WO2004099191A2 - Benzofuranyl-and benzothienyl-piperazinyl quinolines as serotonin reuptake inhib itors - Google Patents

Abstract

Benzofuranyl-and benzothienyl-piperzinyl quinoline derivatives and compositions containing such compounds are disclosed. Methods of using benzofuranyl- and benzothienyl-piperzinyl quinoline derivatives and compositions containing such composition in the treatment and/or prevention of serotonin-related disorders, such as depression and anxiety, are also disclosed. In addition, processes for the preparation of benzofuranyl- and benzothienyl-piperzinyl quinoline derivatives are disclosed.

Description

BENZOFURANYL- AND BENZOTHIENYL- PIPERAZINYL QUINOLINES AND METHODS OF THEIR USE

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims benefit of Provisional Application Serial No. 60/467,368, filed May 2, 2003, the disclosure of which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention relates to benzofuranyl- or benzothienyl-piperazinyl quinoline derivatives and, in particular, to their activity both as serotonin reuptake inhibitors and as 5- HT_IA receptor antagonists, and to their related use for, inter alia, the treatment and/or prevention of serotonin-related disorders.

BACKGROUND OF THE INVENTION

[0003] Major depressive disorder affects an estimated 340 million people worldwide. Depression is the most frequently diagnosed psychiatric disorder and, according to the World Health Organization, is the fourth greatest public health problem. If left untreated, the effects of depression can be devastating, robbing people of the energy or motivation to perform everyday activities and, in some cases, leading to suicide. Symptoms of the disorder include feelings of sadness or emptiness, lack of interest or pleasure in nearly all activities, and feelings of worthlessness or inappropriate guilt. In addition to the personal costs of depression, the disorder also has been estimated to result in more than $40 billion in annual costs in the United States alone, due to premature death, lost productivity, and absenteeism. [0004] Pharmaceuticals that enhance serotonergic neurotransmission have had success in preventing and/or treating many psychiatric disorders, including depression and anxiety. The first generation of non-selective serotonin-affecting drugs operated through a variety of physiological functions that endowed them with several side-effect liabilities. A class of more recently-developed drugs, selective serotonin reuptake inhibitors (SSRIs), have had significant success in preventing and/or treating depression and related illnesses and have become among the most prescribed drugs since the 1980s. Although they have a favorable side effect profile compared to tricyclic antidepressants (TCAs), they have their own particular set of side effects due to the non-selective stimulation of serotonergic sites. They typically have a slow onset of action, often taking several weeks to produce their full therapeutic effect. Furthermore, they have generally been found to be effective in less than two-thirds of patients.

[0005] SSRIs are believed to work by blocking the neuronal reuptake of serotonin, increasing the concentration of serotonin in the synaptic space, thus increasing the activation of postsynaptic serotonin receptors. Although a single dose of an SSRI can inhibit the neuronal serotonin transporter, and thus would be expected to increase synaptic serotonin, long-term treatment is usually required before clinical improvement is achieved. It has been suggested that the delay in onset of antidepressant action of the SSRIs is the result of an increase in serotonin levels in the vicinity of the serotonergic cell bodies. This excess serotonin is believed to activate somatodendritic autoreceptors, i.e., 5-HT_IA receptors, reduce cell firing activity, and, in turn, decrease serotonin release in major forebrain areas. This negative feedback limits the increment of synaptic serotonin that can be induced by antidepressants acutely. Over time, the somatodendritic autoreceptors become desensitized, allowing the full effect of the SSRIs to be expressed in the forebrain. This time period has been found to correspond to the latency for the onset of antidepressant activity. [Perez, et al, The Lancet, 1997, 349:1594-1597].

[0006] In contrast to the SSRIs, a 5-HTIA agonist or partial agonist acts directly on postsynaptic serotonin receptors to increase serotonergic neurotransmission during the latency period for the SSRI effect. Accordingly, the 5-HT_IA partial agonists buspirone and gepirone [Feiger, A., Psychopharmacol Bull, 1996, 32: 659-665, Wilcox, C, Psychopharmacol Bull, 1996, 32: 335-342], and the 5-HTIA agonist flesinoxan [Grof, P., International Clinical Psychopharmacology, 1993, 8: 167-172], have shown efficacy in clinical trials for the treatment of depression. Furthermore, such agents are believed to stimulate the somatodendritic autoreceptors, thus hastening their desensitization and decreasing the SSRI latency period. Indeed, buspirone augmentation to standard SSRI therapy has been shown to produce marked clinical improvement in patients initially unresponsive to standard antidepressant therapy [Dimitriou, E., J. Clinical Psychopharmacol, 1998, 18: 465-469].

[0007] There is still an unfulfilled need for a single agent with a dual mechanism of antidepressant action, i.e., one that not only inhibits or blocks serotonin reuptake (to increase levels of serotonin in the synapse) but also antagonizes the 5-HT_IA receptors (to reduce the latency period). The present invention is directed to these, as well as other important ends.

SUMMARY OF THE INVENTION

[0008] The present invention relates to bei-zofuranyl- or benzothienyl-piperazinyl quinoline derivatives and, more particularly, to methods of their use in the treatment and/or prevention of serotonin-related disorders, such as depression, anxiety, cognitive deficits, such as those resulting from Alzheimer's disease and other neurodegenerative disorders, schizophrenia, and prostate cancer. Preferred compounds have the ability to bind and antagonize 5-HT_IA receptors, as well as being serotonin reuptake inhibitors.

In one aspect, the present invention provides benzofurynyl- and benzothienyl- piperazino quinoline derivatives of formula I:

or a prodrug, stereoisomer, N-oxide or pharmaceutically-acceptable salt thereof; wherein:

X is O or S;

Ri, R₂, R , R₄, R₅, R_<5, and R₇ are independently hydrogen, halo, cyano, -N(R₉)(R₉), hydroxy, C(=O)ORι₀, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkenyloxy, al ynyloxy, aryloxy, heteroaryloxy, perfluoroalkyl, (R₉)(R₉)N-alkoxy, (R₉)(R₉)N-alkoxyaryl, S(O)_q-alkyl where q is 0-2, S(O)_q-aryl where q is 0-2, CONRnRι , guanidino, cyclic guanidino, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, heterocycle, arylalkenyl, - SO₂NRnR₁ , aryloxyaryl, arylalkoxyalkyl, aryloxyalkyl, aryloxyheteroaryl, heteroaryloxyaryl, alkylaryloxyaryl, alkylaryloxyheteroaryl, heteroaryloxyalkyl, or where any two of said R _s R , R₃, R₄, R₅, R₆, or R located on adjacent carbon atoms together form an alkylene dioxy group; R₈ is a linker selected from cycloalkyl, alkyl optionally substituted with one or two Rι₃, and a moiety of formula:

where Z is N or CH; t is an integer from 1 to 3; and u is an integer from 0 to 3;

R₉ is hydrogen, alkyl, aryl, heteroaryl, aryloxy, heterocycle, cycloalkyl, alkenyl with the proviso that the double bond of the alkenyl is not present at the carbon atom that is directly linked to N, alkynyl with the proviso that the triple bond of the alkynyl is not present at the carbon atom that is directly linked to N, perfluoroalkyl, -S(O)₂alkyl, -S(O)₂aryl, -S(O)₂aheteroaryl, -(C=O)heteroaryl, -(C=O)aryl, -(C=O)(Cι-C₆) alkyl, -(C=O)cycloalkyl, -(C=O)heterocycle, alkyl-heterocycle, arylalkenyl, -CONRnRπ, -SO₂NRπRι₂, arylalkoxyalkyl, arylalkylalkoxy, heteroarylalkylalkoxy, aryloxyalkyl, heteroaryloxyalkyl, aryloxyaryl, aryloxyheteroaryl, alkylaryloxyaryl, alkylaryloxyheteroaryl, all-ylaryloxyalkyamine, alkoxycarbonyl, aryloxycarbonyl, or heteroaryloxycarbonyl;

Rio is hydrogen, alkyl, aryl, heteroaryl, alkylaryl, arylalkyl, heteroarylalkyl, or alkylheteroaryl;

Rn and Rι are independently hydrogen, alkyl, aryl, heteroaryl, alkylaryl, arylalkyl, heteroarylalkyl, or alkylheteroaryl; and each Rχ₃ is hydrogen, alkyl, aryl, heteroaryl, alkylaryl, arylalkyl, heteroarylalkyl, alkyl heteroaryl, or -N(R₉)(R₉).

[0009] In another aspect, the present invention is directed to compositions comprising a compound of formula I and one or more pharmaceutically-acceptable carriers. [0010] In another aspect, the present invention is directed to methods of treating and/or preventing a patient suspected to suffer from a serotonin-related disorder, comprising the step of administering to the patient a therapeutically effective amount of a compound of formula I. [0011] In yet another aspect, the present invention describes methods of antagonizing 5- HT_IA receptors in a patient in need thereof, comprising the step of administering to the patient a therapeutically effective amount of a compound of formula I. [0012] The present invention is also directed to methods of inhibiting the reuptake of in a patient in need thereof, comprising the step of administering to the patient a therapeutically effective amount of a compound of formula I.

[0013] In another aspect, this invention is drawn to processes for the preparation of benzofuranyl- and benzothienyl-piperzinyl quinoline derivatives, comprising the step of reacting a compound of formula II:

II

with a compound of formula III:

III in the presence of at least one aprotic polar solvent and at least one acid binding agent. [0014] As 5-HT_IA antagonists, the novel compounds are useful for the treatment and/or prevention of several diseases and disorders, including anxiety, depression, cognitive deficits, such as those resulting from Alzheimer's disease and other neurodegenerative disorders, schizophrenia, and prostate cancer. They are also useful as co-administered therapeutic agents to enhance the onset of the antidepressant action of SSRIs and for relief of the symptoms resulting from nicotine withdrawal.

DETAILED DESCRIPTION OF THE INVENTION

[0015] The term "alkyl", as used herein, whether used alone or as part of another group, refers to a substituted or unsubstituted, preferably unsubstituted aliphatic hydrocarbon chain attached via at least one sp hybridized carbon atom preferably straight and branched chains containing from 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, unless explicitly specified otherwise. For example, methyl, ethyl, propyl, isopropyl, butyl, /^"-butyl and t-butyl are encompassed by the term "alkyl." Specifically included within the definition of "alkyl" are those aliphatic hydrocarbon chains that are optionally substituted. [0016] The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.

[0017] The term "alkenyl", as used herein, whether used alone or as part of another group, refers to a substituted or unsubstituted, preferably unsubstituted aliphatic hydrocarbon chain attached via a sp hybridized carbon atom, preferably selected from straight and branched chains having 2 to 8 carbon atoms and containing at least one double bond. Preferably, the alkenyl moiety has 1 or 2 double bonds. Such alkenyl moieties may exist in the E or Z conformations and the compounds of this invention include both conformations. Specifically included within the definition of "alkenyl" are those aliphatic hydrocarbon chains that are optionally substituted. Heteroatoms, such as O, S or N-Ri, attached to an alkenyl should not be attached to a carbon atom that is bonded to a double bond.

[0018] The term "alkynyl", as used herein, whether used alone or as part of another group, refers to a substituted or unsubstituted, preferably unsubstituted aliphatic hydrocarbon chain attached via a sp hybridized carbon atom, and includes, preferably selected from straight and branched chains having 2 to 6 carbon atoms and containing at least one triple bond. More preferably, the alkynyl moiety has 3 to 6 carbon atoms. In certain embodiments, the alkynyl may contain more than one triple bond and, in such cases, the alknyl group must contain at least four carbon atoms. Specifically included within the definition of "all ynyl" are those aliphatic hydrocarbon chains that are optionally substituted. Heteroatoms, such as O, S or N- Ri, attached to an alkynyl should not be attached to the carbon that is bonded to a triple bond. [0019] The term "cycloalkyl", as used herein, whether used alone or as part of another group, refers to a substituted or unsubstituted, preferably unsubstituted alicyclic hydrocarbon group having 3 to 7 carbon atoms. Specifically included within the definition of "cycloalkyl" are those alicyclic hydrocarbon groups that are optionally substituted. [0020] The term "aryl", as used herein, whether used alone or as part of another group, is defined as a substituted or unsubstituted aromatic hydrocarbon ring group preferably selected from phenyl, α-naphthyl, β -naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenaphthenyl. Specifically included within the definition of "aryl" are those aromatic groups that are optionally substituted.

[0021] The term "heteroaryl", as used herein, whether used alone or as part of another group, is defined as a substituted or unsubstituted aromatic heterocyclic ring system (monocyclic or bicyclic) where the heteroaryl moiety is:

(1) furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N- methylpyrrole, pyrazole, N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1- methyl-l,2,4-triazole, lH-tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline;

(2) a bicyclic aromatic heterocycle where a phenyl, pyridine, pyrimidine or pyridizine

(a) fused to a 6-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom;

(b) fused to a 5- or 6-membered aromatic (unsaturated) heterocyclic ring having two nitrogen atoms;

(c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one nitrogen atom together with either one oxygen or one sulfur atom; or

(d) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having one heteroatom selected from O, N or S. Specifically included within the definition of "heteroaryl" are those aromatic heterocyclic rings that are optionally substituted. An optionally substituted heteroaryl may be substituted with 1 or 2 substituents.

[0022] An optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl may be substituted with one or two substituents. Suitable optionally substituents may be selected independently f om nitro, cyano, -N(Rπ)(Rι₂), halo, hydroxy, carboxy, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, heteroaryloxy, alkylalkoxy, alkoxycarbonyl, alkoxyalkoxy, perfluoroalkyl, perfluoroalkoxy, arylalkyl, alkylaryl, hydroxyalkyl, alkoxyalkyl, alkylthio, -S(O)₂-N(R_π)(Rι₂),

(Rn)(R_l2)N- alkyl, (R_n)(Rι₂)N-alkoxyalkyl, (Rπ)(Rι₂)N-a-kylaryloxyalkyl, -S(O)_s-aryl (where s=0-2) or -

S(O)_s-heteroaryl (where s^O-2). In certain embodiments of the invention, preferred substitutents for alkyl, alkenyl, alkynyl and cycloalkyl include nitro, cyano, -N(Rπ)(Rι₂), halo, hydroxyl, aryl, heteroaryl, alkoxy, alkoxyalkyl, and alkoxycarbonyl. In certain embodiments of the invention, preferred substituents for aryl and heteroaryl include -

N(Rιι)(Rι ), alkyl, halo, perfluoroalkyl, perfluoroalkoxy, arylalkyl and alkylaryl.

[0023] The term "alkoxy", as used herein, whether used alone or as part of another group, refers to the group R_a-O-, where R_a is an alkyl group, as defined above.

[0024] The term "alkenyloxy", as used herein, whether used alone or as part of another group, refers to the group R_e-O-, where R_e is an alkenyl group as defined above.

[0025] The term "alkynyloxy", as used herein, whether used alone or as part of another group, refers to the group Rr O-, where Rf is an alkynyl group as defined above.

[0026] The term "aryloxy", as used herein, whether used alone or as part of another group, refers to the group R_D-O-, where R is an aryl group, as defined above.

[0027] The term "heteroaryloxy", as used herein, whether used alone or as part of another group, refers to the group R_c-O-, where R_e is a heteroaryl group, as defined above.

[0028] The term "alkylaryl", as used herein, whether used alone or as part of another group, whether used alone or as part of another group, refers to the group -R_b-R_a, where R_b is an aryl group, as defined above, substituted by R_a, an alkyl group as defined above.

[0029] The term "heteroarylalkyl", as used herein, whether used alone or as part of another group, refers to the group -R_a-R_c, where R_a is an alkyl group as defined above, substituted with R_e,, a heteroaryl group, as defined above. Heteroarylalkyl moieties include, but are not limited to, heteroaryl-(CH₂)ι.₆(CH₃). [0030] The term "arylalkyl", as used herein, whether used alone or as part of another group, refers to the group -R_a-R_b, where R_a is an alkyl group as defined above, substituted by R_b, an aryl group, as defined above. Preferred arylalkyl moieties are benzyl, 1-phenylethyl, 2- phenylethyl, 3-phenylpropyl and 2-phenylproρyl.

[0031] The term "alkylheteroaryl", as used herein, whether used alone or as part of another group, refers to the group -R_c-R_a, where R_e is a heteroaryl group as defined above, substituted with R_a, an alkyl group as defined above.

[0032] The term "arylalkenyl", as used herein, whether used alone or as part of another group, refers to the group -Re-Rb. containing a total of 8 to 16 carbon atoms, where R is an aryl group, as defined above, and Re is an alkenyl group as defined above, with the proviso that no heteroatom such as O, S or N-Ri is attached to a carbon atom, which is attached to a double bond.

[0033] The term "heterocycle", as used herein, whether used alone or as part of another group, refers to a stable 3 to 8-member ring containing carbons atoms and from 1 to 3 heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen, and sulfur. A heterocycle of this invention may be either a monocyclic or bicyclic ring system, and may either be saturated or partially saturated. Preferred heterocyclic groups are aziridinyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzothienyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, dihydro- 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. [0034] The term "arylalkoxyalkyl", as used herein, whether used alone or as part of another group, refers to the group R_b-R_a-O-R_a-, where R_b is an aryl group, as defined above, and R_a is an alkyl group as defined above.

[0035] The term "alkoxyalkyl", as used herein, whether used alone or as part of another group, refers to the group Ra-O-R_a-, where R_a is an alkyl group as defined above. [0036] The term "aryloxyalkyl", as used herein, whether used alone or as part of another group, refers to the group Rb-O-R_a-, where R_b is an aryl group, as defined above, and R_a is an alkyl group as defined above.

[0037] The term "aryloxyaryl", as used herein, whether used alone or as part of another group, refers to the group Rb-O-R_b-, where R_b is an aryl group, as defined above.

[0038] The term "aryloxyheteroaryl", as used herein, whether used alone or as part of another group, refers to the group R_b-O-Rc-, where Rb is an aryl group, as defined above, and

R_e is a heteroaryl group, as defined above.

[0039] The term "alkylaryloxyaryl", as used herein, whether used alone or as part of another group, refers to the group R_a-R_b-O-R_b-, where R_a is an alkyl group as defined above, and R is an aryl group, as defined above.

[0040] The term "alkoxycarbonyl", as used herein, whether used alone or as part of another group, refers to the group R_a-O-C(=O)-, where R_a is an alkyl group as defined above.

[0041] The term "aryloxycarbonyl", as used herein, whether used alone or as part of another group, refers to the group R_b-O-C(=O)-, where R_b is an aryl group, as defined above.

[0042] The term "heteroaryloxycarbonyl", as used herein, whether used alone or as part of another group, refers to the group Rc-O-C(=O)-, where R_e is a heteroaryl group, as defined above.

[0043] The term "alkoxyalkoxy", as used herein, whether used alone or as part of another group, refers to the group R_a-O-R_a-O-, where R_a is an alkyl group, as defined above.

[0044] The term "alkylene dioxy", as used herein, is defined as

or 2 and where the alkylene portion may be substituted with substituents as defined for "alkyl".

[0045] The term "heteroaryloxyalkyl", as used herein, whether used alone or as part of another group, refers to the group R_c-O-R_a-, where R_e is a heteroaryl group, as defined above, and R_a is a alkyl group, as defined above.

[0046] The term "heteroaryloxyaryl", as used herein, whether used alone or as part of another group, refers to the group R_c-O-R_b-, where R_e is a heteroaryl group, as defined above, and R is an aryl group, as defined above. [0047] The term "perfluoroalkyl", as used herein, whether used alone or as part of another group, refers to a saturated aliphatic hydrocarbon having 1 to 6 carbon atoms and two or more fluorine atoms and includes, but is not limited to, straight or branched chains, such as - CF₃, -CH₂CF₃, -CF₂CF₃ and -CH(CF₃)₂.

[0048] The term "perfluoroalkoxy", as used herein, whether used alone or as part of another group, refers to the group R_a-O-, where Ra is a saturated aliphatic hydrocarbon having 1 to 6 carbon atoms and two or more fluorine atoms and includes, but is not limited to, straight or branched chains, such as -OCF₃, -OCH₂CF₃, -OCF₂CF₃ and -OCH(CF₃)₂. [0049] The term "halo", as used herein, refers to chloro, bromo, fluoro, or iodo. [0050] The term "guanidino", as used herein, refers to

[0051] The term "cyclic guanidino", as used herein, refers to

where p is 1 or 2, and q is 0 to 2. [0052] Suitable aprotic polar solvents include, but are not limited to, dimethyl sulfoxide, dimethyl formamide, tetrahydrofuran, acetone and ethanol.

[0053] Suitable acid binding agents include, but are not limited to, organic tertiary bases, such as, for example, triethyl amine,triethanol amine, l,8-diazabicyclo[5.4.0]undec-7-ene DBU, and diisopropylethylamine; and alkaline metal carbonates, such as, for example, potassium carbonate and sodium carbonates.

[0054] It is understood that compounds according to formula I can include asymmetric carbons, and that formula I encompasses all possible stereoisomers and mixtures thereof, as well as racemic modifications, particularly those that possess the activity discussed below. Optical isomers may be obtained in pure form by standard separation techniques. [0055] Preferred among the above noted Ri to R₇ groups are alkyl, halo, alkoxy, cyano, alkoxycarbonyl, amido, carboxy, N(R₉)(R ), and C(=O)ORι₀. Particularly preferred are methyl, isopropyl, methoxy, chloro, and fluoro.

[0056] Preferred R₈ groups are cycloalkyl and (Cι-C₈)alkyl optionally substituted with alkyl, aryl, heteroaryl, cycloalkyl, or heterocycle. Particularly preferred are ethyl, propyl, isopropyl, butyl, hexyl and cyclohexyl.

[0057] Preferred R₉ groups are hydrogen, alkyl, aryl, heteroaryl, heterocycle, cycloalkyl, perfluoroalkyl, -S(O)₂alkyl, -S(O)₂aryl, -(C=O)aryl, -(C=O)(Cι-C₆)alkyl, -(C=O)cycloalkyl,

(C=O)heterocycle, -(C=O)NRπRι , and -SO NRπRι₂. Particularly preferred is alkyl.

[0058] Preferred Rio groups are hydrogen and alkyl.

[0059] Preferred Rπ and Rχ₂ are hydrogen, alkyl, alkylaryl, and alkylheteroaryl.

[0060] Preferred Rι₃ groups are hydrogen and alkyl.

