62 (d, IH). l-(4-Iodobutyl)-l-(4-fluorDphenyl)-l,3-dihydroisobenzofiiran-5-carboratrile (14c): yellow oil, 'H NMR (CDCUS 1.1-1.5 (m, 2H), 1.81 (tt, 2H), 2.00-2.30 (m, 2H), 3.U (t, 2H), 5.14 (d, IH), 5.20 (d, IH), 7.01 (t, 2H), 7.35-7.47 (m, 3H), 7.51 (s, IH), 7.60 (d, IH). Example IS l-(3-(Ethylaniino)propy!)-l-(4-fluorophenyl)-l,3-dihydroisoben2ofiiran-5-cart>onitrile (15a). To a stirred solution of l-(3-iodopropyl)-l-(4-fluorophenyl)-U3-dihydroisobenzoiiiran-5-carbonitrile (12.9 g, 30 mmol, 8 % pure) in cthanol (150 mL) was added a solution of eftylamine (20.3 g, 450 nunol) in THF (50 mL) portionwise, and the mixture was stirred over night. The solution was evaporated, and was dissolved/suspended in water. Tlie pH was adjusted to 12 using aqueous sodium hydroxide sohition (2 M) and was extracted with ether. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and ev^orated to give an oil. This oil was purified by silica chromalograpby using 50% v/v etbyl acetate^eptane as elueiM, fallowed by 10% vA' triethylamine/ 40% v/v ethyl acetate/heptane followed by 20% v/v trieftiylamine/ethyl acetate to give the title compound (5.52 g, 57%) as a pale yellow oil. 'H NMR (CDCI3) 5 1.05 (t, 3 H), 1.2-1.6 (m, 2H). 2.15 (ddd, IH), 2.24 (ddd, IH), 2.57 (q, 2H) 2.58 (t, 2H). 5.12 (dt, IH), 5.20 (dt, IH), 7.00 (t, 2H), 7.38 (d, IH), 7.42 (dd, 2H), 7.49 (s, IH), 7.58 (ddt, IH). The following compoimds were prepared analogously: 1 -(2-{Methy Ianimo)ethy I)-1 -(4-fIuorophenyI)-1,3-dihydroisobeiizofuran-5-cartxHiitrile (15b): yeUow oil; 'H NMR (CDCy 6 238 (s, 3H). 2.33-2.72 (m, 4H). 5.13 (d, IH), 5.20 (d, IH), 7.01 (t, 2H). 7.37-7.47 (m, 3H), 7.50 (s, IH), 7.59 (d, IH). i-urthCTmore, the 5-HT,A antagonistic activity of some of the compoimds of fteiaventioii has been estimated in vitro at cloned 5-HT,^ receptors stably eiqjressed in transfected HeLa cells (HA7). In this test, 5-HT|A antagonistic activity is estimated by mearairing the ability of the compounds to antagonize the 5-HT induced inhibition of forskoBn induced cAMP accumulation. The assay was performed as a modification of the method described by Pauwels, PJ. et al, Biochem. Pharmacol. 1993,45, 375. As seen from the above, the compounds of fte invention show afSnity for the S-HTi^ receptor. Furthemiore, many of the compounds of the present invention possess valuable activity as sCTotonin re-uptake inhibitors. Accordingly, the compounds are considered useful for the treatment of psychiatnc and neurological disorders as mentioned previously. Pitarmaceutica] formulation The phaim^eutical fonnulations of the invention may be prepared by conventional methods in the art For example: Tablets may be prepared by mixing the active ingredient with ordinary adjuvants and/or diluents and subsequently conqiressing the mixtnre in a conventional tabletting machine. Examples of adjuvants or diluente conQ}iise: ctsn staicfa, ;x»tato starch, talcum, m^nesium stearate, gelatine, lactose, gimis, and die tike. Any otber ^juvants or additives usually used for such purposes such