USOORE48059E (19 ) United States ( 12 ) Reissued Patent (10 ) Patent Number : US RE48,059 E Yamashita et al. ( 45 ) Date of Reissued Patent: * Jun . 23 , 2020

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Oshiro et al. , “ Novel Antipsychotic Agents With Dopamine Autorecep Stahl, Dopamine System Stabilizers , Aripiprazole and the Next tor Agonist Properties : Synthesis and Pharmacology of 7-[ 4- ( 4 Generation of Antipsychotics, Part I, J. Clin . Psychology , 62 ( 11 ) : 841 Phenyl- 1 - Piperazinyl /Butoxy ]-3,4 -Dihydro - 2 ( 1H )-Quinolinone Deriva 42 ( 2001 ) . tives " , J. Med . Chem ., vol. 41 , pp . 658-667, ( 1998 ). Stahl, Dopamine System Stabilizers , Aripiprazole . and the Next Moloney et al. , “ Synthesis and Serotonergic Activity of Variously Generation of Antipsychotics, Part 2 , J Clin . Psychiatry, 62 ( 12 ) :923 Substituted ( 3 - Amido ) Phenylpiperazine Derivatives and 924 (2001 ) . Benzothiophene -4 - Piperazine Derivatives : Novel Antagonists for Stahl, Mechanism of Action of Brexpiprazole : Comparison with the Vascular 5 -HT1B Receptor" , European Journal of Medicinal Aripiprazole , CNS Spectrums, 21: 1-6 (2016 ) . Chemistry, vol. 39 , pp . 305-321, ( 2004 ) . US RE48,059 E Page 5

( 56 ) References Cited OTHER PUBLICATIONS Toru et al ., “ Creativity in the Development of the Drug , Aripiprazole : A Novel Partial Dopamine D , Receptor Agonist for the Treatment of Schizophrenia ”, Seishin -Igaku , (Psychiatry ) , vol. 46 , pp . 855-864 , ( 2004 ) . Kikuchi et al. , “ Aripiprazole , A Novel Antipsychotic — A Dopamine D , Partial Agonist” , Nou -no -Kagaku , (Brain Science) , vol. 25 , pp . 579-583 , (2003 ) . * cited by examiner US RE48,059 E 1 2 PIPERAZINE - SUBSTITUTED ( wherein A is (CH2 ) mCH2 - ( CH2) m 10 or the like; m BENZOTHIOPHENES FOR TREATMENT OF is an integer of 2 to 5 ; D is N , C or the like ; Z and Q are MENTAL DISORDERS independently N , C or CH , provided that at least one of Z and Q is N ; X and Y are independently C , N or the like, and Matter enclosed in heavy brackets [ ] appears in the 5 the bond between X and Y is a single or double bond ; R ' is original patent but forms no part of this reissue specifica hydrogen , ( C , -C3 ) alkyl group or the like ; R4, RS, R and R ? tion ; matter printed in italics indicates the additions each represents hydrogen , alkyl group or the like; and G made by reissue ; a claim printed with strikethrough represents a group of monocyclic or bicyclic compound ) , indicates that the claim was canceled , disclaimed , or held which bind to dopamine D2 receptors . WO 2005/019215 A1 invalid by a prior post- patent action or proceeding. 10 teaches that some compounds disclosed therein have an activity as partial agonists of D2 receptors or an activity as antagonists of D2 receptors , and may be effective for the This patent application is a reissue application of U.S. treatment of schizophrenia and other central nervous system . Pat. No. 7,888,362, issued Feb. 15, 2011 , on application Ser. However, WO 2005/019215 Al does not specifically ApplicationNo. 11 /659,005 of PCT, filed/ JP2006 Apr. 12/308162 , 2006, , filed as the Apr. National 12, 2006 Stage, and 15 disclose the compounds of the present invention . claims foreign priority to JP 2005-116698, filed Apr. 14 , 2005 . DISCLOSURE OF THE INVENTION TECHNICAL FIELD An object of the present invention is to provide an 20 antipsychotic drug which has a wider treatment spectrum , The present invention relates to a novel heterocyclic less side effects and excellent tolerability and safety as compound . compared with well -known typical and atypical antipsy BACKGROUND ART chotic drugs. The present inventors have conducted intensive studies on Since causal factor of schizophrenia as well as of bipolar 25 the above -described problem and consequently succeeded in disorder, mood disorders and emotional disorders is hetero synthesizing a novel compound which has dopamine D2 geneous, it is desirable that a drug has multiple pharmaco receptor partial agonist activity ( D , receptor partial agonist logical effects so as to develop wide treatment spectrum . activity ), serotonin 5 -HT24 receptor antagonist activity WO2004 /026864A1 discloses that a carbostyril derivative (5 -HT2A receptor antagonist activity ) and adrenalin ay represented by the general formula : 30 receptor antagonist activity (Q , receptor antagonist activity ) and further has serotonin uptake inhibitory effect (or sero tonin reuptake inhibitory effect ) together in addition to these effects . The present invention has been completed based on this finding . 35 The present invention provides a heterocyclic compound represented by the general formula ( 1 ) : a -A ' N ( 1 ) - 40 R2 RA (wherein A ' represents (CH2 ) m CH2 ( CH2) , 0– etc .; m represents an integer of 1 to 4 ; and R4 represents a hydrogen atom , a C1-4 alkyl group which may be substituted 45 with 1 to 3 fluorine atoms, etc. ) has D2 receptor antagonist activity and serotonin 2A ( 5 -HT2 ) receptor antagonist activity and it is effective for treatment of schizophrenia and [ wherein ring Q represented by other central nervous system disorders ) . However, there is no description in WO2004 /026864A1 50 that carbostyril derivatives described in the document have D , receptor partial agonist activity , 5 -HT24 receptor antago nist activity , Q , receptor antagonist activity and serotonin represents (wherein uptake inhibitory activity together and have a wide treatment spectrum . 55 -Z -- Y WO 2005/019215 A1 discloses the compounds repre sented by the following formula : represents --NH - CH2- , -N = CH CH2 NH- or CH = N— ; and the carbon -carbon bond R ? R4 60 X between the 3 -position and 4 -position of the heterocyclic skeleton containing Z and Y represents a single bond or a double bond ); Ro RS the ring Q may have at least one substituent selected from 65 the group consisting of a lower alkyl group , a lower alkenyl R ! group , a lower alkynyl group, a hydroxy group , a lower alkoxy group , a halogenated lower alkyl group , an aryl US RE48,059 E 3 4 group , an aryl lower alkyl group, an aryl lower alkoxy C3 - C8 alkyl group , a cyclo C3 - C8 alkyl lower alkyl group , group , an arylcarbonyl group , a lower alkenyloxy group , a a halogen atom , a carbamoyl group which may have a lower lower alkanoyl group , a lower alkanoyloxy group , a alkyl group , a carboxy group , a lower alkoxycarbonyl group , cycloalkyl group , a cycloalkyl lower alkyl group, a halogen an amino group which may have lower alkanoyl group , a atom , a carbamoyl group which may have a lower alkyl 5 nitro group , a hydroxy lower alkyl group , an amino lower group , a carboxy group , a lower alkoxycarbonyl group, an alkyl group which may have a lower alkyl group , a thienyl amino group which may have a lower alkanoyl group , a nitro group and a saturated 5- to 6 -membered heteromonocyclic group , a hydroxy lower alkyl group , an amino lower alkyl group containing 1 to 2 nitrogen atoms- substituted lower group which may have a lower alkyl group , a thienyl group , alkyl group ; and a saturated 3- to 8 -membered heteromonocyclic group con 10 A represents 0 - A , - ( wherein . Aj represents a C1- C6 taining 1 to 2 nitrogen atoms- substituted lower alkyl group alkylene, group which may be substituted with a hydroxy and an oxo group ; group (wherein the alkylene group may contain one oxygen R , represents a hydrogen atom or a lower alkyl group ; and atom )) , or a salt thereof . A represents -O -A1- (wherein A , represents an alkylene The present invention provides a heterocyclic compound group which may be substituted with a hydroxy group 15 represented by the general formula ( 1 ) , wherein the ring Q (wherein the alkylene group may contain one oxygen atom ) represents a bicyclic group selected from the group consist or a lower alkenylene group ) or a lower alkylene group ; ing of: provided that when A represents a lower alkylene group , the ring Q represents a bicyclic group selected from the 20 group consisting of: and N N