[0061] The following compounds are particularly preferred:

8-{4-[2-(l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-fluoroquinoline;

8-{4-[2-(l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-chloroquinoline;

8- {4-[2-(l -benzofuran-3-yl)ethyl]- 1 -piperazinyl} -6-methylquinoline;

8-{4-[2-(l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-methoxyquinoline;

8- {4-[2-(6-chloro- 1 -benzofuran-3 -yl)ethyl]- 1 -piperazinyl} -quinoline;

8-{4-[2-(6-chloro-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-fluoro-quinoline;

8- {4-[2-(6-chloro-l -benzofuran-3-yl)ethyl]- 1 -piperazinyl} -6-chloro-quinoline;

8-{4-[2-(6-chloro-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-methyl-quinoline;

8-{4-[2-(6-methoxy-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-quinoline;

8-{4-[2-(6-methoxy-l-ber-zofuran-3-yl)ethyl]-l-piperazinyl}-6-methyl-quinoline;

8-{4-[2-(6-methoxy-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-chloro-quinoline;

8- {4-[2-(5-chloro- 1 -benzofuran-3 -yl)ethyl]- 1 -piperazinyl} -quinoline;

8-{4-[2-(5-chloro-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-chloro-quinoline;

8-{4-[2-(5-chloro-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-methyl-quinoline; 8- -{4- 2-(5-fluoro- 1 -benzofuran-3-yl)ethyl]- 1 -piperazinyl} -quinoline; 8 -{4- 2-(5-fluoro- 1 -benzofuran-3 -yl)ethyl]- 1 -piperazinyl} -6-methoxy-quinoline; 8 ^■{4- 2-(5-fluoro- 1 -benzofuran-3 -yl)ethyl]- 1 -piperazinyl} -6-fluoro-quinoline; 8- ■{4- 2-(7-methoxy-l-benzofuran-3-yl)ethyl]-l-piρerazinyl}-quinoline; 8- -{4- 2-(7-methoxy- 1 -benzofuran-3-yl)ethyl]-l -piperazinyl} -6-methoxy-quinoline; 8 -{4- 2-(7-methoxy- 1 -benzofuran-3 -yl)ethyl] - 1 -piperazinyl} -6-chloro-quinoline; 8 ^■{4-12-(5-methoxy-l -benzofuran-3-yl)ethyl]- 1 -piperazinyl} -quinoline; 8 ^■{4-12-(5-methoxy-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-chloro-quinoline; 8.{4-ⁱ 2-(5-methoxy-l-benzoJiuran-3-yl)ethyl]-l-piperazinyl}-6-methyl-quinoline; 8 ^■{4-12-(5-methoxy- 1 -benzofuran-3-yl)ethyl]- 1 -piperazinyl} -6-isopropyl-quinoline; 8- -{4- 2-(5-methoxy- 1 -benzofuran-3-yl)ethyl]- 1 -piperazinyl} -6-methoxy -quinoline; 8 ^■{4- 2-(5-methoxy-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-fluoro-quinoline; 8 ^■{4- 2-(l -benzofuran-3-yl)propyl]- 1 -piperazinyl} quinoline; 8 ^■{4- 2-( 1 -benzofuran-3-yl)propyl]- 1 -piperazinyl} -6-chloro-quinoline; 8 -{4- 2-(l -benzofuran-3-yl)propyl]-l -piperazinyl} -6-fluoro-quinoline; 8 -{4- 2-(l -benzofuran-3-yl)propyl]- 1 -piperazinyl} -6-methyl-quinoline; 8 -{4- 2-(7-methoxy- 1 -benzofuran-3-yl)propyl]- 1 -piperazinyl} quinoline; 8 -{4- 2-(7-methoxy- 1 -benzofuran-3-yl)propyl]- 1 -piperazinyl} -6-methyl-quinoline; 8- -{4- 2-(7-methoxy- 1 -benzofuran-3-yl)propyl]- 1 -piperazinyl} -6-chloro-quinoline; 8 -{4- 2-(7-methoxy- 1 -benzofuran-3-yl)propyl]- 1 -piperazinyl} -6-methyl -quinoline; 8 -{4- 2-(7-methoxy- 1 -benzofuran-3-yl)- 1 -methylethyl)piperazin- 1 -yljquinoline;

6-me ;hoxy-8-{4-[2-(7-methoxy-l-ben--;ofuran-3-yl)-l-methylethyl)piperazin-l yljquinoline; 6-methyl-8- {4-[2-(7-methoxy- 1 -benzofuran-3-yl)- 1 -methylethyl)piperazin- 1 - yljquinoline;

8-{4-[2-(5-methoxy-l-benzofuran-3-yl)-l-methylethyl)piperazin-l-ylJquinoline;

6-chloro-8- {4-[2-(5-methoxy- 1 -benzofuran-3 -yl)- l-methylethyl)piperazin- 1 - yljquinoline;

6-methyl-8- {4-[2-(5-methoxy- 1 -bei-zofuran-3-yl)- 1 -methylethyl)piperazin- 1 - yljquinoline;

8-{4-[4-cis-(l-benzothien-3-yl)cyclohexylJ-l-piperazinyl}-6-chloroquinoline;

8-{4-[4-trans(l-benzothien-3-yl)cyclohexylJ-l-piperazinyl}-6-chloroquinoline;

8-{4-[4-cis(l-benzothien-3-yl)cyclohexyl]-l-ρiρerazinyl}-6-fluoroquinoline;

8- {4-[4-trans(l -benzothien-3-yl)cyclohexylJ- 1 -piperazinyl} -6-fluoroquinoline;

8-{4-[4-cis(l-benzothien-3-yl)cyclohexylJ-l-piperazinyl}-6-methoxyquinoline;

8- {4-[4-trans (1 -benzothien-3-yl)cyclohexylJ- 1 -piperazinyl} -6-methoxyquinoline;

6-fluoro-8- {4-[4-cis(5-fluoro- 1 -benzothien-3 -yl)cyclohexylJpiperazin- 1 -yl} quinoline;

6-fluoro-8- {4-[4-trans(5-fluoro- 1 -benzothien-3-yl)cyclohexyl]piperazin- 1 - yl} quinoline;

6-methoxy-8- {4-[4-cis(5-fluoro- 1 -benzothien-3-yl)cyclohexylJρiperazin- 1 - yl} quinoline;

6-methoxy-8- {4-[4-trans(5-fluoro- 1 -benzothien-3-yl)cyclohexyl]piperazin- 1 - yl} quinoline;

5-chloro-8- {4-[4-cis(5-fluoro-l -benzothien-3-yl)cyclohexylJpiperazin- 1 -yl} quinoline;

5-chloro-8- {4-[4-trans(5-fluoro- 1 -benzothien-3-yl)cyclohexylJpiperazin-l - yl} quinoline;

8- {4-[4-cis(l -benzofuran-3-yl)cyclohexylJ- 1 -piperazinyl} -5-fluoroquinoline;

8- {4-[4-trans(l -benzofuran-3 -yl)cyclohexyl]- 1 -piperazinyl} -5-fluoroquinoline;

8-{4-[4-cis(l-benzofuran-3-yl)cyclohexylJ-l-piperazinyl}-6-fluoroquinoline;

8-{4-[4-trans(l-benzofuran-3-yl)cyclohexylJ-l-piperazinyl}-6-fluoroquinoline;

5-fluoro-8- {4-[4-cis(7-methoxy- 1 -benzofuran-3-yl)cyclohexylJ- 1 - piperazinyl} quinoline; 5-fluoro-8-{4-[4-frans(7-methoxy-l-beι-zofuran-3-yl)cyclohexyl]-l- piperazinyl} quinoline;

6-fluoro-8-{4-[4-cis(7-methoxy-l-benzofuran-3-yl)cyclohexyl]-l- piperazinyl} quinoline;

6-fluoro-8-{4-[4-fraι s(7-methoxy-l-benzofuran-3-yl)cyclohexyl]-l- piperazinyl} quinoline;

8-{4-[4-cis(7-methoxy-l-benzofuran-3-yl)cyclohexyl]-l-piperazinyl}quinoline;

8-{4-[4-frans(7-methoxy-l-benzofuran-3-yl)cyclohexyl]-l-piperazinyl}quinoline;

5-chloro-8- {4-[4-cis(7-methoxy-l -benzofuran-3-yl)cyclohexyl]piperazin- 1 - yljquinoline;

5-chloro-8- {4-[4-trans(7-methoxy- l-benzofuran-3-yl)cyclohexylJpiperazin- 1 - yl} quinoline;

5 -chloro-8- {4- [4-cis(5 -methoxy- 1 -benzofuran-3 -yl)cyclohexyl]piperazin- 1 - yl} quinoline;

5-chloro-8-{4-[4-frans(5-methoxy-l-benzofuran-3-yl)cyclohexylJpiperazin-l- yl} quinoline;

6-fluoro-8-{4-[4-cis(5-methoxy-l-benzofuran-3-yl)cyclohexylJpiperazin-l- yl} quinoline;

6-fluoro-8- {4- [4-trans(5 -methoxy- 1 -benzofuran-3-yl)cyclohexyl]piperazin- 1 - yl} quinoline;

8-[4-(4-benzofuran-2-yl-yclohexyl)-piperazin-l-ylJ-6-fluoro-quinoline; cis-8-[4-(4-thiophene-2-yl-cyclohexyl)-piperazin-l-ylJ-6-methoxy-quinoline; trans-8-[4-(4-thiophene-2-yl-cyclohexyl)-piperazin-l-yl]-6-methoxy-quinoline;

8-[4-(4-Benzofuran-2-yl-yclohexyl)-piperazin-l-ylJ-6-fluoro-quinoline; cis-8-[4-(4-thiophene-2-yl-cyclohexyl)-piperazin-l-yl]-6-methoxy-quinoline; or trans-8-[4-(4-thiophene-2-yl-cyclohexyl)-piperazin-l-ylJ-6-methoxy-quinoline.

[0062] The present invention provides a process for the preparation of a compound of general formula I. These compounds may be prepared by condensing the appropriately substituted 8-piperazino quinoline derivatives 13 with the appropriately substituted heterocycles 14 in solvents such as DMF, THF or DMSO, acetone or ethanol, in the presence of an acid binding agent such as an organic tertiary base, such as triethylamine, triethanolamine, DBU, or diisopropylethylamine, an alkaline metal carbonate such as potassium carbonate or sodium carbonate, at 100-150°C, as illustrated below in Scheme 1. See also, J. March, Advanced Organic Chemistry, Mechanisms and Structure, John Wiley and Sons, 4th edition, 1992.

Scheme.1

Y = Halogen, Mesylate or Tosylate: a = DMSO/ Diisopropyl ethylamine/ 120°C

[0063] Alternatively, when the linkers connecting the 8-piperazino quinoline and benzo[l]furan or benzo[l]thioρhene are moieties of the following formula:

where Z is N or CH; t is an integer from 1 to 3; and u is an integer from 1 to 3; the resultant compounds may be prepared as indicated in Scheme 2, 3 or 4, as illustrated below.

a. Ph₃P=CR₁₃COOEt/ Toluene/ Reflux; b. Pt/H₂; c. LiAIH₄/THF; d. Ph₃P/l₂/lmidazole e.Ph₃P/Base; f.35/Reflux; g. HCl

Scheme.3

a. Ph₃P=CHCOOEt/ Toluene. Reflux; b. Pt/H₂; c. LiAIH₄/ THF; d. Ph₃P/ CBr₄; e. 13/ Diisopropyl ethyl amine/ DMSO/ 120°C

Scheme.4

25

a. DMSO/Diisopropyl ethyl amine; b. HCI/Dioxane; c. DMSO/Diisopropyl ethyl amine ; d. Ph₃P/ CBr₄; e. 13/ Diisopropyl ethylamine/ DMSO/ 120°C

[0064] Alternatively, when the linkers connecting the piperazino quinoline and benzo[l]thiophene are

where Z= N or CH, t= 1 to 3, u= 0, the resultant compounds may be prepared as indicated in Scheme 5, as illustrated below. Scheme.5

a. DMSO/Diisopropyl ethyl amine; b. HCI/Dioxane

[0065] The benzo[l]furan and benzo[lJthiophene 14 may be prepared from the commercially available substituted salicyclic acid derivatives 30, as illustrated below in Scheme 6. Generally, the appropriately substituted salicyclic acid derivatives or thiosalicyclic acid derivatives were esterified using the alcoholic hydrochloric acid. Compound 31 was reacted with ethyl bromoacetate in refluxing acetone/ K₂CO₃. The resultant diester 32 was hydrolyzed to the diacid 33. The diacid obtained was cyclized using anhydrous CH₃COONa/ (CH₃CO)₂O to compound 34. This was hydrolyzed using IN HCl to produce compound 35. This compound, on reaction with

(triphenylphosphoranylidene)ethylacetate or the appropriately substituted (triphenylphosphoranylidene)ethylacetate derivative in boiling organic solvents such as toluene or xylene, yields compound 36 . This can be converted to 14 by reduction using LAH and converting it to either tosylate or iodide using I₂/ imidazole. Scheme. 6

30 31

32

35

14

36

37

Y = I or tosylate x = 0 or S

(a) MeOH. HCl/ Reflux; (b) BrCH₂COOEt/ K₂CO₃/ Acetone/ Reflux; (c) NaOH/ EtOH/ THF/ Reflux; (d) (CH₃CO)₂O/ CH₃COONa CH₃COOH/ reflux; (e) IN. HCl/ MeOH/ reflux; (f) Ph₃P=CHRιCOOEt/ Toluene/ Reflux; (g) LAH/ THF/ O^°C; (h) p-Toluene sulfonyl chloride/ Pyridine or PPh₃/ 1₂/ Imidazole/ THF

[0066] Alternatively, compound 35 can be reacted with l-triphenylphosphoranylidene-2- propanone to yield 38, which can be reacted with 8-piperazinoquinoline derivatives 13 using sodium triacetoxyborohydride to give 39, as illustrated in Scheme 7. How ever, when the linker is (R₈) cycloalkyl, these class of compounds can be prepared by the methods as indicated in Scheme 8 and Scheme 9.

Scheme. 7

39 a) Ph₃P=CHCOCH₃/Toluene/ reflux; b) Reductive amination

Scheme.8

b. (CF₃S0₂)₂0/ LDA

13 / Reductive amination

b. (CF₃S0₂)₂0/ LDA; c.Pinacoleborane/Et3N/PdCI2,dpp ferrocene (Suzuki Coupling) 1 ,2-Dimethoxy ethane/ LiCI/ (Ph₃)₄Pd(0)

a. Ph₃P=CR₁₃COOEt/ Toluene/ Reflux; b. Pt/H₂; c. LiAIH₄/THF; d. Ph₃P/CBr₄ e. DMSO/Diisopropyl ethylamine, 120°C

[0067] The terms "effective amount", "therapeutically effective amount" and "effective dosage" as used herein, refer to the amount of a compound of formula I that, when administered to a patient, is effective to at least partially ameliorate a condition from which the patient is suspected to suffer. Such conditions include serotonin-related disorders, including but not limited to, anxiety, depression, cognitive deficits, such as those resulting from Alzheimer's disease and other neurodegenerative disorders, schizophrenia, prostate cancer, and nicotine withdrawal.

[0068] The term "pharmaceutically acceptable salt", as used hererin, refers to salts derived from organic and inorganic acids as, for example, lactic, citric, acetic, cinnamic, tartaric, succinic, maleic, malonic, mandelic, malic, oxalic, propionic, fumaric, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic, benzoic, and similarly known acceptable acids. Where Ri to R₉ and Rii contain a carboxyl group, salts of the compounds of this invention may be formed with bases such as alkali metals, such as sodium, potassium, and lithium or the allcaline earth metals, such as calcium or magnesium.

[0069] The term "patient", as used herein, refers to a mammal, preferably a human. [0070] The terms "administer", "administering" or "administration", as used herein, refer to either directly administering a compound or composition to a patient, or administering a prodrug derivative or analog of the compound to the patient, which will form an equivalent amount of the active compound or substance within the patient's body. [0071] Compounds of formula I have been found to have affinity for the 5-HT reuptake transporter. They are therefore useful in the treatment and/or prevention of serotonin-related disorders. The present invention accordingly provides pharmaceutical compositions that include the compound of formula I; and optionally one or more pharmaceutically-acceptable carriers, excipients, or diluents. The term "carrier", as used herein, shall encompass carriers, excipients and diluents.

[0072] Examples of such carriers are well know to those skilled in the art and are prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington 's Pharmaceutical Sciences, 17th edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Easton, Pa (1985), which is incorporated herein by reference in its entirety. Pharmaceutical acceptable carriers are those carriers that are compatible with the other ingredients in the formulation and are biologically acceptable.

[0073] The compounds of formula I can be administered orally or parenterally, neat, or in combination with conventional pharmaceutical carriers. Representative solid carriers include one or more substance that can act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders, tablet-disintegrating agents, or encapsulating materials. They are formulated in conventional manner, for example, in a manner similar to that use for known antihypertensive agents, diuretics and β-blocking agents. Oral formulations containing the active compounds of this invention may comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. In powders, the carrier is a finely divided solid that 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 proportion and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. [0074] Capsules may contain mixtures of the active comρound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc.

[0075] Useful tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, dismtegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, microcrystalline cellulose, methyl cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, starches, sugars, low melting waxes, and ion exchange resins. Preferred surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidol silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein may utilize standard delay or time release formulations to alter the absorption of the active compound(s). The oral formulation may also consist of administering the active ingredient in water or a fruit juice, containing appropriate solubilizers or emulsifiers as needed. [0076] Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups, and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable oil or fat. The liquid carrier can obtain other suitable pharmaceutical additives such as, for example, solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stablizers or osmo- regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), 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 myistrate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant. [0077] Liquid pharmaceutical compositions that are sterile solutions or suspensions can be administered by, for example, intramuscular, intraperitoneal, or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration may be in either liquid or solid form.

[0078] hi 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 may be administered from 1 to 6 times a day, more usually from 1 to 4 times a day.

[0079] When administered for the treatment and/or prevention of a particular disease state or disorder, it is understood that the effective dosage may vary depending upon the particular compound utilized, the mode of administration, the condition, and severity thereof, of the condition being treated, as well as the various physical factors related to the individual being treated. In therapeutic applications, compounds of formula I are provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. An amount adequate to accomplish this is defined as a "therapeutically effective amount". The dosage to be used in the treatment and/or prevention of a specific case must be subjectively determined by the attending physician. The variables involved include the specific condition and the weight, age, and response pattern of the patient. Effective administration of the compounds of this invention may be given at an oral dose of from about 0.1 mg/day to about 1,000 mg/day. Preferably, administration will be from about 10 mg/day to about 600 mg/day, more preferably from about 50 mg/day to about 600 mg/day, in a single dose or in two or more divided doses. The projected daily dosages are expected to vary with route of administration. [0080] Such doses may be administered in any manner useful in directing the active compounds herein to the patient's bloodstream, including orally, via implants, parentally (including intravenous, intraperitoneal, intraarticularly and subcutaneous injections), rectally, intranasally, topically, ocularly (via eye drops), vaginally, and transdermally. [0081] In some cases it may be desirable to administer the compounds directly to the airways in the form of an aerosol. For administration by intranasal or intrabrochial inhalation, the compounds of formula I can be formulated into an aqueous or partially aqueous solution.

[0082] The compounds of this invention may also be administered parenterally or intraperitoneaUy. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to inhibit the growth of microorganisms. [0083] The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the foπn must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[0084] The compounds of formula I can also be admimstered transdermally through the use of a transdermal patch. For the purposes of this disclosure, transdermal. administrations are understood to include all administrations across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administrations may be carried out using the present compounds, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).

[0085] Transdermal administration may be accomplished through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semi-permeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature. [0086] The compounds of formula I may be administered rectally or vaginally in the form of a conventional suppository. Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin. Water soluble suppository bases, such as polyethylene glycols of various molecular weights, may also be used. [0087] In certain embodiments, the present invention is directed to prodrugs of compounds of formula I. The term "prodrug" as used herein, refers to a compound that is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of formula I. Narious forms of prodrugs are known in the art such as those discussed in, for example, Bundgaard (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al, (ed.), "Design and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al, Journal of Drug Delivery Reviews, 8:1-38 (1992); Bundgaard, Journal of Pharmaceutical Sciences, 77:285 etseq. (1988); Higuchi and Stella (eds.), Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975), each of which is incorporated by reference in its entirety.

[0088] The present invention further provides compounds of the invention for use as an active therapeutic substance. Compounds of formula I are of particular use in the treatment and/or prevention of diseases related to serotonin-related disorders.

[0089] The present invention further provides methods of treating and/or preventing serotonin-related disorders, including depression, anxiety, cognitive deficits, schizophrenia, prostate cancer, or nicotine withdrawal, in mammals including humans, which comprises administering to the afflicted mammal an effective amount of a compound or a pharmaceutical composition of the invention. EXAMPLES

Preparation of Intermediates

Example 1: Intermediate 1 — 8-piperazino quinoline

[0090] This intermediate has been prepared by generally following the procedure described in WO 00/40554, which is incorporated herein by reference.

Example 2: Intermediate 2 — 6-fluoro-8-bromo-quinoline

[0091] To a mixture of 7.0 g of 2-bromo-4-fluoro-aniline, 7.0 g of glycerol and 13.0 g of m- nitrobenzene sulfonic acid sodium salt, 20 ml of 70% sulfuric acid was added drop by drop. The reaction temperature was raised to 150° C for 4 hr. The mixture was cooled, poured on water neutralized with NaOH and the formed precipitate was filtered to yield 34.7 g of 6- fluoro-8-bromo-quinoline. MS (ES) m/z (relative intensity): 227 (-VT+H, 100).

Example 3: Intermediate 3 — 6-fluoro-8-( t-Boc)-piperazino-quino!ine

[0092] To a mixture of 2.2 g of 6-fluoro-8-bromo-quinoline in THF, was added 0.045 g of Pd₂(dba)₃, 1.3 g of NaOt-Bu, 0.044 g of binap , 0.052 g of tetrakis (triphenylphosphine) palladium (0) and 2.2 g of t-Boc piperazine. The mixture was refluxed for 3 hours. The reaction mixture was then cooled to room temperature, diluted with ether, filtered through celite and concentrated in vacuo. The crude material was then purified by flash chromatography to give 3.0 g of 6-fluoro-8(t-Boc)-piperazino-quinoline. MS (ES) m z (relative intensity): 332 (Wf+ΕL, 100).

Example 4: Intermediate 4 — 6-fluoro-8-piperazino-quinoIine

[0093] To a solution of 3.0 g 6-fluoro-8-(t-Boc)-piperazino-quinoline in 10 ml of dioxane, 10 ml of 4 N HCl /dioxane was added. The mixture was stirred at room temperature overnight. The formed precipitate was filtered, dissolved in water and extracted with CH₂C1 , dried, and the solvent removed to yield 1.9 g of 6-fluoro-S- piperazino-quinoline. MP: 103°C; MS (ES) m z (relative intensity): 233 (M⁺+H, 100).

Example 5: Intermediate 5 — 5-fluoro-8-piperazino-quinoline

[0094] To a mixture of 9 g of 8-chloro-6-methoxy-quinoline in 75ml of dry THF, was added 0.64 g of Pd₂(dba)₃, 6.2 g of NaOt-Bu, 0.274 g of 2-dicyclohexylρhosρhino-2'-(N,N- dimethyl-amino)biphenyl (also known as cymap) and 11.2 g of t-Boc piperazine. The mixture was refluxed for 5 hours. The reaction mixture was then cooled to room temperature, diluted with ether and filtered through celite. The filtrate was concentrated in vacuo. The crude material was then purified by flash chromatography using 300 ml of silica gel and 100% CH₂C1₂ then 50% ethyl acetate/hexane to yield 16.5 g of 5-fluoro-8-piperazino- quinoline.