as colomings, flavouzings, TTcsraratives etc. may be used provided that they are compatible with the active ingredients. Solutions for injections may be prepared by dissolving the active ingredient and possible idditives in a part of the solvent for injection, preferably sterile water, adjusting the Hslution to desired volume, st^lisation of the solution and filling in suitable ampules or nals. Any suitable additive conventionally used in the art may be added, such as tonicity igents, preservatives, antioxidants, etc. [he phannaceutical compositions of this invention or those which are manufectured in iccordance with this invention may be administered by any suitable route, for example irally in the forai of tablets, capsules, powders, syrups, etc., or parenterally in ttie form of solutions for injection. For preparing such conqwsitions, methods well known in the art may be used, and any phannaceutically acceptable caiiiers, diluents, excipients, or other additives normally used in the art may be used. ConveniMitly, the compounds of the invention are administered in unit dosage form containing said compounds in an amount of about 0.01 to 1000 mg. The total daily dose is usually in the range of about 0.05 -500mg, and most preferably about 0.1 to 50 mg of the active compound of the invention. WE CLAIM: 1. An isobenzofuiran having the general Formula I: A is selected from the following groups: 48 Ar and Aryl are independently selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyrmiidyl, 1-indolyl, 2-indolyI, 3-indolyl, l-indol-2-onyl, 3-indol-2-onyl, 2- or 3-benzofuranyl, 2- or 3-benzothiophenyl, 1-naphthyl or 2-naphthyl, each optionally substituted with halogen, C].^ alkyl, C].6 alkoxy, Ci^ alkylthio, hydroxy, C]^ alkylsulfonyl, cyano, trifluoromethyl, trifluoromethylsuifonyloxy, C3.g cycloalkyi, C3.8 cycIoaIkyI-Ci.5 alkyl, nitro, amino, C|.6 alkylamino, C2.12 diaikylamino, acylamino or alkylenedioxy; its enantiomers, and pharmaceutically acceptable acid addition salt thereof. 2. The compound as claimed in claim 1, wherein R' is methyl, ethyl, propyl, 2-propen-1-yl, 2-furylmethyl, 2-phenoxyethyl; 3. The compound as claimed in clahn 1, wherein at least one of R^ R^ and R', is methoxy. 4. The compound as claimed in claim 1, wherein Formula (II) is a benzodioxan group or a 1,2-methylenedioxybenzene group. 5. The compoimd as claimed in claim 1, wherein Formula (IH) is a 3-indolyl. 6. The compound as claimed in claim 5, wherein the 3-indolyl is substituted in 5-position by methyl, fluoro, chloro, bromo, iodo, /-butyl or /-propyl, or in 7-position by fluoro, chloro or carboxy; or disubstituted by 5,7-difluoro, 4-fluoro-7-methyl or 4-chloro-7-methyl or the two substituents together form a pyridyl ring fused to the 3-indolyl. 7. The compound as claimed in claim 1, wherein Formula (IV) is a 4-indolyl or a 5-indolyl group. 8. The compound as claimed in any of the claims 1 - 7, wherein Ar is phenyl or phenyl substituted with halogen or CF3; 9. The compound as claimed in any of the claims 1 - 8, wherein R' is H, CN or F in the 5-position of the isobenzofuran group. 