and 25 H H N the ring Q may have 1 to 3 substituents selected from the ? group consisting of a lower alkyl group , a lower alkenyl group, a lower alkynyl group , a hydroxy group , a lower (wherein the carbon - carbon bond 30 alkoxy group , a halogenated lower alkyl group , a phenyl ----- group , a phenyl lower alkyl group , a naphthyl lower alkyl represents a single bond or a double bond )] or a salt thereof. group , a phenyl lower alkoxy group , a naphthyl lower The present invention provides a heterocyclic compound alkoxy group , a benzoyl group , a lower alkenyloxy group , a represented by the general formula (1 ) , lower alkanoyl group , a lower alkanoyloxy group , a cyclo wherein the ring Q represents a bicyclic group selected from 35 C3 -C8 alkyl group, a cyclo C3 -C8 alkyl lower alkyl group , the group consisting of: a halogen atom , a carbamoyl group which may have a lower alkyl group , a carboxy group , a lower alkoxycarbonyl group , an amino group which may have a lower alkanoyl group , a nitro group , a hydroxy lower alkyl group , an amino lower 40 alkyl group which may have a lower alkyl group , a phenyl group , a thienyl group and a pyrrolidinyl lower alkyl group ; and A represents O - A - (wherein A , represents a C1- C6 H w H alkylene group which may be substituted with a hydroxy 45 group (wherein the alkylene group may contain one oxygen atom )) , or a salt thereof. H The present invention provides a heterocyclic compound represented by the general formula ( 1 ) , wherein the ring Q represents a bicyclic group selected from the group consist N. N 50 ing of: H and

(wherein the carbon - carbon bond 55 and --- H H between the 3 -position and 4 -position of the bicyclic het erocyclic skeleton represents a single bond or a double bond ) ; the ring Q may have 1 to 3 substituents selected from the 60 ( the ring Q may have 1 to 3 substituents selected from the group consisting of a lower alkyl group, a lower alkenyl group consisting of a lower alkyl group, a lower alkenyl group , a lower alkynyl group , a hydroxy group , a lower group, a lower alkynyl group , a hydroxy group , a lower alkoxy group , a halogenated lower alkyl group , a phenyl alkoxy group , a halogenated lower alkyl group , a phenyl group , a phenyl lower alkyl group , a naphthyl lower alkyl group , a phenyl lower alkyl group , a naphthyl lower alkyl group , a phenyl lower alkoxy group , a naphthyl lower 65 group, a phenyl lower alkoxy group , a naphthyl lower alkoxy group , a benzoyl group , a lower alkenyloxy group , a alkoxy group , a benzoyl group , a lower alkenyloxy group , a lower alkanoyl group , a lower alkanoyloxy group , a cyclo lower alkanoyl group , a lower alkanoyloxy group , a cyclo US RE48,059 E 5 6 C3 -C8 alkyl group , a cyclo C3 - C8 alkyl lower alkyl group , lower alkanoyl group , a lower alkanoyloxy group , a cyclo a halogen atom , a carbamoyl group which may have a lower C3 -C8 alkyl group , a cyclo C3 - C8 alkyl lower alkyl group , alkyl group , a carboxy group , a lower alkoxycarbonyl group , a halogen atom , a carbamoyl group which may have a lower an amino group which may have a lower alkanoyl group , a alkyl group , a carboxy group , a lower alkoxycarbonyl group , nitro group, a hydroxy lower alkyl group , an amino lower 5 an amino group which may have a lower alkanoyl group , a alkyl group which may have a lower alkyl group , a thienyl nitro group , a hydroxy lower alkyl group , an amino lower group and a pyrrolidinyl lower alkyl group ) or a salt thereof. alkyl group which may have a lower alkyl group , a thienyl The present invention provides a heterocyclic compound group and a pyrrolidinyl lower alkyl group , or a salt thereof. represented by the general formula (1 ) , wherein the ring Q Among the heterocyclic compounds or salts thereof rep represents a bicyclic group selected from the group consist- 10 aresented compound by theor aformula salt thereof ( 1) , preferable selected from compounds : include ing of: (1 ) 7- [4- (4 - benzo [b ] thiophen -4 - yl- piperazin - 1- yl) butoxy ] 1H - quinolin - 2 - one , ( 2 ) 7-( 3- ( 4 -benzo [ b ]thiophen - 4 - yl- piperazin - 1 - yl) propoxy ] 15 1H - quinolin - 2 - one , and ( 3 ) 7- [3- ( 4 -benzo [b ] thiophen - 4 -yl - piperazin - 1- yl ) propoxy ] 3,4 - dihydro - 1H - quinolin - 2 -one , ( 4 ) 7-[ 4-( 4 -benzo [ b ] thiophen - 4 - yl- piperazin - 1 - yl) butoxy ] ? 3,4 -dihydro - 1H -quinolin - 2 -one , 20 (5 ) 7-[ 4- ( 4 -benzo [b ]thiophen -4 -yl - piperazin - 1 -yl ) butoxy ] (wherein the carbon -carbon bond 1 -methyl - 3,4 -dihydro - 1H - quinolin - 2 -one and (6 ) 6-( 3- ( 4 -benzo [b ] thiophen -4 - yl -piperazin - 1 -yl ) propoxy ] between the 3 -position and 4 -position of the above -men 3,4 -dihydro - 1H -quinolin - 2 -one ; or a salt thereof. tioned bicyclic heterocyclic skeleton represents a single In addition , among the heterocyclic compounds or salts bond or a double bond) ; 25 thereof represented by the formula (1 ), preferable com the ring Q may have 1 to 3 substituents thereon selected pounds include a compound or a salt thereof selected from : from the group consisting of a lower alkyl group , a lower ( 1 ) 7- [ 3-( 4 -benzo [ b ] thiophen - 4 - yl - piperazin - 1 - yl) propoxy ] alkenyl group , a lower alkynyl group , a hydroxy group , a 3,4 - dihydro -2H - isoquinolin - 1 -one lower alkoxy group , a halogenated lower alkyl group , a (2 ) 7- (3- (4 -benzo [b ] thiophen -4 -yl - piperazin - 1 -yl ) propoxy ) phenyl group , a phenyl lower alkyl group , a naphthyl lower 30 2 -methyl -3,4 -dihydro - 2H - isoquinolin - 1 -one , alkyl group , a phenyl lower alkoxy group , a naphthyl lower (3 ) 7- [4- (4 -benzo [b ] thiophen -4 - yl- piperazin - 1- yl ) butoxyl 2 -methyl - 3,4 -dihydro -2H - isoquinolin - 1 -one , alkoxy group , a benzoyl group, a lower alkenyloxy group , a ( 4 ) 7-[ 4- ( 4 -benzo [ b ]thiophen -4 -yl - piperazin - 1 -yl ) butoxy ] lower alkanoyl group , a lower alkanoyloxy group , a cyclo 3,4 - dihydro - 2H - isoquinolin -1 -one , aC3 halogen -C8 alkyl atom group , a carbamoyl , a cyclo C3 group - C8 whichalkyl lowermay have alkyl a grouplower , 35 (5 ) 7- ( 3- ( 4 - benzo [ b ] thiophen - 4 - yl- piperazin - 1 - yl) propoxy ) alkyl group , a carboxy group , a lower alkoxycarbonyl group , 2H - isoquinolin - 1 -one and an amino group which may have a lower alkanoyl group , a (6 ) 7- ( 3- ( 4 -benzo [b ] thiophen - 4 - yl -piperazin - 1 -yl ) propoxy ] nitro group, a hydroxy lower alkyl group , an amino lower 2 -methyl - 2H - isoquinolin - 1 -one ; or a salt thereof. alkyl group which may have a lower alkyl group , a thienyl The present invention provides a pharmaceutical compo group , a pyrrolidinyl lower alkyl group and an oxo group ; 40 sition comprising a heterocyclic compound represented by and the formula ( 1 ) or a salt thereof as an active ingredient mixed A represents a lower alkylene group , or a salt thereof. with a pharmaceutically acceptable carrier . The pharmaceu The present invention provides a heterocyclic compound tical composition according to the present invention can be represented by the general formula ( 1 ) , wherein the ring Q effectively used for the treatment or prevention of central represents a bicyclic group selected from the group consist- 45 nervousThe pharmaceutical system disorders composition. according to the present ing of: invention can be used as a pharmaceutical composition for treating or preventing central nervous system disorders selected from the group consisting of schizophrenia ; refrac 50 tory , intractable or chronic schizophrenia ; emotional