Example 6: Intermediate 6 - 6-chloro-8-piperazino-quinoline and 6-methyl-8- piperazino-quinoline

[0095] These intermediates have been prepared generally using the method used to prepare 6-fluoro-8-piperazino-quinoline as detailed above, using the corresponding starting material substituted with aniline. Example 7: Intermediate 7 — 5-chIoro-8-(trifluoromethylsuIfonyIoxy)-quinoIine

[0096] To a suspension of 5-chloro-8-hydroxy-quinoline (8.95g) in 100 ml of CH₂C1 , 20 ml of TEA was added. The suspension was dissolved then cooled to -15°C. A solution of 21.1 g of triflic anhydride in 50 ml of CH₂C1₂ was added dropwise, with cooling. After complete addition, the reaction was stirred at -15°C for 30 min. The reaction was diluted with CH₂C1₂, washed with a solution of NaHCO₃, then with water, dried, and the solvent was removed to yield 15.0 g of 5-chloro-8- (trifluoromethylsulfonyloxy)-quinoline. MP: 80-83°C; MS (ES) m/z (relative intensity): 312 (M⁺+H,100). Elemental analysis for Cι₀ H₅ Cl F₃ N O₃; Calculated: C : 38.54; H : 1.62; N : 4.4; Found: C : 38.3; H : 1.73; N : 4.5.

Example 8: Intermediate 8 — 5-chloro-8-(t-Boc)-piperazino-quinoline

[0097] To a mixture of 4.0 g of 5-chloro-8-trifluoromethyl-quinoline in 30 ml of THF, was added 5.9 g of cesium carbonate, 0.360 g of BINAP, 0.120 g of Palladium acetate and 2.8 g of t-Boc piperazine. The mixture was refluxed for 5 hours. The reaction mixture was then cooled to room temperature, diluted with ether, filtered through celite and concentrated in vacuo. The crude material was then purified by flash chromatography to yield 2.4 g of 5- chloro-8-( t-Boc)-piperazino- quinoline. MP: 127°C; MS (ES) m/z (relative intensity): 348 (M⁺+H, 100). Elemental analysis for Cι₈ H₂₂ Cl N₃ O₂; Calculated: C : 62.15; H : 6.37; N : 12.0; Found: C : 62.5; H : 6.23; N : 11.66. Example 9: Intermediate 9 — 5-chIoro-8-piperazino-quinoline

[0098] To a solution of 2.2 g 5-Chloro- 8-(t-Boc)-piperazino- quinoline in 10 ml dioxane, 5 ml of 4 N HCl / Dioxane were added. The mixture was stirred at room temperature overnight. The formed precipitate was filtered, dissolved in water and extracted with CH₂C1₂ , dried and solvent removed to give 1.0 g of the desired product. MS (ES) m/z (relative intensity): 248 (M÷+H, 100). Elemental analysis for ₃ H Cl F₃ N₃; Calculated: C : 63.03; H : 5.7; N : 16.96; Found: C : 62.49; H : 5.32; N : 15.73.

Example 10: Intermediate 10 — 8-chloro~6-hydroxy~quinoIine

[0099] In a 500 ml 3-necked flask equipped with a mechanical stirrer and a reflux condenser, added in order were 2.0 g ferrous sulfate, 6.4 g 4-amino, 3-chloro-phenol (generated from 9.0 g of the corresponding commercially available HCl salt), 2.9 m nitrobenzene and a cold solution of 3.0 g boric acid in 16 g of glycerol. Then, 9 ml of concentrated sulfuric acid was added drop by drop with cooling. The ice bath was removed and replaced by an oil bath and the mixture was heated cautiously to 120°C for 2 hrs, then at 150°C and kept stirring under this temperature for 20 hrs. The mixture was then cooled and poured on crushed ice and the resulting solution was neutralized to with K CO₃ (saturated solution in water) till exactly pH 5. The product separated as a light brown solid which was filtered off, washed with water and hexane and dried in a vacuum oven (35°C) overnight. The product was purified by dissolving it in a minimal amount of THF, and the solution poured in 20X volume of hexane, giving 7 g (77 %) of the desired product. Example 11: Intermediate 11 — 8-chloro-6-methoxy-quinoline

[0100] To a solution of 15 g of 8-chloro-6-hydroxy- quinoline in (50 ml) DMF, 23 g of K CO₃ were added followed by 18 g iodomethane. The mixture was stirred at room temperature overnight. Water was added and the product was extracted with CH₂C1 dried and the solvent removed. The crude product was filtered through 250 ml of silica gel using 50% ethyl acetate /hexane to give 11 g of the desired product.

Example 12: Intermediate 12 — 6-methoxy- 8-(t-Boc)-piperazino-quinoline

[0101] To a mixture of 9 g of 8-chloro-6-methoxy- quinoline in 75 ml dry THF, was added 0.64 g Pd₂(dba)₃, 6.2 g NaOt-Bu, 0.274g of 2-Dicyclohexylρhosρhino-2'-(N,N-dimethyl- amino)biphenyl (also known as cymap) and 11.2 g t-Boc piperazine. The mixture was refluxed for 5 hrs. The reaction mixture was then cooled to room temperature, diluted with ether, and filtered through celite. The filtrate was concentrated in vacuo. The crude material was then purified by flash chromatography using 300 ml of silica gel and 100% CH₂C1₂ then 50% ethyl acetate / hexane to give 16.5 g of the desired product. Example 13: Intermediate 13 — 6-methoxy- 8-piperazino-quinoline

[0102] To a solution of 16.0 g 6-methoxy-8-( t-Boc)-piperazino-quinoline in 100 ml dioxane, 30 ml of 4 N HCl /dioxane were added. The mixture was stirred at room temperature overnight. The formed precipitate was filtered, dissolved in water and extracted with CH₂C1₂ , dried and solvent removed to give 10.5 g of the desired product.

Example 14: Intermediate 14 — trifluoro-methanesulfonic acid 5-fluoro- benzo[b]thiophen-3-yl ester

[0103] To a cold solution (-20°C) of 5-fluoro-benzothiophenone (15 g) in CH₂C1₂ (100 ml), TEA (27g) was added. To the cold mixture, a solution of triflic anhydride (37.7g) in CH₂C1₂

(25 ml) was added drop by drop. The temperature was left to rise to 0 C and kept at this temperature for 1 hr. It was then quenched with a solution of NaHCO and the product extracted with CH₂C1₂, dried over MgSO₄, and the solvent was removed to give 23.0 g of the desired product.

Example 15: Intermediate 15 — 7-methoxytrifluoro-methanesulfonic acid 5-flnoro- benzo[b]thiophen-3-yl ester

[0104] 125To a cold solution (-20°C) of 7-MeO-Benzofuranone (3.3 g) in CH₂C1₂ (30 ml), TEA (8.3ml) was added. To the cold mixture, a solution of triflic anhydride (8.5g) in CH C1₂ (20 ml) was added drop by drop. The temperature was kept at this temperature for 1 hr. It was then quenched with a solution of NaHCO₃ and the product extracted with CH₂C1₂, dried over MgSO₄, and the solvent was removed to give 5.6 g of the desired product.

Example 16: Intermediate 16 ~ 2-(benzo[b]thiophen-3-yI0-4,4,5,5-tetramethyl- [l,2]oxaborolane

[0105] To a solution of 3-bromobenzothiophene (lOg) in dioxane (30 ml) a solution of pinacoleborane (1 M, 9.0 g) in THF (70 ml) was added followed by TEA (10.7 g) and PdCl₂, dpp ferrocene . The reaction was heated at 60 C overnight. The solvent was removed under vacuum. Ether was added and the insoluble was filtered. The filtrate was evaporated and filtered through silica gel (300 ml) using 5% Ethyl acetate / Hexane to give 9.0 g of desired product.

Example 17: Intermediate 17 — 2-(5-fluoro-benzo[b]thiophen-3-yI0-4,4,5,5-tetramethyl- [l,2]oxaborolane

[0106] To a solution of 5-fluoro-3-trifluoromethyl-benzothiophene (10g) in dioxane (50 ml) a solution of pinacoleborane (1 M, 7.2 g) in THF (56 ml) was added,followed by TEA (15 ml) and PdCl₂,dpp ferrocene (.913g). The reaction is heated at 60^°C overnight. The solvent was removed under vacuum. Ether was added and the insoluble was filtered. The filtrate was evaporated and filtered through (200 ml) of silica gel using 5% Ethyl acetate/hexane to give 3.5 g of desired product. MP: 80-83°C; MS (ES) m/z (relative intensity): 312 (M⁺+H,100). Elemental analysis for C_i4Hι₆BFO₂S; Calculated: C: 60.45; H: 5.8; Found: C: 60.48; H: 5.68. Example 18: Intermediate 18-- 2-(benzo[b]furan-3-yl0-4,4,5,5-tetramethyI- [l,2]oxaborolane

[0107] To a mixture of 3-bromo-benzofuran (500g) in TEA (1 ml) a solution of (IM) pinacoleborane in THF (.476 g/3.75 ml) in THF was added followed by PdCl ,dpp ferrocene .

The reaction is heated at 150 C for 3 min in the microwave. The solvent was removed under vacuum. The residue was taken in water and extracted with ether, dried over magnesium sulfate and the solvent removed. The residue was filtered through 50 ml of silica gel using 10% Ethyl acetate/hexane to give .350 g of desired product.

Example 19: Intermediate 19 — 2-(7-methoxy benzo [b]furan-3~yl0-4,4,5,5~tetramethyl- [1,2] oxaborolane

[0108] To a mixture of 7-methoxy-3-trifluoromethylsulfonyl-benzofuran (.660g) in TEA (1 ml) a solution of (IM) pinacoleborane in THF (.476 g / 3.75 Ml) was added followed by PdCl ,dpp ferrocene . The reaction was heated at 150^°C for 3 min in the microwave. The solvent was removed under vacuum. The residue was taken in water and extracted with ether, dried over magnesium sulfate and the solvent removed. The residue was filtered through 50 ml of silica gel using 10% ethyl acetate/hexane to give .350 g of desired product. Example 20: Intermediate 20 - trifmoro-methanesulfonic acid l,4-dioxa-spiro[4,5]dec- 7-en-8yl ester

[0109] To a cold solution of LDA (2.35g) in THF (20 ml) at -78^°C, a solution of 1,4 cyclohexanedione mono ethylene ketal (3.0g) in THF (20 ml) was added drop wise with cooling. After 90 min at -78^°C, a solution of N-phenyl trifluoromethane sulfonimide (7.8 g) in THF (20 ml) was added drop wise with cooling and the reaction temperature was left to rise to room temperature. The THF is removed under vacuum, and the residue was filtered through silica gel (500 ml) and 2% ethyl acetate/hexane to give 2.0 g of the desired product.

Example 21: Intermediate 21 — 8-benzo[b]thiophen-3-yl-l,4-dioxa-spiro[4,5]dec-7-ene

[0110] To a mixture of 2-(benzo [b]thiophen-3 -y 10-4,4, 5 , 5 -tetramethyl- [ 1 ,2 J oxaborolane (2.6g) and trifluoro-methanesulfonic acid l,4-dioxa-spiro[4.5]dec-7-en-8yl ester (2.9g) in 1,2-dimethoxyethane (DME, 10 ml ), Na₂CO₃ (2.8g in 10 ml H₂O) was added followed by LiCl (.421g) in water and Tefralris(triphenylphosphine)Palladium(0) (.100g). The reaction was heated at 70^°C overnight. The reaction was then cooled to room temperature and the solvent removed under vacuum. The residue was taken in CH₂C1₂ and washed with aqueous 2N Na₂CO₃. The organic phase was separated and dried over MgSO . The solvent was then removed and the residue filtered through 200 ml of silica gel using 15% ethyl acetate/hexane to give 2.0 g of the title compound. MP: 80-83°C; MS (ES) m/z (relative intensity): 273 (M⁺+H,100). Elemental analysis for Cι₆ Hι₆ O₂ S: Calculated: C: 70.56; H: 5.92; Found: C: 68.79; H: 5.88. Example 22: Intermediate 22 » 8-(5-fluoro-benzo[b]thiophen-3-yl)-l,4-dioxa- spiro[4,5]dec-7-ene

[0111] To a mixture of 2-(5-fluoro-benzo[b]thiophen-3-yl0-4,4,5,5-tetramethyl-

[l,2]oxaborolane (1.6 g) and trifluoro-methanesulfonic acid l,4-dioxa-spiro[4.5Jdec-7-en-8yl ester (2.0 g) in 1,2-dimethoxyethane (DME, 10 ml ), Na₂CO₃ (1.2g in 6 ml H₂O) was added followed by LiCl (.530 g) in water and Tetrakis(triphenylphosphine)Palladium(0) (100 g). The reaction was heated at 80 C for 2 hours. The reaction was then cooled to room temperature and the solvent removed under vacuum. The residue was taken in ether and filtered over celite. The organic phase was separated and dried over MgSO₄. The solvent was removed and the residue filtered tlirough 150 ml of silica gel using 15% ethyl acetate/hexane to give 2.2 g of the title compound. MP: 80-83°C; MS (ES) m/z (relative intensity): 291 (M⁺+H,100).

Example 23: Intermediate 23 — 8-benzofuran-3-yI-l,4-dioxa-spiro[4,5]dec-7-ene

[0112] To a mixture of 2-(benzo[b]furan-3-yl0-4,4,5,5-tetramethyl-[l,2]oxaborolane (2.44 g) and trifluoro-methanesulfonic acid l,4-dioxa-spiro[4,5Jdec-7-en-8yl ester (2.9 g) in DME (20 ml), Na₂CO₃ (2.9 g in 10 ml H₂O) was added followed by a solution of LiCl (1.26g) in water and Tetrakis(triphenylphosphine)Palladium(0) (.600 g). The reaction was heated at

80 C for 1 hr. It was then cooled to room temperature and the solvent was removed under vacuum. The residue was taken in ether and filtered over celite. The organic phase was separated washed with a solution of Na₂CO₃, then with a 10% solution of NH₄OH, dried over MgSO₄. The solvent was then removed and the residue was filtered through 200 ml of silica gel using 10% ethyl acetate/hexane to give .800 g of the title compound. MS (ES) m/z (relative intensity): 257 (N^+H-lOO).

Example 24: Intermediate 24 — 8-(7-methoxy-benzofuran-3-yI)-l,4-dioxa-spiro[4,5]dec- 7-ene

[0113] 8-(7-methoxy-benzofuran-3-yl)-l,4-dioxa-spiro[4,5Jdec-7-ene has been prepared in the same manner as the non substituted analog using 7-methoxy-bezofuranone. MS (ES) m/z (relative intensity): 287 (M⁺+H,100).

Example 25: Intermediate 25 — 8-benzo[b]thiophen-3-yl-l,4-dioxa-spiro[4,5]decane

[0114] A mixture of 8-benzo[bJthiophen-3-yl-l,4-dioxa-spiro[4,5]dec-7-ene (2.0g) and 10%) palladium on carbon (.700g) in ethanol/THF (25 ml/35 ml) was hydrogenated for 90 min. The catalyst was filtered off and the solvent was removed under vacuum to give 1.8 g of the desired product. MP: 80-83°C; MS (ES) m/z (relative intensity): 275 (IV^HTLIOO). Elemental analysis for C₁₆ His O₂; Calculated: C: 70.04; H: 6.61; N: 0; Found: C: 69.94; H: 6.72; N: 0 Example 26: Intermediate 26 — 5-fluoro-8-benzo[b]thiophen-3-yl-l,4-dioxa- spiro[4,5]decane

[0115] A mixture of 8-(5-fluoro-benzo[b]thiophen-3-yl)-l,4-dioxa-spiro[4,5Jdec-7-ene

(l.lg) and 10% palladium on carbon (.400g) in ethanol/THF (25 ml/35 ml) was hydrogenated for 6 hrs. The catalyst was filtered off and the solvent was removed under vacuum to give 1.0 g of the desired product. MS (ES) m/z (relative intensity): 293 (M⁺+H, 100).

Example 27: Intermediate 27 — 8-benzofuran-3-yl-l,4-dioxa-spiro[4,5]decane

[0116] A mixture of 8-benzofuran-3-yl-l,4-dioxa-spiro[4.5Jdec-7-ene (.420g) and 10% palladium on carbon (.100g) in ethanol/THF (20 ml / 10 ml) was hydrogenated for 3 hours. The catalyst was filtered off and the solvent was removed under vacuum. The product was filtered through 50 ml of silica gel and 25% ethyl acetate to give .350 g of the desired product. MS (ES) m/z (relative intensity): 259 (M⁺+H, 100).

Example 28: Intermediate 28 — 7-methoxy-benzomran-3-yl-l,4-dioxa-spiro[4,5]decane

[0117] A mixture of 8-(7-methoxy-benzofuran-3-yl-l,4-dioxa-spiro[4,5]dec-7-ene and 10% palladium on carbon in ethanol/THF was hydrogenated for 3 hrs. The catalyst was filtered off and the solvent was removed under vacuum. The product was filtered through 50 ml of silica gel and 25% ethyl acetate/hexane to give the desired product. MS (ES) m/z (relative intensity): 289 (M⁺+H, 100).

Example 29: Intermediate 29 — 4-(3H~inden-l-yl)-cyclohexanone

[0118] A solution of 8-benzo [b]thiophene-3-yl-l,4-dioxa-spiro[4,5J decane (1.8 g) in (50 ml) 1:1 tetral ydrofuran-hydrochloric acid (2 N) was stirred at room temperature for 5 hrs. THF was removed under vacuum and the product was extracted with CH₂C1₂, dried and solvent removed under reduced pressure to give 1.2 g of the desired product. MP: 97-100°C; MS (ES) m/z (relative intensity): 231 (M⁺+H,100). Elemental analysis for C_J4 H_J4 O S; Calculated: C: 73.01; H: 6.13; N: 0; Found: C: 73.38; H: 6.3; N: 0.

Example 30: Intermediate 30 — 4-(6-fluoro-3H-inden-l-yl)-cyclohexanone

[0119] A solution of 8-benzo[b]thio ^■p*hene-^?3-yl-l,4-dioxa-spiro[4,5Jdecane (1.0 g) in (20 ml) tetrahydrofuran-hydrochloric acid (2 N) was stirred at room temperature for 3 hrs. THF was removed under vacuum and the product was extracted with ether, dried and the solvent removed under reduced pressure to give .650 g of the desired product. MS (ES) m/z (relative intensity): 237 Q/ +U, 100). Example 31: Intermediate 31 — 4-(benzofuran-3-yl)-cyclohexanone

[0120] A solution of 8-benzofuran-3-yl-l,4-dioxa-spiro[4,5]decane (.350 g) in (20 ml) 1 :1 tetraliydrofuran-hydrochloric acid (2 N) was stirred at room temperature for 6 hours. THF was removed under vacuum and the product extracted with methylene chloride, dried and solvent removed under reduced pressure to give .300 g of the desired product. MS (ES) m/z (relative intensity): 215 (M⁺+H, 100).

Example 32: Intermediate 32 — 4-(7-methoxy-benzofuran-3-yϊ)-cyclohexanone

[0121] A solution of 7-memoxy-benzofuran-3-yl-l,4-dioxa-spiro[4,5Jdecane (3.0 g) in (45 ml) 1:1 tetrahydrofuran-hydrochloric acid (2 N) was stirred at room temperature for 3 hrs. THF was removed under vacuum and the product extracted with ethyl acetate, dried and solvent removed under reduced pressure to give 1.3 g of the desired product. MS (ES) m/z (relative intensity): 245 (M⁺+H, 100).

Example 33: Intermediate 33 — 8-benzofuran-2-yl-l,4-dioxa-spiro[4,5]decan-8-ol

[0122] To a cold solution of 2.5 M BuLi (2.35g) in hexane, 60 ml of THF was added and cooled to -78^°C, followed by the addition of a solution of benzofuran (5.0g) in THF (30 ml), drop by drop. After 30 min at -78 °C, a solution of 1,4 cyclohexanedione monoethylene ketal (7.27 g) in THF (30 ml) was added drop wise with cooling, and the reaction temperature was left to rise to room temperature. The reaction mixture was poured on a cold aqueous solution of NH₄C1. The THF was removed under vacuum, and the product was extracted with CH₂C1₂ dried over magnesium sulfate to give 7.0 g of the desired product.

Example 34: Intermediate 34 ~ 4-benzofuran-2-yl-cyclohex-3-enone

[0123] To a solution of benzofuran-2-yl-1.4-dioxa-spiro [4.5] decan-8-ol (2.0 g) in CH C1₂ (20 ml) was added TFA (4 ml) and the reaction was stirred at room temperature overnight. Water was added and the product was extracted with CH₂C1₂. The organic phase was washed with sodium bicarbonate dried over magnesium sulfate and the solvent removed to give 1.20 g of the desired product. MS (ES) m/z (relative intensity): 213 (-V-^+H, 100).

Example 35: Intermediate 35 ~ 4-benzofuran-2~yl-cyclohexanone

[0124] A mixture of 4-benzofuran-2-yl-cyclohex-3-enone (1.2 g) and 10% palladium on carbon in ethanol/THF was hydrogenated for 6 hours. The catalyst was filtered off and the solvent was removed under vacuum. The product was filtered through 50 ml of silica gel and 25% ethyl acetate/Hexane to give 1.1 g of the desired product. MS (ES) m/z (relative intensity): 215 (-v +H, 100).

Example 36: Intermediate 36 ~ 8-benzo[Z)]thiophen-2-yl-l,4-dioxa-spiro[4,5]decan-8-oI

[0125] A solution of benzo[bJthiophene (lOg, 75 mmol) in still-dried THF (100 ml) was cooled to -78 °C, and n-BuLi (36 ml, 2.5 M in hexane) was added. The reaction was stirred 15 min, then a solution of 1,4-cyclohexanedione mono ethylene ketal (11.12 g, 71 mmol) in THF (20 ml) was added. The reaction mixture was stirred at -78°C for 10 min, and then slowly warmed to room temperature. The reaction was slowly quenched with water (200 ml) and extracted into EtOAc (2 x 200 ml). The organic phases were combined, dried over Na₂SO₄ and concentrated to a clear oil. The product was precipitated from 40% ethyl acetate/hexane and washed with hexane to give 12.87 g (66%) of the title compound as a white solid. The mother liquor was concentrated and purified by column chromatography (40%) EtOAc/hexane) to afford an additional 4.91 g (25%) of the product as a white solid: MP:> 145°C. Elemental Analysis for Cι₆H₁₈O₃S; Calculated: C, 66.18; H, 6.25; Found: C, 66.26; H, 6.22.

Example 37: Intermediate 37 ~ 4-benzo[b]thiophen-2-yl-cyclohex-3-enone [0126] A solution of 8-benzo[b]thiophen-2-yl-l,4-dioxa-spiro[4,5Jdecan-8-ol (12 g, 44 mmol) was dissolved in THF (150 ml), 1 N aqueous HCl (150 ml) was added, and the mixture was stirred at room temperature overnight. The THF was removed under vacuum, the aqueous residue was made basic with 1 M aqueous NaOH (150 ml) and extracted into ethyl acetate (3 x 150 ml). The organic phases were combined, dried over Na₂SO , and concentrated under vacuum, affording 9.8 g (90%) of the title compound as a pale yellow solid: MP: > 120°C. Elemental Analysis for Ci₄Hi₄O₂S; Calculated: C, 68.26; H, 5.73; 'Found: C, 67.98; H, 5.71.

