CN1812984A - Benzofuryl-piperazinylquinolines and benzothienyl-piperazinylquinolines as serotonin reuptake inhibitors - Google Patents

Abstract

Benzofuranyl-piperazinyl and benzothienyl-piperazinyl quinoline derivatives and compositions containing them are disclosed. Also disclosed are methods of using benzofuranyl-and benzothienyl-piperazinyl quinoline derivatives and compositions comprising them for the treatment and/or prevention of 5-hydroxytryptamine-related disorders such as depression and anxiety. In addition, methods of making benzofuranyl-piperazinyl and benzothienyl-piperazinyl quinoline derivatives are disclosed.

Description

Benzofuryl-piperazinylquinolines and benzothienyl-piperazinylquinolines as serotonin reuptake inhibitors

Cross References to Related Applications

This application claims the benefit of Provisional Application Serial No. 60/467,368, filed May 2, 2003, the contents of which are hereby incorporated by reference in their entirety.

field of invention

The present invention relates to benzofuryl-piperazinylquinoline derivatives or benzothienyl-piperazinylquinoline derivatives, in particular to their use as serotonin reuptake inhibitors and as 5-HT _1A receptors activity of body antagonists, and in particular to their use in the treatment and/or prevention of serotonin-related diseases.

Background of the invention

An estimated 340 million people worldwide suffer from major depressive disorder. Depression is the most frequently diagnosed disorder among mental illnesses, and according to the World Health Organization, it is also the fourth-largest public health problem. If left untreated, depression can have devastating results, disrupting a person's energy or motivation to perform everyday activities and sometimes 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 toll of depression, the disease is estimated to cost more than $40 billion annually in premature death, lost labor and absenteeism in the United States alone.

Drugs that enhance serotonergic neurotransmission have been used successfully to prevent and/or treat many psychiatric disorders, including depression and anxiety. The first generation of non-selective serotonin-affecting drugs acted through various physiological functions, giving them some side effects. The most recent class of drugs to be developed are the selective serotonin reuptake inhibitors (SSRIs), which have had significant success in the prevention and/or treatment of depression and related disorders and have become the most commonly used drug since the 1980s prescription drugs. Although they have favorable side effects compared with tricyclic antidepressants (TCAs), they also have their own unique side effects due to non-selective stimulation of serotonergic sites. They generally work slowly, often taking several weeks to produce the full therapeutic effect. Furthermore, they are often found to be effective in less than two-thirds of patients.

SSRIs are believed to act by blocking the neuronal reuptake of serotonin, increasing the concentration of serotonin in the synaptic cleft, thereby increasing the activation of postsynaptic serotonin receptors. Although a single dose of an SSRI can inhibit the neuronal serotonin transporter and thus increase synaptic serotonin expectedly, however, long-term treatment is usually required to achieve clinical improvement. It has been shown that the delayed onset of action of SSRI antidepressants is the result of increased serotonin levels near the serotonergic cell body. It is believed that such excess serotonin activates the somatotree autoreceptors (i.e., 5-HT _1A receptors), reducing cell firing activity, which in turn reduces serotonin release in the major forebrain area . Such negative feedback limits the increase in synaptic serotonin that can be acutely induced by antidepressants. Over time, this somatic tree autoreceptor is desensitized, allowing SSRIs to fully function in the forebrain. This time period has been found to correspond to the latency period for the onset of antidepressant activity. [Perez et al., The Lancet, 1997, 349:1594-1597].

Unlike SSRIs, 5-HT _1A agonists or partial agonists act directly on postsynaptic serotonin receptors to increase serotonergic neurotransmission during the latency period of SSRI action. Therefore, the 5-HT _1A partial agonists buspirone and gepirone [Feiger, A., Psychopharmacol.Bull., 1996, 32:659-665, Wilcox, C., Psychopharmacol.Bull, 1996, 32:335 -342] and the 5-HT _1A agonist fluxinxan [Grof, P., International Clinical Psychopharmacology, 1993, 8: 167-172] have shown efficacy in clinical trials for the treatment of depression. In addition, the drug is believed to stimulate the somatotree autoreceptors, thus promoting their desensitization and shortening SSRI latency. In fact, augmentation of standard SSRI therapy by buspirone has shown marked clinical improvement in patients initially unresponsive to standard antidepressant therapy [Dimitriou, E., J. Clinical Psychopharmacol., 1998, 18: 465-469].

There remains a need for a single agent with a dual mechanism of antidepressant action, i.e. one that not only inhibits or blocks serotonin reuptake (increases serotonin levels in the synapse) but also antagonizes 5-HT _1A receptors (reduces latency) Drug. The present invention addresses these and other important aspects.

Summary of the invention

The present invention relates to benzofuryl-piperazinylquinoline derivatives or benzothienyl-piperazinylquinoline derivatives, and more particularly to their use in the treatment and/or prevention of serotonin-related diseases Methods of diseases such as depression, anxiety, cognitive deficits such as those caused by Alzheimer's disease and other neurodegenerative diseases, schizophrenia and prostate cancer. Preferred compounds have the ability to bind and antagonize 5-HT _1A receptors, as well as act as serotonin reuptake inhibitors.

On the one hand, the present invention provides the following formula I benzofuryl-piperazino quinoline derivatives and benzothienyl-piperazino quinoline derivatives or their prodrugs, stereoisomers, N- Oxides or pharmaceutically acceptable salts:

in:

X is O or S;

R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are independently hydrogen, halogen, cyano, -N(R ₉ )(R ₉ ), hydroxyl, C(=O)OR ₁₀ , alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, perfluoroalkyl, (R ₉ )(R ₉ ) N-alkoxyl, (R ₉ )(R ₉ )N-alkoxyaryl, S(O) _q -alkyl (wherein q is 0-2), S(O) _q -aryl ( where q is 0-2), CONR ₁₁ R ₁₂ , guanidino, cyclic guanidino, alkylaryl, arylalkyl, alkylheteroaryl, heteroarylalkyl, heterocyclyl, arylalkene radical, -SO ₂ NR ₁₁ R ₁₂ , aryloxyaryl, arylalkoxyalkyl, aryloxyalkyl, aryloxyheteroaryl, heteroaryloxyaryl, alkylaryloxyaryl radical, alkylaryloxyheteroaryl, heteroaryloxyalkyl, or any two of R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ or R ₇ together on adjacent carbon atoms Forming an alkylenedioxy group;

R ₈ is a linker selected from the group consisting of cycloalkyl, alkyl, and moieties of the formula optionally substituted by one or two R ₁₃ :

Where Z is N or CH;

t is an integer from 1 to 3; and

u is an integer of 0-3;

_R9 is hydrogen, alkyl, aryl, heteroaryl, aryloxy, heterocyclyl, cycloalkyl, alkenyl (provided that the double bond of the alkenyl is not on the carbon atom directly attached to N), alkyne (provided that the triple bond of the alkynyl group is not on the carbon atom directly attached to N), perfluoroalkyl, -S(O) _2alkyl , -S(O) _2aryl , -S(O) ₂ Heteroaryl, -(C=O)heteroaryl, -(C=O)aryl, -(C=O)(C ₁ -C ₆ )alkyl, -(C=O)cycloalkyl, -(C=O)heterocycle, alkyl-heterocycle, arylalkenyl, -CONR ₁₁ R ₁₂ , -SO ₂ NR ₁₁ R ₁₂ , arylalkoxyalkyl, arylalkylalkoxy, Heteroarylalkylalkoxy, aryloxyalkyl, heteroaryloxyalkyl, aryloxyaryl, aryloxyheteroaryl, alkylaryloxyaryl, alkylaryloxyheteroaryl group, alkylaryloxyalkylamine, alkoxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl;

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

R and _R are independently hydrogen, alkyl, aryl, heteroaryl, alkylaryl, arylalkyl, heteroarylalkyl, _or alkylheteroaryl; and

Each R ₁₃ is hydrogen, alkyl, aryl, heteroaryl, alkylaryl, arylalkyl, heteroarylalkyl, alkylheteroaryl, or -N(R _{9 )(R 9 )} .

In another aspect, the present invention relates to compositions comprising a compound of formula I and one or more pharmaceutically acceptable carriers.

In another aspect, the present invention relates to a method of treating and/or preventing a patient suspected of suffering from a serotonin-related disease, said method comprising the step of administering to said patient a therapeutically effective amount of a compound of formula I.

In yet another aspect, the invention describes a method of antagonizing 5-HT _1A receptors in a patient in need thereof, said method comprising the step of administering to said patient a therapeutically effective amount of a compound of formula I.

The present invention also relates to a method of inhibiting body weight uptake in a patient in need thereof, said method comprising the step of administering to said patient a therapeutically effective amount of a compound of formula I.

In another aspect, the present invention relates to a method for the preparation of benzofuryl-piperazinylquinoline derivatives and benzothienyl-piperazinylquinoline derivatives, said method comprising the steps of: Reacting a compound of formula II below with a compound of formula III below in the presence of a polar solvent and at least one acid binding agent:

As 5-HT _1A antagonists, the novel compounds are useful in the treatment and/or prevention of several diseases and disorders including anxiety, depression, cognitive deficits, such as those caused by Alzheimer's disease and other neurodegeneration disease, schizophrenia, and prostate cancer. They can also be used as combination therapy to boost the onset of SSRI antidepressants and reduce symptoms caused by nicotine withdrawal.

Detailed description of the invention

Unless expressly stated otherwise, the term "alkyl" as used herein, whether used alone or as part of another group, refers to a ^substituted or unsubstituted, preferably The unsubstituted aliphatic hydrocarbon chains are preferably straight and straight chains containing 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl are included within the term "alkyl". Especially included within the definition of "alkyl" are optionally substituted aliphatic hydrocarbon chains.

The number of carbons used in each definition herein refers to the carbon backbone and carbon branches, but does not include the carbon atoms of substituents (eg, alkoxy substituents, etc.).

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 linked through an ^sp hybridized carbon atom, It is 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. The alkenyl moiety can exist in either the E or Z conformation, and the compounds of the invention include both conformations. Especially included within the definition of "alkenyl" are optionally substituted aliphatic hydrocarbon chains. A heteroatom (eg O, S or NR ₁ ) attached to an alkenyl group should not be attached to a double bonded carbon atom.

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 through sp hybridized carbon atoms, and Included are 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 3-6 carbon atoms. In certain embodiments, the alkynyl group may contain more than one triple bond, in which case the alkynyl group must contain at least 4 carbon atoms. Especially included within the definition of "alkynyl" are optionally substituted aliphatic hydrocarbon chains. A heteroatom (eg O, S or NR ₁ ) attached to an alkynyl group should not be attached to a triple bonded carbon atom.

The term "cycloalkyl" as used herein, whether used alone or as part of another group, refers to a substituted or unsubstituted, preferably unsubstituted, aliphatic hydrocarbon group having 3 to 7 carbon atoms. Especially included within the definition of "cycloalkyl" are optionally substituted aliphatic hydrocarbon chains.

The term "aryl" as used herein, whether alone or as part of another group, is defined as a substituted or unsubstituted aromatic hydrocarbon cyclic group preferably selected from the group consisting of phenyl, alpha-naphthalene yl, β-naphthyl, biphenyl, anthracenyl, tetrahydronaphthyl, fluorenyl, 2,3-indanyl, biphenylene and acenaphthyl. Especially included in the definition of "aryl" are optionally substituted aryl groups.

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) in which the heteroaryl The base is divided into:

(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-1,2,4-triazole, 1H-tetrazole, 1- Methyltetrazole, benzoxazole, benzothiazole, benzofuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinol phylloline and quinoline;

(2) A bicyclic aromatic heterocycle, wherein the phenyl, pyridine, pyrimidine or pyrazine (pyridizine) ring is:

(a) fused with a 6-membered aromatic (unsaturated) heterocyclic ring having 1 nitrogen atom;

(b) fused with a 5-membered or 6-membered aromatic (unsaturated) heterocyclic ring having 2 nitrogen atoms;

(c) fused to a 5-membered aromatic (unsaturated) heterocyclic ring having 1 nitrogen atom and either 1 oxygen atom or a sulfur atom; or

(d) Condensation with a 5-membered aromatic (unsaturated) heterocyclic ring having 1 heteroatom selected from O, N or S.

Especially included in the definition of "heteroaryl" are optionally substituted aromatic heterocycles. Optionally substituted heteroaryl may be substituted with 1 or 2 substituents.

Optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl groups may be substituted with one or two substituents. Suitable optional substituents may be independently selected from nitro, cyano, -N(R ₁₁ )(R ₁₂ ), halogen, hydroxy, carboxy, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, hetero Aryl, alkoxy, aryloxy, heteroaryloxy, alkylalkoxy, alkoxycarbonyl, alkoxyalkoxy, perfluoroalkyl, perfluoroalkoxy, arylalkyl radical, alkylaryl, hydroxyalkyl, alkoxyalkyl, alkylthio, -S(O) ₂ -N(R ₁₁ )(R ₁₂ ), -C(=O)-N(R ₁₁ ) (R ₁₂ ), (R ₁₁ )(R ₁₂ )N-alkyl, (R ₁₁ )(R ₁₂ )N-alkoxyalkyl, (R ₁₁ )(R ₁₂ )N-alkylaryloxyalkane radical, -S(O) _s -aryl (wherein s=0-2) or -S(O) _s -heteroaryl (wherein s=0-2). In certain embodiments of the invention, preferred substituents for alkyl, alkenyl, alkynyl, and cycloalkyl include nitro, cyano, -N(R ₁₁ )(R ₁₂ ), halogen, hydroxy, aryl , heteroaryl, alkoxy, alkoxyalkyl and alkoxycarbonyl. In certain embodiments of the present invention, preferred substituents for aryl and heteroaryl groups include -N(R ₁₁ )(R ₁₂ ), alkyl, halogen, perfluoroalkyl, perfluoroalkoxy, Aralkyl and alkaryl.

The term "alkoxy" as used herein, either alone or as part of another group, refers to the group R _a -O-, wherein R _a is alkyl as defined above.

The term "alkenyloxy" as used herein, either alone or as part of another group, refers to the group Re _- O, wherein Re _is alkenyl as defined above.

The term "alkynyloxy" as used herein, either alone or as part of another group, refers to the group R _f -O-, wherein R _f is alkynyl as defined above.

The term "aryloxy" as used herein, whether alone or as part of another group, refers to the group _Rb -O-, wherein _Rb is aryl as defined above.

The term "heteroaryloxy" as used herein, either alone or as part of another group, refers to the group _Rc -O-, wherein _Rc is heteroaryl as defined above.

The term "alkaryl" as used herein, either alone or as part of another group, refers to the group -R _b -R _a -, wherein R _b is aryl as defined above, replaced by R _a is alkyl substitution as described above.

The term "heteroaralkyl" as used herein, whether alone or as part of another group, refers to the group _{-Ra- Rc-} , where _{Ra is} alkyl as defined above, which is represented by R _c is heteroaryl substitution as described above. Heteroaralkyl moieties include, but are not limited to, heteroaryl-(CH ₂ ) _1-6 (CH ₃ ).

The term "aralkyl" as used herein, whether alone or as part of another group _, refers to the group -Ra _{- Rb} , where _{Ra is} alkyl as defined above, which is replaced by R That is, aryl substitution as described above. Preferred aralkyl moieties are benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl and 2-phenylpropyl.

The term "alkylheteroaryl" as used herein, whether alone or as part of another group, refers to the group _-Rc - _Ra , wherein _Rc is heteroaryl as defined above, which Substituted by R _a ie alkyl as defined above.

The term "arylalkenyl" as used herein, either alone or as part of another group, refers to a group -R _e -R _b containing a total of 8 to 16 carbon atoms, wherein R _b is Aryl as defined above, Re _is alkenyl as defined above, with the proviso that no heteroatoms such as O, S or NR are attached to _{the double} bonded carbon atom.

The term "heterocycle" as used herein, whether used alone or as part of another group, refers to a stable 3 -8-membered ring. The heterocyclic rings of the present invention may be monocyclic or bicyclic, and may be saturated or partially saturated. Preferred heterocyclic groups are aziridinyl, azetidinyl, 1,4-dioxanyl, hexahydroazepanyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholino Linyl, thiomorpholinyl, dihydrobenzimidazolyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzoxazolyl, dihydrofuryl, dihydroimidazolyl, dihydro Indolyl, Dihydroisoxazolyl, Dihydroisothiazolyl, Dihydrooxadiazolyl, Dihydrooxazolyl, Dihydropyrazinyl, Dihydropyrazolyl, Dihydropyridyl, Dihydropyrimidine Dihydropyrrolyl, dihydroquinolyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl , dihydro-1,4-dioxanyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydroquinolyl and tetrahydroisoquinolyl.

The term "arylalkoxyalkyl" as used herein, either alone or as part of another group, refers to R _b -R _a -OR _a -, wherein R _b is aryl as defined above , R _a is an alkyl group as defined above.

The term "alkoxyalkyl" as used herein, either alone or as part of another group, refers to the group R _a -OR _a - wherein R _a is alkyl as defined above.

The term "aryloxyalkyl" as used herein, either alone or as part of another group, refers to the group _Rb - _ORa- , wherein _Rb is aryl as defined above and _Ra is an alkyl group as defined above.

The term "aryloxyaryl" as used herein, either alone or as part of another group, refers to the group _Rb - _ORb- , wherein _Rb is aryl as defined above.

The term "aryloxyheteroaryl" as used herein, either alone or as part of another group, refers to the group _Rb - _ORc- , wherein _Rb is aryl as defined above, R _e is heteroaryl as defined above.

As used herein, the term "alkylaryloxyaryl", whether used alone or as part of another group, refers to the group R _a -R _b -OR _b -, wherein R _a is as defined above Alkyl, R _b is aryl as defined above.

The term "alkoxycarbonyl" as used herein, either alone or as part of another group, refers to the group R _a -OC(=O)-, wherein R _a is alkyl as defined above.

The term "aryloxycarbonyl" as used herein, either alone or as part of another group, refers to the group _Rb -OC(=O)-, wherein _Rb is aryl as defined above.

The term "heteroaryloxycarbonyl" as used herein, whether used alone or as part of another group, refers to the group R _c -OC(=O)-, wherein R _e is heteroaryl as defined above base.

The term "alkoxyalkoxy" as used herein, either alone or as part of another group, refers to the group R _a -OR _a -O-, wherein R _a is alkyl as defined above .

The term "alkylenedioxy" as used herein is defined as

wherein n = 1 or 2 and wherein said alkylene moiety may be substituted with a substituent defined as "alkyl".

The term "heteroaryloxyalkyl" as used herein, either alone or as part of another group, refers to the group R _c -OR _a -, wherein _{R is} heteroaryl as defined above, R _a is alkyl as defined above.

The term "heteroaryloxyaryl" as used herein, whether used alone or as part of another group, refers to the group R _c -OR _b -, R _e is heteroaryl as defined above, R _b is aryl as defined above.

The term "perfluoroalkyl" as used herein, either alone or as part of another group, means a saturated aliphatic hydrocarbon having 1 to 6 carbon atoms and 2 or more fluorine atoms , and include but not limited to linear or branched chains such as -CF ₃ , -CH ₂ CF ₃ , -CF ₂ CF ₃ and -CH(CF ₃ ) ₂ .

The term "perfluoroalkoxy" as used herein, whether used alone or as part of another group, refers to the group R _a -O-, wherein R _a is a group having 1 to 6 carbon atoms and Saturated aliphatic hydrocarbons with 2 or more fluorine atoms, and include but not limited to linear or branched chains, such as -OCF ₃ , -OCH ₂ CF ₃ , -OCF ₂ CF ₃ and -OCH(CF ₃ ) ₂ .

The term "halogen" as used herein refers to chlorine, bromine, fluorine or iodine.

The term "guanidino" as used herein refers to

The term "cyclic guanidino" as used herein refers to

Where p is 1 or 2, and q is 0-2.

Suitable aprotic polar solvents include, but are not limited to, dimethylsulfoxide, dimethylformamide, tetrahydrofuran, acetone, and ethanol.

Suitable acid binders include, but are not limited to, organic tertiary bases such as triethylamine, triethanolamine, 1,8-diazabicyclo[5.4.0]undec-7-ene DBU, and diisopropylethylamine and carbonates of alkali metals, such as potassium carbonate and sodium carbonate.

It is known that compounds of formula I may contain asymmetric carbons, and that formula I includes all possible stereoisomers and mixtures thereof, as well as racemic modifications, especially those compounds having the activities described below. Optical isomers can be obtained in pure form by standard separation techniques.