distur and bance ; psychotic disorder ; mood disorder ; bipolar I type N disorder; bipolar II type disorder ; depression ; endogenous depression ; major depression ; melancholy and refractory depression ; dysthymic disorder ; cyclothymic disorder ; panic 55 attack ; panic disorder ; agoraphobia ; social phobia ; obses (wherein the carbon -carbon bond sive- compulsive disorder ; post- traumatic stress disorder ; generalized anxiety disorder ; acute stress disorder ; hysteria ; between the 3 -position and 4 -position of the above -men somatization disorder ; conversion disorder ; pain disorder; tioned bicyclic heterocyclic skeleton represents a single hypochondriasis ; factitious disorder ; dissociative disorder ; bond or a double bond ) ; 60 sexual dysfunction ; sexual desire disorder ; sexual arousal the ring Q may have 1 to 3 substituents selected from the disorder ; erectile dysfunction ; anorexia nervosa; bulimia group consisting of a lower alkyl group , a lower alkenyl nervosa ; sleep disorder ; adjustment disorder ; alcohol abuse ; group , a lower alkynyl group , a hydroxy group , a lower alcohol intoxication ; drug addiction ; stimulant intoxication ; alkoxy group , a halogenated lower alkyl group , a phenyl narcotism ; anhedonia ; iatrogenic anhedonia ; anhedonia of a group , a phenyl lower alkyl group, a naphthyl lower alkyl 65 psychic or mental cause ; anhedonia associated with depres group , a phenyl lower alkoxy group , a naphthyl lower sion ; anhedonia associated with schizophrenia ; delirium ; alkoxy group , a benzoyl group , a lower alkenyloxy group , a cognitive impairment; cognitive impairment associated with US RE48,059 E 7 8 Alzheimer's disease , Parkinson's disease and other neuro As a lower alkyl group, a linear or branched alkyl group degenerative diseases; cognitive impairment caused by having 1 to 6 carbon atoms can be mentioned . More spe Alzheimer's disease , Parkinson's disease and associated cifically , methyl, ethyl, n - propyl, isopropyl, n -butyl , isobu neurodegenerative diseases; cognitive impairment of schizo tyl , tert -butyl , sec- butyl, n - pentyl, 1 -ethylpropyl , isopentyl, phrenia ; cognitive impairment caused by refractory, intrac- 5 neopentyl , n -hexyl , 1,2,2 -trimethylpropyl , 3,3 -dimethylbu table or chronic schizophrenia ; vomiting ; motion sickness ; tyl, 2 -ethylbutyl , isohexyl , 3 -methylpentyl groups are included . obesity ; migraine ; pain (ache ) ; mental retardation ; autism As a lower alkoxy group , a linear or branched alkoxy disorder ( autism ) ; Tourette's disorder ; tic disorder ; atten group having 1 to 6 carbon atoms can be mentioned . More tion - deficit/ hyperactivity disorder; conduct disorder; and 10 specifically , methoxy, ethoxy , n - propoxy, isopropoxy , n - bu Down's syndrome. toxy , isobutoxy, tert -butoxy , sec -butoxy , n -pentyloxy , iso The present invention provides a process for producing a pentyloxy , neopentyloxy, n - hexyloxy, isohexyloxy , 3 -meth pharmaceutical composition comprising mixing a heterocy ylpentyloxy groups are included . clic compound represented by the above -described formula As a lower alkenyl group , a linear or branched alkenyl ( 1 ) or a salt thereof with a pharmaceutically acceptable 15 group having 1 to 3 double bonds and 2 to 6 carbon atoms carrier. can be mentioned including the both of trans and cis The present invention provides use of a heterocyclic configurations . More specifically , vinyl, 1 - propenyl , 2 -pro compound represented by the above -described formula ( 1 ) penyl, 1 -methyl - 1 - propenyl, 2 -methyl - 1 - propenyl, or a salt thereof as a drug . Specifically provided is of a 2 -methyl - 2 -propenyl , 2 -propenyl , 2 -butenyl , 1 -butenyl , heterocyclic compound represented by the above- described 20 3 - butenyl, 2 - pentenyl, 1- pentenyl, 3 -pentenyl , 4 - pentenyl, formula (1 ) or a salt thereof, as a dopamine D2 receptor 1,3 -butadienyl , 1,3 - pentadienyl, 2 - penten -4 - yl, 2- hexenyl , partial agonist and / or a serotonin 5 -HT24 receptor antagonist 1 -hexenyl , 5 -hexenyl , 3 - hexenyl, 4 -hexenyl , 3,3 -dimethyl and / or an adrenaline Q , receptor antagonist and /or a sero 1 -propenyl , 2 - ethyl- 1 - propenyl , 1,3,5 - hexatrienyl, 1,3 - hexa tonin uptake inhibitor (or a serotonin reuptake inhibitor ). dienyl, 1,4 -hexadienyl groups are included . The present invention provides a method for treating or 25 As a lower alkynyl group , a linear or branched alkynyl preventing a central nervous system disorder comprising group having 2 to 6 carbon atoms can be mentioned . More administering a compound represented by the above -de specifically , ethynyl, 2 -propynyl , 2 -butynyl , 3 -butynyl , scribed formula (1 ) or a salt thereof to human or animal. 1 -methyl - 2 -propynyl , 2 -pentynyl , 2- hexynyl groups are The present invention provides a process for producing a included . heterocyclic compound represented by the above -described 30 As a halogen atom , fluorine atom , chlorine atom ,bromine atom and iodine atom can be mentioned . formula ( 1 ): As a halogenated lower alkyl group , a lower alkyl group as illustrated above substituted with 1 7 halogen atoms, ( 1 ) preferably 1 to 3 halogen atoms can be mentioned . More R2 35 specifically , fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl , trichloromethyl, bromom A - N ethyl , dibromomethyl , dichlorofluoromethyl, 2,2 -difluoro ( 9) ethyl, 2,2,2 - trifluoroethyl, pentafluoroethyl, 2 - fluoroethyl , 2 - chloroethyl, 3,3,3 - trifluoropropyl, heptafluoropropyl, 2,2 , 40 3,3,3 -pentafluoropropyl , heptafluoroisopropyl, 3 - chloropro pyl, 2 -chloropropyl , 3 -bromopropyl , 4,4,4 - trifluorobutyl, 4,4,4,3,3 -pentafluorobutyl , 4 -chlorobutyl , 4 -bromobutyl , or a salt thereof, characterized by comprising a reaction of 2 -chlorobutyl , 5,5,5 -trifluoropentyl , 5 - chloropentyl, 6,6,6 a compound represented by the formula : trifluorohexyl, 6 - chlorohexyl, perfluorohexyl are included . 45 As an aryl group , for example, phenyl , biphenyl, naphthyl groups can be mentioned and as a substituent on the phenyl ring or naphthalene ring , a lower alkyl group (preferably -A - X1 linear or branched alkyl group having 1 to 6 carbon atoms) e7 as illustrated above , lower alkoxy group (preferably linear or 50 branched alkoxy group having 1 to 6 carbon atoms) as (wherein the ring Q and A are the sameas defined above, and illustrated above , and phenyl, biphenyl, or naphthyl groups X , represents a halogen atom or a group which causes a which may have 1 to 3 groups selected from a nitro group substitution reaction the same as in a halogen or salt and a halogen atom are included . thereof with a compound represented by the formula : Specific examples of an aryl group include phenyl, 2- ( or 55 3- or 4-) methylphenyl , 2- (or 3- or 4-) nitrophenyl, 2- (or 3 or 4-) methoxyphenyl , 2- (or 3- or 4-) chlorophenyl , biphenyl , R2 a -naphthyl , ß -naphthyl groups . As an aryl lower alkyl group , a lower alkyl group (pref HN erably linear or branched alkyl group having 1 to 6 carbon 60 atoms) as illustrated above which has 1 to 3 , preferably one aryl group as illustrated above can be mentioned . S Specific examples of an aryl lower alkyl group include benzyl , 2- (or 3- or 4-) methylbenzyl , 2- ( or 3- or 4-) nitrobenzyl, 2- ( or 3- or 4-) methoxybenzyl , 2- (or 3- or 4-) (wherein R , is the same as defined above) or a salt thereof . 