Example 38: Intermediate 38 ~ 4-benzo[b]thiophen-2-yl-cyclohexanone

[0127] A mixture of 4-benzo[b]thiophen-2-yl-cyclohex-3-enone (0.95 g, 4.2 mmol) and 0.5 g 10% Pd/C in ethanol (100 ml) was hydrogenated at 40 psi overnight. The catalyst was removed by filtration through celite and was washed with ethyl acetate (100 ml) and methylene chloride (100 ml). The filtrate was concentrated under vacuum, and the residue was purified by flash chromatography on silica gel (30% ethyl acetate/hexane), to afford 0.75 g of a yellow oil which crystallized on standing. NMR indicated this product was 2-(4,4- diethoxycyclohexyl)-benzo[b]thiophene. A solution of this ketal in 25 ml THF and 25 ml 1 N HCl was stirred at room temperature over a weekend. The THF was removed under vacuum, and the aqueous residue was made basic with 1 M NaOH (50 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic layers were dried over Na SO₄, filtered and concentrated under vacuum to afford 0.53 g (55%) of the title compound as a brownish solid. MS (ES) m/z (relative intensity): 231 (M*+H, 100).

Preparation of compounds of the invention

Example 39: Preparation of 8-{4-[2-(l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6- fluoroquinoline ("Compound 1")

[0128] Step 1: To a stirred solution of methyl salicylate (15. 2 g, 0.1 mol) and anhydrous potassium carbonate (50.0 g, excess) in acetone (500 ml), ethyl bromoacetate (16.7 g, 0.1 mol) was added. The reaction mixture was refluxed for 24 hrs and cooled to room temperature. It was then filtered and concentrated. The oily residue was extracted with chloroform and washed well with water. The organic layer was dried over anhydrous MgSO₄ and filtered. It was concentrated and taken to the next step without any purification. White oil; Yield: 22.0 g (92%); (M+H): 239.

[0129] Step 2: The methyl-2-(ethoxy-2-oxoethoxy)benzoate obtained from the step 1, (11.9 g, 50 mmol ) was dissolved in THF:MeOH (I.T) (300 ml) and 5N NaOH (100 ml) was added. The reaction mixture was refluxed for 24 hrs and cooled to room temperature. Afterwards, it was concentrated to dryness and dissolved in water. The aqueous layer was acidified with con. HCl and the separated solid were filtered. The product was then washed well with water and dried. The product was taken to the next step without any purification. White solid; Yield: 9.0 g 91%; MP: 125-128^°C: 197 (M+H).

[0130] Step 3: The 2-(carboxymethoxy)-benzoic acid compound obtained from the step 2 (9.8 g, 50 mmol) was dissolved in acetic anhydride (100 ml) and anhydrous sodium acetate (10.0 g, excess) was added. The reaction mixture was heated to 150^°C for 4 hrs. During this time the reaction mixture turned dark red. The reaction mixture was cooled to room temperature and quenched carefully with ice cold water. The red solid obtained was filtered and washed well with water. The red solid was then suspended in 1 N HCl and refluxed for 2 hrs. A dark red solid, benzofuran-3 (2H)-one precipitated from the reaction mixture. It was filtered and washed well with water. It was dried at 40^°C and used for the next step with out further purification. Yield: 3.5 g (51%); (M+H): 135. [0131] Step 4: A mixture of benzofuran-3 (2H)-one (1.34 g, 10 mmol) and

(carboxymethylene) triphenylphosphorane (5.22 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, the reaction mixture was concentrated and loaded over a silica-gel column. The column was eluted with hexane (500 ml) and then with 25% ethyl acetate. The product, ethyl(-l-benzofuran-3-yl)acetate was obtained as a white oil. Yield: 2.0 g (98%); (M+H): 205.

[0132] Step 5: To a stirred suspension of LiAlH₄ (200 mg, excess) in THF at 0^°C, ethyl(-l- berιzofuran-3-yl)acetate (1.02 g, 5 mmol) in THF (20 mL) was added slowly. After the addition, the reaction mixture was stirred at room temperature for 1 hr and quenched with saturated NH₄C1 solution. The product was extracted with chloroform and washed well with water. It was dried over anhydrous MgSO , filtered and concentrated. The product 2-(l- benzofuran-3-yl)ethanol obtained as a white oil was pure enough to be taken to next step without further purification. Yield: 800 mg (98%); (M+H): 163.

[0133] Step 6: To a stirred solution of 2-(l-benzofuran-3-yl)ethanol (815 mg, 5 mmol) in anhydrous pyridine (20 ml), ?-toluenesulfonyl chloride (1.14 g, 6.0 mmol) was added. The reaction mixture was kept at 0^°C for 48 hrs and quenched with ice cold water. The reaction mixture was extracted with chloroform, washed well with water, and dried over anhydrous MgSO₄. It was then filtered and concentrated. The crude product obtained was taken to next step without any purification. A mixture of tosylate (316 mg. 1 mmol) (obtained by the above mentioned process) and 6-fluoro-8-piperazino quinoline (231 mg, 1 mmol) was heated at 120^°C in DMSO in the presence of N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end, reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous MgSO₄ and concentrated to dryness. The dark colored solid was purified by silica-gel column chromatography by initially eluting it with 70% ethyl acetate:hexane and then with 55% methanol: ethyl acetate. The product, 8-{4-[2-(l-benzofuran-3-yl)ethylJ-l-piperazinyl}-6-fluoroquinoline, was isolated as yellow oil. Yield: 220 mg (58%); (M+H): 376. ¹HNMR (400MHz, CDCl₃):δ 8.82 ~ 8.80 (dd, J, = 1.7Hz, J₂ = 1.7Hz, IH), 8.08 ~ 8.03 (dd, =1.8Hz, J₂ = 1.8Hz, IH), 7.69 ~ 6.32 ( m, 8H), 3.50 ~ 2.63 (m, 12H). Example 40: Preparation of 8-{4-[2-(l-benzofuran-3~yI)ethyI]-l-piperazinyl}-6- chloroquinoline ("Compound 2")

[0134] 8-{4-[2-(l-benzofuran-3-yl)ethylJ-l-piperazinyl}-6-chloroquinoline was prepared by generally following the procedure outlined in example 1, step 6, starting from the tosylate (316 mg, 1 mmol) and 6-chloro-8-piperazino quinoline (247 mg, 1 mmol). The product was purified by silica-gel column chromatography by initially eluting it with 70% ethyl acetate:hexane and then with 5%o methano ethyl acetate to yield a brown oil. Yield: 80 mg (20%); (M+H): 392; 'HNMR (400MHz, CDCl₃):δ 8.86 ~ 8.82 (dd, Ji = 1.7Hz, J₂ = 1.7 Hz, IH); 8.02 ~ 8.00 (dd, i = 1.8, J₂ = 1.8 Hz, IH); 7.78 ~ 6.86); (m, 8H); 3.51 ~ 2.58 (m, 12H).

Example 41: Preparation of 8-{4~[2-(l-benzofuran-3~yI)ethyI]-l~piperazinyl}-6- methylquinoline ("Compound 3")

[0135] 8-{4-[2-(l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-methylquinoline was prepared by generally following the procedure outlined in example 1, step 6, starting from the tosylate (316 mg, 1 mmol) and 6-methyl-8-piperazino quinoline (227 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 70% ethyl acetate :hexane and then with 5% methanol; ethyl acetate. Brown oil; Yield: 120 mg, 32%; (M+H): 372; ¹HNMR (400MHz, CDCl₃):δ 8.86 ~ 8.80 (dd, Ji = 1.7 Hz, J₂ = 1.7 Hz, IH); 8.02 ~ 8.00 (dd, i = 1.8 Hz, J₂ = 1.8 Hz, IH); 7.78 ~ 6.98 (m, 8H); 3.50 ~ 2.56 (m, 12H); 2.50 (s, 3H).

Example 42: Preparation of 8-{4-[2-(l-benzofuran-3-yl)ethyI]-l~piperazinyl}-6- methoxyquinoline ("Compound 4")

[0136] 8-{4-[2-(l-benzofuran-3-yl)ethylJ-l-piρerazinyl}-6-methoxyquinoline was prepared by generally following the procedure outlined in example 1, step 6, starting from the tosylate (316 mg, 1 mmol) and 6-methoxy-8-piperazino quinoline (243 mg, 1 mmol) (213 mg, 1 mmol). The product was purified by silica-gel column chromatography by initially eluting it with 80% ethyl acetate:hexane and then with 5% methanol: ethyl acetate to yield a brown liquid. Yield: 180 mg (46%); (M+H):388; 1H NMR 68.72 (d, IH), 8.05 (q, IH), 7.68 (m, IH), 7.59-7.25 (m, 5H), 6.81 (d, IH), 6.71 (d, IH), 3.91 (s, 3H), 3.49 (bs, 4H), 3.07-2.85 (m, 8H). Example 43: Preparation of 8-{4-[2-(6-chIoro-l-benzofuran-3-yl)ethyl]-l-piperazinyl}- quinoline ("Compound 5")

[0137] Step 1: To a stirred solution of methyl-4-chloro-2-hydroxy- benzoate (18. 6 g, 0.1 mol) and anhydrous potassium carbonate (50.0 g, excess) in acetone (500 ml) ethyl bromoacetate (16.7 g, 0.1 mol) was added. The reaction mixture was refluxed for 24 hrs and cooled to room temperature. It was then filtered and concentrated. The oily residue was extracted with chloroform and washed well with water. The organic layer was dried over anhydrous MgSO₄ and filtered. It was concentrated and taken to the next step without any purification. White oil; Yield: 27.0 g (99%); (M+H): 273.

[0138] Step 2: The methyl-2-(ethoxy-2-oxoethoxy)-4-chloro-benzoate obtained from the step 1, (13.6 g, 50 mmol) was dissolved in THF:MeOH (1:1) (300 ml) to which was added 5N NaOH (100 ml). The reaction mixture was refluxed for 24 hrs and cooled to room temperature. Afterwards, it was concentrated to dryness and dissolved in water. The aqueous layer was acidified with con. HCl and the separated solid were filtered. It was then washed well with water and dried. The product was taken to the next step without any purification. White solid; Yield: 10.0 g (86%); (M+H): 231.

[0139] Step 3: The 2-(carboxymethoxy)-4-chloro-benzoic acid compound obtained from the step 2 (11.5 g, 50 mmol) was dissolved in acetic anhydride (100 ml) and anhydrous sodium acetate (10.0 g, excess) was added. The reaction mixture was heated to 150^°C for 4 hrs. During this time the reaction mixture turned dark red. The reaction mixture was cooled to room temperature and quenched carefully with ice cold water. The red solid obtained was filtered and washed well with water. The red solid obtained was suspended in 1 N HCl and refluxed for 2 hrs. A dark red solid, 6-chloro-benzofuran-3 (2H)-one, precipitated from the reaction mixture. It was filtered and washed well with water. It was dried at 40^°C and used for the next step without further purification. Yield: 5.8 g (69%); (M+H): 169.

[0140] Step 4: A mixture of 6-chloro-benzofuran-3 (2H)-one (1.68 g, 10 mmol) and (carboxymethylene)triphenylphosphorane (5.22 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. Afterwards, the reaction mixture was concentrated and loaded over a silica-gel column. The column was eluted with hexane (500 ml) and then with 25% ethyl acetate. The product, ethyl(6-chloro-l-benzofuran-3-yl)acetate, was obtained as a white oil. Yield: 2.1 g (87%); (M+H): 239.

[0141] Step 5: To a stirred suspension of LiAlH₄ (200 mg, excess) in THF at 0^°C, ethyl(6- chloro -l-benzofuran-3-yl)acetate (1.19 g, 50 mmol) in THF (20 mL) was added slowly. After the addition, reaction mixture was stirred at room temperature for 1 hr and quenched with saturated NH₄C1 solution. The product was extracted with chloroform and washed well with water. It was dried over anhydrous MgSO₄, filtered and concentrated. The product obtained, 2-(6-chloro-l-benzofuran-3-yl)ethanol, was a white oil was pure enough and taken to next step without purification. Yield: 900 mg (91%); (M+H): 197.

[0142] Step 6: To a stirred solution of 2-(6-chloro-l-benzofuran-3-yl)ethanol (980 mg, 5 mmol) in anhydrous pyridine (20 ml), -toluenesulfonyl chloride (1.14 g, 6.0 mmol) was added. The reaction mixture was kept at 0 C for 48 hrs and quenched with ice cold water. The reaction mixture was extracted with chloroform, washed well with water and dried over anhydrous MgSO . It was filtered and concentrated. The crude product obtained was taken to next step without any purification. A mixture of tosylate (350 mg. 1 mmol) (obtained by the above mentioned process) and 8-piperazino-quinoline (213 mg, 1 mmol) was heat at 120^°C in DMSO in the presence of N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end, reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous MgSO₄ and concenfrated to dryness. The dark colored solid was purified by silica-gel column chromatography by eluting it initially with 70% ethyl acetate:hexane and then with 5% methanol: ethyl acetate. 8-{4-[2-(6-chloro-l- benzofuran-3-yl)ethyl]-l -piperazinyl} -quinoline was isolated as a yellow oil. Yield: 120 mg (30%); (M+H): 392; ¹HNMR (400MHz, CDCl₃):δ 8.82 ~ 8.81 (dd, Ji = 1.7Hz, J₂ = 1.7Hz, IH); 8.40 ~ 8.20 (dd, Ji = 1.8Hz, J₂ = 1.8Hz, IH); 7.46 ~ 6.92 (m, 8H); 3.50 ~ 2.70 (m, 12H).

Example 44: Preparation of 8-{4-[2-(6-chloro-l-benzofuran-3-yl)ethyl]-l-piperazinyI}- 6-fluoro-quinoIine ("Compound 6")

[0143] 8- {4-[2-(6-chloro- l-benzofuran-3-yl)ethylJ- 1 -piperazinyl} -6-fluoro-quinoline_ was prepared by generally following the procedure outlined in example 5, step 6, starting from the tosylate (350 mg, 1 mmol) and 6-fluoro-8-piperazino quinoline (231 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80%) ethyl acetate :hexane and then with 5% methanol: ethyl acetate, to yield a brown oil. Yield: 90 mg, (22%); (M+H): 410; ¹HNMR (400MHz, CDC1₃): δ 8.82 ~ 8.81 (dd, Ji = 1.7Hz, J₂ = 1.7Hz, IH); 8.05 ~ 8.03 (dd, i = 1.8Hz, J₂ = 1.8Hz, IH); 7.64 ~ 6.43 (m, 7H); 3.51 ~ 2.80 (m, 12H).

Example 45: Preparation of 8-{4~[2-(6-chIoro-l-benzofuran-3-yI)ethyI]-l-piperazinyI}- 6-chloro-quinoline ("Compound 7")

[0144] 8-{4-[2-(6-chloro-l-benzofuran-3-yl)ethylJ-l-piperazinyl}-6-chloro-quinoline was prepared by generally following the procedure outlined in example 5, step 6, starting from the tosylate (350 mg, 1 mmol) and 6-chloro-8-piperazino quinoline (247 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methano ethyl acetate, to yield a brown oil. Yield: 110 mg, (25%); (M+H): 427; ¹HNMR (400MHz, CDC1₃): δ 8.80 ~ 8.81 (dd, Ji = 1.7Hz, J₂ = 1.7 Hz, IH); 8.22 ~ 8.23 (dd, Ji = 1.8Hz, J₂ = 1.8Hz, IH); 7.87 ~ 6.99 (m, 7H); 3.50 ~ 2.58 (m, 12H).

Example 46: Preparation of 8-{4-[2~(6-chloro-l-benzofuran-3-yl)ethyl]~l-piperazinyl}- 6-methyl-quinoline ("Compound 8")

[0145] 8-{4-[2-(6-chloro-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-methyl-quinoline was prepared by following the procedure outlined in example 5, step 6, starting from the tosylate (350 mg, 1 mmol) and 6-methyl-8-ρiperazino quinoline (227 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol: ethyl acetate, to yield a brown oil. Yield: 89 mg, (21%); (M+H): 406; ¹HNMR (400MHz, CDCl₃):δ 8.74 ~ 8.72 (dd, Ji = 1.7Hz, J₂ = 1.7Hz, IH); 8.13 ~ 7.94 (dd, Ji = 1.8Hz, J₂ = 1.8Hz, IH); 7.40 ~ 6.71 (m, 7H); 3.40 ~ 2.73 (m, 12H); 2.42 (s, 3H). Example 47: Preparation of 8-{4-[2-(6-methoxy-l-benzofuran-3-yϊ)ethyl]-l- piperazinyl}-quinoline ("Compound 9")

[0146] Step 1: To a stirred solution of methyl-4-methoxy-2-hydroxy-benzoate (18.2 g, 0.1 mol) and anhydrous potassium carbonate (50.0 g, excess) in acetone (500 ml) ethyl bromoacetate (16.7 g, 0.1 mol) was added. The reaction mixture was refluxed for 24 hrs and cooled to room temperature. It was filtered and concentrated. The oily residue was extracted with chloroform and washed well with water. The organic layer was dried over anhydrous MgSO₄ and filtered. It was concentrated and taken to the next step without any purification. White oil; Yield: 24.0 g (89%); (M+H): 269.

[0147] Step 2: The methyl-2-(ethoxy-2-oxoethoxy)-4-methoxy-benzoate obtained from the step 1, (13.4 g, 50 mmol) was dissolved in THF MeOH (1:1) (300 ml) to which was added 5N NaOH (100 ml). The reaction mixture was refluxed for 24 hrs and cooled to room temperature. Afterwards, it was concentrated to dryness and dissolved in water. The aqueous layer was acidified with con. HCl and the separated solid was filtered. The product was then washed well with water and dried. The product was taken to step without any purification. White solid; Yield: 8.5 g (75%); (M+H): 227.

[0148] Step 3: The 2-(carboxymethoxy)-4-methoxy-benzoic acid compound obtained from the step 2 (11.3 g, 50 mmol) was dissolved in acetic anhydride (100 ml) and anhydrous sodium acetate (10.0 g, excess) was added. The reaction mixture was heated to 150^°C for 4 hrs. During this time the reaction mixture turned dark red. The reaction mixture was cooled to room temperature and quenched carefully with ice cold water. The red solid obtained was filtered and washed well with water. The red solid obtained was suspended in 1 N HCl and refluxed for 2 hrs. A dark red solid, 6-methoxy-benzofuran-3 (2H)-one, precipitated from the reaction mixture. It was filtered and washed well with water. It was dried at 40^°C and used for the next step without further purification. Yield: 4.7 g (57%); (M+H): 165.

[0149] Step 4: A mixture of 6-methoxy-benzofuran-3 (2H)-one (1.64 g, 10 mmol) and (carboxymethylene)triphenylphosphorane (5.22 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. Afterwards, reaction mixture was concentrated and loaded over a silica-gel column. The column was eluted with hexane (500 ml) and then with 25% ethyl acetate. The product, emyl(6-methoxy-l-benzofuran-3-yl)acetate, was obtained as a white oil. Yield: 1.8 g (76%); (M+H): 235.

[0150] Step 5: To a stirred suspension of LiAlH₄ (200 mg, excess) in THF at 0^°C, ethyl(6- methoxy-1 -benzofuran-3 -yl)acetate (1.17 g, 5 mmol) in THF (20 mL) was added slowly. After the addition, the reaction mixture was stirred at room temperature for 1 hr and quenched with saturated NH₄C1 solution. The product was extracted with chloroform and washed well with water. It was dried over anhydrous MgSO₄, filtered and concentrated. The product, 2-(6-methoxy-l -benzofuran-3 -yl)ethanol, was obtained as a white oil and was pure enough to be taken to the next step without purification. Yield: 850 mg (88%); (M+H): 193.

[0151] Step 6: To a stirred solution of 2-(6-methoxy-l-benzofuran-3-yl)ethanol (960 mg, 5 mmol) in anhydrous THF (50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hrs and quenched with water. The product was then extracted with chloroform, washed well with 5% Na₂S₂O₃ solution and the organic layer dried over anhydrous MgSO₄. It was then filtered and concentrated. The residue was purified by silica-gel column chromatography by eluting it with 30% ethyl acetate:hexane. The product, 2-(6-methoxy-l-benzofuran-3-yl)ethyl iodide, was obtained as a brown liquid. Yield: 1.2 g (80%); (M+H): 302.

[0152] A mixture of 2-(6-methoxy-l-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) (obtained by the above mentioned process) and 8-piperazino quinoline (213 mg, 1 mmol) was heated at 120^°C in DMSO in the presence of N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. Afterwards, the reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous MgSO₄ and concenfrated to dryness. The dark colored solid was purified by silica-gel column chromatography by eluting it initially with 70% ethyl acetate:hexane and then with 5% methanol: ethyl acetate. 8-{4-[2-(6-methoxy-l-benzofuran-3-yl)ethyl]-l-piperazinyl}- quinoline was isolated as yellow oil. Yield: 120 mg (31%); (M+H): 388; ¹HNMR (400MHz, CDC1₃): δ8.82 ~ 8.81 (dd, J, = 1.8Hz, J₂ = 1.8Hz, IH); 8.05 ~ 8.02 (dd, J, = 1.8Hz, J₂ = 1.8Hz, IH); 7.44 ~ 6.35 (m, 8H); 3.9 (s, 3H); 3.60 ~ 2.70 (m, 12H). Example 48: Preparation of 8-{4-[2-(6-methoxy-l-benzofuran-3-yl)ethyl]-l- piperazinyl}-6-methyl-quinoline ("Compound 10")

[0153] 8-{4-[2-(6-methoxy-l-beι zofuran-3-yl)ethyl]-l-piperazinyl}-6-methyl-quinoline was prepared by generally following the procedure outlined in example 9, step 6, starting from the step of 2-(6-methoxy-l-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6- methyl-8-piperazino quinoline (227 mg, 1 mmol). The product was purified by silica-gel column chromatography by initially eluting it with 80% ethyl acetate:hexane and then with 5% methanol: ethyl acetate, yielding a brown oil Yield: 210 mg (52%); (M+H): 402; ¹HNMR (400MHz, CDCl₃):δ 8.81 ~ 8.80 (dd, J! = 1.8Hz, J₂ = 1.8Hz, IH); 8.02 ~ 7.99 (dd, Ji = 1.8Hz, J₂ = 1.8Hz, IH) 7.46 ~ 6.88 (m, 7H); 3.9 (s, 3H); 3.60 ~ 2.82 (m, 12H); 2.5 (s, 3H).

Example 49: Preparation of 8-{4-[2-(6-methoxy-l-benzofuran-3-yl)ethyl]-l- piperazinyl}-6-chloro-quinoline ("Compound 11")

[0154] 8- {4-[2-(6-methoxy- 1 -benzofuran-3 -yl)ethylj- 1 -piperazinyl} -6-chloro-quinoline was prepared by generally following the procedure outlined in example 9, step 6, starting from 2-(6-methoxy-l-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-chloro -8- piperazino quinoline (247 mg, 1 mmol). The product was purified by silica-gel column chromatography by initially eluting it with 80% ethyl acetate :hexane and then with 5% methano ethyl acetate, yielding a brown oil Yield: 140 mg (33%); (M+H): 422; ¹HNMR (400MHz, CDCl₃):δ 8.86 -8.68 (dd, Ji = 1.8Hz, J₂ = 1.8Hz, IH); 8.02 ~ 7.99 (dd, Ji = 1.8Hz, J₂ = 1.8Hz, IH); 7.45 ~ 6.63 (m, 7H); 3.9 (s, 3H); 3.65 ~ 2.71 (m, 12H).