Preferred groups among the above R ₁ -R ₇ groups are alkyl, halogen, alkoxy, cyano, alkoxycarbonyl, amido, carboxyl, N(R ₉ )(R ₉ ) and C(=O ) OR ₁₀ . Particular preference is given to methyl, isopropyl, methoxy, chlorine and fluorine.

Preferred R ₈ groups are cycloalkyl and (C ₁ -C ₈ )alkyl optionally substituted by: alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl. Particular preference is given to ethyl, propyl, isopropyl, butyl, hexyl and cyclohexyl.

Preferred _R groups are hydrogen, alkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, _{perfluoroalkyl} , -S(O)alkyl, -S(O) _aryl , -(C=O)aryl, -(C=O)(C ₁ -C ₆ )alkyl, -(C=O)cycloalkyl, -(C=O)heterocycle, -(C=O ) NR ₁₁ R ₁₂ and -SO ₂ NR ₁₁ R ₁₂ . Alkyl groups are particularly preferred.

Preferred _R10 groups are hydrogen and alkyl.

Preferred _R11 and _R12 are hydrogen, alkyl, alkylaryl and alkylheteroaryl.

Preferred _R13 groups are hydrogen and alkyl.

The following compounds are particularly preferred compounds:

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

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

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

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

5) 8-{4-[2-(6-chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline;

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

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

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

9) 8-{4-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline;

10) 8-{4-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methyl-quinoline;

11) 8-{4-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-chloro-quinoline;

12) 8-{4-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline;

13) 8-{4-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-chloro-quinoline;

14) 8-{4-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methyl-quinoline;

15) 8-{4-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline;

16) 8-{4-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methoxy-quinoline;

17) 8-{4-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-fluoro-quinoline;

18) 8-{4-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline;

19) 8-{4-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methoxy-quinoline;

20) 8-{4-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-chloro-quinoline;

21) 8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline;

22) 8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-chloro-quinoline;

23) 8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methyl-quinoline;

24) 8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-isopropyl-quinoline;

25) 8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methoxy-quinoline;

26) 8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-fluoro-quinoline;

27) 8-{4-[2-(1-benzofuran-3-yl)propyl]-1-piperazinyl}quinoline;

28) 8-{4-[2-(1-benzofuran-3-yl)propyl]-1-piperazinyl}-6-chloro-quinoline;

29) 8-{4-[2-(1-benzofuran-3-yl)propyl]-1-piperazinyl}-6-fluoro-quinoline;

30) 8-{4-[2-(1-benzofuran-3-yl)propyl]-1-piperazinyl}-6-methyl-quinoline;

31) 8-{4-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1-piperazinyl}quinoline;

32) 8-{4-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1-piperazinyl}-6-methyl-quinoline;

33) 8-{4-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1-piperazinyl}-6-chloro-quinoline;

34) 8-{4-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1-piperazinyl}-6-methyl-quinoline;

35) 8-{4-[2-(7-methoxy-1-benzofuran-3-yl)-1-methylethyl]piperazin-1-yl}quinoline;

36) 6-methoxy-8-{4-[2-(7-methoxy-1-benzofuran-3-yl)-1-methylethyl]piperazin-1-yl}quinoline ;

37) 6-methyl-8-{4-[2-(7-methoxy-1-benzofuran-3-yl)-1-methylethyl]piperazin-1-yl}quinoline;

38) 8-{4-[2-(5-methoxy-1-benzofuran-3-yl)-1-methylethyl]piperazin-1-yl}quinoline;

39) 6-chloro-8-{4-[2-(5-methoxy-1-benzofuran-3-yl)-1-methylethyl]piperazin-1-yl}quinoline;

40) 6-methyl-8-{4-[2-(5-methoxy-1-benzofuran-3-yl)-1-methylethyl]piperazin-1-yl}quinoline;

41) 8-{4-[4-cis-(1-benzothiophen-3-yl)cyclohexyl]-1-piperazinyl}-6-chloroquinoline;

42) 8-{4-[4-trans(1-benzothiophen-3-yl)cyclohexyl]-1-piperazinyl}-6-chloroquinoline;

43) 8-{4-[4-cis(1-benzothiophen-3-yl)cyclohexyl]-1-piperazinyl}-6-fluoroquinoline;

44) 8-{4-[4-trans(1-benzothiophen-3-yl)cyclohexyl]-1-piperazinyl}-6-fluoroquinoline;

45) 8-{4-[4-cis(1-benzothiophen-3-yl)cyclohexyl]-1-piperazinyl}-6-methoxyquinoline;

46) 8-{4-[4-trans(1-benzothiophen-3-yl)cyclohexyl]-1-piperazinyl}-6-methoxyquinoline;

47) 6-fluoro-8-{4-[4-cis(5-fluoro-1-benzothiophen-3-yl)cyclohexyl]piperazin-1-yl}quinoline;

48) 6-fluoro-8-{4-[4-trans(5-fluoro-1-benzothiophen-3-yl)cyclohexyl]piperazin-1-yl}quinoline;

49) 6-methoxy-8-{4-[4-cis(5-fluoro-1-benzothiophen-3-yl)cyclohexyl]piperazin-1-yl}quinoline;

50) 6-methoxy-8-{4-[4-trans(5-fluoro-1-benzothiophen-3-yl)cyclohexyl]piperazin-1-yl}quinoline;

51) 5-chloro-8-{4-[4-cis(5-fluoro-1-benzothiophen-3-yl)cyclohexyl]piperazin-1-yl}quinoline;

52) 5-chloro-8-{4-[4-trans(5-fluoro-1-benzothiophen-3-yl)cyclohexyl]piperazin-1-yl}quinoline;

53) 8-{4-[4-cis(1-benzofuran-3-yl)cyclohexyl]-1-piperazinyl}-5-fluoroquinoline;

54) 8-{4-[4-trans(1-benzofuran-3-yl)cyclohexyl]-1-piperazinyl}-5-fluoroquinoline;

55) 8-{4-[4-cis(1-benzofuran-3-yl)cyclohexyl]-1-piperazinyl}-6-fluoroquinoline;

56) 8-{4-[4-trans(1-benzofuran-3-yl)cyclohexyl]-1-piperazinyl}-6-fluoroquinoline;

57) 5-fluoro-8-{4-[4-cis(7-methoxy-1-benzofuran-3-yl)cyclohexyl]-1-piperazinyl}quinoline;

58) 5-fluoro-8-{4-[4-trans(7-methoxy-1-benzofuran-3-yl)cyclohexyl]-1-piperazinyl}quinoline;

59) 6-fluoro-8-{4-[4-cis(7-methoxy-1-benzofuran-3-yl)cyclohexyl]-1-piperazinyl}quinoline;

60) 6-fluoro-8-{4-[4-trans(7-methoxy-1-benzofuran-3-yl)cyclohexyl]-1-piperazinyl}quinoline;

61) 8-{4-[4-cis(7-methoxy-1-benzofuran-3-yl)cyclohexyl]-1-piperazinyl}quinoline;

62) 8-{4-[4-trans(7-methoxy-1-benzofuran-3-yl)cyclohexyl]-1-piperazinyl}quinoline;

63) 5-chloro-8-{4-[4-cis(7-methoxy-1-benzofuran-3-yl)cyclohexyl]piperazin-1-yl}quinoline;

64) 5-chloro-8-{4-[4-trans(7-methoxy-1-benzofuran-3-yl)cyclohexyl]piperazin-1-yl}quinoline;

65) 5-chloro-8-{4-[4-cis(5-methoxy-1-benzofuran-3-yl)cyclohexyl]piperazin-1-yl}quinoline;

66) 5-chloro-8-{4-[4-trans(5-methoxy-1-benzofuran-3-yl)cyclohexyl]piperazin-1-yl}quinoline;

67) 6-fluoro-8-{4-[4-cis(5-methoxy-1-benzofuran-3-yl)cyclohexyl]piperazin-1-yl}quinoline;

68) 6-fluoro-8-{4-[4-trans(5-methoxy-1-benzofuran-3-yl)cyclohexyl]piperazin-1-yl}quinoline;

69) 8-[4-(4-benzofuran-2-yl-cyclohexyl)piperazin-1-yl]-6-fluoro-quinoline;

70) cis-8-[4-(4-thiophen-2-yl-cyclohexyl)-piperazin-1-yl]-6-methoxy-quinoline;

71) Trans-8-[4-(4-thiophen-2-yl-cyclohexyl)-piperazin-1-yl]-6-methoxy-quinoline;

72) 8-[4-(4-benzofuran-2-yl-cyclohexyl)-piperazin-1-yl]-6-fluoro-quinoline;

73) cis-8-[4-(4-thiophen-2-yl-cyclohexyl)-piperazin-1-yl]-6-methoxy-quinoline; or

74) trans-8-[4-(4-thiophen-2-yl-cyclohexyl)-piperazin-1-yl]-6-methoxy-quinoline.

The present invention provides methods for preparing compounds of general formula I. These compounds can be prepared as shown in Scheme 1 below at 100-150°C in a solvent such as DMF, THF or DMSO, acetone or ethanol in an acid binder such as an organic tertiary base such as triethylamine, triethanolamine, DBU or diisopropylethylamine, an alkali metal carbonate such as potassium carbonate or sodium carbonate, by condensing an appropriately substituted 8-piperazinoquinoline derivative. 13 with an appropriately substituted heterocycle. 14 reaction. See also J. March, Advanced Organic Chemistry, Mechanisms and Structure, John Wiley and Sons, 4th ed., 1992.

Process 1

Y=halogen, methanesulfonyloxy or toluenesulfonyloxy: a=DMSO/diisopropylethylamine/120°C

Alternatively, when the linker linking 8-piperazinoquinoline and benzo[1]furan or benzo[1]thiophene is part of the formula:

Where Z is N or CH; t is an integer of 1-3; u is an integer of 1-3; then the obtained compound can be prepared according to the following scheme 2, 3 or 4.

Process 2

a.Ph ₃ P=CR ₁₃ COOEt/toluene/reflux; b.Pt/H ₂ ; c.LiAlH ₄ /THF; d.Ph ₃ P/I ₂ /imidazole

e.Ph ₃ P/base; f 35/reflux; g.HCl

Process 3

a.Ph ₃ P=CHCOOEt/toluene/reflux; b.Pt/H ₂ ; c.LiAlH ₄ /THT; d.Ph ₃ P/CBr ₄ ; e.13/diisopropylethylamine/DMSO/120°C

Process 4

a.DMSO/Diisopropylethylamine; b.HCl/Dioxane; c.DMSO/Diisopropylethylamine; d.Ph ₃ P/CBr ₄ ;

e.13/Diisopropylethylamine/DMSO/120℃

Alternatively, when linking piperazinylquinoline and benzo[1]thiophene as:

Where Z=N or CH, t=1-3, u=0, the obtained compound can be prepared as shown in Scheme 5 below.

Process 5

a.DMSO/Diisopropylethylamine; b.HCl/Dioxane

Benzo[1]furans and benzo[1] thiophenes14 can be prepared from commercially available substituted salicylic acid derivatives30 as shown in Scheme 6. Typically, appropriately substituted salicylic acid derivatives or thiosalicylic acid derivatives are esterified with alcoholic hydrochloric acid. Compound 31 was reacted with ethyl _bromoacetate in refluxing acetone/ _K2CO3 . The resulting diester 32 is hydrolyzed to the diacid 33 . The resulting diacid was cyclized to compound 34 with anhydrous _CH3COONa /( _CH3CO ) _2O . It is hydrolyzed with 1N HCl to afford compound 35 . Reaction of this compound with ethyl (triphenylphosphino)acetate or an appropriately substituted ethyl (triphenylphosphino)acetate derivative in boiling organic solvent such as toluene or xylene affords compound 36 . It can be converted to 14 by reduction with LAH and conversion to the tosylate or iodide with _I2 /imidazole.

Process 6

Y=I or tosyloxy

x=O or S

(a) MeOH.HCl/reflux; ₍ b) _BrCH2COOEt / _K2CO3 /acetone/reflux; (c) NaOH/EtOH/THF/reflux; (d) ( _CH3CO ) _2O / _CH3COONa /CH ₃ COOH/reflux; (e) 1N HC1/MeOH/reflux; (f) Ph ₃ P=CHR ₁ COOEt/toluene/reflux; (g) LAH/THF/0°C; (h) p-toluenesulfonyl chloride/ Pyridine or PPh ₃ /I ₂ /imidazole/THF

Alternatively, compound 35 can be reacted with 1-triphenylphosphino-2-propanone as shown in Scheme 7 to afford 38 , which can be reacted with 8-piperazinoquinoline derivative 13 and using triacetyl Sodium oxyborohydride, 39 was obtained. However, when the linker is (R ₈ )cycloalkyl, such compounds can be prepared by the methods shown in Scheme 8 and Scheme 9.

Process 7

a) Ph ₃ P=CHCOCH ₃ /toluene/reflux; b) reductive amination

Process 8

b. (CF ₃ SO ₂ ) ₂ O/LDA; c. Boronic acid pinacol ester/Et ₃ N/PdCl ₂ , dpp ferrocene (Suzuki coupling) 1,2-dimethoxyethane/LiC1/ (Ph ₃ ) ₄ Pd(O)

Process 9

a.Ph ₃ P=CR ₁₃ COOEt/toluene/reflux; b.Pt/H ₂ ; c.LiAlH ₄ /THF; d.Ph ₃ P/CBr ₄ e.DMSO/diisopropylethylamine, 120°C

As used herein, the terms "effective amount", "therapeutically effective amount" and "effective dose" refer to an amount of a compound of formula I which, when administered to a patient, is sufficient to at least partially ameliorate the condition the patient is suspected of suffering from. Such conditions include serotonin-related disorders, including but not limited to anxiety disorders, depression, cognitive deficits such as those caused by Alzheimer's disease and other neurodegenerative diseases, schizophrenia, prostate cancer, and nicotine withdrawal Diseases caused by syndromes.

As used herein, the term "pharmaceutically acceptable salt" refers to salts derived from organic and inorganic acids such as lactic acid, citric acid, acetic acid, cinnamic acid, tartaric acid, succinic acid, maleic acid, malonic acid, mandelic acid , malic acid, oxalic acid, propionic acid, fumaric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, glycolic acid, pyruvic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, salicylic acid, benzoic acid and Similar known acceptable acids. When R ₁ -R ₉ and R ₁₁ contain a carboxyl group, salts of the compounds of the invention can be formed with bases such as alkali metals (eg sodium, potassium and lithium) or alkaline earth metals (eg calcium or magnesium).

The term "patient" as used herein refers to a mammal, preferably a human.

As used herein, the terms "administering" and "administering" refer to either directly administering a compound or composition to a patient, or administering a prodrug derivative or analog of said compound to a patient, which will form an equivalent amount in the patient's body. active compounds or substances.

Compounds of formula I have been found to have an affinity for the 5-HT reuptake transporter. Therefore, they are useful in the treatment and/or prevention of serotonin-related diseases. The present invention therefore provides pharmaceutical compositions comprising a compound of formula I; and optionally one or more pharmaceutically acceptable carriers, excipients or diluents. The term "carrier" as used herein shall include vehicles, excipients and diluents.

Examples of such carriers are well known to those skilled in the art and can be prepared according to accepted pharmaceutical methods such as Remington's Pharmaceutical Sciences, 17th Edition, edited by Alfonso R. Gennaro, Mack Publishing Company, Easton , the method described in Pa (1985), which is hereby incorporated by reference in its entirety. A pharmaceutically acceptable carrier is one that is compatible with the other ingredients of the formulation and is biologically acceptable.

Compounds of formula I can be administered orally or parenterally, alone or in combination with conventional pharmaceutical carriers. Representative solid carriers include one or more substances which may act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, tabletting aids, binders, tablet Disintegrant or encapsulating material. They can be formulated, for example, in a conventional manner analogous to known antihypertensives, diuretics and beta-blockers. Oral formulations containing the active compounds of this invention may comprise any dosage form conventionally used for oral administration, including tablets, capsules, buccal lozenges, troches, lozenges and oral liquids, suspensions or solutions. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active component. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Powders and tablets preferably contain up to 99% active ingredient.

Capsules may contain the active compounds in admixture with inert fillers and/or diluents such as pharmaceutically acceptable starches such as corn starch, potato starch, or tapioca starch, sugar, artificial sweeteners, powdered cellulose such as crystalline Cellulose and microcrystalline cellulose, flour, gelatin, gums, etc.

Useful tablet formulations can be prepared by conventional compression, wet granulation or dry granulation methods using the following pharmaceutically acceptable diluents, binders, lubricants, disintegrants, surface modifiers (including surface active agent), suspending agent or stabilizer: including but not limited to magnesium stearate, stearic acid, sodium lauryl sulfate, microcrystalline cellulose, methyl cellulose, sodium carboxymethyl cellulose, carboxymethyl Calcium cellulose, polyvinylpyrrolidone, gelatin, alginic acid, gum arabic, xanthan gum, sodium citrate, complex silicate, calcium carbonate, glycine, dextrin, sucrose, sorbitol, calcium phosphate, calcium sulfate, Lactose, kaolin, mannitol, sodium chloride, talc, starch, sugar, low melting waxes and ion exchange resins. Preferred surface modifiers include nonionic and anionic surface modifiers. Representative examples of surface modifiers include, but are not limited to, Poloxamer 188, Benzalkonium Chloride, Calcium Stearate, Cetostearyl Alcohol, Cecilitol Emulsifying Wax, Sorbitan Ester, Colloidal Silicon dioxide, phosphate esters, sodium lauryl sulfate, magnesium aluminum silicate and triethanolamine. Oral formulations herein may employ standard delay or time-release formulations to alter the absorption of the active compounds. Oral formulations may also consist of the active ingredient dissolved in water or fruit juice, with suitable solubilizers or emulsifiers, if desired.

Liquid carriers can be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmotic agents. pressure regulator. Suitable examples of liquid carriers for oral and parenteral administration include water (especially containing the above additives, such as cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric and polyhydric alcohols, such as ethyl glycols) and their derivatives and oils (such as fractionated coconut oil and peanut oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions in the form of sterile solutions or suspensions can be administered, for example, by intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Compositions for oral administration may be in liquid or solid form.

In order to achieve stability of administration, it is preferred that the compositions of the present invention are in unit dosage form. Suitable unit dosage forms include tablets, capsules and powders in sachets or vials. The unit dosage form may contain 0.1-100 mg of a compound of the invention, preferably 2-50 mg. More preferred unit dosage forms contain 5-25 mg of a compound of the invention. The compounds of the present invention can be administered orally in a dosage range of about 0.01-100 mg/kg, or preferably 0.1-10 mg/kg. The composition may be administered 1-6 times per day, more usually 1-4 times per day.

When administered for the treatment and/or prophylaxis of a particular disease state or disorder, it is understood that effective amounts may vary depending on the particular compound used, the mode of administration, the condition being treated and its severity, and the amount being treated. Individual related different physical factors. In therapeutic applications, compounds of formula I are administered to an already afflicted patient in an amount sufficient to cure or at least partially ameliorate the symptoms of the afflicted disease and its complications. An amount adequate for this purpose is defined as a "therapeutically effective amount". The dosage used in the treatment and/or prophylaxis of a particular case must be determined subjectively by the attending physician. The variables involved include the specific condition and the patient's weight, age and response pattern. The compounds of the present invention can be effectively administered at an oral dosage of about 0.1 mg/day to about 1,000 mg/day. Preferred administration may 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 planned daily dosage is expected to vary with the route of administration.

The dosage may be administered by any means that delivers the active compounds of this invention to the patient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal, intraarticular and subcutaneous injections), rectal , intranasal, topical, ophthalmic (by eye drops), vaginal and transdermal administration.

In some instances it may be desirable to administer the compound directly to the respiratory tract in the form of an aerosol. For intranasal or intrabronchial inhalation, compounds of formula I may be formulated as aqueous solutions or partially aqueous solutions.

The compounds of the present invention may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as free base or pharmacologically acceptable salts can be formulated in water in admixture with a surfactant such as hydroxy-propylcellulose. Dispersions can also be formulated in glycerol, liquid polyethylene glycols, and mixtures thereof dissolved in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to inhibit the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be liquid to the extent that easy syringes are present. It must be stable under the conditions of manufacture and storage and must be protected against the contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Compounds of formula I may also be administered transdermally through the use of transdermal patches. For this purpose, transdermal administration is understood to include all administration through the surface of the body and the lining of bodily passages, including epithelial and mucosal tissues. The compounds of this invention, or pharmaceutically acceptable salts thereof, may be administered in lotions, creams, foams, patches, suspensions, solutions and suppositories (rectal and vaginal).