65 chlorobenzyl , 1- (or 2-) phenylethyl , 1 -methyl - 1- phenyl Specifically , respective groups shown in the above gen ethyl, 1,1- dimethyl -2 -phenylethyl , 1,1 -dimethyl - 3 - phenyl eral formula ( 1 ) are as follows. propyl, a -naphthylmethyl , ß -naphthylmethyl groups . US RE48,059 E 9 10 As an aryl lower alkoxy group , a lower alkoxy group As an amino group which may have a lower alkanoyl ( preferably linear or branched alkoxy group having 1 to 6 group , those having one lower alkanoyl group as illustrated carbon atoms) as illustrated above which has 1 to 3 , pref above (preferably a linear or branched alkanoyl group erably one aryl group as illustrated above can be mentioned . having 1 to 6 carbon atoms) can be mentioned . More Specific examples of an aryl lower alkoxy group include 5 specifically , examples include amino , N - formylamino , benzyloxy, 2- (or 3- or 4-) methylbenzyloxy, 2- (or 3- or 4-) N -acetylamino groups. nitrobenzyloxy, 2- (or 3- or 4-) methoxy benzyloxy , 2-( or 3 As a hydroxy lower alkyl group , a lower alkyl group or 4-) chlorobenzyl, 1- (or 2-) phenylethoxy , 1 -methyl - 1 (preferably , a linear or branched alkyl group having 1 to 6 phenyl ethoxy, 1,1 -dimethyl - 2 -phenyl ethoxy , 1,1- dimethyl carbon atoms) as illustrated above having 1 to 5 , preferably 3 -phenyl propoxy , a -naphthylmethoxy , B -naphthylmethoxy 10 1 to 3 hydroxy groups can be mentioned . More specifically groups . included are hydroxymethyl, 2 -hydroxyethyl , 1 -hydroxy As an aryl moiety of an arylcarbonyl group , an aryl group ethyl , 3 -hydroxypropyl , 2,3 -dihydroxypropyl , 4 -hydroxybu as illustrated above can bementioned . Specific examples of tyl , 3,4 - dihydroxybutyl , 1,1 -dimethyl - 2 -hydroxyethyl , 5 -hy an arylcarbonyl group include benzoyl, 2- (or 3- or 4- )meth droxypentyl, 6 -hydroxyhexyl , 3,3 -dimethyl - 3 ylbenzoyl, 2- ( or 3- or 4-) nitrobenzoyl, 2- (or 3- or 15 hydroxypropyl, 2 -methyl - 3 -hydroxypropyl , 2,3,4 4-) methoxybenzoyl, 2- ( or 3- or 4-) chlorobenzoyl, a -naph trihydroxybutyl, perhydroxyhexyl groups . thoyl, ß -naphthoyl groups . As an amino lower alkyl group which may have a lower As a lower alkenyloxy group , a lower alkenyloxy group alkyl group , a lower alkyl group (preferably , a linear or having a lower alkenyl group (preferably a linear or branched alkyl group having 1 to 6 carbon atoms ) as branched alkenyloxy group having 1 to 3 double bonds and 20 illustrated above having 1 to 5 , preferably one amino group 2 to 6 carbon atoms) as illustrated above can be mentioned . which may have 1 to 2 lower alkyl group (preferably , a linear More specifically included are vinyloxy, 1- propenyloxy , or branched alkyl group having 1 to 6 carbon atoms) as 1 -methyl - 1 -propenyloxy , 2 -methyl - 1 - propenyloxy , 2 -prope illustrated above can be mentioned . More specifically , nyloxy, 2 - butenyloxy, 1 -butenyloxy , 3 -butenyloxy , 2 -pente examples of such an amino lower alkyl group which may nyloxy, 1 -pentenyloxy , 3 -pentenyloxy , 4 -pentenyloxy , 1,3- 25 have a lower alkyl group include aminomethyl, 2 -amino butadienyloxy, 1,3 -pentadienyloxy , 2 -penten -4 -yloxy , ethyl, 1- aminoethyl, 3 -aminopropyl , 4 - aminobutyl , 2 -hexenyloxy , 1 -hexenyloxy , 5 -hexenyloxy , 3 - hexenyloxy, 5 -aminopentyl , 6 - aminohexyl, 1,1- dimethyl - 2 -methyl - 3 4 -hexenyloxy , 3,3- dimethyl- 1 - propenyloxy , 2 - ethyl- 1 -pro aminopropyl , N ,N -dimethylaminomethyl , N -methyl -N - eth penyloxy , 1,3,5- hexatrienyloxy , 1,3 -hexadienyloxy , 1,4 ylaminomethyl, N -methylaminomethyl , 2- (N -methylamino ) hexadienyloxy groups . 30 ethyl , 1 -methyl - 2- ( N ,N -dimethylamino )ethyl , 2- (N ,N As a lower alkanoyl group , a linear or branched alkanoyl dimethylamino ) ethyl, 2-( N , N -diethylamino ) ethyl, 2- (N , N group having 1 to 6 carbon atoms can be mentioned . More diisopropylamino )ethyl , 3-( N , N - dimethylamino )propyl , specifically, formyl , acetyl, propionyl, butyryl, isobutyryl, 3-( N ,N -diethylamino )propyl groups . pentanoyl , tert - butylcarbonyl , hexanoyl groups are included . As a saturated 3- to 8 -membered heteromonocyclic group As a lower alkanoyloxy group , a linear or branched 35 containing 1 to 2 nitrogen atoms group , for example , aze alkanoyloxy group having 1 to 6 carbon atoms can be tidinyl , pyrrolidinyl, imidazolidinyl , pyrazolidinyl , piperidi mentioned . More specifically , formyloxy, acetyloxy , propio nyl, piperazinylmorpholinyl , thiomorpholinyl groups (pref nyloxy, butyryloxy, isobutyryloxy, pentanoyloxy , tert -butyl erably a saturated 5- to 6 -membered heteromonocyclic carbonyloxy, hexanoyloxy groups are included . group containing 1 to 2 nitrogen atoms group such as As a cycloalkyl group , a cyclo C3 -C8 alkyl group having 40 pyrrolidinyl , imidazolidinyl, piperidinyl, piperidino , pyra 3 to 8 carbon atoms can be mentioned . Examples thereof zolidinyl and piperazinyl) can be mentioned . include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, As a saturated 3- to 8 -membered heteromonocyclic group cycloheptyl , cyclooctyl groups . containing 1 to 2 nitrogen atoms- substituted lower alkyl As a cycloalkyl lower alkyl group , a lower alkyl group as group , a lower alkyl (preferably , a linear or branched alkyl illustrated above which has 1 to 3 , preferably one cycloalkyl 45 group having 1 to 6 carbon atoms) as illustrated above group (preferably , cyclo C3 - C8 alkyl group having 3 to 8 having 1 to 2 (preferably one ) a saturated 3- to 8 -membered carbon atoms) as illustrated above can be mentioned . More (preferably 5- to 6 -membered ) heteromonocyclic group con specifically included are cyclopropylmethyl, cyclohexylm taining 1 to 2 nitrogen atoms as illustrated above can be ethyl, 2 - cyclopropylethyl, 1 -cyclobutylethyl , cyclopentylm mentioned . More specifically , [( 1-, 2- or 3- ) azetidinyl ] ethyl, 3 -cyclopentylpropyl , 4 - cyclohexylbutyl, 5 -cyclohep- 50 methyl, [ (1- , 2- or 3-) pyrrolidinyl ]methyl , [( 1- , 2- or 4 - ) tylpentyl, 6 -cyclooctylhexyl , 1,1 -dimethyl - 2 imidazolidinyl] methyl , [ ( 1- , 3- or 4 - ) -pyrazolidinyl ] methyl , cyclohexylethyl, 2 -methyl - 3 -cyclopropylpropyl groups . [ (1- , 2-, 3- or 4 -) -piperidyl ] methyl , [( 2-, 3- or 4-) morpholi As a carbamoyl group which may have a lower alkyl nyl ]methyl , 2 -[ ( 1-, 2- or 3- )pyrrolidinyl ] ethyl, 1- [( 1- , 2- or group , a carbamoyl group which may have 1 to 2 lower alkyl 3 - ) -pyrrolidinyl ] ethyl, 3 - [ ( 1-, 2- or 3-) piperidyl] propyl, group (preferably , alkyl group having 1 to 6 carbon atoms) 55 4 - [ ( 1- , 2- or 3-) pyrrolidinyl ] butyl , 5 - [( 1-, 2- or 3 - )- piperidyl ] as illustrated above can be mentioned . More specifically pentyl are included . included are carbamoyl, N -methylcarbamoyl , N ,N - dimeth Examples of an alkylene group which may be substituted ylcarbamoyl, N -methyl - N - ethylcarbamoyl groups. with a hydroxy group (wherein the alkylene group may As a lower alkoxycarbonyl group , those having a lower contain one oxygen atom ) include a linear or branched alkoxy moiety as illustrated above, preferably a linear or 60 alkylene group ( wherein the alkylene group may contain one branched alkoxycarbonyl group having 1 to 6 carbon atoms oxygen atom ) having 1 to 12 (preferably 1 to 6 ) carbon can be mentioned . More specifically included are methoxy atoms such as methylene, ethylene, trimethylene , 2 -methyl carbonyl, ethoxycarbonyl, n -propoxycarbonyl , isopropoxy trimethylene , 2- hydroxytrimethylene , 3- hydroxytetrameth carbonyl, n -butoxycarbonyl , isobutoxycarbonyl , tert -bu ylene, 3 -methyltetramethylene , 2,2 - dimethyltrimethylene , toxycarbonyl , sec - butoxycarbonyl, n -pentyloxycarbonyl , 65 1 -methyltrimethylene , methylmethylene , ethylmethylene , neopentyloxy, n -hexyloxy carbonyl, isohexyloxycarbonyl, tetramethylene , pentamethylene , hexamethylene, 2 - ethoxy 3 -methylpentyloxycarbonyl groups. ethylene ( CH2CH OCH CH2– ) , methoxymethylene US RE48,059 E 11 12 ( CHQOCH2– ) , 1 -ethoxyethylene ( CH.CH OCH A halogen atom shown as X , in the general formula ( 2 ) is (CH ) ), 2 -methoxyethylene ( CHOCH , CH , - ), the same as defined above . 