Example 50: Preparation of 8~{4-[2-(5~chloro-l-benzofuran-3-yl)ethyl]-l-piperazinyl}- quinoline ("Compound 12")

[0155] Step 1: To a stirred solution of methyl-5-chloro-2-hydroxy-benzoate (18. 6 g, 0.1 mol) and anhydrous potassium carbonate (50.0 g, excess) in acetone (500 ml) ethyl bromoacetate (16.7 g, 0.1 mol) was added. The reaction mixture was refluxed for 24 hrs and cooled to room temperature. It was filtered and concenfrated. The oily residue was extracted with chloroform and washed well with water. The organic layer was dried over anhydrous MgSO₄ and filtered. It was concentrated and taken to the next step without any purification. White oil; Yield: 22.0 g (80%); (M+H): 273. [0156] Step 2: The methyl-2-(ethoxy-2-oxoethoxy)-5-chloro-benzoate obtained from the step 1, (13.6 g, 50 mmol) was dissolved in THF:MeOH (1:1) (300 ml) and 5N NaOH (100 ml) was added. The reaction mixture was refluxed for 24 hrs and cooled to room temperature. Afterwards, it was concentrated to dryness and dissolved in water. The aqueous layer was acidified with con. HCl and the separated solid were filtered. The product was then washed well with water and dried. The product was taken to step without any purification. White solid; Yield: 8.0 g (69%); (M+H): 231.

[0157] Step 3: The 2-(carboxymethoxy)-5-chloro-benzoic acid compound obtained from the step 2 (11.5 g, 50 mmol) was dissolved in acetic anhydride (100 ml) and anhydrous sodium acetate (10.0 g, excess) was added. The reaction mixture was heated to 150 C for 4 hrs. During this time, the reaction mixture turned dark red. The reaction mixture was cooled to room temperature and quenched carefully with ice cold water. The red solid obtained was filtered and washed well with water. The red solid was then suspended in 1 N HCl and refluxed for 2 hrs. A dark red solid, 5-chloro-benzofuran-3 (2H)-one, precipitated from the reaction mixture. It was filtered and washed well with water. It was dried at 40^°C and used for the next step without further purifications. Yield: 6.2 g (73%); (M+H): 169.

[0158] Step 4: A mixture of 5-chloro-benzofuran-3 (2H)-one (1.68 g, 10 mmol) and (carboxymethylene)triphenylphosphorane (5.22 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, reaction mixture was concentrated and loaded over silica-gel column. The column was eluted with hexane (500 ml) and then with 25% ethyl acetate. The product, ethyl(5-chloro-l-benzofuran-3-yl)acetate, was obtained as a white oil. Yield: 1.8 g (75%); (M+H): 239.

[0159] Step 5: To a stirred suspension of LiAlIL (200 mg, excess) in THF at 0^°C, ethyl(5- chloro -l-beι--zofuran-3-yl)acetate (1.19 g, 50 mmol) in THF (20 mL) was added slowly. After the addition, reaction mixture was stirred at room temperature for 1 hr and quenched with saturated NH₄C1 solution. The product was exfracted with chloroform and washed well with water. It was dried over anhydrous MgSO₄, filtered and concentrated. The product, 2- (5-chloro-l-benzofuran-3-yl)ethanol, was obtained as a white oil and was pure enough and be taken to the next step without purification. Yield: 850 mg (86%); (M+H): 197.

[0160] Step 6: To a stirred solution of 2-(5-chloro-l-benzofuran-3-yl)ethanol (980 mg, 5 mmol) in anhydrous THF (50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hrs and quenched with water. It was then extracted with chloroform, washed well with 5% Na₂S₂O₃ and the organic layer dried over anhydrous MgSO₄. It was filtered and concentrated. The residue was purified by silica-gel column chromatography by eluting it with 30% ethyl acetate:hexane. The product, 2-(5- chloro-l-benzofuran-3-yl)ethyl iodide, was obtained as brown liquid; Yield: 1.2 g (80%); (M+H): 306.

[0161] A mixture of 2-(5-chloro-l-benzofuran-3-yl)ethyl iodide (305 mg. 1 mmol) (obtained by the above mentioned process) and 8-piρerazino quinoline (213 mg, 1 mmol) was heated at 120^°C in DMSO in the presence of N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. Afterwards, the reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous MgSO₄ and concentrated to dryness. The dark colored solid was purified by silica-gel column chromatography by initially eluting it with 70% ethyl acetate:hexane and then with 5% methanol :ethyl acetate. 8-{4-[2-(5-chloro-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-quinoline was isolated as a yellow oil. Yield: 120 mg (30%); (M+H): 392; ^!HNMR (400MHz, CDC1₃): δ 8.86 ~ 8.85 (dd, Ji = 1.8Hz, J₂ = 1.8Hz, IH); 8.03 ~ 8.01 (dd, J, = 1.8Hz, J₂ = 1.8Hz, IH); 7.57 ~ 7.10 (m, 8H); 3.51 ~ 2.50 (m,12H).

Example 51: Preparation of 8-{4-[2-(5-chloro-l~benzoraran-3-yl)ethyI]-l-piperazinyl}- 6-chloro-quinoline ("Compound 13")

[0162] 8- {4-[2-(5-chloro- 1 -benzofuran-3-yl)ethylJ- 1 -piperazinyl} -6-chloro-quinoline was prepared by generally following the procedure outlined in example 12, step 6, starting from the 2-(5-chloro-l-benzofuran-3-yl)ethyl iodide (306 mg, 1 mmol) and 6-chloro-8-piperazino quinoline (247 mg, 1 mmol). The product was purified by silica-gel column chromatography by initially eluting it with 80% ethyl acetate:hexane and then with 5% methanokethyl acetate, yielding a brown oil. Yield: 110 mg (25%); (M+H): 427; ¹HNMR (400MHz, CDCl₃):δ 8.86 ~ 8.85 (dd, i = 1.8Hz, J₂ = 1.8Hz, IH); 8.03 ~ 8.01 (dd, J, = 1.8Hz, J₂ = 1.8Hz, IH); 7.57 7.10 (m, 7H); 3.51 ~ 2.50 (m, 12H).

Example 52: Preparation of 8-{4-[2-(5-chloro-l~benzofuran-3-yI)ethyI]-l-piperazinyl}- 6-methyl-quinoIine ("Compound 14")

[0163] 8- {4-[2-(5-chloro- 1 -benzofuran-3-yl)ethylJ- 1 -piperazinyl} -6-methyl-quinoline was prepared by generally following the procedure outlined in example 12, step 6, starting from the 2-(5-chloro-l-benzofuran-3-yl)ethyl iodide (306 mg, 1 mmol) and 6-methyl-8-piperazino quinoline (227 mg, 1 mmol). The product was purified by silicargel column chromatography by initially eluting it with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a brown oil. Yield: 140 mg (34%); (M+H): 406; ¹HNMR (400MHz, CDC1₃): δ8.82 ~ 8.80 (dd, Ji = 1.7Hz, J₂ = 1.7Hz, IH), 8.03 ~ 7.80 (dd, Ji = 1.7Hz, J₂ = 1.7Hz IH), 7.60 ~ 6.70 (m, 7H), 3.48 ~ 2.81 (m, 12H), 2.5 (s, 3H).

Example 53: Preparation of 8-{4-[2-(5-fluoro-l-benzofuran-3-yl)ethyl]-l-piperazinyl}- quinoline ("Compound 15")

[0164] Step 1: To a stirred solution of 5-fluoro-2-hydroxy-methyl benzoate (17.0 g, 0.1 mol) and anhydrous potassium carbonate (50.0 g, excess) in acetone (500 ml) ethyl bromoacetate (16.7 g, 0.1 mol) was added. The reaction mixture was refluxed for 24 hrs and cooled to room temperature. It was filtered and concentrated. The oily residue was extracted with chloroform and washed well with water. The organic layer was dried over anhydrous MgSO₄ and filtered. It was concentrated and taken to the next step without any purification. White oil; Yield: 23.0 g (89%); (M+H): 257.

[0165] Step 2: The methyl-5-fluoro-2-(ethoxy-2-oxoethoxy)benzoate obtained from the step 1, (12.8 g, 50 mmol ) was dissolved in THF:MeOH (1:1) (300 ml) and 5N NaOH (100 ml) was added. The reaction mixture was refluxed for 24 hrs and cooled to room temperature. Afterwards, it was concentrated to dryness and dissolved in water. The aqueous layer was acidified with con. HCl and the separated solid were filtered. It was then washed well with water and dried. The product was taken to the next step without any purification. White solid; Yield: 8.3 g (77%); (M+H): 215. [0166] Step 3: The 2-(carboxymethoxy)-5-fluoro-benzoic acid compound obtained from step 2 (10.7 g, 50 mmol) was dissolved in acetic anhydride (100 ml) and anhydrous sodium acetate (10.0 g, excess) was added. The reaction mixture was heated to 150^°C for 4 hrs. During this time, the reaction mixture turned dark red. The reaction mixture was cooled to room temperature and quenched carefully with ice cold water. The red solid obtained was filtered and washed well with water. The red solid obtained was suspended in 1 N HCl and refluxed for 2 hrs. A dark red solid, 5-fluoro-benzofuran-3 (2H)-one, precipitated from the reaction mixture. It was filtered and washed well with water. It was dried at 40^°C and used for the next step with out further purifications. Yield: 5.8 g (76%); (M+H): 153.

[0167] Step 4: A mixture of 5-fluoro-benzofuran-3 (2H)-one (1.52 g, 10 mmol) and (carboxymethylene)triphenylphosphorane (5.22 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, reaction mixture was concentrated and loaded over a silica-gel column. The column was eluted with hexane (500 ml) and then with 25% ethyl acetate. The product, ethyl(5-fluoro-l-benzofuran-3-yl)acetate, was obtained as a white oil. Yield: 1.8 g (80%); (M+H): 223.

[0168] Step 5: To a stirred suspension of LiAlH₄ (200 mg, excess) in THF at 0^°C, ethyl(5- fluoro-1 -benzofuran-3 -yl)acetate (1.11 g, 5 mmol) in THF (20 mL) was added slowly. After the addition, reaction mixture was stirred at room temperature for 1 hr and quenched with saturated NH₄C1 solution. The product was extracted with chloroform and washed well with water. It was dried over anhydrous MgSO , filtered and concentrated. The product, 2-(5- fluoro-l-benzofuran-3-yl)ethanol, was obtained as a white oil and was pure enough to be taken to the next step without purification. Yield: 820 mg (91%); (M+H): 181.

[0169] Step 6: To a stirred solution of 2-(5-fluoro-l-benzofuran-3-yl)ethanol (900 mg, 5 mmol) in anhydrous pyridine (20 ml), jp-toluenesulfonyl chloride (1.14 g, 6.0 mmol) was added. The reaction mixture was kept at 0^°C for 48 hrs and quenched with ice cold water; The reaction mixture was extracted with chloroform, washed well with water and dried over anhydrous MgSO₄. It was filtered and concentrated. The crude product obtained was taken to the next step without any purification. [0170] A mixture of tosylate (334 mg. 1 mmol) (obtained by the above mentioned process) and 8-piperazino quinoline (213 mg, 1 mmol) was heated at 120 C in DMSO in the presence of N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end, reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous MgSO₄ and concentrated to dryness. The dark colored solid was purified by silica-gel column chromatography by initially eluting it with 70% ethyl acetate:hexane and then with 5% methanol: ethyl acetate. 8-{4-[2-(5-fluoro-l-benzofuran-3- yl)ethylJ-l-piperazinyl}-quinoline was isolated as a yellow solid, mp 54 C; Yield: 90 mg (21%); (M+H): 412; 1H NMR: δ 11.6 9bs,lH), 9.2 (bs, IH), 8.7 (bs, IH), 8.0 - 7.2 (m, 9H), 4.0 - 3.3 (m, 12H).

Example 54: Preparation of 8-{4-[2-(5-fluoro-l-benzofuran-3-yl)ethyl]-l-piperazinyI}- 6-methoxy-quinoline ("Compound 16")

[0171] 8-{4-[2-(5-fluoro-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-methoxy-quinoline was prepared by following the procedure outlined in example 15, step 6, starting from the tosylate (334 mg, 1 mmol) and 6-methoxy-8-pierazino quinoline (243 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol: ethyl acetate, yielding a yellow solid. MP: 80^°C (HCl salt); Yield: 110 mg, (25%); (M+H): 406; 1H NMRδll.3 (bs, IH), 8.9 (bs, IH), 8.43 (bs, IH), 8.32 (s, IH), 8.03 (s, IH), 7.7 - 7.11 (m, 5H), 3.9 (s, 3H), 3.77 - 3.25 (m, 12H).

Example 55: Preparation of 8-{4-[2-(5-fmoro~l-benzofuran-3-yI)ethyl]-l-piperazinyl}- 6-fluoro-quinoIine ("Compound 17")

[0172] 8-{4-[2-(5-fluoro-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-fluoro-quinoline was prepared by following the procedure outlined in example 15, step 6, starting from the tosylate (334 mg, 1 mmol) and 6-fluoro-8-pierazino quinoline (231 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate; hexane and latter with 5% methanol; ethyl acetae. Yellow solid; MP: 55^°C (HCl salt); Yield: 140 mg, 32%; 394 (M+H); 1H NMR: δ 11.5 (bs, IH), 8.8 9m, IH), 8.43 (dd,lH), 8.04 (s, IH), 7.7-7.23 (m, 6H), 4.19-3.20 (m, 12H). Example 56: Preparation of 8-{4-[2-(7-methoxy-l-benzofuran-3-yI)ethyI]-l- piperazinyI}-quinoline ("Compound 18")

[0173] Step 1: A mixture of 7-methoxy-benzofuran-3 (2H)-one (1.64 g, 10 mmol) and (carboxymethylene)triphenylphosphorane (5.22 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, reaction mixture was concentrated and loaded over a silica-gel column. The column was eluted with hexane (500 ml) and then with 25% ethyl acetate. The product, ethyl(7-methoxy-l-benzofuran-3-yl)acetate, was obtained as a white oil. Yield: 1.9 g (81%); (M+H): 235.

[0174] Step 2: To a stirred suspension of LiAlH₄ (200 mg, excess) in THF at 0^°C, ethyl(7- methoxy -l-benzofuran-3-yl)acetate (1.17 g, 5 mmol) in THF (20 mL) was added slowly. After the addition, the reaction mixture was stirred at room temperature for 1 hr and quenched with saturated NH₄C1 solution. The product was extracted with chloroform and washed well with water. It was dried over anhydrous MgSO₄, filtered and concentrated. The product, 2-(7-methoxy-l-benzofuran-3-yl)ethanol, was obtained as a white oil and was pure enough to be taken to the next step without purification. Yield: 800 mg (83%); (M+H): 193.

[0175] Step 3: To a stirred solution of 2-(7-methoxy-l-benzofuran-3-yl)ethanol (960 mg, 5 mmol) in anhydrous THF (50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hrs and quenched with water. The mixture was then extracted with chloroform, washed well with 5% Na₂S₂O₃ solution and the organic layer dried over anhydrous MgSO₄. It was then filtered and concentrated. The residue was purified by silica-gel column chromatography by eluting it with 30% ethyl acetate:hexane. The product, 2-(7-methoxy-l-benzofuran-3-yl)ethyl iodide, was obtained as a brown liquid. Yield: 1.3 g (86%); (M+H): 302.

[0176] A mixture of 2-(7-methoxy-l-benzofuran-3-yl)ethyl iodide (301 mg. 1 mmol) (obtained by the above mentioned process) and 8-ρiperazino quinoline (213 mg, 1 mmol) was heated at 120 C in DMSO in the presence of N,N-diisoρropylethylamine (5 ml, excess) for 24 hrs. Afterwards, the reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous MgSO₄ and concentrated to dryness. The dark colored low melting solid was purified by silica-gel column chromatography by initially eluting it with 70% ethyl acetae:hexane and then with 5% methano ethyl acetate. 8-{4-[2-(7-methoxy-l-benzofuran-3-yl)ethyl]-l-piperazinyl}- quinoline was isolated as a dark brown low melting solid. Yield: (HCl salt) 90 mg (21%); (M+H): 388; 1H NMR: δl l.9 (bs, IH), 9.2 (d,lH), 9.0 (bs IH), 8.2 (m,2H), 7.9 (slH), 7.84 (m, 2H), 7.45 (d, IH), 7.21 (t,lH), 6.98 (d, IH), 4.01 9s,3H), 3.77 (m, 4H), 3.67 9m,2H), 3.59 (m, 4H), 3.3 (m,2H).

Example 57: Preparation of 8-{4-[2-(7-methoxy-l-benzofuran-3-yl)ethyl]-l- piperazinyI}-6-methoxy-quinolinen ("Compound 19")

[0177] 8-{4-[2-(7-methoxy-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-methoxy-quinoline was prepared by generally following the procedure outlined in example 18, step 3, starting from 2-(7-methoxy-l -benzofuran-3 -yl)ethyl iodide (301 mg, 1 mmol) and 6-methoxy-8- piperazino quinoline (243 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol: ethyl acetate. A HCl salt was prepared, yielding a green spongy solid. MP: 86^°C; Yield: 300 mg, (66%); (M+H): 418; 1H NMR δ 11.8 (bs, IH), 9.0 (bs, IH), 8.9 (bs, IH), 8.0 (s,lH), 7.8 (m, IH), 7.5 (m, 2H), 7.3 (m, 2H), 6.9 (d,lH), 4.0 (s, 6H), 3.8 (m, 6H), 3.4- 3.1 (m, 6H).

Example 58: Preparation of 8-{4-[2-(7-methoxy-l-benzofuran-3-yl)ethyl]-l- piperazinyl}-6-chloro-quinoline ("Compound 20")

[0178] 8- {4-[2-(7-methoxy- 1 -benzofuran-3 -yl)ethyl]- 1 -piperazinyl} -6-chloro-quinoline was prepared by generally following the procedure outlined in example 18, step 3, starting from 2-(7-methoxy-l-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-chloro-8- piperazino quinoline (247 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol: ethyl acetate. A HCl salt was prepared, yielding a green spongy solid, mp 248^°C; Yield: 320 mg (69%); (M+H): 424; 1H NMR δ 11.8 (bs, IH), 9.0 (d,lH), 8.5 (d, IH), 8.0 (s, IH), 7.8-7.0 (m, 5H), 6.8 (d. IH), 4.2 (d, 2H), 3.9 (s, 3H), 3.7- 3.2 (m, 10H). Example 59: Preparation of 8-{4-[2-(5-methoxy-l-benzofuran-3-yl)ethyl]-l- piperazinyl}-quinoline ("Compound 21")

[0179] Step 1: To a stirred solution of methyl-5-methoxy-2-hydroxy benzoate (18. 2 g, 0.1 mol) and anhydrous potassium carbonate (50.0 g, excess) in acetone (500 ml) ethyl bromoacetate (16.7 g, 0.1 mol) was added. The reaction mixture was refluxed for 24 hrs and cooled to room temperature. It was filtered and concentrated. The oily residue was extracted with chloroform and washed well with water. The organic layer was dried over anhydrous MgSO₄ and filtered. It was concentrated and taken to the next step without any purification. Yellow oil; Yield: 21.0 g (78%); (M+H): 269.

[0180] Step 2: The methyl-2-(ethoxy-2-oxoethoxy)-5-methoxy-benzoate obtained from step 1, (13.4 g, 50 mmol) was dissolved in THF:MeOH (1:1) (300 ml) and 5N NaOH (100 ml) was added. The reaction mixture was refluxed for 24 hrs and cooled to room temperature. At the end it was concentrated to dryness and dissolved in water. The aqueous layer was acidified with con. HCl and the separated solid were filtered. It was then washed well with water and dried. The product was taken to the next step without any purification. White solid; Yield: 10.2 g (90%); MP: 150-153 C; (M+H): 227.

[0181] Step 3: The 2-(carboxymethoxy)-5-methoxy-benzoic acid compound obtained from the step 2 (11.3 g, 50 mmol) was dissolved in acetic anhydride (100 ml) and anhydrous sodium acetate (10.0 g, excess) was added. The reaction mixture was heated to 150^°C for 4 hrs. During this time the reaction mixture turned dark red. The reaction mixture was cooled to room temperature and quenched carefully with ice cold water. The red solid obtained was filtered and washed well with water. The red solid obtained was suspended in 1 N HCl and refluxed for 2 hrs. A dark red solid, 5-methoxy-benzofuran-3 (2H)-one, precipitated from the reaction mixture. It was filtered and washed well with water. It was dried at 40^°C and used for the next step without further purification. Yield: 6.2 g (75%); (M+H): 165.

[0182] Step 4: A mixture of 5-methoxy-benzofuran-3 (2H)-one (1.64 g, 10 mmol) and (carboxymethylene)triphenylphosphorane (5.22 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, reaction mixture was concentrated and loaded over a silica-gel column. The column was eluted with hexane (500 ml) and then with 25% ethyl acetate. The product, ethyl(5-methoxy-l-benzofuran-3-yl)acetate, was obtained as a white oil. Yield: 1.6 g (68%); (M+H): 235.

[0183] Step 5: To a stirred suspension of LiAlH₄ (200 mg, excess) in THF at 0^°C, ethyl(5- methoxy -l-benzofuran-3-yl)acetate (1.17 g, 5 mmol) in THF (20 ml) was added slowly. After the addition, reaction mixture was stirred at room temperature for 1 hr and quenched with saturated NH₄C1 solution. The product was exfracted with chloroform and washed well with water. It was dried over anhydrous MgSO₄, filtered and concentrated. The product, 2- (5-methoxy-l-benzofuran-3-yl)ethanol, was obtained as a white oil and was pure enough to be taken to the next step without purification, yielding a yellow oil. Yield: 900 mg (93%); (M+H): 193.

[0184] Step 6: To a stirred solution of 2-(5-methoxy-l-benzofuran-3-yl)ethanol (960 mg, 5 mmol) in anhydrous THF (50 ml), triphenylphosphine (1.572 g, 6 mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol) were added at room temperature. The reaction mixture was stirred at room temperature for 4 hrs and quenched with water. It was then extracted with chloroform, washed well with 5% Na S₂O₃ and the organic layer dried over anhydrous MgSO₄. It was filtered and concentrated. The residue was purified by silica-gel column chromatography by eluting it with 30%> ethyl acetate :hexane. The product, 2-(5- methoxy-1 -benzofuran-3 -yl)ethyl iodide, was obtained as a brown liquid. Yield: l.l g (73%); (M+H): 302.