Transdermal administration can be accomplished through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, nontoxic to the skin, and allows the administered drug to be absorbed systemically through the skin into the bloodstream middle. The carrier can be in various forms, such as creams and ointments, pastes, gels and inclusion devices. Creams and ointments may be viscous liquid or semisolid emulsions, either in oil-in-water or water-in-oil form. Pastes comprising absorbable powders dispersed in petroleum, or hydrophilic petroleum containing the active ingredient are also suitable. Various inclusion devices may be used to release the active ingredient into the bloodstream, such as a semipermeable membrane covering a depot containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other inclusion devices can be found in the literature.

Compounds of formula I can be administered rectally or vaginally, in the form of conventional suppositories. Suppository formulations may be prepared from conventional 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.

In certain embodiments, the present invention relates to prodrugs of compounds of formula I. The term "prodrug" as used herein refers to a compound which can be converted into a compound of formula I in vivo by metabolic means (eg hydrolysis). Various forms of prodrugs are known in the art, such as those described in: Bundgaard (Ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (Ed.), Methods in Enzymology, pp. 4 volumes, Academic Press (1985); Krogsgaard-Larsen et al. (eds.), "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 these All are incorporated herein by reference in their entirety.

The present invention also provides compounds of the invention for use as active therapeutic substances. Compounds of formula I are especially useful in the treatment and/or prophylaxis of diseases associated with serotonin-related diseases.

The present invention also provides methods of treating and/or preventing serotonin-related disorders in mammals, including humans, including depression, anxiety, cognitive deficits, schizophrenia, prostate cancer, or nicotine withdrawal syndrome symptoms, the method comprising administering to the affected mammal an effective amount of a compound or pharmaceutical composition of the invention.

Example

The preparation method of the intermediate

Embodiment 1: Intermediate 1--8-piperazino quinoline

This intermediate can generally be prepared according to the methods described in WO 00/40554, which is hereby incorporated by reference.

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

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

Example 3: Intermediate 3--6-fluoro-8-(t-Boc)-piperazino-quinoline

To a THF mixture of 2.2 g of 6-fluoro-8-bromo-quinoline 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 t-Boc piperazine. The resulting 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 product was purified by flash chromatography to afford 3.0 g of 6-fluoro-8-(t-Boc)-piperazino-quinoline. MS (ES) m/z (relative intensity): 332 (M ⁺ +H, 100).

Example 4: Intermediate 4--6-fluoro-8-piperazino-quinoline

To a solution of 3.0 g of 6-fluoro-8-(t-Boc)-piperazino-quinoline in 10 ml of dioxane was added 10 ml of 4N HCl/dioxane. The resulting mixture was stirred overnight at room temperature. The formed precipitate was _filtered , dissolved in water, extracted with _CH2Cl2 , dried and the solvent removed to yield 1.9 g of 6-fluoro-8-piperazino-quinoline. MP: 103°C; MS (ES) m/z (relative intensity): 233 (M ⁺ +H, 100).

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

To a mixture of 9 g of 8-chloro-6-methoxy-quinoline in 75 ml of anhydrous THF was added 0.64 g of _Pd2 (dba) ₃ , 6.2 g of NaOt-Bu, 0.274 g of 2-dicyclohexylphosphino-2 '-(N,N-Dimethyl-amino)biphenyl (also known as cymap) and 11.2 g t-Boc piperazine. The resulting mixture was refluxed for 5 hours. Then, the reaction mixture was cooled to room temperature, diluted with ether, and filtered through celite. The filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using 300 ml of silica gel and 100% _CH2Cl2 , then 50% ethyl acetate/ _hexanes to give 16.5 g of 5-fluoro-8-piperazino-quinoline.

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

These intermediates can generally be prepared following the procedure described above for the preparation of 6-fluoro-8-piperazino-quinolines, using the corresponding starting materials instead of anilines.

Example 7: Intermediate 7--5-chloro-8-(trifluoromethylsulfonyloxy)-quinoline

To _a suspension of 5-chloro-8-hydroxy-quinoline (8.95 g) in 100 ml _CH2Cl2 was added 20 ml TEA. The resulting suspension was dissolved and cooled to -15°C. While cooling, a solution of 21.1 g of triflic anhydride in 50 ml _{of CH2Cl2} was added dropwise. After the addition was complete, the reaction was stirred at -15°C for 30 minutes. The reaction was diluted with CH ₂ Cl ₂ , washed with NaHCO ₃ solution, then water, dried and the solvent removed to give 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 C10H5ClF3NO3} ; 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

To a mixture of 4.0 g 5-chloro-8-trifluoromethyl-quinoline in 30 ml THF was added 5.9 g cesium carbonate, 0.360 g BINAP, 0.120 g palladium acetate and 2.8 g t-Boc piperazine. The resulting mixture was refluxed for 5 hours. Then, the reaction mixture was cooled to room temperature, diluted with ether, filtered through celite and concentrated in vacuo. The crude product was 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 _C18N22ClN3O2 ; 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-chloro-8-piperazino-quinoline

To a solution of 2.2 g of 5-chloro-8-(t-Boc)-piperazino-quinoline in 10 ml of dioxane was added 5 ml of 4N HCl/dioxane. The resulting mixture was stirred overnight at room temperature. The resulting precipitate was filtered, dissolved in water, extracted with _CH2Cl2 , dried and _the solvent removed to give 1.0 g of the desired product. MS (ES) m/z (relative intensity): 248 (M ⁺ +H, 100). Elemental _analysis for _C13H14ClF3N3 ; 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-hydroxyl-quinoline

In a 500ml three-necked flask equipped with a mechanical stirrer and a reflux condenser, 2.0g of ferrous sulfate, 6.4g of 4-amino, 3-chloro-phenol (produced by 9.0g of the corresponding commercially available HCl salt), 2.9g of ferrous sulfate were added successively. m-Nitrobenzene and 3.0 g boric acid in 16 g glycerol cooling solution. Then, 9 ml of concentrated sulfuric acid was added dropwise while cooling. The ice bath was removed and replaced with an oil bath, and the resulting mixture was carefully heated to 120°C for 2 hours, then heated at 150°C and stirring continued at this temperature for 20 hours. Then, the resulting mixture was cooled and poured into crushed ice _, and the resulting solution was neutralized with _K2CO3 (sat. aq.) until just pH5. The product was filtered off as a light brown solid, washed with water and hexanes, and dried overnight in a vacuum oven (35°C). The resulting product was purified by dissolving in a minimum amount of THF and pouring the solution into 20 volumes of hexane to yield 7 g (77%) of the desired product.

Example 11: Intermediate 11--8-chloro-6-methoxy-quinoline

To a solution of 15 _g of 8-chloro-6-hydroxy-quinoline (50 ml) in DMF was added 23 g of _K2CO3 followed by 18 g of iodomethane. The resulting mixture was stirred overnight at room temperature. Water was added and the resulting product was extracted with _CH2Cl2 , dried and _the solvent removed. The crude product was filtered through 250ml of silica gel using 50% ethyl acetate/hexanes to give 11g of the desired product.

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

To a mixture of 9 g of 8-chloro-6-methoxy-quinoline in 75 ml of dry THF was added 0.64 g of Pd ₂ (dba) ₃ , 6.2 g of NaOt-Bu, 0.274 g of 2-dicyclohexylphosphino-2′- (N,N-Dimethyl-amino)biphenyl (also known as cymap) and 11.2 g t-Boc piperazine. The resulting mixture was refluxed for 5 hours. Then, the reaction mixture was cooled to room temperature, diluted with ether, and filtered through celite. The filtrate was concentrated in vacuo. The crude product was purified by flash chromatography using 300 mL of silica gel and 100% _CH2Cl2 followed by 50% ethyl acetate/hexanes to give 16.5 g of _the desired product.

Example 13: Intermediate 13--6-methoxy-8-piperazino-quinoline

To a solution of 16.0 g of 6-methoxy-8-(t-Boc)-piperazino-quinoline in 100 ml of dioxane was added 30 ml of 4N HCl/dioxane. The resulting mixture was stirred overnight at room temperature. The resulting precipitate was filtered, dissolved in water and extracted with _CH2Cl2 , dried and _the solvent removed to give 10.5 g of the desired product.

Example 14: Intermediate 14--5-fluoro-benzo[b]thiophen-3-yl trifluoro-methanesulfonate

To a cooled solution (-20°C) of 5-fluoro-benzophenone (15 g) in _CH2Cl2 (100 ml) was added TEA (27 _g ). To the resulting cooled mixture, a solution of trifluoromethanesulfonic anhydride (37.7 g) in _CH2Cl2 ( ₂₅ ml) was added dropwise. The temperature was allowed to rise to 0°C and held at this temperature for 1 hour. It was then quenched with NaHCO ₃ solution, the product was extracted with CH ₂ Cl ₂ , dried over MgSO ₄ and the solvent was removed to give 23.0 g of the desired product.

Example 15: Intermediate 15--7-Methoxytrifluoro-methanesulfonic acid 5-fluoro-benzo[b]thiophen-3-yl ester

To a cooled solution (-20°C) of 7-MeO-benzofuranone (3.3g) in _CH2Cl2 ( _30ml ) was added TEA (8.3ml). To the resulting cooled _mixture , a solution of trifluoromethanesulfonic anhydride (8.5 g) in _CH2Cl2 (20 ml) was added dropwise. The temperature was maintained at this temperature for 1 hour. Then, quenched with NaHCO ₃ solution, the product was extracted with CH ₂ Cl ₂ , dried over MgSO ₄ , and the solvent was removed to give 5.6 g of the desired product.

Example 16: Intermediate 16—2-(Benzo[b]thiophen-3-yl)-4,4,5,5-tetramethyl-[1,2]oxaborolane

To a solution of 3-bromobenzothiophene (10 g) in dioxane (30 ml) was added pinacol borate (1M, 9.0 g) in THF (70 ml) followed by TEA (10.7 g) and _PdCl2 , dpp ferrocene. The reaction was heated at 60°C overnight. Solvent was removed in vacuo. Diethyl ether was added and the insolubles were filtered. The filtrate was evaporated and filtered through silica gel (300ml) using 5% ethyl acetate/hexanes to give 9.0g of the desired product.

Example 17: Intermediate 17--2-(5-fluoro-benzo[b]thiophen-3-yl)-4,4,5,5-tetramethyl-[1,2]oxaborine Pentane

To a solution of 5-fluoro-3-trifluoromethyl-benzothiophene (10 g) in dioxane (50 ml) was added a solution of boric acid pinacol ester (1 M, 7.2 g) in THF (56 ml) followed by TEA (15ml) and _PdCl2 , dpp ferrocene (.913g). The reaction was heated at 60°C overnight. Solvent was removed in vacuo. Diethyl ether was added and the insolubles were filtered. The filtrate was evaporated and filtered through silica gel (200ml) with 5% ethyl acetate/hexanes to give 3.5g of the desired product. MP: 80-83°C; MS (ES) m/z (relative intensity): 312 (M ⁺ +H, 100). Elemental _{analysis for C14H16BFO2S} ; Calculated: C: 60.45; H: 5.8; Found: C: 60.48; H: 5.68.

Example 18: Intermediate 18--2-(Benzo[b]furan-3-yl)-4,4,5,5-tetramethyl-[1,2]oxaborolane

To a mixture of 3-bromo-benzofuran (500 g) in TEA (1 ml) was added a THF solution (1 M) of pinacol borate ester (.476 g/3.75 ml) followed by PdCl ₂ , dpp dichloromethane iron. The reaction was heated at 150°C for 3 minutes in a microwave oven. Solvent was removed in vacuo. The residue was dissolved in water and extracted with ether, dried over magnesium sulfate and the solvent was removed. The residue was filtered through 50ml of silica gel using 10% ethyl acetate/hexanes to give .350g of the desired product.

Example 19: Intermediate 19--2-(7-methoxybenzo[b]furan-3-yl-4,4,5,5-tetramethyl-[1,2]oxaborine Pentane

To a mixture of 7-methoxy-3-trifluoromethylsulfonyl-benzofuran (.660g) in TEA (1ml) was added a solution of boric acid pinacol ester in THF (.476g/3.75Ml) (1M ), followed by the addition of PdCl ₂ , dpp ferrocene. The reaction was heated at 150°C for 3 minutes in a microwave oven. Solvent was removed in vacuo. The residue was dissolved in water and extracted with ether, dried over magnesium sulfate and the solvent was removed. The residue was filtered through 50ml of silica gel using 10% ethyl acetate/hexanes to give .350g of the desired product.

Example 20: Intermediate 20 - 1,4-dioxa-spiro[4,5]dec-7-en-8-yl trifluoro-methanesulfonate

To a cooled solution of LDA (2.35 g) in THF (20 ml) was added dropwise a solution of 1,4-cyclohexanedione monoethylene glycol (3.0 g) in THF (20 ml) under cooling at -78°C. After 90 minutes at -78°C, a solution of N-phenylbis(trifluoromethanesulfonyl)imide (7.8g) in THF (20ml) was added dropwise and the reaction was allowed to warm to room temperature. The THF was removed in vacuo and the residue was filtered through silica gel (500ml) using 2% ethyl acetate/hexanes to give 2.0g of the desired product.

Example 21: Intermediate 21--8-Benzo[b]thiophen-3-yl-1,4-dioxa-spiro[4,5]dec-7-ene

To 2-(benzo[b]thiophen-3-yl)-4,4,5,5-tetramethyl-[1,2]oxaborolane (2.6g) and trifluoro-methanesulfonate To a mixture of acid 1,4-dioxa-spiro[4.5]dec-7-en-8-yl ester (2.9 g) in 1,2-dimethoxyethane (DME, 10 ml) was added Na ₂ CO ₃ (2.8 g in 10 ml _H2O ), followed by an aqueous solution of LiCl (.421 g) and tetrakis(triphenylphosphine)palladium(0) (.100 g). The reaction was heated at 70°C overnight. The reaction was then cooled to room temperature and the solvent was removed in vacuo. The residue was extracted with _CH2Cl2 and washed with 2N _{aqueous Na2CO3 .} The organic phase was separated and dried over _MgSO4 . The solvent was then removed and the residue was filtered through 200 ml of silica gel with 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 C16H16O2S} ; 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)-1,4-dioxa-spiro[4,5]dec-7-ene

To 2-(5-fluoro-benzo[b]thiophen-3-yl)-4,4,5,5-tetramethyl-[1,2]oxaborolane (1.6g) and tri In a mixture of 1,4-dioxa-spiro[4.5]dec-7-en-8-yl fluoro-methanesulfonate (2.0 g) in 1,2-dimethoxyethane (DME, 10 ml) , Na ₂ CO ₃ (1.2 g in 6 ml H ₂ O) 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. Then, the reaction was cooled to room temperature and the solvent was removed in vacuo. The residue was extracted with ether and filtered through celite. The organic phase was separated and dried over _MgSO4 . The solvent was removed and the residue was filtered through 150 mL of silica gel with 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-yl-1,4-dioxa-spiro[4,5]dec-7-ene

To 2-(benzo[b]furan-3-yl)-4,4,5,5-tetramethyl-[1,2]oxaborolane (2.44g) and trifluoro-methanesulfonate To a mixture of 1,4-dioxa-spiro[4,5]dec-7-en-8-yl ester (2.9 g) in DME (20 ml), Na ₂ CO ₃ (2.9 g in 10 ml H ₂ O solution), followed by an aqueous solution of LiCl (1.26 g) and tetrakis(triphenylphosphine)palladium(0) (.600 g). The reaction was heated at 80°C for 1 hour. It was then cooled to room temperature and the solvent was removed in vacuo. The residue was extracted with ether and filtered through celite. The organic phase was separated, washed with _{Na2CO3 solution} , then with 10% _NH4OH solution and dried over _MgSO4 . The solvent was removed and the residue was filtered through 200ml of silica gel using 10% ethyl acetate/hexanes to give .800g of the title compound. MS (ES) m/z (relative intensity): 257 (M ⁺ +H, 100).

Example 24: Intermediate 24--8-(7-methoxy-benzofuran-3-yl)-1,4-dioxa-spiro[4,5]dec-7-ene

8-(7-Methoxy-benzofuran-3-yl)-1,4-dioxa-spiro [4,5]dec-7-ene. MS (ES) m/z (relative intensity): 287 (M ⁺ +H, 100).

Example 25: Intermediate 25--8-Benzo[b]thiophen-3-yl-1,4-dioxa-spiro[4,5]decane

8-Benzo[b]thiophen-3-yl-1,4-dioxa-spiro[4,5]dec-7-ene (2.0 g) and 10% palladium on carbon (.700 g) in ethanol/ The mixture in THF (25ml/35ml) was hydrogenated for 90 minutes. The catalyst was filtered off and the solvent removed in vacuo to give 1.8 g of the desired product. MP: 80-83°C; MS (ES) m/z (relative intensity): 275 (M ⁺ +H, 100). Elemental analysis for _C16H18O2 ; 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-1,4-dioxa-spiro[4,5]decane

8-(5-Fluoro-benzo[b]thiophen-3-yl)-1,4-dioxa-spiro[4,5]dec-7-ene (1.1 g) and 10% palladium on carbon ( .400 g) of the mixture in ethanol/THF (25ml/35ml) was hydrogenated for 6 hours. The catalyst was filtered off and the solvent was removed in vacuo 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-1,4-dioxa-spiro[4,5]decane

8-Benzofuran-3-yl-1,4-dioxa-spiro[4.5]dec-7-ene (.420g) and 10% palladium on carbon (.100g) in ethanol/THF (20ml/10ml ) was hydrogenated for 3 hours. The catalyst was filtered off and the solvent was removed in vacuo. The product was filtered through 50ml of silica gel using 25% ethyl acetate to give .350g of the desired product. MS (ES) m/z (relative intensity): 259 (M ⁺ +H, 100).

Example 28: Intermediate 28--7-methoxy-benzofuran-3-yl-1,4-dioxa-spiro[4,5]decane

A mixture of 8-(7-methoxy-benzofuran-3-yl-1,4-dioxa-spiro[4,5]dec-7-ene and 10% palladium on carbon in ethanol/THF Hydrogenation for 3 hours. The catalyst was filtered off and the solvent was removed in vacuo. The product was filtered through 50 ml of silica gel using 25% ethyl acetate/hexanes to give the desired product. MS (ES) m/z (relative intensity): 289 (M ⁺⁺ H, 100).

Example 29: Intermediate 29--4-(3H-inden-1-yl)-cyclohexanone

8-Benzo[b]thiophen-3-yl-1,4-dioxa-spiro[4,5]decane (1.8 g) (50 ml) was mixed 1:1 with tetrahydrofuran-hydrochloric acid ( 2N) solution was stirred for 5 hours. The THF was removed in vacuo and the product was extracted with _CH2Cl2 , dried and _the 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 _C14H14OS ; _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-1-yl)-cyclohexanone

A solution of 8-benzo[b]thiophen-3-yl-1,4-dioxa-spiro[4,5]decane (1.0 g) in (20 ml) tetrahydrofuran-hydrochloric acid (2N) was stirred at room temperature 3 hours. The THF was removed in vacuo 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 (M ⁺ +H, 100).

Example 31: Intermediate 31--4-(benzofuran-3-yl)-cyclohexanone

A solution of 8-benzofuran-3-yl-1,4-dioxa-spiro[4,5]decane (.350 g) in (20 mL) 1:1 tetrahydrofuran-hydrochloric acid (2N) was stirred at room temperature 6 hours. The THF was removed in vacuo and the product was extracted with dichloromethane, dried and the 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-yl)-cyclohexanone

7-Methoxy-benzofuran-3-yl-1,4-dioxa-spiro[4,5]decane (3.0 g) (45 ml) 1:1 tetrahydrofuran-hydrochloric acid ( 2N) solution was stirred for 3 hours. The THF was removed in vacuo and the product was extracted with ethyl acetate, dried and the 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-1,4-dioxa-spiro[4,5]decanol

To a cooled solution of 2.5M BuLi (2.35g) in hexane was added 60ml THF and cooled to -78°C, followed by dropwise addition of a solution of benzofuran (5.0g) in THF (30ml). After 30 minutes at -78°C, a solution of 1,4-cyclohexanedione monoethylene glycol (7.27 g) in THF (30 ml) was added dropwise while cooling, and the temperature of the reaction was allowed to rise to room temperature. The reaction mixture was poured into cooled aqueous _NH4Cl solution. The THF was removed in vacuo and the product _was extracted with _CH2Cl2 and dried over magnesium sulfate to give 7.0 g of the desired product.