2 -propoxyethylene ( CH_CH_CH_OCH ,CH - ) , 3 - iso As a lower alkanesulfonyloxy group shown as X1, propoxytrimethylene ( CH (CH3 ) CH2OCH2CH2– ), 4 -bu examples include a linear or branched alkanesulfonyloxy toxytetramethylene 5 group having 1 to 6 carbon atoms such as methanesulfony loxy, ethanesulfonyloxy , n -propanesulfonyloxy , isopropane ( CH CH , CH, CH, OCH- CH- CH- CH2- ), 5 -pentyloxy sulfonyloxy, n -butanesulfonyloxy , tert- butanesulfonyloxy, pentamethylene n -pentanesulfonyloxy and n -hexanesulfonyloxy groups. ( CH2CH2CH2CH2CH2OCH2CH2CH2CH2CH2- ) As an arylsulfonyloxy group shown as X , examples 6 -hexyloxyhexamethylene 10 include phenylsulfonyloxy and naphthylsulfonyloxy groups ( CH - CH- CH - CH - CH- CH - OCH - CH - CH- CH - CH- CH2- ) which may have 1 to 3 substituents selected from the group 1,1- dimethyl - 2 -methoxyethylene ICH OCH , C consisting of a linear or branched alkyl group having 1 to 6 (CH3 ) 2– ) . 2 -methyl -3 - ethoxytrimethylene carbon atoms, a linear or branched alkoxy group having 1 to CH , CH , OCH , CH (CH3 ) CH2 ) , 3 -methoxytrimethyl 6 carbon atoms, a nitro group and a halogen atom on the ene ( CHOCH2CH2CH2CH2– ) groups . 15 phenyl ring , for example . Specific examples of a phenylsul Examples of a lower alkenylene group include a linear or fonyloxy group which may have a substituent include phe branched alkenylene group having 1 to 3 double bonds and nylsulfonyloxy, 4 -methylphenylsulfonyloxy , 2 -methylphe 2 to 6 carbon atoms such as vinylene, 1 -propenylene , nylsulfonyloxy, 4 -nitrophenylsulphonyloxy , 1 -methyl - 1- propenylene , 2 -methyl - 1 - propenylene, 2- prope 4 -methoxyphenylsulfonyloxy , 2 -nitrophenylsulphonyloxy , nylene, 2 -butenylene , 1 - butenylene , 3 -butenylene , 2 - pente- 20 3 -chlorophenylsulphonyloxy groups . Specific examples of a nylene, 1 -pentenylene , 3 -pentenylene , 4 -pentenylene , 1,3 naphthylsulfonyloxy group include a -naphthyl sulfonyloxy , butadienylene, 1,3 - pentadienylene , 2 -pentene - 4 - ylene , B -naphthyl sulfonyloxy groups. 2 -hexenylene , 1 -hexenylene , 5 -hexenylene , 3 -hexenylene , As an aralkylsulfonyloxy group shown as X?, examples 4 -hexenylene , 3,3 - dimethyl- 1- propenylene, 2 - ethyl- 1 -pro include a linear or branched alkanesulfonyloxy group having penylene , 1,3,5 -hexatrienylene , 1,3 - hexadienylene, 1,4- 25 1 to 6 carbon atoms and substituted with a phenyl group, a hexadienylene groups. linear or branched alkanesulfonyloxy group having 1 to 6 Examples of a lower alkylene group include a linear or carbon atoms and substituted with a naphthyl group , which branched alkenylene group having 1 to 6 carbon atoms such groups which may have 1 to 3 substituents selected from the as methylene, ethylene, trimethylene , 2 -methyltrimethylene , group consisting of a linear or branched alkyl group having 30 1 to 6 carbon atoms, a linear or branched alkoxy group 3 -methyltetramethylene , 2,2 -dimethyltrimethylene , 1- meth having 1 to 6 carbon atoms, a nitro group and a halogen atom yltrimethylene, methylmethylene , ethylmethylene, tetram on the phenyl ring, for example . Specific examples of a ethylene , pentamethylene and hexamethylene groups . phenylsulfonyloxy group substituted with a naphthyl group The heterocyclic compound represented by the above as mentioned above include benzylsulfonyloxy , 2 -phenyl described general formula ( 1) can be produced in various 35 ethylsulfonyloxy, 4 -phenylbutylsulfonyloxy , 4 -methylben kinds of methods , but, for example , it can be produced by a zylsulfonyloxy, 2 -methylbenzylsulfonyloxy , 4 -nitrobenzyl method shown in the following reaction formula . sulfonyloxy , 4 -methoxybenzylsulfonyloxy , 3 - chlorobenzylsulfonyloxy groups. Specific examples of an alkanesulfonyloxy group substituted with a naphthyl group [Reaction Formula 1 ] 40 as mentioned above include a - naphthylmethyl sulfonyloxy , R2 B -naphthylmethyl sulfonyloxy groups. The reaction of a compound represented by the general formula ( 2 ) and a compound represented by the general HN formula ( 3 ) is performed without solvent or in an inert 45 solvent in the absence or presence of a basic compound . Examples of an inert solvent include water; ethers such as S dioxane , tetrahydrofuran , diethyl ether , diethylene glycol ( 3 ) dimethyl ether , ethylene glycol dimethyl ether; aromatic A — X1 hydrocarbons such as benzene, toluene, xylene ; lower alco 50 hols such as methanol, ethanol, isopropanol; ketones such as ( 2 ) acetone , methyl ethyl ketone ; polar solvents such as N ,N R2 dimethylformamide (DMF ) , dimethylsulfoxide ( DMSO ) , hexamethylphosphoric triamide, acetonitrile . -A - N As a basic compound , known compounds can be widely 55 used and examples include alkali metal hydroxides such as sodium hydroxide , potassium hydroxide , cesium hydroxide, S lithium hydroxide; alkali metal carbonates such as sodium carbonate , potassium carbonate , cesium carbonate , lithium ( 1 ) carbonate ; alkaline metal hydrogen carbonates such as 60 lithium hydrogen carbonate , sodium hydrogen carbonate , (wherein ring Q , A and R , are the same as defined above, and potassium bicarbonate ; alkaline metals such as sodium , X ,1 represents a halogen atom or a group which causes a potassium ; inorganic bases such as sodium amide , sodium substitution reaction the same as in a halogen atom ). hydride , potassium hydride and alkaline metal alcoholates Here, examples of a group which causes a substitution such as sodium methoxide, sodium ethoxide , potassium reaction the same as in a halogen atom include a lower 65 methoxide , potassium ethoxide ; organic bases such as tri alkanesulfonyloxy group , an arylsulfonyloxy group and an ethylamine , tripropylamine, pyridine, quinoline , piperidine , aralkylsulfonyloxy group . imidazole , N -ethyldiisopropylamine , dimethylaminopyri US RE48,059 E 13 14 dine , trimethylamine , dimethylaniline , N -methylmorpho As a condensing agent, azocarboxylates such as diethyl line , 1,5 -diazabicyclo [ 4.3.0 ]nonene - 5 (DBN ) , 1,8 -diazabi azodicarboxylate and a mixture of phosphorus compounds cyclo [ 5.4.0 ]undecene -7 (DBU ), 1,4 -diazabicyclo [ 2.2.2 ] such as triphenylphosphine can be mentioned . octane (DABCO ) . The amount of a condensing agent to be used is usually at As for these basic compounds, one kind of compound 5 least equimolar, preferably equimolar to 2 times the amount alone or two or more in combination can be used . of compound ( 4 ) The amount to be used of a basic compound is usually 0.5 The amount of compound (5a ) to be used is usually at to 10 times , preferably 0.5 to 6 times molar amount of a least equimolar, preferably equimolar to 2 times the amount compound of the general formula ( 2 ) . of compound ( 4 ) . The above -described reaction can be performed with 10 This reaction precedes usually 0 to 200 ° C., preferably 0 addition of an alkaline metal iodide such as potassium iodide , sodium iodide as a reaction accelerator, if necessary . to 150 ° C. and generally completed in about 1 to 10 hours . As for the ratio to be used of a compound of the general formula ( 2 ) and a compound of the general formula ( 3 ) in the above -mentioned reaction Formula 1 , the latter may be 15 [ Reaction Formula 3 ] usually at least 0.5 times , preferably , 0.5 to 5 times molar R2 amount of the former. The above -described reaction is performed usually from room temperature to 200 ° C., preferably from room tem X3 - A2 - N perature to 150 ° C. and generally completed in about 1 to 30 20 hours . S ( 5b ) [Reaction Formula 2 ] Q1 H R2 25 ( 6) R2 X2 — A - N Q1 + A2 - N 30 S