[0185] A mixture of 2-(5-methoxy-l-benzofuran-3-yl)ethyl iodide (301 mg. 1 mmol) (obtained by the above mentioned process) and 8-piperazino quinoline(213 mg, 1 mmol) was heated at 120 C in DMSO in the presence of N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. At the end, reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous MgSO and concenfrated to dryness. The dark colored solid was purified by silica-gel column chromatography by eluting it initially with 70% ethyl acetae:hexane and then with 5% methanol: ethyl acetate. 8- {4-[2-(5-methoxy-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-quinoline was isolated as brown solid, mp 78°C; Yield: 120 mg (31%); (M+H): 388; ¹HNMR (400 MHz, CDC1₃): δ 8.90 ~ 8.88 (dd, J! = 1.7Hz, J₂ = 1.7Hz„ IH); 8.13 ~ 8.10 (dd, J, = 1.8Hz, J₂ = 1.8Hz, IH); 7.51 ~ 6.88 (m, 8H); 3.68 (s, 3H); 3.68 ~ 2.82 (m, 12H). Example 60: Preparation of 8-{4-[2-(5-methoxy-l-benzofuran-3-yl)ethyI]-l- piperazinyl}-6-chloro-quinoline ("Compound 22")

[0186] 8-{4-[2-(5-methoxy-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-chloro-quinoline was prepared by generallyfollowing the procedure outlined in example 21, step 6, starting from 2-(5-methoxy-l-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-chloro-8- piperazino quinoline (247 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80%> ethyl acetate:hexane and then with 5% methanokethyl acetate, yield a brown solid. MP: 72^°C; Yield: 130 mg (30%); (M+H): 422; ¹HNMR (400MHz, CDC1₃): δ 8.86-8.84 (dd, Ji = 1.7 Hz, J₂= 1.7Hz, IH); 8.05 ~ 8.02 (dd, Ji = 1.7Hz,J₂= 1.7Hz, IH); 7.60 - 6.88 (m, 7H); 3.86 (s, 3H); 3.69-2.57 (m, 12H).

Example 61: Preparation of 8-{4-[2-(5-methoxy-l-benzofuran-3-yl)ethyl]-l- piperazinyl}-6-methyl-quinoline ("Compound 23")

[0187] 8-{4-[2-(5-methoxy-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-methyl-quinoline was prepared by generally following the procedure outlined in example 21, step 6, starting from 2-(5-methoxy-l-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-methyl-8- piperazino quinoline (227 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol: ethyl acetate, yielding a brown oil. Yield: 150 mg (37%); (M+H): 402; ¹HNMR (400 MHz, CDC1₃): δ 8.82 - 8.73 (dd, Ji = 1.7 Hz, J₂ = 1.7 Hz, IH); 8.03 - 802 (dd, Ji = 1.7 Hz, J₂ = 1.7 Hz, IH), 8.00 - 6.88 (m, 7H); 3.87 (s, 3H) 3.49 -2.57 (m, 12H), 2.5 (s, 3H).

Example 62: Preparation of 8-{4-[2-(5-methoxy-l-benzofuran-3~yl)ethy_]-l- piperazinyl}-6-isopropyl-quinoline ("Compound 24")

[0188] 8-{4-[2-(5-methoxy-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-isopropyl-quinoline was prepared by generally following the procedure outlined in example 21, step 6, starting from 2-(5-methoxy-l-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-isoprpyl-8- piperazino quinoline (255 mg, 1 mmol). The product was purified by silica-gel column cliromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methano ethyl acetate, yielding a brown oil. Yield: 90 mg (20%); (M+H): 430; ¹HNMR (400 MHz, CDC1₃): δ 8.83 - 8.12 (dd, J! = 1.8Hz, J₂ = 1.8Hz, IH), 8.08 - 804 (dd,Ji = 1.8Hz, J₂ = 1.8 Hz, IH), 7.75 - 6.70 (m, 7H), 3.84 (s, 3H), 3.50 - 2.86 (m, 12H), 2.90 -3.01 (m, IH), 1.34 - 1.33 (d, 7Hz, 6H).

Example 63: Preparation of 8-{4-[2-(5-methoxy-l-benzofuran-3-yl)ethyl]-l- piperazinyl}-6-methoxy -quinoline ("Compound 25")

[0189] 8-{4-[2-(5-methoxy-l-ber-zofuran-3-yl)ethyl]-l-piperazinyl}-6-methoxy - quinoline was prepared by generally following the procedure outlined in example 21, step 6, starting from 2-(5 -methoxy- 1 -benzofuran-3 -yl)ethyl iodide (301 mg, 1 mmol) and 6-methoxyl-8-piperazino quinoline (243 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol: ethyl acetate, yielding a brown oil. Yield: 90 mg, (21%); (M+H): 418; ¹HNMR (400 MHZ, CDC1₃): δ 8.73 - 8.71 (dd, = 1.7Hz, = 1.7Hz, IH) 8.03 - 8.00 (dd, Ji = 1.7 Hz, J₂ = 1.7Hz, IH), 7.50 - 6.71 (m, 7H); 3.91 (s, 3H), 3.87 (s, 3H), 3.55 - 2.82 (12H).

Example 64: Preparation of 8-{4-[2~(5-methoxy-l-benzofuran-3-yl)ethyl]-l- piperazinyl}-6-fluoro-quinoline ("Compound 26")

[0190] 8-{4-[2-(5-methoxy-l-benzo-nran-3-yl)ethyl]-l-piperazinyl}-6-fluoro-quinoline was prepared by following the procedure outlined in example 21, step 6, starting from 2-(5- methoxy-1 -benzofuran-3 -yl)ethyl iodide (301 mg, 1 mmol) and 6-fluoro-8-piperazino quinoline (231 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80%> ethyl acetate:hexane and then with 5% methanol: ethyl acetate, yielding a brown low melting solid. Yield: 130 mg (32%); (M+H): 406; ¹HNMR (400MHz, CDC1₃); δ 8.83 - 8.82 (dd, J, = 1.6Hz, J₂ = 1.6Hz, IH); 8.06 - 8.05 (dd, Ji = 1.7Hz, J₂ = 1.7Hz, IH); 7.60 - 6.88 (m, 7H); 3.86 (s, 3H); 3.66 -3.56 (broad s, 4H); 2.93 - 2.82 (m, 8H).

Example 65: Preparation of 8-{4-[2-(l-benzofuran-3-yl)propyl]-l-piperazinyl}quinoline ("Compound 27")

[0191] Step 1: A mixture of benzofuran-3 (2H)-one (1.34 g, 10 mmol) and ethyl-2- (triphenylphosphoranylidene)propionate (5.436 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, reaction mixture was concentrated and loaded over a silica-gel column. The column was eluted with hexane (500 ml) and later with 25% ethyl acetate. The product, ethyl(-l-benzofuran-3-yl)propanoate, was obtained as a white oil. Yield: 1.6 g (67%); (M+H): 219.

[0192] Step 2: To a stirred suspension of LiAlH₄ (200 mg, excess) in THF at 0^°C, ethyl(-l- benzofuran-3-yl)propanoate (1.09 g, 5 mmol) in THF (20 mL) was added slowly. After the addition, reaction mixture was stirred at room temperature for 1 hr and quenched with saturated NH₄C1 solution. The product was exfracted with chloroform and washed well with water. It was dried over anhydrous MgSO₄, filtered and concentrated. The product, 2-(l- benzofuran-3-yl)-l-propanol, was obtained as a white oil pure enough to be taken to the next step without purification. Yield: 700 mg (79%); (M+H): 177.

[0193] Step 3: To a stirred solution of 2-(l-benzofuran-3-yl)-l-propanol (880 mg, 5 mmol) in anhydrous pyridine (20 ml), .-toluenesulfonyl chloride (1.14 g, 6.0 mmol) was added. The reaction mixture was kept at 0^°C for 48 hrs and quenched with ice cold water. The reaction mixture was extracted with chloroform, washed well with water and dried over anhydrous MgSO₄. It was filtered and concentrated. The crude product obtained was taken to the next step without any purification.

[0194] A mixture of tosylate (331 mg. 1 mmol) (obtained by the above mentioned process) and 8-piperazino quinoline (213 mg, 1 mmol) was heat at 120 C in DMSO in the presence of N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. Afterwards, reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous MgSO₄ and concentrated to dryness. The dark colored solid was purified by silica-gel column chromatography by eluting it with 70% ethyl acetate :hexane .8- {4-[2-(l -benzofuran-3 -yl)propylJ-l -piperazinyl} quinoline was isolated as a yellow oil. Yield: 50 mg (13%); (M+H): 372; 'HNMR (400MHZ, CDC1₃): δ 8.88 - 8.87 (dd, Ji = 1.8Hz, J₂ = 1.8Hz, IH); 8.11 - 8.09 (dd, J, =1.8Hz, J₂ = 1.8Hz, IH); 7.65 - 6.92 (m, 9H); 3.54 - 2.58 (m, 11H); 1.45 - 1.43 (d, J = 7.0Hz, 3H).

Example 66: Preparation of 8-{4-[2-(l-benzofuran-3-yl)propyl]-l-piperazinyl}-6- chloro-quinoline ("Compound 28")

[0195] 8-{4-[2-(l-benzofuran-3-yl)propyl]-l-piperazinyl}-6-chloro-quinoline was prepared by generally following the procedure outlined in example 27, step 3, starting from the tosylate (example 27, step 3) (331 mg, 1 mmol) and 6-chloro-8-piperazino quinoline (247 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and latter with 5% methano ethyl acetate, yielding a brown oil. Yield: 40 mg (10%); (M+H): 406; ¹HNMR (400MHz, CDC1₃): δ 8.85 - 8.83 (dd, Ji = 1.8 Hz, J₂ = 1.8 Hz, IH); 8.01 - 7.99 (dd, Ji = 1.8Hz, J₂ = 1.8Hz, IH), 7.73 - 6.83 (m, 8H); 3.50 - 2.56 (m, 1 IH); 1.44 - 1.41 (d, J = 7.0Hz, 3H).

Example 67: Preparation of 8-{4-[2-(l-benzofuran-3-yl)propyI]-l-piperazinyl}-6- fluoro-quinoline ("Compound 29")

[0196] 8-{4-[2-(l-benzofuran-3-yl)propylJ-l-piperazinyl}-6-fluoro-quinoline was prepared by generally following the procedure outlined in example 27, step 3, starting from the tosylate (example 27, step 3) (331 mg, 1 mmol) and 6-fluoro-8-piperazino quinoline (231 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol: ethyl acetate, yielding a brown oil. Yield: 45 mg (11%); (M+H): 390; ¹HNMR (400MHz, CDC1₃): δ 8.81 - 8.80 (dd, Ji = 1.7Hz, J₂ = 1.7Hz IH); 8.12 - 8.01 (dd, Ji = 1.8Hz, J₂= 1.8Hz, IH), 7.65 - 6.88 (m, 8H); 3.50 - 2.61 (m, 11H); 1.44 - 1.43 (d, J = 7.0Hz, 3H).

Example 68: Preparation of 8-{4-[2-(l-benzofuran-3-yl)propyl]-l-piperazinyl}-6- methyl-quinoline ("Compound 30")

[0197] 8-{4-[2-(l-benzofuran-3-yl)propyl]-l-piperazinyl}-6-methyl-quinoline was prepared by generally following the procedure outlined in example 27, step 3, starting from the tosylate (example 27, step 3) (331 mg, 1 mmol) and 6-methyl-8-piperazino quinoline (227 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methano ethyl acetate, yielding a brown oil. Yield: 60 mg (15%); (M+H): 386; ¹HNMR (400MHz, CDC1₃): δ 8.81 - 880 (dd, Ji = 1.7Hz, J₂ = 1.7 Hz, IH); 8.01 - 8.00 (dd, Ji = 1.7Hz, J₂ = 1.7Hz, IH); 7.66 - 6.93 (m, 8H); 3.50 - 2.47 (m, 11H); 2.48 (s, 3H); 1.43 - 1.40 (d, J = 7.0Hz, 3H). Example 69: Preparation of 8-{4-[2~(7-methoxy-l-benzofuran-3-y_)propyl]-l- piperazinyljquinoline ("Compound 31")

[0198] Step 1: A mixture of 7-methoxy-benzofuran-3 (2H)-one (1.64 g, 10 mmol) and ethyl-2-(triphenylphosphoranylidene)propionate (5.436 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, the reaction mixture was concentrated and loaded over a silica-gel column. The column was eluted with hexane (500 ml) and later with 25% ethyl acetate. The product, ethyl(7-methoxy-l -benzofuran-3 -yl)propanoate, was obtained as a white oil. Yield: 1.9 g (76%); (M+H): 249.

[0199] Step 2: To a stirred suspension of LiAlH₄ (200 mg, excess) in THF at 0^°C, ethyl(7- methoxy-1 -benzofuran-3 -yl)propanoate (1.24 g, 5 mmol) in THF (20 mL) was added slowly. After the addition, reaction mixture was stirred at room temperature for 1 hr and quenched with saturated NH₄C1 solution. The product was extracted with chloroform and washed well with water. It was dried over anhydrous MgSO₄, filtered and concentrated. The product, 2- (7-methoxy-l -benzofuran-3 -yl)-l-propanol, was obtained as a white oil pure enough to be taken to the next step without purification. Yield: 900 mg (87%); (M+H): 207.

[0200] Step 3: To a stirred solution of 2-(7-methoxy-l-benzofuran-3-yl)-l-propanol (1.03 g, 5 mmol) in anhydrous pyridine (20 ml), ^-toluenesulfonyl chloride (1.14 g, 6.0 mmol) was added. The reaction mixture was kept at 0^°C for 48 hrs and quenched with ice cold water. The reaction mixture was extracted with chloroform, washed well with water and dried over anhydrous MgSO . It was filtered and concenfrated. The crude product obtained was taken to next step without any purification.

[0201] A mixture of tosylate (360 mg. 1 mmol) (obtained by the above mentioned process) and 8-piperazino quinoline (213 mg, 1 mmol) was heated at 120^°C in DMSO in the presence of N,N-diisopropylethylamine (5 ml, excess) for 24 hrs. Afterwards, the reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water and dried over anhydrous MgSO₄ and concentrated to dryness. The dark colored solid was purified by silica-gel column chromatography by eluting it initially with 70% ethyl acetae:hexane and then with 5% methanol: ethyl acetate. 8-{4-[2-(7-methoxy-l-benzofuran-3- yl)propyl]-l-piperazinyl}quinoline was isolated as a yellow solid. A HCl salt was prepared. p 192 C; Yield: 315 mg (72%); (M+H): 402; 10.1 (bs, IH), 8.95 (d, IH), 8.51 (bs, IH), 8.01 (s, IH), 7.7-7.58 (m, 3H), 7.41 9d,lH), 7.39 (bs,lH), 7.23 (t, IH), 6.97 (d, IH), 3.9 (s,3H), 3.7-3.25 (m, 11H), 1.46 (d, 3H).

Example 70: Preparation of 8-{4-[2-(7-methoxy-l-benzofuran-3-yl)propyl]-l- piperazinyl}~6-methyl-quinoline ("Compound 32")

[0202] 8-{4-[2-(7-methoxy-l-beι--zofuran-3-yl)propyl]-l-piperazinyl}-6-methyl-quinoline was prepared by generally following the procedure outlined in example 31, step 3, starting from the tosylate (example 31, step 3) (360 mg, 1 mmol) and 6-methyl-8-piperazino quinoline (227 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate :hexane and then with 5% methano ethyl acetate, yielding a brown oil; Yield: 45 mg (10%); (M+H): 416; ¹HNMR (400MHz, CDC1₃): δ 8.81 -

8.79 (dd, Ji = 1.8Hz, J₂ = 1.8Hz, IH); 8.01 - 7.99 (dd, Ji = 1.8Hz, J₂ = 1.8Hz, IH); 7.32 -

6.80 (m, 7H); 3.9 (s,3H); 3.65 - 2.80 (m, 11H); 2.39 (s, 3H); 1.44 - 1.42 (d, J = 7.0Hz, 3H)

Example 71: Preparation of 8-{4-[2-(7-methoxy-l-benzofuran-3-yI)propyI]-l- piperazinyl}-6-chloro-quinoline ("Compound 33")

[0203] 8-{4-[2-(7-methoxy-l-benzofuran-3-yl)propyl]-l-piperazinyl}-6-chloro-quinoline was prepared by generally following the procedure outlined in example 31, step 3, starting from the tosylate (example 31, step 3) (360 mg, 1 mmol) and 6-chloro-8-piperazino quinoline (247 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5%> methano ethyl acetate. A HCl salt was prepared, yielding a greenish yellow solid. MP: 55-58^°C; Yield: 270 mg (57%); (M+H): 438.

Example 72: Preparation of 8-{4-[2-(7-methoxy-l-benzofuran-3-yl)propyl]-l- piperazinyl}-6-methyl-quinoline ("Compound 34")

[0204] 8-{4-[2-(7-methoxy-l-benzofuran-3-yl)propyl]-l-piperazinyl}-6-methyl -quinoline was prepared by generally following the procedure outlined in example 31, step 3, starting from the tosylate (example 31, step 3) (360 mg, 1 mmol) and 6-methyl-8-piperazino quinoline (227 mg, 1 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and latter with 5% methanol: ethyl acetate, yielding a brown oil. Yield: 120 mg (28%); (M+H): 416; ¹HNMR (400MHz, CDC1₃): δ 8.69 (d, IH), 8.01 (d,lH), 7.56 (s, IH) , 7.33 (m, IH), 7.26-6.74 (m, 6H), 3.56 - 2.78 (m, 11H); 2.39 (s, 3H); 1.44 - 1.42 (d, J = 7.0Hz, 3H). The racemic mixture was separated by preparative HPLC using a chiral column.

Example 73: Preparation of 8-{4-[2-(7-methoxy-l-benzofuran-3-yl)-l- methylethyl)piperazin-l-yl]quinoline ("Compound 35")

[0205] Step 1: A mixture of 7-methoxy-benzofuran-3 (2H)-one (1.64 g, 10 mmol) and 1- triphenylphosphoranylidene-2-propanone (4.77 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, reaction mixture was concentrated and loaded over a silica-gel column. The column was eluted with hexane (500 ml) and later with 25% ethyl acetate. The product, 1 -(7 -methoxy- 1 -benzofuran-3 -yl)acetone, was obtained as a red oil. Yield: 1.4 g (68%); (M+H): 205.

[0206] Step 2: To a stirred mixture of l-(7-methoxy-l-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 8-piperazino quinoline (213.0 mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium triacetoxyborohydride (422 mg, 2 mmol) was added at room temperature. Reaction mixture was stirred at room temperature for 72 hrs. At the end, the reaction mixture was neutralized with 10% NaHCO₃ and exfracted with chloroform. The organic layer was dried over anhydrous MgSO , filtered and concentrated. The product obtained was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate :hexane and then with 5% methanol: ethyl acetate, yielding a yellow oil. Yield: 60 mg (14%); (M+H): 402; ¹HNMR (400MHz, CDC1₃): δ 8.90 - 8.14 (dd, J, = 1.8Hz, J₂ = 1.8Hz, IH); 8.13 - 7.56 (dd, Ji = 1.8Hz, J₂ = 1.8Hz, IH); 7.46 - 6.80 (m, 8H); 4.01 (s, 3H); 3.51 - 1.60 (m, 11H); 1.14(d, J = 6.0Hz, 3H). Example 74: Preparation of 6-methoxy- 8-{4-[2-(7-methoxy-l~benzofuran-3-yI)-l- methylethyl)piperazin-l-yl] quinoline ("Compound 36")

[0207] 6-methoxy- 8-{4-[2-(7-methoxy-l-benzofuran-3-yl)-l-methylethyl)piperazin-l- yljquinoline was prepared by generally following the procedure outlined in example 35, step 2, starting from the l-(7-methoxy-l-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 6- methoxy-8-piperazino quinoline (243.0 mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium triacetoxyborohydride (422 mg, 2 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol: ethyl acetate, yielding a brown semi-solid. Yield: 75 mg (17%); (M+H): 432.

Example 75: Preparation of 6-methyl- 8-{4-[2-(7-methoxy-l-benzofuran-3-yl)-l- methylethyl)piperazin-l-yl]quinoline ("Compound 37")

[0208] 6-methyl- 8- {4-[2-(7-methoxy-l-benzofuran-3-yl)-l-methylethyl)piperazin-l- yl] quinoline was prepared by generally following the procedure outlined in example 35, step 2, starting from the l-(7-methoxy-l -benzofuran-3 -yl)acetone (204 mg, 1 mmol) and 6- methyl-8-piperazino quinoline (227.0 mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium triacetoxyborohydride (422 mg, 2 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol: ethyl acetate, yielding a yellow oil. Yield: 40 mg (9%); (M+H): 416; ¹HNMR (400MHz, CDC1₃): δ 8.86 - 8.79 (dd, J, = 1.8Hz, J₂ = 1.8 Hz, IH), 8.02 - 7.56 (dd, Ji = 1.8Hz, J₂ = 1.8Hz, IH), 7.56 - 6.80 (m, 7 H), 3.89 (s, 3H), 3.50 - 2.60 (m, 11H); 2.50 (s, 3H) 1.12 - 114 (d, J = 7.0Hz, 3H).

Example 76: Preparation of 8-{4-[2-(5~methoxy-l-benzofuran-3-yl)-l- methylethyl)piperazin-l-yl]quinoline ("Compound 38")

[0209] Step 1: A mixture of 5-methoxy-benzofuran-3 (2H)-one (1.64 g, 10 mmol) and 1- triphenylphosphoranylidene-2-propanone (4.77 g, 15 mmol) was refluxed in toluene (100 ml) for 48 hrs. At the end, reaction mixture was concentrated and loaded over silica-gel column. The column was eluted with hexane (500 ml) and later with 25% ethyl acetate. The product, l-(5-methoxy-l-benzofuran-3-yl)acetone, was obtained as a red oil. Yield: 1.1 g (53%); (M+H): 205.

[0210] Step 2: To a stirred mixture of l-(5-methoxy-l-berιzofuran-3-yl)acetone (204 mg, 1 mmol) and 8-piperazino quinoline (213.0 mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium triacetoxyborohydride (422 mg, 2 mmol) was added at room temperature. Reaction mixture was stirred at room temperature for 72 hrs. At the end, reaction mixture was neutralized with 10% NaHCO₃ and exfracted with chloroform. The organic layer was dried over anhydrous MgSO₄, filtered and concentrated. The product obtained was purified by silica-gel column chromatography by eluting it initially with 80%) ethyl acetate :hexane and then with 5% methanol: ethyl acetate, yielding a brown semi-solid. Yield: 60 mg (14%); (M+H): 402; ¹HNMR (400MHz, CDC1₃): δ 8.90 - 8.88 (dd, Ji = 1.8Hz, J₂ = 1.8Hz, IH); 8.13 - 8.10 (dd, J,= 1.8 Hz, J₂ = 1.8 Hz, IH); 7.60 - 6.70 (m, 8H); 3.87 (s, 3H); 3.50 - 2.50 (m, 11H); 1.15 - 1.13 (d, J = 6.0Hz, 3H).