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

To a solution of benzofuran-2-yl-1,4-dioxa-spiro[4.5]dec-8-ol (2.0 g) in CH ₂ Cl ₂ (20 ml) was added TFA (4 ml), and the reactant Stir overnight at room temperature. Water was added and _the product was extracted with _CH2Cl2 . The organic phase was washed with sodium bicarbonate, dried over magnesium sulfate and the solvent was removed to give 1.20 g of the desired product. MS (ES) m/z (relative intensity): 213 (M ⁺ +H, 100).

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

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 in vacuo. The product was filtered through 50 ml of silica gel using 25% ethyl acetate/hexanes to give 1.1 g of the desired product. MS (ES) m/z (relative intensity): 215 (M ⁺ +H, 100).

Example 36: Intermediate 36--8-Benzo[b]thiophen-2-yl-1,4-dioxa-spiro[4,5]dec-8-ol

A solution of benzo[b]thiophene (10 g, 75 mmol) in distilled dry THF (100 ml) was cooled to -78°C and then n-BuLi (36 ml, 2.5M in hexane) was added. After the reaction was stirred for 15 minutes, a solution of 1,4-cyclohexanedione monoethylene glycol (11.12 g, 71 mmol) in THF (20 mL) was added. The reaction mixture was stirred at -78°C for 10 minutes and slowly warmed to room temperature. The reaction was quenched slowly with water (200ml) and extracted into EtOAc (2 x 200ml). The organic phases _were combined, dried over _Na2SO4 , and concentrated to a clear oil. The product was precipitated from 40% ethyl acetate/hexanes and washed with hexanes to afford 12.87 g (66%, white solid) of the title compound. The mother liquor was concentrated and purified by column chromatography (40% EtOAc/hexanes) to give an additional 4.91 g (25%, white solid) of product: MP: >145C. Elemental _analysis for _C16H18O3S ; 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

A solution of 8-benzo[b]thiophen-2-yl-1,4-dioxa-spiro[4,5]dec-8-ol (12g, 44mmol) was dissolved in THF (150ml) and 1N HCl was added aqueous solution (150ml), and the resulting mixture was stirred at room temperature overnight. THF was removed in vacuo, the aqueous residue was basified with 1M aqueous NaOH (150ml) and extracted into ethyl acetate (3 x 150ml). The combined organic phases were dried over _Na2SO4 and concentrated _in vacuo to afford 9.8 g (90%, pale yellow solid) of the title compound: MP: >120°C. Elemental analysis for _C14H14O2S ; 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

A mixture of 4-benzo[b]thiophen-2-yl-cyclohex-3-enone (0.95 g, 4.2 mmol) and 0.5 g of 10% Pd/C in ethanol (100 ml) was hydrogenated at 40 psi overnight. The catalyst was removed by filtration through celite, then washed with ethyl acetate (100ml) and dichloromethane (100ml). The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (30% ethyl acetate/hexanes) to give 0.75 g of a yellow oil which crystallized on standing. NMR indicated that the product was 2-(4,4-diethoxycyclohexyl)-benzo[b]thiophene. A solution of the ketal in 25 ml THF and 25 ml 1N HCl was stirred at room temperature over the weekend. THF was removed in vacuo, the aqueous residue was basified with 1M NaOH (50ml) and extracted with ethyl acetate (2 x 100ml). The combined organic layers were dried over _Na2SO4 , filtered and concentrated _in vacuo to afford 0.53 g (55%, beige solid) of the title compound. MS (ES) m/z (relative intensity): 231 (M ⁺ +H, 100).

The preparation method of the compound of the present invention

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

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) was added ethyl bromoacetate (16.7 g, 0.1 mol). The reaction mixture was refluxed for 24 hours and cooled to room temperature. Then filtered and concentrated. The oily residue was extracted with chloroform and washed thoroughly with water. The organic layer was dried over anhydrous MgSO ₄ and filtered. It was concentrated and used in the next step without any purification. White oil; Yield: 22.0 g (92%); (M+H): 239.

Step 2: Dissolve methyl 2-(ethoxy-2-oxoethoxy)benzoate (11.9 g, 50 mmol) from Step 1 in THF:MeOH (1:1) (300 ml) and add 5N NaOH (100ml). The reaction mixture was refluxed for 24 hours and cooled to room temperature. Then, concentrate to dryness and dissolve in water. The aqueous layer was acidified with conc. HCl and the solid separated was filtered. The product was washed thoroughly with water and dried. The product was used in the next step without any purification. White solid; Yield: 9.0 g 91%; MP: 125-128°C: 197 (M+H).

Step 3: 2-(Carboxymethoxy)-benzoic acid compound (9.8 g, 50 mmol) from Step 2 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 hours. During this time, the reaction mixture turned dark red. The reaction mixture was cooled to room temperature and carefully quenched with ice-cold water. The resulting red solid was filtered and washed thoroughly with water. The red solid was then suspended in 1N HCl and refluxed for 2 hours. A dark red solid, benzofuran-3(2H)-one, precipitated from the reaction mixture. Filter and wash thoroughly with water. It was dried at 40°C and used in the next step without further purification. Yield: 3.5 g (51%); (M+H): 135.

Step 4: A mixture of benzofuran-3(2H)-one (1.34g, 10mmol) and (carboxymethylene)triphenylphosphorane (5.22g, 15mmol) was refluxed in toluene (100ml) for 48 hours. Then, the reaction mixture was concentrated and applied to a silica gel column. The cartridge was eluted with hexane (500ml) followed by 25% ethyl acetate. The product, ethyl (-1-benzofuran-3-yl)acetate, was obtained as a white oil. Yield: 2.0 g (98%); (M+H): 205.

Step 5: To a stirred suspension of LiAlH ₄ (200 mg, excess) in THF at 0° C. was slowly added a solution of ethyl (1-benzofuran-3-yl)acetate (1.02 g, 5 mmol) in THF (20 ml) . After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour, then quenched with saturated _NH4Cl solution. The product was extracted with chloroform and washed thoroughly with water. Dry over anhydrous _MgSO4 , filter and concentrate. The product, 2-(1-benzofuran-3-yl)ethanol, was obtained as a white oil pure enough to be used in the next step without further purification. Yield: 800 mg (98%); (M+H): 163.

Step 6: To a stirred solution of 2-(1-benzofuran-3-yl)ethanol (815mg, 5mmol) in anhydrous pyridine (20ml) was added p-toluenesulfonyl chloride (1.14g, 6.0mmol). The reaction mixture was kept at 0°C for 48 hours and quenched with ice-cold water. The reaction mixture was extracted with chloroform, washed thoroughly with water, and dried over anhydrous MgSO ₄ . Then filtered and concentrated. The resulting crude product was used in the next step without any purification. In the presence of N,N-diisopropylethylamine (5ml, excess), tosylate (316mg.1mmol) (from the above method) and 6-fluoro-8-piperazinoquinoline (231mg , 1 mmol) was heated at 120°C in DMSO for 24 hours. Then, the reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water, dried over anhydrous MgSO ₄ and concentrated to dryness. The dark solid was purified by column chromatography on silica gel, eluting initially with 70% ethyl acetate: hexanes and then 55% methanol: ethyl acetate. The product 8-{4-[2-(1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-fluoroquinoline was isolated as a yellow oil. Yield: 220 mg (58%); (M+H): 376. ¹ H NMR (400MHz, CDCl ₃ ): δ8.82～8.80 (dd, J ₁ =1.7Hz, J ₂ =1.7Hz, 1H), 8.08～8.03 (dd, J ₁ =1.8Hz, J ₂ =1.8Hz , 1H), 7.69 ~ 6.32 (m, 8H), 3.50 ~ 2.63 (m, 12H).

Example 40: Preparation of 8-{4-[2-(1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-chloroquinoline (“Compound 2”)

8-{4-[2 -(1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-chloroquinoline. The product was purified by column chromatography on silica gel, eluting initially with 70% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a brown oil. Yield: 80mg (20%); (M+H): 392; ¹ H NMR (400MHz, CDCl ₃ ): δ8.86～8.82 (dd, J ₁ =1.7Hz, J ₂ =1.7Hz, 1H); 8.02-8.00 (dd, J ₁ =1.8, J ₂ =1.8 Hz, 1H); 7.78-6.86); (m, 8H); 3.51-2.58 (m, 12H).

Example 41: Preparation of 8-{4-[2-(1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methylquinoline (“Compound 3”)

8-{4-[ 2-(1-Benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methylquinoline. The product was purified by column chromatography on silica gel, eluting initially with 70% ethyl acetate:hexanes and then 5% methanol:ethyl acetate. Brown oil; yield: 120mg, 32%; (M+H): 372; ¹ H NMR (400MHz, CDCl ₃ ): δ8.86～8.80 (dd, J ₁ =1.7Hz, J ₂ =1.7Hz, 1H); 8.02-8.00 (dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H); 7.78-6.98 (m, 8H); 3.50-2.56 (m, 12H); 2.50 (s, 3H).

Example 42: Preparation of 8-{4-[2-(1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methoxyquinoline (“Compound 4”)

Generally following the procedure outlined in Example 1, Step 6, from tosylate (316 mg, 1 mmol) and 6-methoxy-8-piperazinoquinoline (243 mg, 1 mmol) (213 mg, 1 mmol), 8 -{4-[2-(1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methoxyquinoline. The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a brown liquid. Yield: 180 mg (46%); (M+H): 388; ¹ H NMR δ8.72 (d, 1H), 8.05 (q, 1H), 7.68 (m, 1H), 7.59-7.25 (m, 5H ), 6.81 (d, 1H), 6.71 (d, 1H), 3.91 (s, 3H), 3.49 (bs, 4H), 3.07-2.85 (m, 8H).

Example 43: Preparation of 8-{4-[2-(6-chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline (“Compound 5”)

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), was added ethyl bromoacetate (16.7 g, 0.1mol). The reaction mixture was refluxed for 24 hours and cooled to room temperature. Then filtered and concentrated. The oily residue was extracted with chloroform and washed thoroughly with water. The organic layer was dried over anhydrous MgSO ₄ and filtered. It was concentrated and used in the next step without any purification. White oil; Yield: 27.0 g (99%); (M+H): 273.

Step 2: 2-(Ethoxy-2-oxoethoxy)-4-chloro-benzoic acid from Step 1

The methyl ester (13.6 g, 50 mmol) was dissolved in THF:MeOH (1:1) (300 ml), to which 5N NaOH (100 ml) was added. The reaction mixture was refluxed for 24 hours and cooled to room temperature. Then, it was concentrated to dryness and dissolved in water. The aqueous layer was acidified with conc. HCl and the solid separated was filtered. Wash it thoroughly with water and dry it. The product was used in the next step without any purification. White solid; Yield: 10.0 g (86%); (M+H): 231.

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

Step 4: A mixture of 6-chloro-benzofuran-3(2H)-one (1.68g, 10mmol) and (carboxymethylene)triphenylphosphorane (5.22g, 15mmol) in toluene (100ml) Reflux for 48 hours. The reaction mixture was then concentrated and applied to a silica gel column. The cartridge was eluted with hexane (500ml) followed by 25% ethyl acetate. The product ethyl (6-chloro-1-benzofuran-3-yl)acetate was obtained as a white oil. Yield: 2.1 g (87%); (M+H): 239.

Step 5: To a stirred suspension of _LiAlH4 (200 mg, excess) in THF at 0 °C was slowly added ethyl (6-chloro-1-benzofuran-3-yl)acetate (1.19 g, 50 mmol) in THF (20ml) solution. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour and quenched with saturated _NH4Cl solution. The product was extracted with chloroform and washed thoroughly with water. Dry over anhydrous _MgSO4 , filter and concentrate. The product 2-(6-chloro-1-benzofuran-3-yl)ethanol was obtained as a white oil pure enough to be used in the next step without purification. Yield: 900 mg (91%); (M+H): 197.

Step 6: To a stirred solution of 2-(6-chloro-1-benzofuran-3-yl)ethanol (980mg, 5mmol) in anhydrous pyridine (20ml) was added p-toluenesulfonyl chloride (1.14g, 6.0mmol ). The reaction mixture was kept at 0°C for 48 hours and quenched with ice-cold water. The reaction mixture was extracted with chloroform, washed thoroughly with water, and dried over anhydrous MgSO ₄ . It was filtered and concentrated. The resulting crude product was used in the next step without any purification. Tosylate (350 mg.1 mmol) (obtained from the above step) and 8-piperazino-quinoline (213 mg, 1 mmol) were mixed in the presence of N,N-diisopropylethylamine (5 ml, excess). The mixture was heated in DMSO at 120 °C for 24 h. Then, the reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water, dried over anhydrous MgSO ₄ and concentrated to dryness. The resulting dark solid was purified by column chromatography on silica gel, eluting initially with 70% ethyl acetate:hexanes and then 5% methanol:ethyl acetate. 8-{4-[2-(6-Chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline was isolated as a yellow oil. Yield: 120mg (30%); (M+H): 392; ¹ H NMR (400MHz, CDCl ₃ ): δ8.82～8.81 (dd, J ₁ =1.7Hz, J ₂ =1.7Hz, 1H); 8.40-8.20 (dd, J ₁ =1.8 Hz, J ₂ =1.8 Hz, 1H); 7.46-6.92 (m, 8H); 3.50-2.70 (m, 12H).

Example 44: 8-{4-[2-(6-Chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-fluoro-quinoline ("Compound 6") preparation method

8-{4-[2 -(6-Chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-fluoro-quinoline. The product was purified by column chromatography on silica gel, eluting with 80% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a brown oil. Yield: 90mg, (22%); (M+H): 410; ¹ H NMR (400MHz, CDCl ₃ ): δ8.82～8.81 (dd, J ₁ =1.7Hz, J ₂ =1.7Hz, 1H) ; 8.05-8.03 (dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H); 7.64-6.43 (m, 7H); 3.51-2.80 (m, 12H).

Example 45: 8-{4-[2-(6-Chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-chloro-quinoline ("Compound 7") preparation method

8-{4-[2 -(6-Chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-chloro-quinoline. The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a brown oil. Yield: 110mg, (25%); (M+H): 427; ¹ H NMR (400MHz, CDCl ₃ ): δ8.80～8.81 (dd, J ₁ =1.7Hz, J ₂ =1.7Hz, 1H) ; 8.22-8.23 (dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H); 7.87-6.99 (m, 7H); 3.50-2.58 (m, 12H).

Example 46: 8-{4-[2-(6-Chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methyl-quinoline (“Compound 8” ) preparation method

8-{4-[ 2-(6-Chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methyl-quinoline. The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a brown oil. Yield: 89mg, (21%); (M+H): 406; ¹ H NMR (400MHz, CDCl ₃ ): δ8.74～8.72 (dd, J ₁ =1.7Hz, J ₂ =1.7Hz, 1H) ; 8.13-7.94 (dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H); 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-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline ("Compound 9") method

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) was added ethyl bromoacetate Ester (16.7 g, 0.1 mol). The reaction mixture was refluxed for 24 hours and cooled to room temperature. It was filtered and concentrated. The resulting oily residue was extracted with chloroform and washed thoroughly with water. The organic layer was dried over anhydrous MgSO ₄ and filtered. It was concentrated and used in the next step without any purification. White oil; Yield: 24.0 g (89%); (M+H): 269.

Step 2: 2-(Ethoxy-2-oxoethoxy)-4-methoxy-benzoic acid methyl ester (13.4 g, 50 mmol) from Step 1 was dissolved in THF:MeOH (1:1 ) (300ml), to which was added 5N NaOH (100ml). The reaction mixture was refluxed for 24 hours and cooled to room temperature. Then, it was concentrated to dryness and dissolved in water. The aqueous layer was acidified with conc. HCl, then the solid separated was filtered. The product was washed thoroughly with water and dried. The product was used in the next step without any purification. White solid; Yield: 8.5 g (75%); (M+H): 227.

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

Step 4: A mixture of 6-methoxy-benzofuran-3(2H)-one (1.64g, 10mmol) and (carboxymethylene)triphenylphosphorane (5.22g, 15mmol) in toluene (100ml ) in reflux for 48 hours. Then, the reaction mixture was concentrated and applied to a silica gel column. The cartridge was eluted with hexane (500ml) followed by 25% ethyl acetate. The product ethyl (6-methoxy-1-benzofuran-3-yl)acetate was obtained as a white oil. Yield: 1.8 g (76%); (M+H): 235.

Step 5: To a stirred suspension of _LiAlH4 (200mg, excess) in THF at 0°C was slowly added ethyl (6-methoxy-1-benzofuran-3-yl)acetate (1.17g, 5mmol) THF (20ml) solution. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour and quenched with saturated _NH4Cl solution. The product was extracted with chloroform and washed thoroughly with water. Dry over anhydrous _MgSO4 , filter and concentrate. The product 2-(6-methoxy-1-benzofuran-3-yl)ethanol was obtained as a white oil pure enough to be used in the next step without purification. Yield: 850 mg (88%); (M+H): 193.

Step 6: To a stirred solution of 2-(6-methoxy-1-benzofuran-3-yl)ethanol (960 mg, 5 mmol) in anhydrous THF (50 ml) at room temperature was added triphenylphosphine ( 1.572g, 6mmol), iodine (1.518g, 6mmol) and imidazole (408mg, 6mmol). The reaction mixture was stirred at room temperature for 4 hours and quenched with water. Then, the product _was extracted with chloroform, washed thoroughly with 5% _{Na2S2O3 solution} , and the organic layer was dried over anhydrous _MgSO4 . Then filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with 30% ethyl acetate: hexanes. The product 2-(6-methoxy-1-benzofuran-3-yl)ethyl iodide was obtained as a brown liquid. Yield: 1.2 g (80%); (M+H): 302.

2-(6-Methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) (obtained from Step above) and 8-piperazinoquinoline (213 mg, 1 mmol) were heated in DMSO at 120°C for 24 hours. Then, the reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water, dried over anhydrous MgSO ₄ and concentrated to dryness. The resulting dark solid was purified by column chromatography on silica gel, eluting initially with 70% ethyl acetate: hexanes and then 5% methanol: ethyl acetate. 8-{4-[2-(6-Methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline was isolated as a yellow oil. Yield: 120mg (31%); (M+H): 388; ¹ H NMR (400MHz, CDCl ₃ ): δ8.82～8.81 (dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H); 8.05-8.02 (dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H); 7.44-6.35 (m, 8H); 3.9 (s, 3H); 3.60-2.70 (m, 12H).

Example 48: 8-{4-[2-(6-Methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methyl-quinoline (“Compound 10") preparation method

Generally following the procedure outlined in Example 9, Step 6, from 2-(6-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-methyl-8-piperazine Proceeding from the procedure for quinoline (227 mg, 1 mmol), the preparation of 8-{4-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}- 6-Methyl-quinoline. The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a brown oil. Yield: 210mg (52%); (M+H): 402; ¹ H NMR (400MHz, CDCl ₃ ): δ8.81～8.80 (dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H); 8.02～7.99(dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H) 7.46～6.88(m, 7H); 3.9(s, 3H); 3.60～2.82(m, 12H); 2.5(s, 3H) ).

Example 49: 8-{4-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-chloro-quinoline (“Compound 11 ") preparation method

Generally following the procedure outlined in Example 9, Step 6, from 2-(6-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-chloro-8-piperazine Starting with quinoline (247 mg, 1 mmol), the preparation of 8-{4-[2-(6-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-chloro -quinoline. The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a brown oil. Yield: 140mg (33%); (M+H): 422; ¹ H NMR (400MHz, CDCl ₃ ): δ8.86～8.68 (dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H); 8.02-7.99 (dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H); 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-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline ("Compound 12")

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) was added ethyl bromoacetate ( 16.7 g, 0.1 mol). The reaction mixture was refluxed for 24 hours and cooled to room temperature. It was filtered and concentrated. The resulting oily residue was extracted with chloroform and washed thoroughly with water. The organic layer was dried over anhydrous MgSO ₄ and filtered. It was concentrated and used in the next step without any purification. White oil; Yield: 22.0 g (80%); (M+H): 273.

Step 2: 2-(Ethoxy-2-oxoethoxy)-5-chloro-benzoic acid methyl ester (13.6 g, 50 mmol) from Step 1 was dissolved in THF:MeOH (1:1) ( 300ml), add 5N NaOH (100ml). The reaction mixture was refluxed for 24 hours and cooled to room temperature. Then, it was concentrated to dryness and dissolved in water. The aqueous layer was acidified with conc. HCl and the solid separated was filtered. The product was washed thoroughly with water and dried. The product was used in the next step without any purification. White solid; Yield: 8.0 g (69%); (M+H): 231.