Q -OH (5a ) @ ( 1b ) ( 4 ) R2 35 [wherein R , is the same as above , Xz represents a halogen atom or a group which causes a substitution reaction similar e -O. - A - N to a halogen atom , A , represents a lower alkylene group , and the ring Q1 represents a bicyclic group selected from the 40 group consisting of: (la ) (wherein ring Q , R2 and A are the same as defined above. 45 and X2 represents a hydroxy group , a halogen atom or a group N. which causes a substitution reaction similar to a halogen atom ). The reaction of a compound represented by the general formula ( 4 ) and a compound represented by the general 50 (wherein the carbon - carbon bond formula (5a ) is performed under similar reaction condition ----- as in the reaction of a compound represented by the general represents a single bond or a double bond ) ; formula ( 2 ) and a compound represented by the general the ring Q1 may have at least one substituent selected formula ( 3 ) in the above -mentioned Reaction Formula 1 . from the group consisting of a lower alkyl group , a lower In the case of a compound (5a ) in which X , represents a 55 alkenyl group , a lower alkynyl group , a hydroxy group , a hydroxy group, the reaction of a compound ( 4 ) and a lower alkoxy group , an aryl group , an aryl lower alkyl compound (5a ) can be performed in an appropriate solvent group , an aryl lower alkoxy group , a lower alkenyloxy in the presence of a condensing agent. group , a lower alkanoyl group , a lower alkanoyloxy group , As for the solvent usable here , specific examples include a cycloalkyl group , a cycloalkyl ( lower ) alkyl group , a halogenated hydrocarbons such as chloroform , dichlo- 60 halogen atom , a carbamoyl group which may have a lower romethane , dichloroethane , carbon tetrachloride ; aromatic alkyl group , a carboxy group , a lower alkoxycarbonyl group , hydrocarbons such as benzene, toluene , xylene ; ethers such an amino group which may have a lower alkanoyl group , a as diethyl ether , diisopropyl ether , tetrahydrofuran , dime nitro group , a hydroxy lower alkyl group , an amino lower thoxyethane ; esters such as methyl acetate , ethyl acetate , alkyl group which may have a lower alkyl group , a thienyl isopropyl acetate ; polar solvent such as acetonitrile , pyri- 65 group , a saturated 3- to 8 -membered heteromonocyclic dine , acetone , DMF, DMSO , hexamethylphosphoric tri group containing 1 to 2 nitrogen atoms- substituted lower amide or a mixed solvent of these . alkyl group and an oxo group ] . US RE48,059 E 15 16 The reaction of a compound represented by the general As for inert solvent usable here, examples include water ; formula ( 6 ) and a compound represented by the general aromatic hydrocarbons such as benzene, toluene , xylene ; formula (5b ) is performed under similar reaction condition ethers such as diethyl ether, tetrahydrofuran , dioxane, mono as in the reaction of a compound represented by the general glyme, diglyme; halogenated hydrocarbons such as dichlo formula ( 2 ) and a compound represented by the general 5 romethane , dichloroethane, chloroform , carbon tetrachlo formula ( 3 ) in the above -mentioned Reaction Formula 1 . ride; lower alcohols such as methanol , ethanol, isopropanol, The compound represented by the general formula ( 2 ), butanol, tert -butanol , ethylene glycol; fatty acids such as which is used as a starting material, can be produced , for acetic acid ; esters such as ethyl acetate , methyl acetate ; example , according to the following reaction Formula 4 and ketones such as acetone , methyl ethyl ketone ; acetonitrile , the compound represented by the general formula ( 5 ) can be 10 pyridine, DMF, DMSO , hexamethylphosphoric triamide or a produced , for example , according to the Reaction Formula 5 mixed solvent of these . below respectively . As for the acid , examples include mineral acids such as hydrobromic acid , hydrochloric acid , concentrated sulfuric 15 acid ; fatty acids such as formic acid , acetic acid , organic [Reaction Formula 4 ] acids such as p - toluenesulfonic acid ; Lewis acids such as X3 — A1 - X1 aluminum chloride , zinc chloride , iron chloride, tin chloride , ( 8 ) boron trifluoride , boron tribromide; iodides such as sodium OH -0 - A1 - X1 iodide , potassium iodides; a mixture of a Lewis acid and an @ 20 iodide as mentioned above . ( 4 ) (2a ) It is suitable that such an acid is usually used at 0.1 to 15 times , preferably 0.5 to 10 times molar amount of compound (wherein ring Q , A1, X , and X3 are the same as above ) . ( 1 ) . When the reaction is effected without solvent, the acid The reaction of a compound represented by the general is usually used in a large excess amount. formula ( 4 ) and a compound represented by the general 25 This reaction is performed usually 0 to 150 ° C., preferably at around 0 to 100 ° C., and generally completed for about formula ( 8 ) is performed under similar reaction condition as 0.5 to 75 hours . in the reaction of a compound represented by the general The starting compounds used in each of the above reac formula (4 ) and a compound represented by the general tion formula may be suitable salt, the object compound formula (5a ) in the above -mentioned Reaction Formula 2 . 30 obtained by each of the reaction may form a suitable salt . Such suitable salts include the preferable salts of compound ( 1) exemplified below . [Reaction Formula 5 ] The preferable salts of compound ( 1) are pharmacologi R2 cally acceptable salts and examples include metal salts such X2 — A - X4 35 as alkali metal salts ( for example , sodium salt potassium HN salt, etc. ), alkaline earth metal salts ( for example , calcium ( 9 ) salt, magnesium salt , etc.) , salts of inorganic bases such as ammonium salt, alkaline metal carbonates ( for example , lithium carbonate , potassium carbonate , sodium carbonate , 40 cesium carbonate , etc.) , alkaline metal hydrogen carbonates ( for example , lithium hydrogen carbonate , sodium hydrogen R2 carbonate , potassium bicarbonate , etc.) , alkali metal hydrox ides ( for example , lithium hydroxide, sodium hydroxide , potassium hydroxide , cesium hydroxide, etc. ); for example, X2 - A — N 45 salts of organic bases such as tri( lower) alkylamine ( for example , trimethylamine, triethylamine, N - ethyldiisopro pylamine) , pyridine , quinoline, piperidine, imidazole , pico line , dimethylaminopyridine , dimethylaniline , N-( lower ) (5 ) alkyl- morpholine ( for example, N -methylmorpholine ), 1,5 50 diazabicyclo [ 4.3.0 ]nonene - 5 (DBN ) , 1,8 -diazabicyclo [5.4.O ] undecene - 7 (DBU ) , 1,4 -diazabicyclo [ 2.2.2 ] octane ( wherein R2, A and X , are the same as above , and X4 (DABCO ) ; salts of inorganic acids such as hydrochloride, represents a halogen atom or a group which causes a hydrobromide , hydroiodide , sulfate , nitrate , phosphate ; salts substitution reaction the same as in a halogen atom ) . of organic acids such as formate , acetate , propionate , The reaction of a compound represented by the general 55 oxalate , malonate , succinate , fumarate , maleate , lactate , formula (3 ) and a compound represented by the general malate , citrate , tartrate , carbonate , picrate , methanesul formula (9 ) is performed under similar reaction condition as fonate , ethanesulfonate , p -toluenesulfonate , glutamate . in the reaction of a compound represented by the general In addition , compounds in the form in which solvate ( for formula ( 2) and a compound represented by the general example , hydrate , ethanolate, etc. ) was added to the starting formula (3 ) in the above- mentioned Reaction Formula 1. 