Example 77: Preparation of 6-chloro-8-{4-[2-(5-methoxy-l-benzofuran-3-yl)-l- methylethyl)piperazin-l-yl]quinoline ("Compound 39")

[0211] 6-chloro-8-{4-[2-(5-methoxy-l-benzoftιran-3-yl)-l-methylethyl)piperazin-l- yljquinoline was prepared by generally following the procedure outlined in example 38, step 2, starting from the l-(5-methoxy-l-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 6-chloro- 8-piperazino quinoline (247.0 mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium triacetoxyborohydride (422 mg, 2 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methano ethyl acetate, yielding a yellow oiLYield: 54 mg (12%); (M+H): 436; ¹HNMR (400MHz, CDC1₃): δ 8.82 - 8.81 (dd, J, = 1.8Hz, J₂ = 1.8Hz, IH); 8.02 - 8.00 (dd, J, = 1.8Hz, J₂ = 1.8Hz, IH); 7.99 - 6.58 (m, 7H); 3.87 (s, 3H); 3.46 - 2.62 (m, 11H); 1.15 - 1.13 (d, J = 6.0Hz, 3H). Example 78: Preparation of 6-methyl-8-{4-[2-(5-methoxy-l-benzofuran~3-yl)-l- methylethyl)piperazin-l-yl]quinoline ("Compound 40")

[0212] 6-methyl-8-{4-[2-(5-methoxy-l-benzofuran-3-yl)-l-methylethyl)piperazin-l- yl] quinoline was prepared by generally following the procedure outlined in example 38, step 2, starting from the l-(5-methoxy-l-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 6- methyl-8-piperazino quinoline (227.0 mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium triacetoxyborohydride (422 mg, 2 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol: ethyl acetate, yielding a yellow oil. Yield: 62 mg (14%); (M+H): 416; 1HNMR (400MHz, CDC1₃): δ8.82 - 8.81 (dd, J_ = 1.8Hz, J₂ = 1.8Hz, IH): 8.02 - 8.00 (dd, Ji = 1.8Hz, J₂ = 1.8Hz, IH); 7.99 - 6.58 (m, 7H); 3.87 (s, 3H); 3.46 - 2.62(m, 11H); 2.5 (s. 3H); 1.15 - 1.13 (d, J = 6.0Hz, 3H).

Example 79: Preparation of 8-{4-[4-cis-(l-benzothien-3-yI)cycIohexyl]-l-piperazinyI}-6- chloroquinoline ("Compound 41")

[0213] To a solution of 6-chloro-8-piperazino-quinoline (0.280 g) in DCE (10 ml), 4-(3H- inden-l-yl)-cyclohexanone (0.300 g) was added, followed by of sodium triacetoxyborohydride (0.333 g) and acetic acid (0.2 ml). The reaction was stirred at room temperature overnight. It was quenched with IN NaOH, and the product was extracted with

CH₂C1₂. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate/hexane, then 75% ethyl acetate/hexane, to give 0.180 g of the cis product. MP: 164-165 °C; MS (ES) m/z

(relative intensity): 463 (M⁺+H, 100). Elemental analysis for C₂₇ H₂₈C1 N₃ S; Calculated: C:

70.19; H: 6.11; N: 9.09; Found: C: 69.87; H: 6.17; N: 8.4. Example 80: Preparation of 8-{4-[4-trans(l-benzothien-3-yl)cyclohexyl]-l-piperazinyl}- 6-chloroquinoline ("Compound 42")

[0214] The trans isomer was isolated at the same time as the cis isomer of example 42 above. Off-white solid, 0.100 g; MP: 143-144°C; MS (ES) m/z (relative intensity): 463

(M⁺+H, 100). Elemental analysis for C₂₇ H₂₈ C1 N₃ S; Calculated: C: 70.19; H: 6.11; N: 9.09;

Found: C: 69.52; H: 6.31; N: 8.39.

Example 81: Preparation of 8-{4-[4-cis(l-benzothien-3-y_)cyclohexyl]~l-piperazinyl}-6- fluoroquinoline ("Compound 43")

[0215] To a solution of 0.200 g of 6-fluoro-8-piperazino-quinoline in DCE (10 ml), was added 0.200 g of 4-(3H-inden-l-yl)-cyclohexanone followed by sodium triacetoxyborohydride (0.230g) and acetic acid (0.2 ml). The reaction was stirred at room temperature overnight. It was quenched with IN NaOH, and the product was extracted with CH₂C1₂. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 25%) ethyl acetate/hexane, then 50% ethyl acetate/hexane, to give 0.130 g of the cis product: MP: 147-151°C; MS (ES) m/z (relative intensity): 446 (M⁺+H, 100). Elemental analysis for C₂₇ H₂₈ F N₃ S; Calculated: C: 72.78; H: 6.33; N: 9.43; Found: C: 71.69; H: 6.71; N: 6.63.

Example 82: Preparation of 8~{4-[4-trans(l-benzothien-3-yl)cyclohexyI]~l-piperazinyl}- 6-fluoroquinoline ("Compound 44")

[0216] The trans isomer was isolated at the same time as the cis-isomer of example 44, above, as an off-white solid, 0.030 g. MP: 195°C; MS (ES) m/z (relative intensity): 446 (M⁺+H, 100). Elemental analysis for C₂₇ H₂₈ F N₃ S; Calculated: C: 72.78; H: 6.33; N: 9.43; Found: C: 71.96; H: 6.49; N: 9.

Example 83: Preparation of 8-{4-[4-cis(l-benzothien-3-yl)cyclohexyl]-l-piperazinyl}-6- methoxyquinoline ("Compound 45")

[0217] To a solution of 6-methoxy-8-piperazino-quinoline (0.200 g) in DCE (10 ml), 4- (3H-Inden-l-yl)-cyclohexanone (0.200 g) was added, followed by sodium triacetoxyborohydride (0.230 g) and acetic acid (0.2 ml). The reaction was stirred at room temperature overnight. It was quenched with IN NaOH, and the product was extracted with CH₂C1₂. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 25% ethyl acetate/hexane, then 50% ethyl acetate/hexane, to give 0.130 g of the cis product. MP: 148-150°C; MS (ES) m/z (relative intensity): 458 (M⁺+H, 100). Elemental analysis for C₂₈ H₃ι N₃ O S; Calculated: C: 73.49; H: 6.83; N: 9.18; Found: C: 73.15; H: 6.9; N: 8.61.

Example 84: Preparation of 8-{4-[4-trans (l-benzothien-3-yϊ)cycIohexyl]~l- piperazinyl}-6-methoxyquinoline ("Compound 46")

[0218] The trans isomer was isolated at the same time as the cis isomer of example 46, above, as an off- white solid, 0.030 g. MP: 166-168°C; MS (ES) m/z (relative intensity): 458 (M⁺+H, 100). Elemental analysis for C₂₈ H₃1 N₃ O S; Calculated: C: 73.49; H: 6.83; N: 9.18; Found: C: 71.14; H: 7.36; N: 8.52. Example 85: Preparation of 6-fluoro-8-{4-[4-cis(5~fluoro-l-benzothien~3- yl)cyclohexyl]piperazin-l-yl}quinoline ("Compound 47")

[0219] To a solution of 6-fluoro-8-piρerazino-quinoline (0.200 g) in DCE (10 ml), 4-(6- fluoro-3H-inden-l-yl)-cyclohexanone (0.200 g) was added, followed by sodium triacetoxyborohydride (0.232 g) and acetic acid (0.2 ml). The reaction was stirred at room temperature overnight. It was quenched with IN NaOH, and the product was extracted with CH₂C1 . The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 30% ethyl acetate/hexane, then 50%) ethyl acetate/hexane, to give 0.068 g of the cis product: MS (ES) m/z (relative intensity): 464 (M⁺+H, 100).

Example 86: Preparation of 6-fluoro-8-{4-[4-trans(5-fluoro-l-benzothien-3- yl)cyclohexyl]piperazin-l-yl}quinoline ("Compound 48")

[0220] The trans isomer was isolated at the same time as the cis isomer of example 48, above, as an off-white solid, 0.040 g. MP: 143-144°C; MS (ES) m/z (relative intensity): 464 V +H, 100).

Example 87: Preparation of 6-methoxy-8-{4-[4-cis(5-fluoro-l-benzothien-3- yl)cyclohexyl]piperazin-l-yl}quinoline ("Compound 49")

[0221] To a solution of 6-methoxy-8-piperazino-quinoline (0.200 g) in DCE (10 ml), 4-(6- fluoro-3H-inden-l-yl)-cyclohexanone (0.200 g) was added, followed by sodium triacetoxyborohydride (0.225 g) and acetic acid (0.2 ml). The reaction was stirred at room temperature overnight. It was quenched with IN NaOH, and the product was extracted with CH₂C1₂. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 30% ethyl acetate/hexane, 50% ethyl acetate/hexane, and then 100% ethyl acetate to give 0.020 g of the cis product. MS (ES) m/z (relative intensity): 476 (M⁺+H, 100). Elemental analysis for C₂₈ H₃₀ FN₃ O S; Calculated: C: 70.71; H: 6.36; N: 8.83; Found: C: 69.13; H: 6.31; N: 8.2.

Example 88: Preparation of 6-methoxy-8~{4-[4-trans(5~fiuoro-l-benzothien-3- yl)cyclohexyl]piperazin-l-yl}quinoline ("Compound 50")

[0222] The trans isomer was isolated at the same time as the cis isomer of example 50, above, as an off-white solid, 0.016 g. MS (ES) m/z (relative intensity): 476 (M⁺+H, 100).

Example 89: Preparation of 5-chIoro-8-{4-[4-cis(5-fluoro-l-benzothien-3- yl)cyclohexyl]piperazin-l-yl}quinoline ("Compound 51")

[0223] To a solution of 5-chloro-8-piperazino-quinoline (0.254 g) in of DCE (10 ml), was added 4-(6-Fluoro-3H-rnden-l-yl)-cyclohexanone (0.200 g) followed by sodium triacetoxyborohydride (0.274 g) and acetic acid (0.2 ml). The reaction was stirred at room temperature overnight. It was quenched with IN NaOH, and the product was extracted with

CH₂C1₂. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 3:1:1 ethyl acetate/hexane/CH₂Cl₂ to give 0.050 g of the cis product. MP: 192-197°C; MS (ES) m/z (relative intensity): 481

(M⁺+H, 100). Elemental analysis for C₂₇ H₂₇ Cl F N₃ S; Calculated: C: 67.56; H: 5.67; N:

8.75; Found: C: 66.29; H: 5.36; N: 7.97. Example 90: Preparation of 5-chloro-8-{4-[4-trans(5-fluoro-l-benzothien-3- yl)cyclohexyl]piperazin-l-yl}quinoline ("Compound 52")

[0224] The trans isomer was isolated at the same time as the cis isomer of example 52, above, as an off-white solid, 0.020 g. MP: 195-197°C; MS (ES) m/z (relative intensity): 481 (-VT'+H, 100). Elemental analysis for C₂₇ H₂₇ Cl F N₃ S; Calculated: C: 67.56; H: 5.67; N: 8.75; Found: C: 66.77; H: 5.6; N: 8.49.

Example 91 : Preparation of 8-{4-[4-cis(l-benzofuran~3-yl)cyclohexyl]~l-piperazinyl}-5- fluoroquinoline ("Compound 53")

[0225] To a solution of 5-fluoro-8-piperazino-quinoline (0.238 g) in of DCE (10 ml), was added 4-benzofuran-3-yl-cyclohexanone (0.200 g) followed by sodium triacetoxyborohydride (0.256 g) and acetic acid (0.2 ml). The reaction was stirred at room temperature overnight. It was quenched with IN NaOH, and the product was extracted with CH₂C1₂. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 75 ml of silica gel using 20% ethyl acetate/hexane, then 50%, to give 0.110 g of the cis product. MP: 142-144°C; MS (ES) m/z (relative intensity): 430 (-VI^+H, 100). Elemental analysis for C₂₇ H₂₈ FN₃ O; Calculated: C: 75.5; H: 6.57; N: 9.78; Found: C: 75.23; H: 6.69; N: 9.55.

Example 92: Preparation of 8-{4-[4-trans(l-benzofuran-3-yl)cyclohexyl]-l- piperazinyI}-5-fluoroquinoline ("Compound 54")

[0226] The trans isomer was isolated at the same time as the cis isomer of example 54, above, as an off- white solid, 0.025 g. MP: 162-164°C; MS (ES) m/z (relative intensity): 430 (M⁺+H, 100). Elemental analysis for C₂₇ H₂₈ FN₃ O; Calculated: C: 75.5; H: 6.57; N: 9.78; Found: C: 75.06; H: 7.1; N: 9.47.

Example 93: Preparation of 8-{4-[4-cis(l-benzofuran-3-yl)cyclohexyl]-l-piperazinyI}-6- fluoroquinohne ("Compound 55")

[0227] To a solution of 6-fluoro-8-piperazino-quinoline (0.130 g) in DCE (10 ml), was added 4-benzofuran-3-yl-cyclohexanone (0.200 g) followed by sodium triacetoxyborohydride (0.166 g) and acetic acid (0.2 ml). The reaction was stirred at room temperature overnight. It was quenched with IN NaOH, and the product was extracted with CH₂C1₂. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 20% ethyl acetate/hexane, then 50%, to give 0.050 g of the cis product. MS (ES) m/z (relative intensity): 430 (M⁺+H, 100). Elemental analysis for C₂₇ H₂₈ FN₃ O; Calculated: C: 75.5; H: 6.57; N: 9.78; Found: C: 73.83; H: 7.29; N: 9.35. Example 94: Preparation of 8-{4-[4-trans(l-benzofuran-3-yl)cyclohexy-]-l- piperazinyI}-6-fluoroquinoline ("Compound 56")

[0228] The trans isomer was isolated at the same time as the cis isomer of example 56, above, as an off-white solid, 0.020 g. MP: 195-197°; MS (ES) m/z (relative intensity): 430 (M⁺+H, 100). Elemental analysis for C₂₇ H₂₈ FN₃ O; Calculated: C: 75.5; H: 6.57; N: 9.78; Found: C: 74.75; H: 6.87; N: 9.62.

Example 95: Preparation of 5-fluoro-8-{4-[4-cis(7-methoxy-l-benzofuran-3- yl)cyclohexyl]-l-piperazinyl}quinoline ("Compound 57")

[0229] To a solution of 5-fluoro-8-piperazino-quinoline (0.200 g) in DCE (10 ml), was added 4-(7-Mehtoxy-Benzofuran-3-yl)-cyclohexanone (0.184 g) followed by sodium triacetoxyborohydride (0.230 g) and acetic acid (0.1 ml). The reaction was stirred at room temperature overnight. It was quenched with IN NaOH, and the product was extracted with CH₂C1₂. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 25% ethyl acetate/hexane, then 50% ethyl acetate/hexane, to give 0.025 g of the cis product. MP: 143-146°C; MS (ES) m/z (relative intensity): 460 (-VJ^+H, 100). Elemental analysis for C₂₈ H₃₀ FN₃ O₂; Calculated: C: 73.18; H: 6.58; N: 9.14; Found: C: 71.95; H: 6.49; N: 8.81.

Example 96: Preparation of 5-fluoro-8-{4-[4-trans(7-methoxy-l-benzofuran-3- yl)cyclohexyl]-l-piperazinyl}quinoline ("Compound 58")

[0230] The trans isomer was isolated at the same time as the cis isomer of example 58, above, as an off-white solid, 0.010 g. MS (ES) m/z (relative intensity): 460 (M⁺+H, 100). Example 97: Preparation of 6-fluoro-8-{4-[4-cis(7-methoxy-l-benzofuran-3~ y-)cyclohexyl]-l-piperazinyl}quinoIine ("Compound 59")

[0231] To a solution of 6-fluoro-8-piperazino-quinoline (0.200 g) in DCE (10 ml), was added 4-(7-methoxy-benzofuran-3-yl)-cyclohexanone (0.200 g) followed by sodium triacetoxyborohydride (0.230 g) and acetic acid (0.1 ml). The reaction was stirred at room temperature overnight. It was quenched with IN NaOH, and the product was extracted with CH₂C1 . The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 30% ethyl acetate/hexane, then 50% ethyl acetate/hexane, to give 0.065 g of the cis product. MP: 75-83°C; MS (ES) m/z (relative intensity): 460 (M⁺+H, 100). Elemental analysis for C₂₈ H₃₀ FN₃ O₂; Calculated: C: 73.18; H: 6.58; N: 9.14; Found: C: 72.26; H: 6.61; N: 8.67.

Example 98: Preparation of 6-fluoro-8-{4-[4-trans(7-methoxy-l-benzofuran-3- yι)cyclohexyl]-l-piperazinyl}quinoline ("Compound 60")

[0232] The trans isomer was isolated at the same time as the cis isomer of example 60, above, as an off white solid, 0.029 g. MP: 195-197°C; MS (ES) m/z (relative intensity): 460 (M⁺+H, 100). Elemental analysis for C₂₈ H₃₀ FN₃ O₂; Calculated: C: 73.18; H: 6.58; N: 9.14; Found: C: 72.47; H: 6.4; N: 8.84. Example 99: Preparation of 8-{4-[4-cis(7-methoxy-l-benzofuran-3-yl)cyclohexyl]-l- piperazinyl} quinoline ("Compound 61")

[0233] To a solution of 8-piperazino-quinoline (0.350 g) in DCE (10 ml), was added 4-(7- Methoxy-Benzofuran-3-yl)-cyclohexanone (0.200 g) followed by sodium triacetoxyborohydride (0.300 g) and acetic acid (0.2 ml). The reaction was stirred at room temperature overnight. It was quenched with IN NaOH, and the product was extracted with CH₂C1₂. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered tlirough 100 ml of silica gel using 50% ethyl acetate/hexane, to give 0.105 g of the cis product. MP: 66-67°C; MS (ES) m/z (relative intensity): 442 (M⁺+H, 100). Elemental analysis for C₂₈ H_3JN₃ O2; Calculated: C: 76.16; H: 7.08; N: 9.52; Found: C: 74.8; H: 7.14; N: 8.88

Example 100: Preparation of 8-{4-[4-trans(7-methoxy-l-benzofuran-3-yl)cyclohexyl]-l- piperazinyl} quinoline ("Compound 62")

[0234] The trans isomer was isolated at the same time as the cis isomer of example 62, above, as an off white solid, 0.015 g. MP: 195-197°C; MS (ES) m/z (relative intensity): 442 (M⁺+H, 100). Elemental analysis for C₂₈ H₃ι N₃ O₂; Calculated: C: 76.16; H: 7.08; N: 9.52; Found: C: 74.9; H: 7.02; N: 8.98.

Example 101: Preparation of 5-chloro-8~{4-[4-cis(7-methoxy-l-benzofuran-3- yl)cyclohexyl]piperazin-l-yl}quinoline ("Compound 63")

[0235] To a solution of 5-chloro-8-piperazino-quinoline (0.200 g) in DCE (10 ml), was added 4-(7-methoxy-benzofuran-3-yl)-cyclohexanone (0.200 g) followed by sodium triacetoxyborohydride (0.224 g) and acetic acid (0.1 ml). The reaction was stirred at room temperature overnight. It was quenched with IN NaOH, and the product was extracted with CH₂C1₂. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate/hexane, then 70% ethyl acetate/hexane, to give 0.035 g of the cis product. MS (ES) m/z (relative intensity): 477 (M'+H, 100).

Example 102: Preparation of 5~chloro-8-{4-[4-trans(7-methoxy-l-benzofuran-3- yl)cyclohexy_]piperazin-l-yl}quinoline ("Compound 64")

The trans isomer was isolated at the same time as the cis isomer of example 64, above, as an off white solid, 0.010 g. MS (ES) m/z (relative intensity): 477 (M^-H, 100).

Example 103: Preparation of 5~chIoro-8-{4-[4-cis(5-methoxy-l-benzofuran-3- yl)cyclohexyl]piperazin-l-yl}quinoline ("Compound 65")

[0236] To a solution of 5-chloro-8-piperazino-quinoline (0.200 g) in DCE (10 ml), was added 4-(7-methoxy-benzofuran-3-yl)-cyclohexanone (0.200 g) followed by sodium triacetoxyborohydride (0.224 g) and acetic acid (0.1 ml). The reaction was stirred at room temperature overnight. It was quenched with IN NaOH, and the product was extracted with CH₂C1₂. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate/hexane, 75% ethyl acetate/hexane, and finally 100% ethyl acetate to give 0.015 g of the is product. MS (ES) m/z (relative intensity): 477 (M⁺+H, 100). Example 104: Preparation of 5-chloro-8-{4-[4-trans(5-methoxy-l-benzofuran-3- yl)cycIohexyl]piperazin-l-yl}quinoline ("Compound 66")

[0237] The trans isomer was isolated at the same time as the cis isomer of example 66, above, as an off-white solid, 0.012 g. MS (ES) m/z (relative intensity): 477 (M⁺+H, 100).

Example 105: Preparation of 6-fluoro-8~{4-[4-cis(5-methoxy-l-benzofuran-3- yl)cyclohexyl]piperazin-l-yl}quinoline ("Compound 67")

[0238] To a solution of 6-fluoro-8-piperazino-quinoline (0.300 g) in DCE (10 ml), was added 4-(7-methoxy-benzofuran-3-yl)-cyclohexanone (0.300 g) followed by of sodium triacetoxyborohydride (0.345 g) and acetic acid (0.2 ml). The reaction was stirred at room temperature overnight. It was quenched with IN NaOH, and the product was exfracted with CH₂C1₂. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate/hexane, to give 0.050 g of the cis product. MP: 153-160°C; MS (ES) m/z (relative intensity): 460 (M⁺+H, 100). Elemental analysis for C₂₈H₃₀ F N₃ O₂; Calculated: C: 73.18; H: 6.58; N: 9.14; Found: C: 71.86; H: 6.86; N: 8.73.

Example 106: Preparation of 6-fluoro-8-{4-[4-trans(5-methoxy-l-benzofuran-3- yl)cyclohexyl]piperazin-l-yl}quinoline ("Compound 68")

[0239] The trans isomer was isolated at the same time as the cis isomer of example 68, above, as an off-white solid (0.030 g). MP: 152-155°C. MS (ES) m/z (relative intensity): 460 (M⁺+H, 100). Elemental analysis for C₂₈ H₃₀C1N₃ O₂; Calculated: C: 73.18; H: 6.58; N: 9.14; Found: C: 71.96; H: 6.64; N: 8.46.