10. The compound as claimed in any of the claims 1 - 9, wherein R and R are selected from hydrogen or methyl. 11. The compound as claimed in any of the claims 1-10, wherein n = 2, 3 or 4. 12. The compound as claimed in any of the claims 1-11, wherein m = 0. 13. The compound as claimed in claim 1 which is (-)-l-[3-[[4-(l,4-Benzodioxan-5-yl)butyl]methyiamino]propyl]-l-{4-fluorophenyl)-l,3-dihydroisobenzofuran-5-carbonitrile, l-[3-[[3-(l,4-Benzodioxan-5-yl)propyl]methylamino]propyl]-l-(4-fluorophenyl)-l,3-dihydroisobenzofiiran-5-carbonitrile oxalate, l-[3-[[2-(l,4-Benzodioxan-5-yl)ethyl]methyIamino]propyl]-l-(4-fluorophenyl)-l,3-dihydroisobenzofuran-5-carbonitrile oxalate, l-[3-[[l,4-Benzodioxan-5-ylmethyl]methylamino]propyl]-l-(4-fluorophenyl)-l,3-dihydroisobenzofuran-S-carbonitrile oxalate. l-(4-Fluorophenyl)-l-[3-[4-(2-methoxyphenyl)piperazinyl]propyl]-l,3-dihydroisobenzofuran-5-carbonitriIe, l-(4-Fluorophenyl)-l-[3-[methyl[2-(2-methoxyphenoxy)ethyl]amino]propyl]-],3-dihy droisobenzofiiran-5-carbonitrile, l-(4-Fluorophenyl)-l-[3-[methyl[2-(3-methoxyphenoxy)ethyl]amino]propyl]-l,3-dihydroisobenzofuran-S-carbonitrile, {5)-I-[3-[(:4-(I//-IndoI-3-yI)butyi]methyiamino]propyI]-I-(4-fluorophenyI)-l,3-dihydroisobenzofuran-5-carbonitrile, l-[3-[[4-(I//-Indol-3-yl)butyl]methyIamino]propyl]-l-phenyl-l,3-dihydroisobenzofuran, (S)-l-[3-[[3-(l//-Indol-3-yl)propyi]methylamino]propyl]-l-(4-fluorophenyl)-l,3-dihydroisobenzofuran-5-carbonitriie, l-[3-[[3-(l/f-Indol-3-yl)propyl]methylamino]propyl]-l-phenyl-l,3-dihydroisobenzofuran, 5-[3-[[3-(l-Phenyl-l,3-dihydroisobenzofliran-l-yl)propyl]methylamino]propyl]-l,4-benzodioxane, 5-[3-[[3-[I-(3-ChIorophenyI)-I,3-dihydroisobenzofuran-i-yl]propyl]methylamino]propyl]-l,4-benzodioxane, 5-[3-[[3-[l-(4-Fluorophenyl)-l,3-dihydroisobeiizofuran-l-yl]propyl]methylamino]propyl]-l,4-benzodioxane, 5-[3-[[3-[l-(3-Trifluoromethylphenyl)-l,3-dihydroisobenzofuran-l-yi]propyI]methyiamino]propyi]-I,4-benzodioxane, l-[3-[[3-(l,4-Benzodioxan-5-yl)propyl]methylamino]propyl]-l-(4-chlorophenyl)-l,3-dihydroisobenzofuran-S-carbonitrile, l-[3-[4-{l/^-Indol-4-yl)piperazinyl]propyl]-l-(4-fluorophenyl)-l,3-dihydroisobeiizofuran-5-carbonitrile, l-[3-[4-(li/-Indol-5-yl)piperazinyl]propyl]-l-(4-fluoropheny!)-l,3- dihydroisobenzofuran-5-carbonitrile, 1 -[3-[4.(l /f_Indol-3-yl)piperidinyl]propyl]-1 -{4-fluorophenyl)-1,3 - dihydroisobenzoftiran-5-carbonitrile, 5-[3-[[3-[-5-Fluoro-l-(4-fluorophenyl)-l,3-dihydroisobenzofiiran-l- yl]propyl]methylamino]propyl]-l,4-benzodioxane, l-[3-[[2-(l//-Indolyl-3-yl)ethyl]methylamino]propyl]-l-(4-fluorophenyl)-l,3-dihy droisobenzofuran-5 -carbonitrile, l-(4-Fluorophenyl)-l-[3-[[2-(3-methoxyphenyl)ethyl]methylamino]propyI]-l,3- dihydroisoben2ofuran-5-carbonitrile, l-(4-Fluorophenyl)-l-[3-[[2-(3-methoxyphenyl)ethyl](prop-2-en-l-yI)amino]propyI]- 1,3-dihydroisobenzofuran-5-carbonitrile, ] -(4-F!uorophenyI)-1 -[3-[[2-(2-methoxyphenyl)ethyI](prop-2-en-1 -yl)amino]propy]]- l,3-dihydroisobenzofuran-5-carbonitrile, l-[3-[[2-(2,5-Dimethoxyphenyl)ethyl]methylamino]propyl]-l-(4-fluorophenyl)- 1,3- dihydroisobenzofuran-5-carbonitrile, l-[3-[[2-(2,5-Dimethoxyphenyl)ethyl](prop-2-en-l-yl)amino]propyl]-l-(4- fluorophenyl)- l,3-dihydroisobenzofuran-5-carbonitrile, l-(4-Fluorophenyl)-l-[3-[[2-phenoxyethyl]methylamino]propyl]-l,3- dihydroisobenzofuran-5 -carbonitrile, l-[3-[[2-(l//-Indolyl-3-yl)ethyl](prop-2-en-l-yl)ammo]propyl]-l-(4-fluorophenyl)- 1,3-dihydroisobenzoftiran-5-carbonitrile, l-(4-Fluorophenyl)-l-[3-[[2-phenoxyethyl](prop-2-en-l-yl)amJno]propyl]-l,3- dihydroisobenzofiiran-S-carbonitrile, l-(4-Fluorophenyl)-l-[3-[[3-(2-methoxyphenyl)propyi]methylamino]propyl]-l,3- dihydroisobenzofuran-5-carbonitrile, l-(4-Fluorophenyl)-l-[3-[[3-(2-methoxyphenyl)propyl](prop-2-en-l-yl)amino]propyi]-l,3-dihydroisobenzoftiran-5-carbonitrile, l-(4-Fluorophenyl)-l-[3-[[3-(3-methoxyphenyl)propyl](prop-2-en-l-yl)amino]propyl]-l,3-dihydroisobenzofuran-5-carbonitrile, l-(4-Fluorophenyl)-l-[3-[[3-{2-methoxyphenoxy)propyl]methylamino]propyl]-l,3-dihydroisobenzofUran-S-carbonitrile, l-(4-Fluorophenyl)-l-[3-[[3-(2-methoxyphenoxy)propyl](prop-2-en-l-yl)amino]propyl]-l,3-dihydroisobenzofuran-5-carbonitrile, l-(4-Fiuorophenyl)-l-[3-[[3-{3-methoxyphenoxy)propyl]methylamino]propyl]-l,3-dihydroisobenzofuran-S -carbonitrile, I-(4-F!uorophenyI)-I-[3-[[3-(3-methoxyphenoxy)propyl](prap-2-en-]-yl)amino]propyl]-l,3-dihydroisobenzofuran-5-carbonitrile, l-[3-[(2-Ben2yloxyethyl)methylamino]propyl]-l-(4-fluoropheny!)-I,3-dihydroisobenzofuran-5-carbonitrile, l-[3-[(2-Benzyloxyethyl)(prop-2-en-l-yl)ammo]propyI]-l-(4-fluorophenyl)-l,3- dihydroisobenzofuran-5-carbonitrile, l-[3-[[3-(l^-Indolyl-3-yl)propyl](prop-2-en-l-yl)amino]propyl]-l-(4-fluoropheny!)- l,3-dihydroisobenzofuran-5-carbonitrile, I-[3-[[3-(l/f-IndolyI-3-yl)propyl](2-propynyl)ammo]propyl]-l-(4-fluorophenyl)-l,3- dihydroisobenzofUran-5-carbonitrile, l-[3-[[3-(l//-Indolyl-3-yl)propyl]methylamino]propyl]-l-(4-fluorophenyl)-l,3- dihydroisobenzofuran-S-carbonitrile, l-[3-[[2-(5-Methyl-l//-indol-3-yl)ethyl]inethylamino]propyl]-l-(4-fluorophenyl)-l,3- dihydroisobenzofuran-5-carbonitrile, l-[3-[[2-(7-Fluoro-l//-indol-3-yl)ethyl]methylamino]propyl]-l-(4-fluorophenyl)-l,3- dihydroisobenzofliran-5-carbonitrile, 5-Fluoro-l-[3-[[3-{5-methyl -l/f-indol-3-yl)propyl]methylamino]propyl]-l-(4- fluorophenyl)-l,3- 5-Fluoro-l-[3-[[3-(7~fluoro-l//-indol-3-yl)propyl]methylamino]propyl]-]-(4- fluorophenyl)-l,3-dihydroisobenzofuran, l-[3-[[3-(5-Methyl -li/-indol-3-yl)propyl]methylamino]propyl]-l-(4-fluorophenyl)- 1,3-dihydroisobenzofuran-5-carbonitrile, l-[3-[Ethyl[3-(l//-indol-3-yl)propyl]amino]propyl]-l-(4-fluorophenyl)-l,3- dihydroisobenzofuran-5 -carbonitrile, l-[3-[Ethyl[2-(5-methyl -l/f-indoI-3-yl)ethyl]amino]propyl]-l-(4-fIuorophenyl)-l,3- dihydroisobenzofuran-5-carbonitri