60 compounds and object compound shown in each of the Both the compound of the general formula ( 3 ) and the reaction formulae are included in each of the general for compound of the general formula ( 9 ) are well -known com mulas. As a preferable solvate , hydrate can be mentioned . pounds readily available . Each of the object compounds obtained by each of the In compound (1 ), a compound having a hydroxy group at general formulas can be isolated and purified from the ring Q can be produced by treating a compound having a 65 reaction mixture by, for example , subjecting the reaction methoxy group at ring Q in compound ( 1 ) in the presence of mixture to isolation operation such as filtration , concentra an acid in an appropriate solvent or without solvent . tion and extraction after cooling to separate a crude reaction US RE48,059 E 17 18 product followed by conventional purification operation preservative, aromatic , flavor , sweetening and other phar such as column chromatography or recrystallization . maceuticals may be further contained as required . The compound represented by the general formula (1 ) of The amount of a compound of the general formula ( 1 ) or the present invention naturally encompasses isomers such as a salt thereof to be contained in the pharmaceutical prepa geometrical isomer , stereoisomer and enantiomer . 5 ration of the present invention is not particularly limited but The compound of the general formula ( 1 ) and a salt usually about 1 to 70 % by weight in the preparation com thereof can be used in a common form of pharmaceutical position is suitable and preferably about 1 to 30 % by weight. preparation . The pharmaceutical preparation is prepared by There is not limitation in particular in the way of admin using usually used diluent or excipient such as filler, extend istration of the pharmaceutical preparation of the present ing agent, binder, humectant, disintegrating agent, surfactant 10 invention and may be administered by a method in accor and lubricant. As for this pharmaceutical preparation , vari dance with specific form of the preparation , age , sex and the ous forms can be selected depending on the purpose of other conditions of a patient, severity of disease , etc. For treatment, and typical examples include a tablet, pill , pow example , in the case of tablet , pill, solution , suspension , der, solution , suspension , emulsion , granule , capsule , sup- 15 emulsion , granule and capsule , it is orally administered . In pository , and injection ( solution , suspension ) . the case of injection , it is intravenously administered alone For shaping in tablet form , various materials convention or in a mixture with conventional replacement fluid such as ally well known as carrier in the art can be widely used . As glucose and amino acids, and if necessary, and the prepa examples, excipient such as lactose, saccharose , sodium ration alone may be also administered intramuscularly , intra chloride , glucose , urea , starch , calcium carbonate , kaolin , 20 cutaneously , subcutaneously or interperitoneally . It is crystalline cellulose , silicate ; binder such as water , ethanol, administered in rectum in the case of suppository. propanol, simple syrup , glucose solution , starch liquid , Applied dose of the pharmaceutical preparation of the gelatine solution , carboxymethylcellulose , shellac , methyl present invention is appropriately selected in accordance cellulose , potassium phosphate , polyvinylpyrrolidone ; dis with dosage regimen , age, sex and the other conditions of a integrating agent such as dried starch , sodium alginate , agar 25 patient, severity of disease , etc. , but it is suitable that the powder , laminaran powder, sodium hydrogen carbonate , amount of the active ingredient compound is usually about calcium carbonate , polyoxyethylene sorbitan fatty acid ester , 0.1 to 10 mg per 1 kg of body weight per day. In addition , sodium lauryl sulfate , stearic acid monoglyceride , starch , it is desirable that the active ingredient compound is con lactose ; disintegration preventing agent such as saccharose , tained in the preparation of a dosage unit form in the range stearin , cacao butter , hydrogenated oil; sorbefacient such as 30 of about 1 to 200 mg. quaternary ammonium base , sodium lauryl sulfate ;moistur The compound of the present invention has D2 receptor izing agent such as glycerine, starch ; absorbing agent such partial agonist effect, 5 -HT2A receptor antagonist effect and as starch , lactose , kaolin , bentonite , colloidal silica ; lubri serotonin uptake inhibitory effect (or serotonin uptake cant such as purified talc , stearate , borate powder , polyeth inhibitory effect ). ylene glycol can be used , for example . Furthermore, the 35 The D , receptor partial agonist effect suppresses dop tablet may be a tablet provided with conventional coating as aminergic (DA ) neurotransmission when it is enhanced , and required , for example, sugar -coated tablet, gelatine encap accelerates the DA neurotransmission when it is lowered and sulated tablet, enteric coating tablet , film coated tablet or thus has a function to stabilize the DA neurotransmission to double tablet, multilayer tablet . a normal state (dopamine system stabilizer ) . According to For shaping in pill form , various materials conventionally 40 this function , excellent clinically improving effect on the well known as carrier in the art can be widely used . As conditions based on the DA abnormal neurotransmission examples , excipient such as glucose, lactose, starch , cacao (enhancement and lowering ), for example, improving effect butter , hydrogenated vegetable oil , kaolin , talc ; binder such on positive and negative symptoms, improving effect on as powdered gum arabic , powdered tragacanth , gelatine, cognitive impairment , improving effect on depressive symp ethanol; disintegrating agent such as laminaran , agar can be 45 tom , etc. are developed without developing side effects (See used , for example . Michio Toru : Seishin -Igaku (Psychiatry ) , Vol. 46 , pp . 855 For shaping in suppository form , various materials con 864 (2004 ) , Tetsuro Kikuchi and Tsuyoshi Hirose : Nou - no ventionally well known as carrier can be widely used . Kagaku (Brain Science) , Vol. 25 , pp . 579-583 (2003 ) and Examples thereof include polyethylene glycol, cacao butter , Harrison , T. S , and Perry , C. M .: Drugs 64 : 1715-1736 , higher alcohol , esters of higher alcohol, gelatine , semisyn- 50 2004 ) . thesized glyceride, for example . 5 -HT2A receptor antagonist effect reduces extrapyramidal A capsule is usually prepared according to a conventional side effects , develops superior clinical effects , and is effec method by mixing active ingredient compounds with vari tive for improvement of negative symptoms, improvement ous carrier exemplified above and filling them into a hard of cognitive impairment, improvement of depression con gelatin capsule, a soft capsule or the like . 55 dition , improvement of insomnia , for example (See Jun When prepared as injection liquid , it is preferable that Ishigooka and Ken Inada: Rinsho -Seishin - Yakuri ( Japanese solution , emulsion and suspension are sterilized and isotonic Journal of Clinical Psychopharmacology ), Vol . 4 , pp . 1653 to the blood and for forming in these modes, any of those 1664 (2001 ), Mitsukuni Murasaki Rinsho -Seishin - Yakuri conventionally used in the art as diluent can be used , and , for ( Japanese Journal of Clinical Psychopharmacology ) , Vol. 1 , example , water , ethyl alcohol, macrogol, propylene glycol, 60 pp. 5-22 ( 1998) , Puller, I. A. et al. , Eur. J. Pharmacol. , ethoxylated isostearyl alcohol, polyoxylated isostearyl alco 407 :39-46 , 2000 , and Meltzer , H. Y. et al, Prog. Neuro hol, polyoxyethylene sorbitan fatty acid ester , etc. can be Psychopharmacol. Biol. Psychiatry 27 : 1159-1172, 2003 ) . used . Serotonin uptake inhibitory effect or serotonin reuptake The pharmaceutical preparation may contain common inhibitory effect ) is effective for improving depressive salt, glucose or glycerine in an amount sufficient to prepare 65 symptoms, for example (See Mitsukuni Murasaki: Rinsho an isotonic solution in this case , and conventional solubi Seishin - Yakuri ( Japanese Journal of Clinical Psychophar lizer , buffer , soothing agent may be also added . Pigment, macology ) , Vol. 1 , pp . 