Example 107: Preparation of 8-[4~(4-benzofuran-2-yl-ycIohexyI)-piperazin-l-yl]-6- fluoro-quinoline ("Compound 69")

[0240] To a solution of 6-fluoro-8-piperazino-quinoline (1.4 g) in DCE (50 ml), was added 4-benzofuran-2-yl-cyclohexanone (0.960 g) followed by sodium triacetoxyborohydride (1.6 g) and acetic acid (2 ml). The reaction was stirred at room temperature for 6 hours. It was quenched with IN NaOH, and the product was extracted with CH₂C1₂. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 50% ethyl acetate/hexane, to give 0.050 g of the cis product. MP 91-93°C; MS (ES) m z (relative intensity): 430 (M⁺+H, 100). Example 108: Preparation of cis-8-[4-(4-thiophene-2-yl~cyclohexy_)~piperazin-l- yl] -6-methoxy-quinoline ("Compound 70")

[0241] A solution of 4-benzo[b]thiophen-2-yl-cyclohexanone (237 mg, 1 mmol), 6- methoxy-8-piperazin- (250 mg, 1 mmol), Na(OAc)₃BH (327 mg, 1.55 mmol) and HO Ac (0.12 ml, 2 mmol) in C1CH₂CH₂C1 (40 ml) was stirred at room temperature overnight. The reaction mixture was quenched with 1 N aqueous NaOH (50 ml) and poured into H₂O (50 ml), and extracted into CH₂C1₂ (1 x 100 ml) and EtOAc (2 x 100 ml). The organic phases were combined, dried over Na₂SO₄ and concentrated under vacuum. Flash chromatogroaphy on silica gel (5% methanol/ethylacetate) afforded a yellow solid which was one spot by TLC. Analytical HPLC indicated an 80:20 mixture of cis and trans isomers. Preparative HPLC (Primesphere silica column, 50 x 250 mm, 50/50 hexane/methyl t-butyl ether) afforded 130 mg (28%) of the cis isomer (first eluting) compound as a pale yellow crystalline solid. MP: 184-186°C. MS (ES) m/z (relative intensity): 458 (M⁺+H, 100). Elemental Analysis for C₂₈H₃ιN₃OS; Calculated: C, 73.49; H, 6.83; N, 9.18; Found: C, 73.19; H, 6.93; N, 9.03.

Example 109: Preparation of trans-8-[4-(4-thiophene-2-yl-cyclohexyl)-piperazin-l-yl]-6- methoxy-quino

[0242] The trans isomer was isolated at the same time as the cis isomer of example 71, above, as an off-white solid. MP: 193-194°C; MS (ES) m/z (relative intensity): 458 (M⁺+H, 100). Elemental Analysis for C₂₈H₃₁N₃OSO.5 H₂O; Calculated: C, 72.07; H, 6.91; N, 9.00; Found: C, 72.23; H, 6.88; N, 8.96. Example 110: Testing affinity of compounds for 5-HT transporter

[0243] The 5-HT transporter affinity of the compounds of this invention was established in accordance with standard pharmaceutically accepted test procedures with representative compounds as follows.

Rat Brain ³H-Paroxetine Binding Assay (RB 5HT Transporter):

[0244] This assay was used to determine a compound's affinity of the 5-HT transporter. [0245] A protocol similar to that used by Cheetham et al. (Neuropharmacol, 1993, 32: 737) was used. Briefly, frontal cortical membranes prepared from male S.D. rats were incubated with ³H-parxetine (0.1 nM) for 60 min at 25°C. All tubes also contained either vehicle, test compound (one to eight concentrations), or a saturating concentration of fluoxetine (10 μM) to define specific binding. All reactions were terminated by the addition of ice cold Tris buffer followed by rapid filtration using a Tom Tech filtration device to separate bound from free H-paroxetine. Bound radioactivity was quantitated using a Wallac 1205 Beta Plate^® counter. Nonlinear regression analysis was used to determine IC₅₀ values which were converted to K; values using the method of Cheng and Prusoff (Biochem. Pharmacol, 1973, 22: 3099).

Ki = IC₅₀/Radioligand concentration/(l+KD)

Inhibition of ³H-5-HT Uptake by cells Possessing the Human 5-HT Transporter (HC 5HT Transporter)

[0246] A human carcinoma cell line (Jar cells) possessing low endogenous levels of the 5- HT-fransporter are seeded into 96 well plates and treated with staurosporine at least 18 hrs prior to assay. [Staurosporine greatly increases the expression of the 5-HT-fransporter.J On the day of assay, vehicle, excess fluoxetine, or test compound was added to various wells on the plate. All wells then received H-5-HT and were incubated at 37°C for 5 min. The wells were then washed with ice cold 50 mM Tris HCl (pH 7.4) buffer and aspirated to remove free ³H-5-HT. 25 μl of 0.25 M NaOH was then added to each well to lyse the cells and 75 μl scintillation coclctail (Microscint™ 20) was 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 subfracted 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 confrol 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. [0247] High affinity for the serotonin 5-HT_1A receptor was established by testing the claimed compound's ability to displace [-1H] 8-OH-DPAT (dipropylaminotetralin) from the 5- HTIA serotonin receptor following a modification of the procedure of Hall et al.( J. Neurochem., 1985, 44: 1685), which utilizes CHO cells stably transfected with human 5- HTiA receptors. The 5-HT_1A affinities for the compounds of the invention are reported below as Ki's.

[0248] Antagonist activity at 5-HT_1A receptors was established by using a ³⁵S-GTPγS binding assay similar to that used by Lazareno and Birdsall (Br. J. Pharmacol, 1993, 109: 1120), in which the test compound's ability to affect the binding of ³⁵S-GTPγS to membranes containing cloned human 5-HT_1A receptors was determined. Agonists produce an increase in binding whereas antagonists produce no increase but rather reverse the effects of the standard agonist 8-OH-DPAT. The test compound's maximum inhibitory effect is represented as the I_max, while its potency is defined by the IC₅₀. [0249] Results from these two assays are presented below in Table I.

Table 1

[0250] Hence, the compounds of this invention not only inhibit or block serotonin reuptake

(thereby increasing levels of serotonin in the synapse) but also antagonize the 5-HT_IA receptors (thereby reducing the latency period). The compounds of the invention would thus be useful in the prevention and/or treatment of diseases affected by disorders of the serotonin affected neurological systems, including depression, anxiety, cognitive deficits, such as those resulting from Alzheimer's disease and other neurodegenerative disorders, schizophrenia, prostate cancer, and nicotine withdrawal, by administration orally, parenterally, or by aspiration to a patient in need thereof.

[0251] When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges specific embodiments therein are intended to be included.

[0252] The disclosures of each patent, patent application, and publication cited or described in this document are herby incorporated herein by reference, in their entirety.

[0253] Those skilled in the art will appreciate that numerous changes and modifications can be made to the preferred embodiments of the invention and that such changes and modifications can be made without departing from the spirit of the invention. It is, therefore, intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the invention.

Claims

e claim:

1. The compound of formula I:

or a prodrug, stereoisomer, N-oxide or pharmaceutically-acceptable salt thereof; wherein:

X is O or S;

Ri, R , R₃, R₄, R₅, R₆, and R₇ are independently hydrogen, halo, cyano, -N(R )(R₉), hydroxy, C(=O)OR₁₀, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, perfluoroalkyl, (R₉)(R )N-alkoxy, (R₉)(R₉)N-alkoxyaryl, S(O)_q-alkyl where q is 0-2, S(O)_q-aryl where q is 0-2, CONR1₁R₁₂. guanidino, cyclic guanidino, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, heterocycle, arylalkenyl, -SO₂NRnRι₂, aryloxyaryl, arylalkoxyalkyl, aryloxyalkyl, aryloxyheteroaryl, heteroaryloxyaryl, alkylaryloxyaryl, alkylaryloxyheteroaryl, heteroaryloxyalkyl or where any two of said i, R₂, R₃, R , R , R_δ, or R₇ located on adjacent carbon atoms together form an alkylene dioxy group;

R₈ is a linker selected from cycloalkyl, alkyl optionally substituted with one or two Rι₃, and a moiety of formula:

where Z is N or CH; t is an integer from 1 to 3; and u is an integer from 0 to 3; R₉ is hydrogen, alkyl, aryl, heteroaryl, aryloxy, heterocycle, cycloalkyl, alkenyl with the proviso that the double bond of the alkenyl is not present at the carbon atom that is directly linked to N, alkynyl with the proviso that the triple bond of the alkynyl is not present at the carbon atom that is directly linked to N, perfluoroalkyl, -S(O)₂alkyl, -S(O) aryl, -S(O)₂aheteroaryl -(C=O)heteroaryl, -(C=O)aryl, -(C=O)(Cι-C₆) alkyl, -(C=O)cycloalkyl,-(C=O)heterocycle, alkyl- heterocycle, arylalkenyl, -CONRπRι₂, -SO₂NRπRι , arylalkoxyalkyl, arylalkylalkoxy, heteroarylalkylalkoxy, aryloxyalkyl, heteroaryloxyalkyl, aryloxyaryl, aryloxyheteroaryl, alkylaryloxyaryl, alkylaryloxyheteroaryl, alkylaryloxyalkyamine, alkoxycarbonyl, aryloxycarbonyl, or heteroaryloxycarbonyl;

Rio is hydrogen, alkyl, aryl, heteroaryl, alkylaryl, arylalkyl, heteroarylalkyl, or alkyl heteroaryl;

Rn and Rι₂ are independently hydrogen, alkyl, aryl, heteroaryl, alkylaryl, arylalkyl, heteroarylalkyl, or alkylheteroaryl; and each Rι₃ is hydrogen, alkyl, aryl, heteroaryl, alkylaryl, arylalkyl, heteroarylalkyl, alkyl heteroaryl, or -N(R₉)(R₉).

2. A compound according to claim 1, wherein said Ri, R₂, R₃, R₄, R₅, R₆, and R₇, independently, are methyl, isopropyl, methoxy, chloro, or fluoro.

3. A compound according to claim 1 or 2, wherein said R₈ is ethyl, propyl, isopropyl, butyl, hexyl or cyclohexyl.

4. A compound according to any one of claims 1 to 3, wherein said R₉ is alkyl.

5. A compound according to any one of claims 1 to 4, wherein said Rio is hydrogen or alkyl.

6. A compound according to any one of claims 1 to 5, wherein said Rπ and R₁₂, independently, are hydrogen, alkyl, alkylaryl, or alkylheteroaryl.

7. A compound according to any one of claims 1 to 6, wherein said Rι₃ is hydrogen or alkyl.

8. A compound according to claim 1, wherein said compound is: 8- {4-[2-(l-benzofuran-3-yl)ethylJ- 1 -piperazinyl} -6-fluoroquinoline;

8-{4-[2-(l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-chloroquinoline;

8-{4-[2-(l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-methylquinoline;

8-{4-[2-(l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-methoxyquinoline;

8-{4-[2-(6-chloro-l-benzofuran-3-yl)ethylJ-l-piperazinyl}-quinoline;

8-{4-[2-(6-chloro-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-fluoro-quinoline;

8- {4-[2-(6-chloro- 1 -benzofuran-3 -yl)ethylj- 1 -piperazinyl} -6-chloro-quinoline;

8-{4-[2-(6-chloro-l-benzofuran-3-yl)ethylJ-l-piperazinyl}-6-methyl-

quinoline;

8-{4-[2-(6-methoxy-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-quinoline;

8-{4-[2-(6-methoxy-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-methyl-

quinoline;

8-{4-[2-(6-methoxy-l-benzofuran-3-yl)ethylJ-l-piperazinyl}-6-chloro-

quinoline;

8-{4-[2-(5-chloro-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-quinoline;

8-{4-[2-(5-chloro-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-chloro-quinoline;

8- {4-[2-(5-chloro- 1 -benzofuran-3 -yl)ethylj- 1 -piperazinyl} -6-methyl-

quinoline;

8-{4-[2-(5-fluoro-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-quinoline;

8- {4-[2-(5-fluoro-l -benzofuran-3-yl)ethyl]- 1 -piperazinyl} -6-methoxyquinoline;

8- {4-[2-(5-fluoro- 1 -benzofuran-3 -yl)ethylj- 1 -piperazinyl} -6-fluoro-quinoline;

8- {4-[2-(7-methoxy- 1 -benzofuran-3-yl)ethyl] - 1 -piperazinyl} -quinoline; 8- {4-[2-(7-methoxy-l -benzofuran-3-yl)ethylJ-l -piperazinyl} -6-methoxyquinoline;

8- {4- [2-(7-methoxy- 1 -b enzofuran-3 -yl)ethyl] - 1 -piperazinyl} -6-chloro- quinoline;

8-{4-[2-(5-methoxy-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-quinoline;

8-{4-[2-(5-methoxy-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-chloro- quinoline;

8-{4-[2-(5-methoxy-l-benzofuran-3-yl)ethylJ-l-piperazinyl}-6-methyl- quinoline;

8-.{4-[2-(5-methoxy-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-isopropyl- quinoline;

8-{4-[2-(5-methoxy-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-methoxy- quinoline;

8-{4-[2-(5-methoxy-l-benzofuran-3-yl)ethyl]-l-piperazinyl}-6-fluoro- quinoline;

8-{4-[2-(l-benzofuran-3-yl)propyl]-l-piperazinyl}quinoline;

8-{4-[2-(l-benzofuran-3-yl)propyl]-l-piperazinyl}-6-chloro-quinoline;

8-{4-[2-(l-benzofuran-3-yl)propyl]-l-piperazinyl}-6-fluoro-quinoline;

8-{4-[2-(l-benzofuran-3-yl)propylJ-l-piperazinyl}-6-methyl-quinoline;

8-{4-[2-(7-methoxy-l-benzofuran-3-yl)propyl]-l-piperazinyl}quinoline;

8- {4-[2-(7-methoxy- 1 -benzofuran-3-yl)propyl]-l -piperazinyl} -6-methyl- quinoline;

8-{4-[2-(7-methoxy-l-benzofuran-3-yl)propyl]-l-piperazinyl}-6-chloro- quinoline;

8-{4-[2-(7-methoxy-l-benzofuran-3-yl)propyl]-l-piperazinyl}-6-methyl- quinoline;

8-{4-[2-(7-methoxy-l-benzofuran-3-yl)-l-methylethyl)piperazin-l- yljquinoline; 6-methoxy-8- {4- [2-(7-methoxy- 1 -benzofuran-3-yl)- 1 -methylethyl)piperazin- 1 -yljquinoline;

6-methyl-8- {4-[2-(7-methoxy- 1 -benzofuran-3-yl)- 1 -methylethyljpiperazin- 1 - yl} quinoline;

8- {4-[2-(5-methoxy- 1 -benzofuran-3-yl)- 1 -methylethyljpiperazin- 1 - yl} quinoline;

6-chloro-8-{4-[2-(5-methoxy-l-beι-zofuran-3-yl)-l-methylethyl]piperazin-l- yl} quinoline;

6-methyl-8-{4-[2-(5-methoxy-l-benzonιran-3-yl)-l-methylethyl]piperazin-l- yl} quinoline;

8- {4-[4-cis-(l -benzothien-3-yl)cyclohexylJ- 1 -piperazinyl} -6-chloroquinoline;

8-{4-[4-trans(l-benzothien-3-yl)cyclohexyl]-l-piperazinyl}-6- chloroquinoline;

8- {4-[4-cis(l -benzothien-3-yl)cyclohexyl]- 1 -piperazinyl} -6-fluoroquinoline;

8-{4-[4-trans(l-benzothien-3-yl)cyclohexylJ-l-piperazinyl}-6-fluoroquinoline;

8- {4-[4-cis(l -benzothien-3-yl)cyclohexyl]- 1 -piperazinyl} -6- methoxyquinoline;

8- {4-[4-frans (1 -benzothien-3-yl)cyclohexyl]-l -piperazinyl} -6- methoxyquinoline;

6-fluoro-8-{4-[4-cis(5-fluoro-l-benzothien-3-yl)cyclohexylJpiperazin-l- yl} quinoline;

6-fluoro-8-{4-[4-trans(5-fluoro-l-benzothien-3-yl)cyclohexylJpiperazin-l- yl} quinoline;

6-methoxy-8-{4-[4-cis(5-fluoro-l-benzothien-3-yl)cyclohexyl]piperazin-l- yl} quinoline;

6-methoxy-8-{4-[4-trans(5-fluoro-l-benzothien-3-yl)cyclohexylJpiperazin-l- yl} quinoline;

5-chloro-8-{4-[4-cis(5-fluoro-l-benzothien-3-yl)cyclohexyl]piperazin-l- yl} quinoline;

5-chloro-8-{4-[4-trans(5-fluoro-l-benzothien-3-yl)cyclohexyl]piperazin-l- yl} quinoline;

8-{4-[4-cis(l-benzofuran-3-yl)cyclohexylJ-l-piperazinyl}-5-fluoroquinoline; 8- {4-[4-trans(l -benzofuran-3-yl)cyclohexylJ-l -piperazinyl} -5- fluoroquinoline;

8-{4-[4-cis(l-benzofuran-3-yl)cyclohexyl]-l-piperazinyl}-6-fluoroquinoline;

8- {4-[4-trans(l -benzofuran-3-yl)cyclohexyl]-l -piperazinyl} -6- fluoroquinoline;

5-fluoro-8-{4-[4-cis(7-methoxy-l-benzofuran-3-yl)cyclohexyl]-l- piperazinyl} quinoline;

5 -fluoro-8- {4- [4-trans(7-methoxy- 1 -benzofuran-3 -yl)cyclohexylJ - 1 - piperazinyl} quinoline;

6-fluoro-8-{4-[4-cis(7-methoxy-l-benzofuran-3-yl)cyclohexylJ-l- piperazinyl} quinoline;

6-fluoro-8- {4- [4-frans(7-methoxy- 1 -benzofuran-3 -yl)cyclohexyl] - 1 - piperazinyl} quinoline;

8- {4- [4-cis(7-methoxy- 1 -benzofuran-3 -yl)cyclohexyl] - 1 - piperazinyl} quinoline;

8- {4- [4-frans(7-methoxy- 1 -benzofuran-3 -yl)cyclohexyl] - 1 - piperazinyl} quinoline;

5-chloro-8-{4-[4-cis(7-methoxy-l-benzofuran-3-yl)cyclohexyl]piperazin-l- yl} quinoline;

5-chloro-8-{4-[4-trans(7-methoxy-l-benzofuran-3-yl)cyclohexylJpiperazin-l- yl} quinoline;

5-chloro-8-{4-[4-cis(5-methoxy-l-benzofuran-3-yl)cyclohexyl]piperazin-l- yl} quinoline;

5-chloro-8-{4-[4-frans(5-methoxy-l-beιιzofuran-3-yl)cyclohexyl]piperazin-l- yl} quinoline;

6-fluoro-8-{4-[4-cis(5-methoxy-l-benzofuran-3-yl)cyclohexylJpiperazin-l- yl} quinoline;

6-fluoro-8-{4-[4-frans(5-methoxy-l-benzofuran-3-yl)cyclohexyl]piperazin-l- yl} quinoline;

8-[4-(4-benzofuran-2-yl-cyclohexyl)-piperazin-l-ylJ-6-fluoro-quinoline; cis-8-[4-(4-thiophene-2-yl-cyclohexyl)-piperazin-l-yl]-6-methoxy-quinoline; frans-8-[4-(4-thiophene-2-yl-cyclohexyl)-piperazin-l-yl]-6-methoxy- quinoline;

8-[4-(4-benzo-man-2-yl-cyclohexyl)-piperazin-l-ylJ-6-fluoro-quinoline; cis-8-[4-(4-thiophene-2-yl-cyclohexyl)-piperazin-l-yl]-6-methoxy-quinoline; or trans-8-[4-(4-thiophene-2-yl-cyclohexyl)-piperazin-l-yl]-6-methoxy- quinoline.

9. A composition, comprising: the compound of claim 1; and one or more pharmaceutically-acceptable carriers.

10. A method of treating a patient suspected to suffer from a serotonin disorder, comprising the step of: administering to the patient a therapeutically effective amount of the compound of claim 1.

11. A method according to claim 10, wherein said serotonin-related disorder is depression, anxiety, cognitive deficits, schizophrenia, prostate cancer, or nicotine withdrawal.

12. A method according to claim 10, wherein said serotonin-related disorder is depression.

13. A method according to claim 10, wherein said serotonin-related disorder is anxiety.

14. A method of antagonizing 5-HTIA receptors in a patient in need thereof, comprising the step of: administering to the patient a therapeutically effective amount of the compound of claim 1.

15. A method of inhibiting the reuptake of serotonin in a patient in need thereof, comprising the step of: administering to the patient a therapeutically effective amount of the compound of claim 1.

16. A method of antagonizing 5-HT_IA receptors and inhibiting the reuptake of serotonin in a patient in need thereof, comprising the step of: administering to the patient a therapeutically effective amount of a compound of claim 1.

17. A method of hastening the onset of an SSRI, comprising the steps of: administering an SSRI, and administering a compound of claim 1.

18. The method of claim 17, wherein said SSRI is co-administered with said compound.

19. A process for the preparation of benzofuranyl- and benzothienyl-piperzinyl quinoline derivatives, comprising the step of reacting a compound of formula II:

II with a compound of formula III:

III

in the presence of at least one aprotic polar solvent and at least one acid binding agent, wherein:

Y is halide, tosylate, mesylate, or triflate;

X is O or S;

Ri, R , R₃, R₄, R₅, R₆, and R₇ are independently hydrogen, halo, cyano, -N(R₉)(R ), hydroxy, C(=O)ORι₀, alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, perfluoroalkyl, alkylene dioxy, (R₉)(R₉)N-alkoxy, (R₉)(R₉)N-alkoxyaryl, S(O)_q-alkyl where q is 0-2, S(O)_q-aryl where q is 0-2, CONR11R12, guanidino, cyclic guanidino, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, heterocycle, arylalkenyl, -SO₂NRπRι₂, aryloxyaryl, arylalkoxyalkyl, aryloxyalkyl, aryloxyheteroaryl, heteroaryloxyaryl, alkylaryloxyaryl, alkylaryloxyheteroaryl or heteroaryloxyalkyl;

R₈ is a linker selected from cycloalkyl, alkyl optionally substituted with one or two Rι₃, and a moiety of formula:

where Z is N or CH; t is an integer from 1 to 3; and u is an integer from 0 to 3;

R is hydrogen, alkyl, aryl, heteroaryl, aryloxy, heterocycle, cycloalkyl, alkenyl with the proviso that the double bond of the alkenyl is not present at the carbon atom that is directly linked to N, alkynyl with the proviso that the triple bond of the alkynyl is not present at the carbon atom that is directly linked to N, perfluoroalkyl, -S(O)₂alkyl, -S(O)₂aryl, -S(O)₂aheteroaryl -(C=O)heteroaryl, -(C=O)aryl, -(C=O)(Cι-C₆) alkyl, -(C=O)cycloalkyl,-(C=O)heterocycle, alkyl- heterocycle, arylalkenyl, -CONRπRι₂, -SO₂NRπRι₂, arylalkoxyalkyl, arylalkylalkoxy, heteroarylalkylalkoxy, aryloxyalkyl, heteroaryloxyalkyl, aryloxyaryl, aryloxyheteroaryl, alkylaryloxyaryl, alkylaryloxyheteroaryl, alkylaryloxyalkyamme, alkoxycarbonyl, aryloxycarbonyl, or heteroaryloxycarbonyl;

Rio is hydrogen, alkyl, aryl, heteroaryl, alkylaryl, arylalkyl, heteroarylalkyl, or alkyl heteroaryl;

Rπ and Rι₂ are independently hydrogen, alkyl, aryl, heteroaryl, alkylaryl, arylalkyl, heteroarylalkyl, or alkylheteroaryl; and each R₁₃ is hydrogen, alkyl, aryl, heteroaryl, alkylaryl, arylalkyl, heteroarylalkyl, alkyl heteroaryl, or -N(R )(R₉).