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

Step 4: A mixture of 5-chloro-benzofuran-3(2H)-one (1.68g, 10mmol) and (carboxymethylene)triphenylphosphorane (5.22g, 15mmol) in toluene (100ml) Reflux for 48 hours. Then, the reaction mixture was concentrated and applied to a silica gel column. The cartridge was eluted with hexane (500ml) followed by 25% ethyl acetate. The product ethyl (5-chloro-1-benzofuran-3-yl)acetate was obtained as a white oil. Yield: 1.8 g (75%); (M+H): 239.

Step 5: To a stirred suspension of _LiAlH4 (200 mg, excess) in THF at 0 °C was slowly added ethyl (5-chloro-1-benzofuran-3-yl)acetate (1.19 g, 50 mmol) in THF (20ml) solution. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour and quenched with saturated _NH4Cl solution. The product was extracted with chloroform and washed thoroughly with water. Dry over anhydrous _MgSO4 , filter and concentrate. The product 2-(5-chloro-1-benzofuran-3-yl)ethanol was obtained as a white oil pure enough to be used in the next step without purification. Yield: 850 mg (86%); (M+H): 197.

Step 6: To a stirred solution of 2-(5-chloro-1-benzofuran-3-yl)ethanol (980mg, 5mmol) in anhydrous THF (50ml) at room temperature was added triphenylphosphine (1.572g, 6mmol), iodine (1.518g, 6mmol) and imidazole (408mg, 6mmol). The reaction mixture was stirred at room temperature for 4 hours and quenched with water. It was extracted with _chloroform , washed _thoroughly with 5% _Na2S2O3 , and the organic layer was dried over anhydrous _MgSO4 . It was filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with 30% ethyl acetate: hexanes. The product 2-(5-chloro-1-benzofuran-3-yl)ethyl iodide was obtained as a brown liquid; yield: 1.2 g (80%); (M+H): 306.

2-(5-Chloro-1-benzofuran-3-yl)ethyl iodide (305 mg.1 mmol) (obtained from the above step ) and 8-piperazinoquinoline (213 mg, 1 mmol) were heated in DMSO at 120°C for 24 hours. Then, the reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water, dried over anhydrous MgSO ₄ and concentrated to dryness. The resulting dark solid was purified by column chromatography on silica gel, eluting initially with 70% ethyl acetate:hexanes and then 5% methanol:ethyl acetate. 8-{4-[2-(5-Chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline was isolated as a yellow oil. Yield: 120mg (30%); (M+H): 392; ¹ H NMR (400MHz, CDCl ₃ ): δ8.86～8.85 (dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H); 8.03-8.01 (dd, J ₁ =1.8 Hz, J ₂ =1.8 Hz, 1H); 7.57-7.10 (m, 8H); 3.51-2.50 (m, 12H).

Example 51: 8-{4-[2-(5-Chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-chloro-quinoline ("Compound 13") preparation method

Generally following the procedure outlined in Example 12, Step 6, from 2-(5-chloro-1-benzofuran-3-yl)ethyl iodide (306 mg, 1 mmol) and 6-chloro-8-piperazinoquinoline 8-{4-[2-(5-Chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-chloro-quinoline was prepared starting from phenoline (247 mg, 1 mmol). The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a brown oil. Yield: 110mg (25%); (M+H): 427; ¹ H NMR (400MHz, CDCl ₃ ): δ8.86～8.85 (dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H); 8.03-8.01 (dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H); 7.57-7.10 (m, 7H); 3.51-2.50 (m, 12H).

Example 52: 8-{4-[2-(5-Chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methyl-quinoline (“Compound 14” ) preparation method

Generally following the procedure outlined in Example 12, Step 6, from 2-(5-chloro-1-benzofuran-3-yl)ethyl iodide (306 mg, 1 mmol) and 6-methyl-8-piperazino Starting from quinoline (227 mg, 1 mmol), preparation of 8-{4-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methyl-quinoline phylloline. The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a brown oil. Yield: 140mg (34%); (M+H): 406; ¹ H NMR (400MHz, CDCl ₃ ): δ8.82～8.80 (dd, J ₁ =1.7Hz, J ₂ =1.7Hz, 1H), 8.03-7.80 (dd, J ₁ ==1.7Hz, J ₂ =1.7Hz1H), 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-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline ("Compound 15")

Step 1: To a stirred solution of 5-fluoro-2-hydroxy-methylbenzoate (17.0 g, 0.1 mol) and anhydrous potassium carbonate (50.0 g, excess) in acetone (500 mL) was added ethyl bromoacetate Ester (16.7 g, 0.1 mol). The reaction mixture was refluxed for 24 hours and cooled to room temperature. It was filtered and concentrated. The resulting oily residue was extracted with chloroform and washed thoroughly with water. The organic layer was dried over anhydrous MgSO ₄ and filtered. It was concentrated and used in the next step without any purification. White oil; Yield: 23.0 g (89%); (M+H): 257.

Step 2: Methyl 5-fluoro-2-(ethoxy-2-oxoethoxy)benzoate (12.8 g, 50 mmol) from Step 1 was dissolved in THF:MeOH (1:1) (300 ml ), add 5N NaOH (100ml). The reaction mixture was refluxed for 24 hours and cooled to room temperature. Then, it was concentrated to dryness and dissolved in water. The aqueous layer was acidified with conc. HCl and the solid separated was filtered. Wash it thoroughly with water and dry it. The product was used in the next step without any purification. White solid; Yield: 8.3 g (77%); (M+H): 215.

Step 3: The 2-(carboxymethoxy)-5-fluoro-benzoic acid compound (10.7 g, 50 mmol) from Step 2 was dissolved in acetic anhydride (100 ml), and anhydrous sodium acetate (10.0 g, excess ). The reaction mixture was heated to 150°C for 4 hours. During this time, the reaction mixture turned dark red. The reaction mixture was cooled to room temperature and carefully quenched with ice-cold water. The resulting red solid was filtered and washed thoroughly with water. The resulting red solid was suspended in 1N HCl and refluxed for 2 hours. A dark red solid, 5-fluoro-benzofuran-3(2H)-one, precipitated from the reaction mixture. Filter it and wash it thoroughly with water. It was dried at 40°C and used in the next step without further purification. Yield: 5.8 g (76%); (M+H): 153.

Step 4: A mixture of 5-fluoro-benzofuran-3(2H)-one (1.52g, 10mmol) and (carboxymethylene)triphenylphosphorane (5.22g, 15mmol) in toluene (100ml) Reflux for 48 hours. Then, the reaction mixture was concentrated and applied to a silica gel column. The cartridge was eluted with hexane (500ml) followed by 25% ethyl acetate. The product ethyl (5-fluoro-1-benzofuran-3-yl)acetate was obtained as a white oil. Yield: 1.8 g (80%); (M+H): 223.

Step 5: To a stirred suspension of _LiAlH4 (200 mg, excess) in THF at 0 °C was slowly added ethyl (5-fluoro-1-benzofuran-3-yl)acetate (1.11 g, 5 mmol) in THF (20ml) solution. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour and quenched with saturated _NH4Cl solution. The product was extracted with chloroform and washed thoroughly with water. Dry over anhydrous _MgSO4 , filter and concentrate. The product 2-(5-fluoro-1-benzofuran-3-yl)ethanol was obtained as a white oil pure enough to be used in the next step without purification. Yield: 820 mg (91%); (M+H): 181.

Step 6: To a stirred solution of 2-(5-fluoro-1-benzofuran-3-yl)ethanol (900mg, 5mmol) in anhydrous pyridine (20ml) was added p-toluenesulfonyl chloride (1.14g, 6.0mmol ). The reaction mixture was kept at 0°C for 48 hours and quenched with ice-cold water. The reaction mixture was extracted with chloroform, washed thoroughly with water, and dried over anhydrous MgSO ₄ . It was filtered and concentrated. The resulting crude product was used in the next step without any purification.

In the presence of N,N-diisopropylethylamine (5ml, excess), a solution of tosylate (334mg.1mmol) (obtained from the above step) and 8-piperazinoquinoline (213mg, 1mmol) The mixture was heated in DMSO at 120°C for 24 hours. Then, the reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water, dried over anhydrous MgSO ₄ and concentrated to dryness. The resulting dark solid was purified by column chromatography on silica gel, eluting initially with 70% ethyl acetate:hexanes and then 5% methanol:ethyl acetate. 8-{4-[2-(5-Fluoro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline was isolated as a yellow solid. mp 54°C; Yield: 90 mg (21%); (M+H): 412; ¹ H NMR: δ11.6 (bs, 1H), 9.2 (bs, 1H), 8.7 (bs, 1H), 8.0～ 7.2 (m, 9H), 4.0-3.3 (m, 12H).

Example 54: 8-{4-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methoxy-quinoline (“Compound 16 ") preparation method

8-{ 4-[2-(5-fluoro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methoxy-quinoline. The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a yellow solid. MP: 80°C (HCl salt); Yield: 110 mg, (25%); (M+H): 406; ¹ H NMR δ11.3 (bs, 1H), 8.9 (bs, 1H), 8.43 (bs, 1H), 8.32 (s, 1H), 8.03 (s, 1H), 7.7-7.11 (m, 5H), 3.9 (s, 3H), 3.77-3.25 (m, 12H).

Example 55: 8-{4-[2-(5-Fluoro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-fluoro-quinoline ("Compound 17") preparation method

Following the procedure outlined in Example 15, Step 6, starting from the tosylate (334 mg, 1 mmol) and 6-fluoro-8-piperazinoquinoline (231 mg, 1 mmol), the preparation of 8-{4-[2- (5-fluoro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-fluoro-quinoline. The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate:hexanes and then 5% methanol:ethyl acetate. Yellow solid; MP: 55°C (HCl salt); Yield: 140 mg, 32%; 394 (M+H); ¹ H NMR: δ11.5 (bs, 1H), 8.8 (m, 1H), 843 (dd , 1H), 8.04 (s, 1H), 7.7-7.23 (m, 6H), 4.19-3.20 (m, 12H).

Example 56: Preparation of 8-{4-[2-(7-Methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline ("Compound 18") method

Step 1: A mixture of 7-methoxy-benzofuran-3(2H)-one (1.64g, 10mmol) and (carboxymethylene)triphenylphosphorane (5.22g, 15mmol) in toluene (100ml ) in reflux for 48 hours. Then, the reaction mixture was concentrated and applied to a silica gel column. The cartridge was eluted with hexane (500ml) followed by 25% ethyl acetate. The product ethyl (7-methoxy-1-benzofuran-3-yl)acetate was obtained as a white oil. Yield: 1.9 g (81%); (M+H): 235.

Step 2: To a stirred suspension of _LiAlH4 (200mg, excess) in THF at 0°C was slowly added ethyl (7-methoxy-1-benzofuran-3-yl)acetate (1.17g, 5mmol) THF (20ml) solution. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour and quenched with saturated _NH4Cl solution. The product was extracted with chloroform and washed thoroughly with water. Dry over anhydrous _MgSO4 , filter and concentrate. The product 2-(7-methoxy-1-benzofuran-3-yl)ethanol was obtained as a white oil pure enough to be used in the next step without purification. Yield: 800 mg (83%); (M+H): 193.

Step 3: To a stirred solution of 2-(7-methoxy-1-benzofuran-3-yl)ethanol (960mg, 5mmol) in anhydrous THF (50ml) at room temperature was added triphenylphosphine (1.572 g, 6 mmol), iodine (1.518 g, 6 mmol) and imidazole (408 mg, 6 mmol). The reaction mixture was stirred at room temperature for 4 hours and quenched with water. Then, _the mixture was extracted with chloroform, washed thoroughly with 5% _{Na2S2O3 solution} , and the organic layer was dried over anhydrous _MgSO4 . Then filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with 30% ethyl acetate: hexanes. The product 2-(7-methoxy-1-benzofuran-3-yl)ethyl iodide was obtained as a brown liquid. Yield: 1.3 g (86%); (M+H): 302.

2-(7-Methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg.1 mmol) (obtained from Step above) and 8-piperazinoquinoline (213 mg, 1 mmol) were heated in DMSO at 120°C for 24 hours. Then, the reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water, dried over anhydrous MgSO ₄ and concentrated to dryness. The resulting dark low-melting solid was purified by column chromatography on silica gel, eluting initially with 70% ethyl acetate:hexanes and then 5% methanol:ethyl acetate. 8-{4-[2-(7-Methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline was isolated as a dark brown low melting solid. Yield: (HCl salt) 90 mg (21%); (M+H): 388, ¹ HNMR: δ11.9 (bs, 1H), 9.2 (d, 1H), 9.0 (bs, 1H), 8.2 (m , 2H), 7.9(s, 1H), 7.84(m, 2H), 7.45(d, 1H), 7.21(t, 1H), 6.98(d, 1H), 4.01(s, 3H), 3.77(m, 4H), 3.67(m, 2H), 3.59(m, 4H), 3.3(m, 2H).

Example 57: 8-{4-[2-(7-Methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methoxy-quinoline (“ Compound 19 ") preparation method

Generally following the procedure outlined in Example 18, Step 3, from 2-(7-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-methoxy-8-piper Starting with azinoquinoline (243 mg, 1 mmol), preparation of 8-{4-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6 -Methoxy-quinoline. The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate:hexanes and then 5% methanol:ethyl acetate. The HCl salt was prepared to give a green spongy solid. MP: 86°C; Yield: 300 mg, (66%); (M+H): 418; ¹ H NMR δ11.8 (bs, 1H), 9.0 (bs, 1H), 8.9 (bs, 1H), 8.0 (s, 1H), 7.8 (m, 1H), 7.5 (m, 2H), 7.3 (m, 2H), 6.9 (d, 1H), 4.0 (s, 6H), 3.8 (m, 6H), 3.4～ 3.1 (m, 6H).

Example 58: 8-{4-[2-(7-Methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-chloro-quinoline (“Compound 20 ") preparation method

Generally following the procedure outlined in step 3 of Example 18, from 2-(7-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-chloro-8-piperazine Starting with quinoline (247 mg, 1 mmol), preparation of 8-{4-[2-(7-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-chloro -quinoline. The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate:hexanes and then 5% methanol:ethyl acetate. The HCl salt was prepared to give a green spongy solid. mp 248°C; Yield: 320 mg (69%); (M+H): 424; ¹ H NMR δ11.8 (bs, 1H), 9.0 (d, 1H), 8.5 (d, 1H), 8.0 (s , 1H), 7.8-7.0 (m, 5H), 6.8 (d.1H), 4.2 (d, 2H), 3.9 (s, 3H), 3.7-3.2 (m, 10H).

Example 59: Preparation of 8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline ("Compound 21") method

Step 1: To a stirred solution of methyl 5-methoxy-2-hydroxybenzoate (18.2 g, 0.1 mol) and anhydrous potassium carbonate (50.0 g, excess) in acetone (500 mL) was added ethyl bromoacetate (16.7 g, 0.1 mol). The reaction mixture was refluxed for 24 hours and cooled to room temperature. It was filtered and concentrated. The resulting oily residue was extracted with chloroform and washed thoroughly with water. The organic layer was dried over anhydrous MgSO ₄ and filtered. It was concentrated and used in the next step without any purification. Yellow oil; Yield: 21.0 g (78%); (M+H): 269.

Step 2: 2-(Ethoxy-2-oxoethoxy)-5-methoxy-benzoic acid methyl ester (13.4 g, 50 mmol) from step 1 was dissolved in THF:MeOH (1:1 ) (300ml), 5N NaOH (100ml) was added. The reaction mixture was refluxed for 24 hours and cooled to room temperature. Then, it was concentrated to dryness and dissolved in water. The aqueous layer was acidified with conc. HCl and the solid separated was filtered. Wash it thoroughly with water and dry it. The product was used in the next step without any purification. White solid; Yield: 10.2 g (90%); MP: 150-153°C; (M+H): 227.

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

Step 4: A mixture of 5-methoxy-benzofuran-3(2H)-one (1.64g, 10mmol) and (carboxymethylene)triphenylphosphorane (5.22g, 15mmol) in toluene (100ml ) in reflux for 48 hours. Then, the reaction mixture was concentrated and applied to a silica gel column. The cartridge was eluted with hexane (500ml) followed by 25% ethyl acetate. The product ethyl (5-methoxy-1-benzofuran-3-yl)acetate was obtained as a white oil. Yield: 1.6 g (68%); (M+H): 235.

Step 5: To a stirred suspension of _LiAlH4 (200mg, excess) in THF at 0°C was slowly added ethyl (5-methoxy-1-benzofuran-3-yl)acetate (1.17g, 5mmol) THF (20ml) solution. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour and quenched with saturated _NH4Cl solution. The product was extracted with chloroform and washed thoroughly with water. It was dried over anhydrous MgSO ₄ , filtered and concentrated. The product 2-(5-methoxy-1-benzofuran-3-yl)ethanol was obtained as a white oil pure enough to be used in the next step without purification to give a yellow oil. Yield: 900 mg (93%); (M+H): 193.

Step 6: To a stirred solution of 2-(5-methoxy-1-benzofuran-3-yl)ethanol (960 mg, 5 mmol) in anhydrous THF (50 ml) at room temperature was added triphenylphosphine ( 1.572g, 6mmol), iodine (1.518g, 6mmol) and imidazole (408mg, 6mmol). The reaction mixture was stirred at room temperature for 4 hours and quenched with water. Then, it was extracted with chloroform, _{washed thoroughly} with 5% _Na2S2O3 , and the organic layer was dried over anhydrous _MgSO4 . It was filtered and concentrated. The residue was purified by column chromatography on silica gel, eluting with 30% ethyl acetate: hexanes. The product 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide was obtained as a brown liquid. Yield: 1.1 g (73%); (M+H): 302.

2-(5-Methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg.1 mmol) (obtained from Step above) and 8-piperazinoquinoline (213 mg, 1 mmol) were heated in DMSO at 120°C for 24 hours. Then, the reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water, dried over anhydrous MgSO ₄ and concentrated to dryness. The resulting dark solid was purified by column chromatography on silica gel, eluting initially with 70% ethyl acetate:hexanes and then 5% methanol:ethyl acetate. 8-{4-[2-(5-Methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-quinoline was isolated as a brown solid. mp 78°C; Yield: 120mg (31%); (M+H): 388; ¹ H NMR (400MHz, CDCl ₃ ): δ8.90～8.88 (dd, J ₁ =1.7Hz, J ₂ =1.7Hz , 1H); 8.13-8.10 (dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H); 7.51-6.88 (m, 8H); 3.68 (s, 3H); 3.68-2.82 (m, 12H).

Example 60: 8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-chloro-quinoline (“Compound 22 ") preparation method

Generally following the procedure outlined in Example 21, Step 6, from 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-chloro-8-piperazine Starting with quinoline (247 mg, 1 mmol), preparation of 8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-chloro -quinoline. The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a brown solid. MP: 72°C; Yield: 130mg (30%); (M+H): 422; ¹ H NMR (400MHz, CDCl ₃ ): δ8.86～8.84 (dd, J ₁ =1.7Hz, J ₂ =1.7 Hz, 1H); 8.05～8.02(dd, J ₁ =1.7Hz, J ₂ =1.7Hz, 1H); 7.60～6.88(m, 7H); 3.86(s, 3H); 3.69～2.57(m, 12H) .

Example 61: 8-{4-[2-(5-Methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methyl-quinoline (“Compound 23") preparation method

Generally following the procedure outlined in Example 21, Step 6, from 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-methyl-8-piperazine Starting with quinoline (227 mg, 1 mmol), the preparation of 8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6- Methyl-quinoline. The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a brown oil. Yield: 150mg (37%); (M+H): 402; ¹ H NMR (400MHz, CDCl ₃ ): δ8.82～8.73 (dd, J ₁ =1.7Hz, J ₂ =1.7Hz, 1H); 8.03～802(dd, J ₁ =1.7Hz, J ₂ =1.7Hz, 1H), 8.00～6.88(m, 7H); 3.87(s, 3H)3.49～2.57(m, 12H), 2.5(s, 3H ).

Example 62: 8-{4-[2-(5-Methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-isopropyl-quinoline (“ Compound 24 ") preparation method

Generally following the procedure outlined in Example 21, Step 6, from 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-isopropyl-8-piper Starting with azinoquinoline (255 mg, 1 mmol), preparation of 8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6 - Isopropyl-quinoline. The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a brown oil. Yield: 90mg (20%); (M+H): 430; ¹ H NMR (400MHz, CDCl ₃ ): δ8.83～8.12 (dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H), 8.08～804(dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H), 7.75～6.70(m, 7H), 3.84(s, 3H), 3.50～2.86(m, 12H), 2.90～3.01( m, 1H), 1.34-1.33 (d, 7Hz, 6H).