le, l-[3-[[3-{7-Fluoro-l/f-indol-3-yl)propyl]methylamino]propyl]-l-(4-fluorophenyl)- l,3-dihydroisobenzofUran-5-carbonitrile, l-[3-[[3-{5-Fluoro-l//-mdol-3-yl)propyl]methylamino]propyl]-l-(4-fluorophenyl)- l,3-dihydroisobenzofuran-5-carbonitrile, l-[3-[EthyI[2-(5-fluoro-l//-indol-3-yl)ethyl]amino]propyl]-l-(4-fluorophenyl)-l,3- dihydroisobenzofuran-S-carbonitrile, ]-[3-[Ethyl[2-(7-fluoro-]//-mdoJ-3-y])ethyI]amino}propy]]-I-(4-fluorophenyI)-I,3- dihydroisobenzofuran-S -carbonitri le, l-[3-[[2-(5-Chloro-177-indol-3-yl)ethyl]methylamino]propyI]-l-(4-fluomphenyI)-l,3- dihydroisobenzofuran-5-carbonitrile, ]-[3-[[3-(5-Chloro-l//-indol-3-yl)propyl]methylamino]propyl] - 5-fluoro -l-(4- fluorophenyl) -1,3-dihydroisobenzofuran, l-[3.[[4.(5.Methyl -l//-indol-3-yl)butyI]methylamino]propyl]-l-(4-fluorophenyl)-l,3- dihydroisobenzofuran-5-carbonitrile, l-[3-[Ethyl[3-(5-methyl -l//-indol-3-yl)propyl]amino]propyl]-l-(4-fluorophenyl)-l,3- dihydroisobenzofLiran-5-carbonitrile, dihydroisobenzofliran-5-carbonitrile, l-[3-[[3-(7-Fluoro -li/-indol-3-yl)propyl](2-furylmethyl)amino]propyl]-l-(4- fluorophenyl)-l,3-tiihydroisobenzofuran-5-carbonitrile, l-[3-[[4-(7-Carboxy-l/f-indol-3-yl)butyl](prop-2-en-l-yl)amino]propyl]-l-(4-fluorophenyl)-l,3-dihydroisobenzofLjran-5-carbonitrile, l-[3-[[2-[5-Bromo-l//-indol-3-yl]ethyl]-propylamino]propyl]-l-(4-fluorophenyl)-l,3- dihydroisobenzofiiran-5-carbonitrile, l-[3-[[3-(I^-Indoi-3-yI)propyi](2-phenoxyethyi)ammo]propyl]-I-(4-fIuorophenyO- l,3-dihydroisobenzofuran-5-carbonitrile, l-[3-[[2-(5-Methy]-l//-mdo]-3-y])ethyl](2-phenoxyethy])amino]propyl]-l-(4- fluorophenyl)-l,3-dihydroisobenzoftiran-5-carbonitriIe, l-[3-[[2-(5-Fluoro-l/f-indol-3-yl)ethyl](2-phenoxyethyl)amino]propyl]-l-(4- fluorophenyl)-l,3-dihydroisobenzofuran-5-carbonitrile, l-[3-[t3-(5-Pyrrolo[3,2-/i]-l//-quinolin-3-yl)propyl]- 2-fuiylmethylamino]propyl]-l- (4-fluorophenyl)-l,3-dihydroisobenzofuran-5-carbonitrile, l-[3-[[3-(5-Methyl-l//-indol-3-yI)propyl]{2-phenoxyethyl)amino]propyl]-l-(4- fluorophenyl)-1,3-dihydroisobeiizofuran-5-carbonitriJe, l-[3-[[3-(5-Fluoro-l/f-indol-3-yl)propyl](2-phenoxyethyI)amino]propyl]-l-(4- fIuorophenyl)-l,3-dihydroisobenzofiaran-5-carbomtrile, l-[3-[[2-{5,7-Difluoro-l//-mdol-3-yl)ethyl](2-phenoxyethyl)amino]propyi]-l-(4- fluorophenyl)-l,3-dihydroisobenzoftiran-5-carbonitrile, l-[3-[[4-(5-Pyrrolo[3,2~/i]-l//-quinolm-3-yl)butyl]- 2-ftirylmethylamino]propyl]-l-(4- f]uorophenyl)-l,3-dihydroisobenzofuran-5-carbonitri!e, l-[3-[2-Phenoxyethyl[2-[5-(2-propyl)-l//-indol-3-yl]ethyl]ainino]propyl]-l-(4- fluorophenyl)-l,3-dihydroisobenzofuran-5-carbonitrile or l-[3-[[2-{5-Bromo-li/-indoi-3-yl)ethyl](2-phenoxyethyl)amino]propyI]-l-{4- fluorophenyl)-l,3-dihydroisobenzofiiran-5-carbonitrile or an acid addition salt thereof.

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in-pct-2001-0769-che correspondence-others.pdf

in-pct-2001-0769-che correspondence-po.pdf

in-pct-2001-0769-che description (complete)-duplicate.pdf

in-pct-2001-0769-che description (complete).pdf

in-pct-2001-0769-che form-1.pdf

in-pct-2001-0769-che form-18.pdf

in-pct-2001-0769-che form-26.pdf

in-pct-2001-0769-che form-3.pdf

in-pct-2001-0769-che form-5.pdf

in-pct-2001-0769-che others.pdf

in-pct-2001-0769-che pct.pdf

in-pct-2001-0769-che petition.pdf