Example 63: 8-{4-[2-(5-Methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-methoxy-quinoline (“ Compound 25 ") preparation method

Generally following the procedure outlined in Example 21, Step 6, from 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-methoxy 1-8- Starting from piperazinoquinoline (243 mg, 1 mmol), the preparation of 8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}- 6-Methoxy-quinoline. The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a brown oil. Yield: 90 mg, (21%); (M+H): 418; ¹ H NMR (400MHz, CDCl ₃ ): δ8.73～8.71 (dd, J ₁ =1.7Hz, J ₂ =1.7Hz, 1H) 8.03～8.00(dd, J ₁ =1.7Hz, J ₂ =1.7Hz, 1H), 7.50～6.71(m, 7H); 3.91(s, 3H), 3.87(s, 3H), 3.55～2.82(12H) .

Example 64: 8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-fluoro-quinoline (“Compound 26 ") preparation method

Following the procedure outlined in Example 21, Step 6, from 2-(5-methoxy-1-benzofuran-3-yl)ethyl iodide (301 mg, 1 mmol) and 6-fluoro-8-piperazino Starting from quinoline (231 mg, 1 mmol), the preparation of 8-{4-[2-(5-methoxy-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-fluoro- quinoline. The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a brown low melting solid. Yield: 130mg (32%); (M+H): 406; ¹ H NMR (400MHz, CDCl ₃ ); δ8.83～8.82 (dd, J ₁ =1.6Hz, J ₂ =1.6Hz, 1H); 8.06～8.05(dd, J ₁ =1.7Hz, J ₂ =1.7Hz, 1H); 7.60～6.88(m, 7H); 3.86(s, 3H); 3.66～3.56(width s, 4H); 2.93～2.82 (m, 8H).

Example 65: Preparation of 8-{4-[2-(1-benzofuran-3-yl)propyl]-1-piperazinyl}quinoline ("Compound 27")

Step 1: A mixture of benzofuran-3(2H)-one (1.34g, 10mmol) and ethyl 2-(triphenylphosphino)propionate (5.436g, 15mmol) was refluxed in toluene (100ml) 48 hours. Then, the reaction mixture was concentrated and applied to a silica gel column. The cartridge was eluted with hexane (500ml) followed by 25% ethyl acetate. The product ethyl (-1-benzofuran-3-yl)propionate was obtained as a white oil. Yield: 1.6 g (67%); (M+H): 219.

Step 2: To a stirred suspension of LiAlH ₄ (200 mg, excess) in THF at 0° C. was slowly added ethyl (-1-benzofuran-3-yl)propanoate (1.09 g, 5 mmol) in THF (20 ml ) solution. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour and quenched with saturated _NH4Cl solution. The product was extracted with chloroform and washed thoroughly with water. It was dried over anhydrous MgSO ₄ , filtered and concentrated. The product 2-(1-benzofuran-3-yl)-1-propanol was obtained as a white oil pure enough to be used in the next step without purification. Yield: 700 mg (79%); (M+H): 177.

Step 3: To a stirred solution of 2-(1-benzofuran-3-yl)-1-propanol (880mg, 5mmol) in anhydrous pyridine (20ml) was added p-toluenesulfonyl chloride (1.14g, 6.0mmol ). The reaction mixture was kept at 0 °C for 48 hours and quenched with ice-cold water. The reaction mixture was extracted with chloroform, washed thoroughly with water, and dried over anhydrous MgSO ₄ . It was filtered and concentrated. The resulting crude product was used in the next step without any purification.

Tosylate (331 mg.1 mmol) (obtained from the above step) and 8-piperazinoquinoline (213 mg, 1 mmol) were mixed in the presence of N,N-diisopropylethylamine (5 ml, excess). The mixture was heated in DMSO at 120°C for 24 hours. Then, the reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water, dried over anhydrous MgSO ₄ and concentrated to dryness. The resulting dark solid was purified by column chromatography on silica gel, eluting with 70% ethyl acetate: hexanes. 8-{4-[2-(1-Benzofuran-3-yl)propyl]-1-piperazinyl}quinoline was isolated as a yellow oil. Yield: 50 mg (13%); (M+H): 372; ¹ H NMR (400MHz, CDCl ₃ ): δ8.88～8.87 (dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H); 8.11～8.09(dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H); 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-(1-benzofuran-3-yl)propyl]-1-piperazinyl}-6-chloro-quinoline ("Compound 28")

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-piperazinoquinoline (247 mg, 1 mmol), Preparation of 8-{4-[2-(1-benzofuran-3-yl)propyl]-1-piperazinyl}-6-chloro-quinoline. The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a brown oil. Yield: 40mg (10%); (M+H): 406; ¹ H NMR (400MHz, CDCl ₃ ): δ8.85～8.83 (dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H); 8.01～7.99(dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H), 7.73～6.83(m, 8H); 3.50～2.56(m, 11H); 1.44～1.41(d, J=7.0Hz, 3H).

Example 67: Preparation of 8-{4-[2-(1-benzofuran-3-yl)propyl]-1-piperazinyl}-6-fluoro-quinoline ("Compound 29")

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-piperazinoquinoline (231 mg, 1 mmol), Preparation of 8-{4-[2-(1-benzofuran-3-yl)propyl]-1-piperazinyl}-6-fluoro-quinoline. The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a brown oil. Yield: 45 mg (11%); (M+H): 390; ¹ H NMR (400MHz, CDCl ₃ ): δ8.81～8.80 (dd, J ₁ =1.7Hz, J ₂ =1.7Hz 1H); 8.12 ～8.01(dd, _J1 ＝1.8Hz, _J2 ＝1.8Hz, 1H), 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-(1-benzofuran-3-yl)propyl]-1-piperazinyl}-6-methyl-quinoline ("Compound 30")

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-piperazinoquinoline (227 mg, 1 mmol) , Preparation of 8-{4-[2-(1-benzofuran-3-yl)propyl]-1-piperazinyl}-6-methyl-quinoline. The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a brown oil. Yield: 60mg (15%); (M+H): 386; ¹ H NMR (400MHz, CDCl ₃ ): δ8.81～880 (dd, J ₁ =1.7Hz, J ₂ =1.7Hz, 1H); 8.01～8.00(dd, J ₁ =1.7Hz, J ₂ =1.7Hz, 1H); 7.66～6.93(m, 8H); 3.50～2.47(m, 11H); 2.48(s, 3H); 1.43～1.40( d, J = 7.0 Hz, 3H).

Example 69: Preparation of 8-{4-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1-piperazinyl}quinoline (“Compound 31”)

Step 1: A mixture of 7-methoxy-benzofuran-3(2H)-one (1.64g, 10mmol) and ethyl 2-(triphenylphosphino)propionate (5.436g, 15mmol) was prepared in Reflux in toluene (100ml) for 48 hours. Then, the reaction mixture was concentrated and applied to a silica gel column. The cartridge was eluted with hexane (500ml) followed by 25% ethyl acetate. The product ethyl (7-methoxy-1-benzofuran-3-yl)propionate was obtained as a white oil. Yield: 1.9 g (76%); (M+H): 249.

Step 2: To a stirred suspension of LiAlH ₄ (200 mg, excess) in THF at 0° C. was slowly added ethyl (7-methoxy-1-benzofuran-3-yl)propionate (1.24 g, 5 mmol ) in THF (20ml). After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour and quenched with saturated _NH4Cl solution. The product was extracted with chloroform and washed thoroughly with water. It was dried over anhydrous MgSO ₄ , filtered and concentrated. The product 2-(7-methoxy-1-benzofuran-3-yl)-1-propanol was obtained as a white oil pure enough to be used in the next step without purification. Yield: 900 mg (87%); (M+H): 207.

Step 3: To a stirred solution of 2-(7-methoxy-1-benzofuran-3-yl)-1-propanol (1.03g, 5mmol) in anhydrous pyridine (20ml) was added p-toluenesulfonate Acid chloride (1.14 g, 6.0 mmol). The reaction mixture was kept at 0°C for 48 hours and quenched with ice-cold water. The reaction mixture was extracted with chloroform, washed thoroughly with water, and dried over anhydrous MgSO ₄ . It was filtered and concentrated. The resulting crude product was used in the next step without any purification.

Tosylate (360mg.1mmol) (obtained from the above step) and 8-piperazinoquinoline (213mg, 1mmol) were mixed in the presence of N,N-diisopropylethylamine (5ml, excess). The mixture was heated in DMSO at 120°C for 24 hours. Then, the reaction mixture was quenched with water and extracted with chloroform. The organic layer was washed with water, dried over anhydrous MgSO ₄ and concentrated to dryness. The resulting dark solid was purified by column chromatography on silica gel, eluting initially with 70% ethyl acetate:hexanes and then 5% methanol:ethyl acetate. 8-{4-[2-(7-Methoxy-1-benzofuran-3-yl)propyl]-1-piperazinyl}quinoline was isolated as a yellow solid. Preparation of the HCl salt. mp 192°C; Yield: 315 mg (72%); (M+H): 402; 10.1 (bs, 1H), 8.95 (d, 1H), 8.51 (bs, 1H), 8.01 (s, 1H), 7.7 ～7.58(m, 3H), 7.41(d, 1H), 7.39(bs, 1H), 7.23(t, 1H), 6.97(d, 1H), 3.9(s, 3H), 3.7～3.25(m, 11H ), 1.46(d, 3H).

Example 70: 8-{4-[2-(7-Methoxy-1-benzofuran-3-yl)propyl]-1-piperazinyl}-6-methyl-quinoline (“Compound 32") preparation method

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-piperazinoquinoline (227 mg, 1 mmol) , Preparation of 8-{4-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1-piperazinyl}-6-methyl-quinoline. The product was purified by silica gel column chromatography, eluting first with 80% ethyl acetate: hexane and then with 5% methanol: ethyl acetate to give a brown oil; yield: 45 mg (10%); (M+H): 416; ¹ H NMR (400MHz, CDCl ₃ ): δ8.81～8.79 (dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H); 8.01～7.99 (dd, J ₁ = 1.8Hz, J ₂ =1.8Hz, 1H); 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 = 7.0 Hz, 3H).

Example 71: 8-{4-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1-piperazinyl}-6-chloro-quinoline (“Compound 33 ") preparation method

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-piperazinoquinoline (247 mg, 1 mmol), Preparation of 8-{4-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1-piperazinyl}-6-chloro-quinoline. The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate:hexanes and then 5% methanol:ethyl acetate. The HCl salt was prepared to give a yellow-green solid. MP: 55-58°C; Yield: 270 mg (57%); (M+H): 438.

Example 72: 8-{4-[2-(7-Methoxy-1-benzofuran-3-yl)propyl]-1-piperazinyl}-6-methyl-quinoline (“Compound 34") preparation method

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-piperazinoquinoline (227 mg, 1 mmol) , Preparation of 8-{4-[2-(7-methoxy-1-benzofuran-3-yl)propyl]-1-piperazinyl}-6-methyl-quinoline. The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a brown oil. Yield: 120 mg (28%); (M+H): 416; ¹ H NMR (400 MHz, CDCl ₃ ): δ8.69 (d, 1H), 8.01 (d, 1H), 7.56 (s, 1H), 7.33 (m, 1H), 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). Purification by preparative HPLC using a chiral column separated the racemic mixture.

Example 73: 8-{4-[2-(7-Methoxy-1-benzofuran-3-yl)-1-methylethyl]piperazin-1-yl}quinoline (“Compound 35 ") preparation method

Step 1: A mixture of 7-methoxy-benzofuran-3(2H)-one (1.64g, 10mmol) and 1-triphenylphosphino-2-propanone (4.77g, 15mmol) was dissolved in toluene ( 100ml) was refluxed for 48 hours. Then, the reaction mixture was concentrated and applied to a silica gel column. The cartridge was eluted with hexane (500ml) followed by 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.

Step 2: Add 1-(7-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 8-piperazinoquinoline (213.0 mg, 1 mmol) to 1 at room temperature , to a stirred mixture of 2-dichloroethane (100ml) and acetic acid (1ml), was added sodium triacetoxyborohydride (422mg, 2mmol). The reaction mixture was stirred at room temperature for 72 hours. Then, the reaction mixture was neutralized with 10% NaHCO ₃ and extracted with chloroform. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated. The resulting product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a yellow oil. Yield: 60mg (14%); (M+H): 402; ¹ H NMR (400MHz, CDCl ₃ ): δ8.90～8.14 (dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H); 8.13～7.56(dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H); 7.46～6.80(m, 8H); 4.01(s, 3H); 3.51～1.60(m, 11H); 1.14(d, J = 6.0 Hz, 3H).

Example 74: 6-Methoxy-8-{4-[2-(7-methoxy-1-benzofuran-3-yl)-1-methylethyl]piperazin-1-yl} Process for the preparation of quinoline ("compound 36")

Generally following the procedure outlined in Example 35, Step 2, from 1-(7-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 6-methoxy-8-piperazine 6-Methoxy-8- {4-[2-(7-Methoxy-1-benzofuran-3-yl)-1-methylethyl]piperazin-1-yl}quinoline. The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a brown semi-solid. Yield: 75 mg (17%); (M+H): 432.

Example 75: 6-Methyl-8-{4-[2-(7-methoxy-1-benzofuran-3-yl)-1-methylethyl]piperazin-1-yl}quinone Process for the preparation of phenoline ("Compound 37")

Generally following the procedure outlined in step 2 of Example 35, from 1-(7-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 6-methyl-8-piperazino Preparation of 6-methyl-8-{4 -[2-(7-Methoxy-1-benzofuran-3-yl)-1-methylethyl]piperazin-1-yl}quinoline. The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a yellow oil. Yield: 40mg (9%); (M+H): 416; ¹ H NMR (400MHz, CDCl ₃ ): δ8.86～8.79 (dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H), 8.02～7.56(dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H), 7.56～6.80(m, 7H), 3.89(s, 3H), 3.50～2.60(m, 11H); 2.50(s, 3H) 1.12~114 (d, J=7.0Hz, 3H).

Example 76: 8-{4-[2-(5-methoxy-1-benzofuran-3-yl)-1-methylethyl]piperazin-1-yl}quinoline (“Compound 38 ") preparation method

Step 1: A mixture of 5-methoxy-benzofuran-3(2H)-one (1.64g, 10mmol) and 1-triphenylphosphino-2-propanone (4.77g, 15mmol) was dissolved in toluene ( 100ml) was refluxed for 48 hours. Then, the reaction mixture was concentrated and applied to a silica gel column. The cartridge was eluted with hexane (500ml) followed by 25% ethyl acetate. The product 1-(5-methoxy-1-benzofuran-3-yl)acetone was obtained as a red oil. Yield: 1.1 g (53%); (M+H): 205.

Step 2: Add 1-(5-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 8-piperazinoquinoline (213.0 mg, 1 mmol) to 1 at room temperature , to a stirred mixture of 2-dichloroethane (100ml) and acetic acid (1ml), was added sodium triacetoxyborohydride (422mg, 2mmol). The reaction mixture was stirred at room temperature for 72 hours. Then, the reaction mixture was neutralized with 10% NaHCO ₃ and extracted with chloroform. The organic layer was dried over anhydrous MgSO ₄ , filtered and concentrated. The resulting product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a brown semi-solid. Yield: 60mg (14%); (M+H): 402; ¹ H NMR (400MHz, CDCl ₃ ): δ8.90～8.88 (dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H); 8.13～8.10(dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H); 7.60～6.70(m, 8H); 3.87(s, 3H); 3.50～2.50(m, 11H); 1.15～1.13( d, J = 6.0 Hz, 3H).

Example 77: 6-Chloro-8-{4-[2-(5-methoxy-1-benzofuran-3-yl)-1-methylethyl]piperazin-1-yl}quinoline ("compound 39") preparation method

Generally following the procedure outlined in Example 38, Step 2, from 1-(5-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 6-chloro-8-piperazinoquinoline 6-Chloro-8-{4-[ 2-(5-Methoxy-1-benzofuran-3-yl)-1-methylethyl]piperazin-1-yl)quinoline. The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a yellow oil. Yield: 54mg (12%); (M+H): 436; ¹ H NMR (400MHz, CDCl ₃ ): δ8.82～8.81 (dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H); 8.02～8.00(dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H); 7.99～6.58(m, 7H); 3.87(s, 3H); 3.46～2.62(m, 11H); 1.15～1.13( d, J = 6.0 Hz, 3H).

Example 78: 6-Methyl-8-{4-[2-(5-methoxy-1-benzofuran-3-yl)-1-methylethyl]piperazin-1-yl}quinone Process for the preparation of phenoline ("compound 40")

Generally following the procedure outlined in Example 38, Step 2, from 1-(5-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 6-methyl-8-piperazino Preparation of 6-methyl-8-{4 -[2-(5-Methoxy-1-benzofuran-3-yl)-1-methylethyl]piperazin-1-yl}quinoline. The product was purified by column chromatography on silica gel, eluting initially with 80% ethyl acetate: hexanes and then 5% methanol: ethyl acetate to give a yellow oil. Yield: 62mg (14%); (M+H): 416; ¹ H NMR (400MHz, CDCl ₃ ): δ8.82～8.81 (dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H): 8.02～8.00(dd, J ₁ =1.8Hz, J ₂ =1.8Hz, 1H); 7.99～6.58(m, 7H); 3.87(s, 3H); 3.46～2.62(m, 11H); 2.5(s. 3H); 115~1.13 (d, J=6.0Hz, 3H).

Example 79: Preparation of 8-{4-[4-cis-(1-benzothiophen-3-yl)cyclohexyl]-1-piperazinyl}-6-chloroquinoline (“Compound 41”)

To a solution of 6-chloro-8-piperazino-quinoline (0.280 g) in DCE (10 ml) was added 4-(3H-inden-1-yl)-cyclohexanone (0.300 g) followed by tris Sodium acetoxyborohydride (0.333g) and acetic acid (0.2ml). The reaction was stirred overnight at room temperature. It was quenched with 1N NaOH and the resulting product _was extracted with _CH2Cl2 . The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel with 50% ethyl acetate/hexanes, then 75% ethyl acetate/hexanes 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 _C27H28ClN3S ; 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(1-benzothiophen-3-yl)cyclohexyl]-1-piperazinyl}-6-chloroquinoline ("Compound 42")

Simultaneously with the isolation of the cis isomer of Example 42 above, the trans isomer was isolated. Off-white solid, 0.100 g; MP: 143-144°C; MS (ES) m/z (relative intensity): 463 (M ⁺ +H, 100). Elemental _analysis for _C27H28ClN3S ; 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(1-benzothiophen-3-yl)cyclohexyl]-1-piperazinyl}-6-fluoroquinoline (“Compound 43”)

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-1-yl)-cyclohexanone followed by triacetoxyboron Sodium hydride (0.230g) and acetic acid (0.2ml). The reaction was stirred overnight at room temperature. It was quenched with 1N NaOH and the resulting product _was extracted with _CH2Cl2 . The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel with 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 _C27H28FN3S ; 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(1-benzothiophen-3-yl)cyclohexyl]-1-piperazinyl}-6-fluoroquinoline ("Compound 44")

While the cis isomer of Example 44 above was isolated, the trans isomer was isolated as an off-white solid, 0.030 g. MP: 195°C; MS (ES) m/z (relative intensity): 446 (M ⁺ +H, 100). Elemental analysis for _C27H28FN3S ; 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(1-benzothiophen-3-yl)cyclohexyl]-1-piperazinyl}-6-methoxyquinoline ("Compound 45") method

To a solution of 6-methoxy-8-piperazino-quinoline (0.200 g) in DCE (10 ml) was added 4-(3H-inden-1-yl)-cyclohexanone (0.200 g), followed by Sodium triacetoxyborohydride (0.230 g) and acetic acid (0.2 ml) were added. The reaction was stirred overnight at room temperature. It was quenched with 1N NaOH and the resulting product _was extracted with _CH2Cl2 . The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel with 25% ethyl acetate/hexanes, then 50% ethyl acetate/hexanes 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 _C28H31N3OS ; 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(1-benzothiophen-3-yl)cyclohexyl]-1-piperazinyl}-6-methoxyquinoline ("Compound 46") method

While the cis isomer of Example 46 above was isolated, the trans isomer was isolated 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 C28H31N3OS} ; Calculated: C: 73.49; H: 6.83; N: _9.18 ; Found: C: 71.14; H: 7.36; N: 8.52.

Example 85: 6-Fluoro-8-{4-[4-cis(5-fluoro-1-benzothiophen-3-yl)cyclohexyl]piperazin-1-yl}quinoline ("Compound 47") preparation method

To a solution of 6-fluoro-8-piperazino-quinoline (0.200 g) in DCE (10 ml) was added 4-(6-fluoro-3H-inden-1-yl)-cyclohexanone (0.200 g) , followed by the addition of sodium triacetoxyborohydride (0.232 g) and acetic acid (0.2 ml). The reaction was stirred overnight at room temperature. It was quenched with 1N NaOH and the resulting product _was extracted with _CH2Cl2 . The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel with 30% ethyl acetate/hexane, then 50% ethyl acetate/hexane to give 0.068 g of cis product: MS (ES) m/z (relative intensity): 464 (M ⁺ +H, 100).

Example 86: 6-Fluoro-8-{4-[4-trans(5-fluoro-1-benzothiophen-3-yl)cyclohexyl]piperazin-1-yl}quinoline ("Compound 48") preparation method

While the cis isomer of Example 48 above was isolated, the trans isomer was isolated as an off-white solid, 0.040 g. MP: 143-144°C; MS (ES) m/z (relative intensity): 464 (M ⁺ +H, 100).

Example 87: 6-methoxy-8-{4-[4-cis(5-fluoro-1-benzothiophen-3-yl)cyclohexyl]piperazin-1-yl}quinoline (“Compound 49 ") preparation method

To a solution of 6-methoxy-8-piperazino-quinoline (0.200 g) in DCE (10 ml) was added 4-(6-fluoro-3H-inden-1-yl)-cyclohexanone (0.200 g), followed by sodium triacetoxyborohydride (0.225 g) and acetic acid (0.2 ml). The reaction was stirred overnight at room temperature. It was quenched with 1N NaOH and the resulting product _was extracted with _CH2Cl2 . The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel with 30% ethyl acetate/hexane, 50% ethyl acetate/hexane, 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 _C28H30FN3OS ; Calculated: C: 70.71; H: 6.36; N: 8.83; Found: C: 69.13; H: 6.31; N: 8.2.

Example 88: 6-Methoxy-8-{4-[4-trans(5-fluoro-1-benzothiophen-3-yl)cyclohexyl]piperazin-1-yl}quinoline (“Compound 50 ") preparation method

While the cis isomer of Example 50 above was isolated, the trans isomer was isolated as an off-white solid, 0.016 g. MS (ES) m/z (relative intensity): 476 (M ⁺ +H, 100).

Example 89: 5-Chloro-8-{4-[4-cis(5-fluoro-1-benzothiophen-3-yl)cyclohexyl]piperazin-1-yl}quinoline ("Compound 51") preparation method

To a solution of 5-chloro-8-piperazino-quinoline (0.254 g) in DCE (10 ml) was added 4-(6-fluoro-3H-inden-1-yl)-cyclohexanone (0.200 g) , followed by the addition of sodium triacetoxyborohydride (0.274 g) and acetic acid (0.2 ml). The reaction was stirred overnight at room temperature. It was quenched with 1N NaOH and the resulting product _was extracted with _CH2Cl2 . The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml _of silica gel with 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 _C27H27C1FN3S ; Calculated: C: 67.56; H: _5.67 ; N _: 8.75; Found: C: 66.29; H: 5.36; N: 7.97.

Example 90: 5-Chloro-8-{4-[4-trans(5-fluoro-1-benzothiophen-3-yl)cyclohexyl]piperazin-1-yl}quinoline ("Compound 52") preparation method

While the cis isomer of Example 52 above was isolated, the trans isomer was isolated as an off-white solid, 0.020 g. MP: 195-197°C; MS (ES) m/z (relative intensity): 481 (M ⁺ +H, 100). Elemental _analysis for _C27H27ClFN3S ; 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(1-benzofuran-3-yl)cyclohexyl]-1-piperazinyl}-5-fluoroquinoline (“Compound 53”)

To a solution of 5-fluoro-8-piperazino-quinoline (0.238g) in DCE (10ml) was added 4-benzofuran-3-yl-cyclohexanone (0.200g) followed by triacetoxy Sodium oxyborohydride (0.256g) and acetic acid (0.2ml). The reaction was stirred overnight at room temperature. It was quenched with 1N NaOH and the resulting product _was extracted with _CH2Cl2 . 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/hexanes then 50% to give 0.110 g of cis product. MP: 142-144°C; MS (ES) m/z (relative intensity): 430 (M ⁺ +H, 100). Elemental _analysis for _C27H28FN3O ; 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(1-benzofuran-3-yl)cyclohexyl]-1-piperazinyl}-5-fluoroquinoline ("Compound 54")

While the cis isomer of Example 54 above was isolated, the trans isomer was isolated 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 _C27H28FN3O ; 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(1-benzofuran-3-yl)cyclohexyl]-1-piperazinyl}-6-fluoroquinoline (“Compound 55”)

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 triacetoxy Sodium borohydride (0.166g) and acetic acid (0.2ml). The reaction was stirred overnight at room temperature. It was quenched with 1N NaOH and the resulting product _was extracted with _CH2Cl2 . The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel with 20% ethyl acetate/hexanes then 50% to give 0.050 g of the cis product. MS (ES) m/z (relative intensity): 430 (M ⁺ +H, 100). Elemental _analysis for _C27H28FN3O ; 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(1-benzofuran-3-yl)cyclohexyl]-1-piperazinyl}-6-fluoroquinoline ("Compound 56")

While the cis isomer of Example 56 above was isolated, the trans isomer was isolated as an off-white solid, 0.020 g. MP: 195-197°C; MS (ES) m/z (relative intensity): 430 (M ⁺ +H, 100). Elemental _analysis for _C27H28FN3O ; Calculated: C: 75.5; H: 6.57; N: 9.78; Found: _C : 74.75; H: 6.87; N: 9.62.

Example 95: 5-fluoro-8-{4-[4-cis(7-methoxy-1-benzofuran-3-yl)cyclohexyl]-1-piperazinyl}quinoline (“Compound 57 ") preparation method

To a solution of 5-fluoro-8-piperazino-quinoline (0.200 g) in DCE (10 ml) was added 4-(7-methoxy-benzofuran-3-yl)-cyclohexanone (0.184 g), followed by sodium triacetoxyborohydride (0.230 g) and acetic acid (0.1 ml). The reaction was stirred overnight at room temperature. It was quenched with 1N NaOH and the resulting product _was extracted with _CH2Cl2 . The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 mL of silica gel with 25% ethyl acetate/hexanes, then 50% ethyl acetate/hexanes to give 0.025 g of the cis product. MP: 143-146°C; MS (ES) m/z (relative intensity): 460 (M ⁺ +H, 100). Elemental analysis for _C28H30FN3O2 ; Calculated: C: _73.18 ; H: 6.58; N: _9.14 ; Found: C: 71.95; H: 6.49; N: 8.81 _.

Example 96: 5-fluoro-8-{4-[4-trans(7-methoxy-1-benzofuran-3-yl)cyclohexyl]-1-piperazinyl}quinoline (“Compound 58 ") preparation method

While the cis isomer of Example 58 above was isolated, the trans isomer was isolated as an off-white solid, 0.010 g. MS (ES) m/z (relative intensity): 460 (M ⁺ +H, 100).

Example 97: 6-fluoro-8-{4-[4-cis(7-methoxy-1-benzofuran-3-yl)cyclohexyl]-1-piperazinyl}quinoline (“Compound 59 ") preparation method

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 overnight at room temperature. It was quenched with 1N NaOH and the resulting product _was extracted with _CH2Cl2 . The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel with 30% ethyl acetate/hexanes, then 50% ethyl acetate/hexanes 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 _C28H30FN3O2 ; Calculated: C: _73.18 ; H: 6.58; N _{: 9.14} ; Found: C: 72.26; H: 6.61; N: 8.67.

Example 98: 6-fluoro-8-{4-[4-trans(7-methoxy-1-benzofuran-3-yl)cyclohexyl]-1-piperazinyl}quinoline (“Compound 60 ") preparation method

While the cis isomer of Example 60 above was isolated, the trans isomer was isolated 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 _C28H30FN3O2 ; 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-1-benzofuran-3-yl)cyclohexyl]-1-piperazinyl}quinoline ("Compound 61") method

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) were added. The reaction was stirred overnight at room temperature. It was quenched with 1N NaOH and the resulting product _was extracted with _CH2Cl2 . The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel with 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 _C28H31N3O2 ; 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-1-benzofuran-3-yl)cyclohexyl]-1-piperazinyl}quinoline ("Compound 62") method

While the cis isomer of Example 62 above was isolated, the trans isomer was isolated 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 _C28H31N3O2 ; Calculated _: C: _76.16 ; H: 7.08; N _: 9.52; Found: C: 74.9; H: 7.02; N: 8.98.

Example 101: 5-chloro-8-{4-[4-cis(7-methoxy-1-benzofuran-3-yl)cyclohexyl]piperazin-1-yl}quinoline (“Compound 63 ") preparation method

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 overnight at room temperature. It was quenched with 1N NaOH and the resulting product _was extracted with _CH2Cl2 . The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel with 50% ethyl acetate/hexanes, then 70% ethyl acetate/hexanes to give 0.035 g of the cis product. MS (ES) m/z (relative intensity): 477 (M ⁺ +H, 100).

Example 102: 5-Chloro-8-{4-[4-trans(7-methoxy-1-benzofuran-3-yl)cyclohexyl]piperazin-1-yl}quinoline (“Compound 64 ") preparation method

While the cis isomer of Example 64 above was isolated, the trans isomer was isolated as an off-white solid, 0.010 g. MS (ES) m/z (relative intensity): 477 (M ⁺ +H, 100).

Example 103: 5-chloro-8-{4-[4-cis(5-methoxy-1-benzofuran-3-yl)cyclohexyl]piperazin-1-yl}quinoline (“Compound 65 ") preparation method

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 overnight at room temperature. It was quenched with 1N NaOH and the resulting product _was extracted with _CH2Cl2 . The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel with 50% ethyl acetate/hexane, 75% ethyl acetate/hexane and finally 100% ethyl acetate to give 0.015 g of product. MS (ES) m/z (relative intensity): 477 (M ⁺ +H, 100).

Example 104: 5-chloro-8-{4-[4-trans(5-methoxy-1-benzofuran-3-yl)cyclohexyl]piperazin-1-yl}quinoline (“Compound 66 ") preparation method

While the cis isomer of Example 66 above was isolated, the trans isomer was isolated as an off-white solid, 0.012 g. MS (ES) m/z (relative intensity): 477 (M ⁺ +H, 100).

Example 105: 6-fluoro-8-{4-[4-cis(5-methoxy-1-benzofuran-3-yl)cyclohexyl]piperazin-1-yl}quinoline (“Compound 67 ") preparation method

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 sodium triacetoxyborohydride (0.345 g) and acetic acid (0.2 ml). The reaction was stirred overnight at room temperature. It was quenched with 1N NaOH and the resulting product _was extracted with _CH2Cl2 . The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel with 50% ethyl acetate/hexanes 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 C28H30FN3O2} ; Calculated: C: 73.18; H: 6.58; N _{: 9.14} ; Found: C: 71.86; H: 6.86; N: 8.73.

Example 106: 6-fluoro-8-{4-[4-trans(5-methoxy-1-benzofuran-3-yl)cyclohexyl]piperazin-1-yl}quinoline (“Compound 68 ") preparation method

While the cis isomer of Example 68 above was isolated, the trans isomer was isolated 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 _C28H30ClN3O2 ; 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-cyclohexyl)-piperazin-1-yl]-6-fluoro-quinoline ("Compound 69")

To a solution of 6-fluoro-8-piperazino-quinoline (1.4g) in DCE (50ml) was added 4-benzofuran-2-yl-cyclohexanone (0.960g) followed by triacetoxy Sodium borohydride (1.6g) and acetic acid (2ml). The reaction was stirred at room temperature for 6 hours. It was quenched with 1N NaOH and the resulting product _was extracted with _CH2Cl2 . The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel with 50% ethyl acetate/hexanes 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-thiophen-2-yl-cyclohexyl)-piperazin-1-yl]-6-methoxy-quinoline (“Compound 70”)

At room temperature, 4-benzo[b]thiophen-2-yl-cyclohexanone (237 mg, 1 mmol), 6-methoxy-8-piperazine- (250 mg, 1 mmol), Na(OAc) ₃ BH (327mg, 1.55mmol) and HOAc ₍ 0.12ml, 2mmol) in _ClCH2CH2Cl (40ml) was stirred overnight. The reaction mixture was quenched with 1N aqueous NaOH (50ml), then poured into _H2O (50ml), _extracted with _CH2Cl2 (1 x 100ml) and EtOAc (2 x 100ml). The organic phases _were combined, dried over _Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (5% methanol/ethyl acetate) afforded a yellow solid which was one spot by TLC. Analytical HPLC indicated an 80:20 mixture of cis and trans isomers. Purification by preparative HPLC (Primesphere silica gel column, 50 x 250 mm, 50/50 hexane/methyl tert-butyl ether) afforded 130 mg (28%) of the cis isomer (first eluting) compound as shallow Yellow crystalline solid. MP: 184-186°C. MS (ES) m/z (relative intensity): 458 (M ⁺ +H, 100). Elemental analysis for _C28H31N3OS ; 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-thiophen-2-yl-cyclohexyl)-piperazin-1-yl]-6-methoxy-quinoline (“Compound 71”)

While the cis isomer of Example 71 above was isolated, the trans isomer was isolated as an off-white solid. MP: 193-194°C; MS (ES) m/z (relative intensity): 458 (M ⁺ +H, 100). Elemental analysis for _{C28H31N3OS - 0.5H2O} ; Calcd: C, 72.07; H, 6.91; N, _9.00 ; Found: C, 72.23; H, 6.88; N, 8.96.

Example 110: Affinity Test of Compounds to 5-HT Transporter

The affinity of the compounds of this invention for the 5-HT transporter was established according to standard pharmaceutically acceptable assay procedures using the following representative compounds.

Rat brain ³ H-paroxetine binding assay (RB 5HT transporter):

This assay is used to determine the affinity of compounds for the 5-HT transporter.

A method similar to that used by Cheetham et al. (Neuropharmacol., 1993, 32:737) was used. Briefly, precortical membranes prepared from male SD rats were incubated with ³ H-paroxetine (0.1 nM) for 60 minutes at 25°C. All tubes also contained either vehicle, test compound (1-8 concentrations), or saturating concentration of fluoxetine (10 [mu]M) to determine specific binding. ^All reactions were terminated by the addition of ice-cold Tris buffer, followed by rapid filtration through Tom Tech filter units to separate bound from free ³ H-paroxetine. Bound radioactivity was quantified using a Wallac 1205 beta plate(R) counter. IC ₅₀ values were calculated by nonlinear regression analysis, and then converted into K _i values using the method of Cheng and Prusoff (Biochem. Pharmacol., 1973, 22: 3099).

K _i =IC ₅₀ /radioligand concentration/(1+KD)

Inhibition of ³ H-5-HT uptake by cells harboring the human 5-HT transporter (HC 5HT transporter)

A human cancer cell line (Jar cells) with low levels of endogenous 5-HT-transporter was seeded in 96-well plates and treated with staurosporine for at least 18 hours prior to the assay. [Sturosporine can greatly enhance the expression of 5-HT-transporter]. On the day of the assay, vehicle, excess fluoxetine, or test compound is added to each well of the plate. Then, ³ H-5-HT was added to all wells and incubated at 37°C for 5 minutes. The wells were then washed with ice-cold 50 mM Tris HCl (pH 7.4) buffer and aspirated to remove free ³ H-5-HT. Then 25 μl of 0.25M NaOH was added to each well to lyse the cells, 75 μl of scintillation mixture (Microscint ^TM 20) was added, and quantification was performed on a Packard TopCount instrument. The tube with vehicle represents the likely total uptake, and the radioactive counts in the tube with fluoxetine represent the non-specific binding/uptake, which is subtracted from the total likely uptake to give the total likely specific uptake. This non-specific binding (usually low numbers) is then subtracted from counts obtained in wells containing different test compounds (or different concentrations of test drug) to obtain specific uptake in the presence of drug. Specific uptake was expressed as % of control and then analyzed using non-linear regression analysis (Prizm) to obtain _IC50 values. If the compound is active in inhibiting 5-HT uptake, the counts are close to those obtained with fluoxetine.

According to the improved method of the method of Hall et al. (J.Neurochem., 1985, 44:1685), the displacement of [ ³ H]8-OH-DPAT from the 5-HT _1A 5-hydroxytryptamine receptor by the claimed compound was determined (di Propylamino-1,2,3,4-tetralin) ability to determine high affinity for the serotonin 5-HT _1A receptor, this method utilizes the human 5-HT _1A receptor stably transfected CHO cells. The affinity of 5-HT _1A for the compounds of the invention is expressed hereinafter as the K _i value.

The activity of antagonists at the 5-HT _1A receptor was determined by using a ³⁵ S-GTPγS binding assay similar to that used by Lazareno and Birdsall (Br.J.Pharmacol., 1993, 109:1120), in which the assay The ability of compounds to affect the binding of ³⁵ S-GTPγS to membranes containing cloned human 5-HT _1A receptors. Agonists produced enhanced binding, whereas antagonists did not, but reversed the effect of the standard agonist 8-OH-DPAT. The maximum inhibitory effect of a test compound is expressed as I _max , while its potency is defined as IC ₅₀ .

The results obtained from these two assays are shown in Table 1 below.

Table 1 compound 5-HT _1A K _i (nM) RB-5HT transporter K _i (nM) HC-5HTC transporter K _i (nM) 1 1.94 6.50 25.30 2 124.20 176 1710 3 1.93 14.00 75.60 4 2.48 60.00 612 5 0.73 31.00 1.6 6 16.14 471 1080 7 15.37 32% ^* 2150 8 36.72 403 1780 9 0.37 33 71.30 10 0.94 97.00 206

compound 5-HT _1A K _i (nM) RB-5HT transporter K _i (nM) HC-5HTC transporter K _i (nM) 11 0.81 37 540 12 2.92 11 42.20 13 41.34 64 270 14 13.48 45 9.82 15 0.37 17 67.20 16 8.05 62.00 180 17 1.59 16.50 50.90 18 0.11 0.65 9.46 19 no test no test no test 20 0.14 3.79 47.70 twenty one 2.83 7.25 43.65 twenty two 2.69 2.00 106 twenty three 19.97 28.50 182.50 twenty four 46% ^* 24% ^* 3730 25 8.71 47.00 210.00 26 14.37 16.50 51.05 27 19.35 32.00 51.90 28 109.90 73.00 125.00 29 112.44 68.00 115.00 30 79.07 93.00 347.00 31 0.91 4.17 9.53 32 2.16 35.00 58.20 33 8.19 58.00 183.0 34 9.13 35.00 881 35 1.22 119.00 1000 36 0.23 4.16 31.00 37 no test 471.00 no test 38 0.14 14.00 59.50 39 0.34 5.50 40.10 40 1.77 130.0 549.00 41 2.25 65.00 338.00 42 140.5 157.00 184.00 43 1.17 311.0 1440.00 44 130.45 380.00 1620.00 45 1.73 259.00 1080.00 46 126.20 21.00 802.00 47 1.72 25% ^* 3490.00 48 0.28 155.00 739.00 49 1.37 92.00 659.00 50 25.94 10.00 65.30 51 4.14 133.00 1150.00 52 42% ^* 48.00 751.00 53 1.74 208.00 3910.00

compound 5-HT _1A K _i (nM) RB-5HT transporter K _i (nM) HC-5HTC transporter K _i (nM) 54 25.09 38.00 220.00 55 0.11 116.00 471.50 56 16.58 77.00 337.00 57 0.40 163.00 3040.00 58 21.06 34.00 272.00 59 1.93 48.00 455.00 60 0.16 50.00 212.00 61 41.37 27.00 96.80 62 0.26 46.00 38.00 63 0.92 87.00 124.00 64 18.69 49.00 176.20 65 10.12 53.00 53.00 66 1.99 89.00 1200.00 67 14.37 146.00 1200.00 68 0.22 121.00 3290.00 69 16.32 106 no test 70 1547 47 3000 71 162 no test no test

^* % inhibition @ 1 μM concentration.

Thus, the compounds of the present invention not only inhibit or block serotonin reuptake (thus increasing synaptic serotonin levels), but also antagonize 5-HT _1A receptors (thus shortening latency). Accordingly, the compounds of the present invention are useful for the prevention and/or treatment of diseases caused by neurological disorders influenced by serotonin, including depression, anxiety, cognitive deficits, for example caused by Alzheimer's disease and other neurodegenerations diseases caused by schizophrenia, schizophrenia, prostate cancer and nicotine withdrawal syndrome, the method includes administering to patients in need by oral administration, parenteral administration or inhalation administration.

When ranges are used herein for physical properties (eg, molecular weight) or chemical properties (eg, chemical formulae), all combinations and subcombinations of ranges of the particular embodiments herein are intended to be included.

The contents of each patent, patent application, and publication cited or described in this application document are hereby incorporated by reference in their entirety.

Those skilled in the art will recognize that various changes and modifications can be made to the preferred embodiments of the invention without departing from the spirit of the invention. Accordingly, the appended claims cover all such equivalents as fall within the spirit and scope of the invention.

Claims (19)

1. a following formula I compound or its prodrug, steric isomer, N-oxide compound or the acceptable salt of medicine,

Wherein:

X is O or S;

R ₁, R ₂, R ₃, R ₄, R ₅, R ₆And R ₇Be independently hydrogen, halogen, cyano group ,-N (R ₉) (R ₉), hydroxyl, C (=O) OR ₁₀, alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, alkoxyl group, alkene oxygen base, alkynyloxy group, aryloxy, heteroaryloxy, perfluoroalkyl, (R ₉) (R ₉) N-alkoxyl group, (R ₉) (R ₉) N-alkoxy aryl, q be the S (O) of 0-2 _q-alkyl, q are the S (O) of 0-2 _q-aryl, CONR ₁₁R ₁₂, guanidine radicals, ring-type guanidine radicals, alkylaryl, arylalkyl, miscellaneous alkyl aryl, heteroarylalkyl, heterocyclic radical, aryl alkenyl ,-SO ₂NR ₁₁R ₁₂, aryloxy aryl, alkoxy aryl alkyl, aryloxy alkyl, aryloxy heteroaryl, heteroaryloxy aryl, alkyl-aryloxy aryl, alkyl-aryloxy heteroaryl, heteroaryloxy alkyl, perhaps any two described R on the adjacent carbons ₁, R ₂, R ₃, R ₄, R ₅, R ₆Or R ₇Form alkylenedioxy group together;

R ₈For being selected from following joint: optional by one or two R ₁₃The cycloalkyl, alkyl and the following formula part that replace:

Wherein Z is N or CH;

T is the integer of 1-3; With

U is the integer of 0-3;

R ₉For hydrogen, alkyl, aryl, heteroaryl, aryloxy, heterocyclic radical, cycloalkyl, its pair key not the thiazolinyl on the carbon atom that directly connects N, its triple bond not the alkynyl on the carbon atom at direct connection N, perfluoroalkyl ,-S (O) ₂Alkyl ,-S (O) ₂Aryl ,-S (O) ₂Heteroaryl ,-(C=O) heteroaryl ,-(C=O) aryl ,-(C=O) (C ₁-C ₆) alkyl ,-(C=O) cycloalkyl ,-(C=O) heterocycle, alkyl-heterocycle, aryl alkenyl ,-CONR ₁₁R ₁₂,-SO ₂NR ₁₁R ₁₂, alkoxy aryl alkyl, arylalkyl alkoxyl group, heteroarylalkyl alkoxyl group, aryloxy alkyl, heteroaryloxy alkyl, aryloxy aryl, aryloxy heteroaryl, alkyl-aryloxy aryl, alkyl-aryloxy heteroaryl, alkyl-aryloxy alkylamine, alkoxy carbonyl, aryloxycarbonyl or heteroaryloxy carbonyl;

R ₁₀Be hydrogen, alkyl, aryl, heteroaryl, alkylaryl, arylalkyl, heteroarylalkyl or miscellaneous alkyl aryl;

R ₁₁And R ₁₂Be hydrogen, alkyl, aryl, heteroaryl, alkylaryl, arylalkyl, heteroarylalkyl or miscellaneous alkyl aryl independently; With

Each R ₁₃All be hydrogen, alkyl, aryl, heteroaryl, alkylaryl, arylalkyl, heteroarylalkyl, miscellaneous alkyl aryl or-N (R ₉) (R ₉).

2. the compound of claim 1, wherein said R ₁, R ₂, R ₃, R ₄, R ₅, R ₆And R ₇Be methyl, sec.-propyl, methoxyl group, chlorine or fluorine independently.

3. claim 1 or 2 compound, wherein said R ₈Be ethyl, propyl group, sec.-propyl, butyl, hexyl or cyclohexyl.

4. each compound among the claim 1-3, wherein said R ₉Be alkyl.

5. each compound among the claim 1-4, wherein said R ₁₀Be hydrogen or alkyl.

6. each compound among the claim 1-5, wherein said R ₁₁And R ₁₂Be hydrogen, alkyl, alkylaryl or miscellaneous alkyl aryl independently.

7. each compound among the claim 1-6, wherein said R ₁₃Be hydrogen or alkyl.

8. the compound of claim 1, wherein said compound is:

1) 8-{4-[2-(1-cumarone-3-yl) ethyl]-the 1-piperazinyl }-6-fluorine quinoline;

2) 8-{4-[2-(1-cumarone-3-yl) ethyl]-the 1-piperazinyl }-the 6-chloroquinoline;

3) 8-{4-[2-(1-cumarone-3-yl) ethyl]-the 1-piperazinyl }-the 6-toluquinoline;

4) 8-{4-[2-(1-cumarone-3-table) ethyl]-the 1-piperazinyl }-the 6-methoxy quinoline;

5) 8-{4-[2-(6-chloro-1-cumarone-3-yl) ethyl]-the 1-piperazinyl }-quinoline;

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

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

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

9) 8-{4-[2-(6-methoxyl group-1-cumarone-3-yl) ethyl]-the 1-piperazinyl }-quinoline;

10) 8-{4-[2-(6-methoxyl group-1-cumarone-3-yl) ethyl]-the 1-piperazinyl }-6-methyl-quinoline;

11) 8-{4-[2-(6-methoxyl group-1-cumarone-3-yl) ethyl]-the 1-piperazinyl }-6-chloro-quinoline;

12) 8-{4-[2-(5-chloro-1-cumarone-3-yl) ethyl]-the 1-piperazinyl }-quinoline;

13) 8-{4-[2-(5-chloro-1-cumarone-3-yl) ethyl]-the 1-piperazinyl }-6-chloro-quinoline;

14) 8-{4-[2-(5-chloro-1-cumarone-3-yl) ethyl]-the 1-piperazinyl }-6-methyl-quinoline;

15) 8-{4-[2-(5-fluoro-1-cumarone-3-yl) ethyl]-the 1-piperazinyl }-quinoline;

16) 8-{4-[2-(5-fluoro-1-cumarone-3-yl) ethyl]-the 1-piperazinyl }-6-methoxy yl-quinoline;

17) 8-{4-[2-(5-fluoro-1-cumarone-3-yl) ethyl]-the 1-piperazinyl }-6-fluoro-quinoline;

18) 8-{4-[2-(7-methoxyl group-1-cumarone-3-yl) ethyl]-the 1-piperazinyl }-quinoline;

19) 8-{4-[2-(7-methoxyl group-1-cumarone-3-yl) ethyl]-the 1-piperazinyl }-6-methoxy yl-quinoline;

20) 8-{4-[2-(7-methoxyl group-1-cumarone-3-yl) ethyl]-the 1-piperazinyl }-6-chloro-quinoline;

21) 8-{4-[2-(5-methoxyl group-1-cumarone-3-yl) ethyl]-the 1-piperazinyl }-quinoline;

22) 8-{4-[2-(5-methoxyl group-1-cumarone-3-yl) ethyl]-the 1-piperazinyl }-6-chloro-quinoline;

23) 8-{4-[2-(5-methoxyl group-1-cumarone-3-yl) ethyl]-the 1-piperazinyl }-6-methyl-quinoline;

24) 8-{4-[2-(5-methoxyl group-1-cumarone-3-yl) ethyl]-the 1-piperazinyl }-6-sec.-propyl-quinoline;

25) 8-{4-[2-(5-methoxyl group-1-cumarone-3-yl) ethyl]-the 1-piperazinyl }-6-methoxy yl-quinoline;

26) 8-{4-[2-(5-methoxyl group-1-cumarone-3-yl) ethyl]-the 1-piperazinyl }-6-fluoro-quinoline;

27) propyl group 8-{4-[2-{1-cumarone-3-yl)]-the 1-piperazinyl } quinoline;

28) 8-{4-[2-(1-cumarone-3-yl) propyl group]-the 1-piperazinyl }-6-chloro-quinoline;

29) 8-{4-[2-(1-cumarone-3-yl) propyl group]-the 1-piperazinyl }-6-fluoro-quinoline;

30) 8-{4-[2-(1-cumarone-3-yl) propyl group]-the 1-piperazinyl }-6-methyl-quinoline;

31) 8-{4-[2-(7-methoxyl group-1-cumarone-3-yl) propyl group]-the 1-piperazinyl } quinoline;

32) 8-{4-[2-(7-methoxyl group-1-cumarone-3-yl) propyl group]-the 1-piperazinyl }-6-methyl-quinoline;

33) 8-{4-[2-(7-methoxyl group-1-cumarone-3-yl) propyl group]-the 1-piperazinyl }-6-chloro-quinoline;

34) 8-{4-[2-(7-methoxyl group-1-cumarone-3-yl) propyl group]-the 1-piperazinyl }-6-methyl-quinoline;

35) 8-{4-[2-(7-methoxyl group-1-cumarone-3-yl)-1-methylethyl] piperazine-1-yl } quinoline;

36) 6-methoxyl group-8-{4-[2-(7-methoxyl group-1-cumarone-3-yl)-1-methylethyl] piperazine-1-yl } quinoline;

37) 6-methyl-8-{4-[2-(7-methoxyl group-1-cumarone-3-yl)-1-methylethyl] piperazine-1-yl } quinoline;

38) 8-{4-[2-(5-methoxyl group-1-cumarone-3-yl)-1-methylethyl] piperazine-1-yl } quinoline;

39) 6-chloro-8-{4-[2-(5-methoxyl group-1-cumarone-3-yl)-1-methylethyl] piperazine-1-yl } quinoline;

40) 6-methyl-8-{4-[2-{5-methoxyl group-1-cumarone-3-yl)-and the 1-methylethyl] piperazine-1-yl } quinoline;

41) 8-{4-[4-suitable-(1-thionaphthene-3-yl) cyclohexyl]-the 1-piperazinyl-the 6-chloroquinoline;

42) anti-(1-thionaphthene-3-yl) cyclohexyl of 8-{4-[4-]-the 1-piperazinyl }-the 6-chloroquinoline;

43) 8-{4-[4-is along (1-thionaphthene-3-yl) cyclohexyl]-the 1-piperazinyl }-6-fluorine quinoline;

44) anti-(1-thionaphthene-3-yl) cyclohexyl of 8-{4-[4-]-the 1-piperazinyl }-6-fluorine quinoline;

45) 8-{4-[4-is along (1-thionaphthene-3-yl) cyclohexyl]-the 1-piperazinyl }-the 6-methoxy quinoline;

46) anti-(1-thionaphthene-3-yl) cyclohexyl of 8-{4-[4-]-the 1-piperazinyl }-the 6-methoxy quinoline;

47) 6-fluoro-8-{4-[4-is along (5-fluoro-1-thionaphthene-3-yl) cyclohexyl] piperazine-1-yl } quinoline;

48) anti-(5-fluoro-1-thionaphthene-3-yl) cyclohexyl of 6-fluoro-8-{4-[4-] piperazine-1-yl } quinoline;

49) 6-methoxyl group-8-{4-[4-is along (5-fluoro-1-thionaphthene-3-yl) cyclohexyl] piperazine-1-yl } quinoline;

50) anti-(5-fluoro-1-thionaphthene-3-yl) cyclohexyl of 6-methoxyl group-8-{4-[4-] piperazine-1-yl } quinoline;

51) 5-chloro-8-{4-[4-is along (5-fluoro-1-thionaphthene-3-yl) cyclohexyl] piperazine-1-yl } quinoline;

52) anti-(5-fluoro-1-thionaphthene-3-yl) cyclohexyl of 5-chloro-8-{4-[4-] piperazine-1-yl } quinoline;

53) 8-{4-[4-is along (1-cumarone-3-yl) cyclohexyl]-the 1-piperazinyl }-5-fluorine quinoline;

54) anti-(1-cumarone-3-yl) cyclohexyl of 8-{4-[4-]-the 1-piperazinyl }-5-fluorine quinoline;

55) 8-{4-[4-is along (1-cumarone-3-yl) cyclohexyl]-the 1-piperazinyl }-6-fluorine quinoline;

56) anti-(1-cumarone-3-yl) cyclohexyl of 8-{4-[4-]-the 1-piperazinyl }-6-fluorine quinoline;

57) 5-fluoro-8-{4-[4-is along (7-methoxyl group-1-cumarone-3-yl) cyclohexyl]-the 1-piperazinyl } quinoline;

58) anti-(7-methoxyl group-1-cumarone-3-yl) cyclohexyl of 5-fluoro-8-{4-[4-]-the 1-piperazinyl } quinoline;

59) 6-fluoro-8-{4-[4-is along (7-methoxyl group-1-cumarone-3-yl) cyclohexyl]-the 1-piperazinyl } quinoline;

60) anti-(7-methoxyl group-1-cumarone-3-yl) cyclohexyl of 6-fluoro-8-{4-[4-]-the 1-piperazinyl } quinoline;

61) 8-{4-[4-is along (7-methoxyl group-1-cumarone-3-yl) cyclohexyl]-the 1-piperazinyl } quinoline;

62) anti-(7-methoxyl group-1-cumarone-3-yl) cyclohexyl of 8-{4-[4-]-the 1-piperazinyl } quinoline;

63) 5-chloro-8-{4-[4-is along (7-methoxyl group-1-cumarone-3-yl) cyclohexyl] piperazine-1-yl } quinoline;

64) anti-(7-methoxyl group-1-cumarone-3-yl) cyclohexyl of 5-chloro-8-{4-[4-] piperazine-1-yl } quinoline;

65) 5-chloro-8-{4-[4-is along (5-methoxyl group-1-cumarone-3-yl) cyclohexyl] piperazine-1-yl } quinoline;

66) anti-(5-methoxyl group-1-cumarone-3-yl) cyclohexyl of 5-chloro-8-{4-[4-] piperazine-1-yl } quinoline;

67) 6-fluoro-8-{4-[4-is along (5-methoxyl group-1-cumarone-3-yl) cyclohexyl] piperazine-1-yl } quinoline;

68) anti-(5-methoxyl group-1-cumarone-3-yl) cyclohexyl of 6-fluoro-8-{4-[4-] piperazine-1-yl } quinoline;

69) 8-[4-(4-cumarone-2-base-cyclohexyl)-piperazine-1-yl]-6-fluoro-quinoline;

70) suitable-8-[4-(4-thiophene-2-base-cyclohexyl)-piperazine-1-yl]-6-methoxy yl-quinoline;

71) anti--8-[4-(4-thiophene-2-base-cyclohexyl)-piperazine-1-yl]-6-methoxy yl-quinoline;

72) 8-[4-(4-cumarone-2-base-cyclohexyl)-piperazine-1-yl]-6-fluoro-quinoline;

73) suitable-8-[4-(4-thiophene-2-base-cyclohexyl)-piperazine-1-yl]-6-methoxy yl-quinoline; Or

74) anti--8-[4-(4-thiophene-2-base-cyclohexyl)-piperazine-1-yl]-6-methoxy yl-quinoline.

9. composition, described composition comprises:

The compound of claim 1; With

One or more medicine acceptable carriers.

10. treat the method for suspecting the patient who suffers from the serotonin disease for one kind, described method comprises the steps:

Give the compound of the claim 1 of described patient treatment significant quantity.

11. the method for claim 10, wherein said serotonin relative disease are dysthymia disorders, anxiety disorder, cognitive defect, schizophrenia, prostate cancer or nicotine abstinence syndrome.

12. the method for claim 10, wherein said serotonin relative disease is a dysthymia disorders.

13. the method for claim 10, wherein said serotonin relative disease is an anxiety disorder.

14. an antagonism has 5-HT in the patient's body that needs _1AThe method of acceptor, described method comprises the steps:

Give the compound of the claim 1 of described patient treatment significant quantity.

15. an inhibition has the method for serotonin reuptake in the patient's body that needs, described method comprises the steps:

Give the compound of the claim 1 of described patient treatment significant quantity.

16. antagonism 5-HT in the patient's body that needs is arranged _1AThe method of acceptor and inhibition serotonin reuptake, described method comprises the steps:

Give the compound of the claim 1 of described patient treatment significant quantity.

17. a method that promotes selectivity serotonin reuptake inhibitor (SSRI) onset, described method comprises the steps:

Give SSRI and

Give the compound of claim 1.

18. the method for claim 17, wherein said SSRI and described compound give jointly.

19. method for preparing benzofuryl-piperazinyl quinoline and benzothienyl-piperazinyl quinoline, described method comprises the steps: in the presence of at least a aprotic polar solvent and at least a acid binding agent, makes the reaction of Formula Il compound and Formula Il I compound:

Wherein:

Y is halogen, tosyloxy, mesyloxy or trifluoro-methanesulfonyl oxy;

X is O or S;

R ₁, R ₂, R ₃, R ₄, R ₅, R ₆And R ₇Be independently hydrogen, halogen, cyano group ,-N (R ₉) (R ₉), hydroxyl, C (=O) OR ₁₀, alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, alkoxyl group, alkene oxygen base, alkynyloxy group, aryloxy, heteroaryloxy, perfluoroalkyl, alkylenedioxy group, (R ₉) (R ₉) N-alkoxyl group, (R ₉) (R ₉) N-alkoxy aryl, q be the S (O) of 0-2 _q-alkyl, q are the S (O) of 0-2 _q-aryl, CONR ₁₁R ₁₂, guanidine radicals, ring-type guanidine radicals, alkylaryl, arylalkyl, miscellaneous alkyl aryl, heteroarylalkyl, heterocyclic radical, aryl alkenyl ,-SO ₂NR ₁₁R ₁₂, aryloxy aryl, alkoxy aryl alkyl, aryloxy alkyl, aryloxy heteroaryl, heteroaryloxy aryl, alkyl-aryloxy aryl, alkyl-aryloxy heteroaryl or heteroaryloxy alkyl;

R ₈For being selected from following joint: optional by one or two R ₁₃The cycloalkyl, alkyl and the following formula part that replace:

Wherein Z is N or CH;

T is the integer of 1-3; With

U is the integer of 0-3;

R ₉For hydrogen, alkyl, aryl, heteroaryl, aryloxy, heterocyclic radical, cycloalkyl, its pair key not the thiazolinyl on the carbon atom that directly connects N, its triple bond not the alkynyl on the carbon atom at direct connection N, perfluoroalkyl ,-S (O) ₂Alkyl ,-S (O) ₂Aryl ,-S (O) ₂Heteroaryl ,-(C=O) heteroaryl ,-(C=O) aryl ,-(C=O) (C ₁-C ₆) alkyl ,-(C=O) cycloalkyl ,-(C=O) heterocycle, alkyl-heterocycle, aryl alkenyl ,-CONR ₁₁R ₁₂,-SO ₂NR ₁₁R ₁₂, alkoxy aryl alkyl, arylalkyl alkoxyl group, heteroarylalkyl alkoxyl group, aryloxy alkyl, heteroaryloxy alkyl, aryloxy aryl, aryloxy heteroaryl, alkyl-aryloxy aryl, alkyl-aryloxy heteroaryl, alkyl-aryloxy alkylamine, alkoxy carbonyl, aryloxycarbonyl or heteroaryloxy carbonyl;

R ₁₀Be hydrogen, alkyl, aryl, heteroaryl, alkylaryl, arylalkyl, heteroarylalkyl or miscellaneous alkyl aryl;

R ₁₁And R ₁₂Be hydrogen, alkyl, aryl, heteroaryl, alkylaryl, arylalkyl, heteroarylalkyl or miscellaneous alkyl aryl independently; With

Each R ₁₃All be hydrogen, alkyl, aryl, heteroaryl, alkylaryl, arylalkyl, heteroarylalkyl, miscellaneous alkyl aryl or-N (R ₉) (R ₉).