5-22 (1998 ) ) . US RE48,059 E 19 20 The compounds of the present invention are excellent in thereto and refluxed for 8 hours . After cooling to room all of these three effects , or remarkably excellent in one or temperature , precipitated crystals were separated by filtra two of these effects . tion . They were purified by silica gel column chromatogra In addition , some of the compounds of the present inven phy ( dichloromethane: methanol = 100 : 3 ) , and 29.6 g of 7-( 4 tion have a , receptor antagonist effect in addition to the 5 chlorobutoxy) -1H - quinolin - 2 -one was obtained in the form above -described effects . The a , receptor antagonist effect is of a white powder . effective for improving positive symptoms of schizophrenia 1H -NMR ( CDC13 ) d ppm : (See Svensson , T. H .: Prog. Neuro -Psychopharmacol . Biol. Psychiatry 27 : 1145-1158 , 2003 ) . 1.95-2.15 (4H , m ) , 3.60-3.70 (2H , m ) , 4.10 (2H , t , J = 5.6 Therefore , the compounds of the present invention have a 10 Hz) , 6.56 ( 1H , dd, J = 9.0 Hz, 3.8 Hz) , 6.81 ( 1H , dd, J = 8.7 Hz , wide treatment spectrum for and excellent clinical effect on 2.4 Hz) , 6.85 ( 1H , d , J = 2.3 Hz) , 7.45 ( 1H , d , J = 8.7 Hz) , 7.75 schizophrenia and other central nervous system disorders . (1H , d , J = 9.4 Hz ), 12.54 (1H , brs) . Accordingly , the compounds of the present invention are extremely effective for the treatment or prevention of central nervous system disorders including the group consisting of 15 Reference Example 2 schizophrenia ; refractory , intractable or chronic schizophre nia ; emotional disturbance ; psychotic disorder ; mood disor Preparation of der; bipolar disorder ( for example , bipolar I type disorder 7-( 4 -chlorobutoxy )-4 - methyl - 1H - quinolin - 2 -one and bipolar II type disorder ); depression ; endogenous depression ; major depression ; melancholy and refractory 20 depression , dysthymic disorder , cyclothymic disorder , anxi 7-( 4 -chlorobutoxy ) -4 -methyl - 1H - quinolin - 2 - one was pre ety disorder ( for example , panic attack , panic disorder, pared from 7 -hydroxy -4 -methyl - 1H - quinolin - 2 -one by a agoraphobia , social phobia , obsessive - compulsive disorder, similar method as in Reference Example 1 . post- traumatic stress disorder, generalized anxiety disorder, White Powder acute stress disorder , etc. ); somatoform disorder ( for 25 H -NMR (DMSO -d ) 8 ppm : example , hysteria , somatization disorder, conversion disor der, pain disorder , hypochondriasis , etc.) ; factitious disorder ; 1.80-2.00 (4H , m ) , 2.37 (3H , s ) , 3.72 (2H , t , J = 6.0 Hz) , dissociative disorder; sexual disorder ( for example , sexual 4.05 (2H , t , J = 6.0 Hz ) , 6.20 (1H , s ) , 6.75-6.90 (2H , m ) , 7.60 dysfunction , sexual desire disorder , sexual arousal disorder, ( 1H , d , J = 8.5 Hz) , 11.42 ( 1H , brs ) . erectile dysfunction , etc. ) ; eating disorder ( for example , 30 anorexia nervosa , bulimia nervosa , etc.) ; sleep disorder ; Reference Example 3 adjustment disorder; substance - related disorder ( for example , alcohol abuse, alcohol intoxication , drug addic Preparation of tion , stimulant intoxication , narcotism , etc.) ; anhedonia ( for example , iatrogenic anhedonia , anhedonia of a psychic or 35 7 -methoxy - 3 -methyl - 1H -quinolin - 2- one mental cause , anhedonia associated with depression , anhe donia associated with schizophrenia , etc. ) ; delirium ; cogni 30.7 ml of triethylsilane was added to a trifluoroacetic tive impairment; cognitive impairment associated with acid ( 300 ml) solution of 13 g of 7 -methoxy - 2 -oxo - 1,2 dihydroquinoline -3 -carbaldehyde while being stirred under Alzheimer'sdegenerative diseasediseases , Parkinson's ; Cognitive disease impairment , and other caused neuro by 40 ice - cooling and stirred at room temperature overnight. The Alzheimer's disease , Parkinson's disease and associated reaction solution was poured into ice water and extracted neurodegenerative diseases; cognitive impairment of schizo with dichloromethane and , after washed with water , dried phrenia ; cognitive impairment caused by refractory , intrac over magnesium sulfate , and the solvent was evaporated table or chronic schizophrenia ; vomiting ; motion sickness ; under reduced pressure. The residue was purified by silica obesity ; migraine; pain (ache ); mental retardation ; autism 45 gel column chromatography (dichloromethane : metha disorder ( autism ) ; Tourette's disorder ; tic disorder; atten nol = 30 : 1 ) , and 11.1 g of 7 -methoxy - 3 -methyl -1H - quinolin tion -deficit / hyperactivity disorder ; conduct disorder ; and 2 -one was obtained in the form of a white powder . Down's syndrome. 1H -NMR ( DMSO -do ) d ppm : Furthermore, the compounds of the present invention have little or no side effects and they are excellent in safety 50 2.02 ( 3H , s ) , 3.77 (3H , s ) , 6.70-6.80 (2H , m ) , 7.45 ( 1H , d , and tolerability . J = 8.4 Hz) , 7.64 ( 1H , s ), 11.56 (1H , brs ). EXAMPLES Reference Example 4 Hereinbelow , the present invention will be further made 55 clear with reference to Reference Examples , Examples, Preparation of Pharmacological Test Examples and Preparation Examples . 7 -hydroxy - 3 -methyl - 1H - quinolin - 2 -one Reference Example 1 47 % hydrobromic acid (60 ml) suspension of 2.12 g of 60 7 -methoxy -3 -methyl - 1H - quinolin - 2 -one was refluxed for Preparation of six hours . After cooling , water was added to the reaction 7-( 4 -chlorobutoxy ) -1H - quinolin - 2 - one solution and precipitated crystals were separated by filtra tion . The crystals were dissolved in a mixed solvent of After 14.7 g of potassium hydroxide was added to a dichloromethane and methanol and dried over magnesium methanol ( 250 ml) suspension of 30 g of 7 -hydroxy - 1H- 65 sulfate , and the solvent was evaporated under reduced quinolin -2 -one , which was stirred at 50 ° C. to form a pressure and 1.7 g of 7 -hydroxy - 3 -methyl - 1H - quinolin -2 solution , 65 ml of 1- bromo -4 -chlorobutane was added one was obtained in the form of a brown powder . US RE48,059 E 21 22 H -NMR (DMSO -d ) d ppm : H -NMR (CDC12 ) d ppm : 1.99 ( 3H , s ), 6.57 (1H , dd , J = 8.5 Hz , 2.5 Hz ), 6.65 (1H , 1.55-1.70 (2H , m ), 1.75-1.95 (4H , m ), 3.56 (2H , t , J = 6.6 d , J= 2.5 Hz) , 7.34 (1H , d , J= 8.5 Hz ) , 7.58 ( 1H , s ) , 9.90 ( 1H , Hz ), 4.31 (2H , t, J = 7.8 Hz) , 6.70 (1H , d , J= 9.5 Hz) , 7.23 ( 1H , dd , J = 7.3 Hz , 7.3 Hz ) , 7.35 ( 1H , d , J = 8.9 Hz) , 7.54-7.60 (2H , s ), 11.48 ( 1H , brs ). 5 m ), 7.67 ( 1H , d , J = 9.4 Hz ) . Reference Example 5 Reference Example 9 Preparation of Preparation of 7- ( 4 - chloro- ( Z ) -2 -butenyloxy ) -3,4 7-( 3 - chloropropoxy ) -3 -methyl - 1H - quinolin - 2 - one 10 dihydro - 1H - quinolin - 2 -one By a similar method as in Reference Example 1 , 7-( 3 A mixture of 1.0 g of 7 -hydroxy -3,4 -dihydro - 1H - quino chloropropoxy ) -3 -methyl - 1H -quinolin -2 -one in the form of lin - 2 -one , 1.7 g of potassium carbonate , 3.2 ml of cis - 1,4 dichloro - 2 -butene and 50 ml of dimethylformamide was a white powder was prepared from 7 -hydroxy -3 -methyl - 1H stirred at room temperature overnight. Water was added to quinolin - 2 - one using 1 -bromo - 3 - chloropropane . 15 the reaction solution , which was then extracted with ethyl H -NMR (DMSO -d ) 8 ppm : acetate and , after washed with water , dried over magnesium 2.05 (3H , s ) , 2.15-2.25 (2H , m ) , 3.81 (2H , t , J = 6.5 Hz ) , sulfate , and the solvent was evaporated under reduced 4.11 (2H , t, J = 6.0 Hz) , 6.75-6.85 (2H , m ), 7.48 (1H , d , J = 8.5 pressure . The residue was purified by silica gel column Hz ), 7.67 ( 1H , s ), 11.59 ( 1H , brs ) . chromatography ( n -hexane : ethyl acetate = 3 : 1 ) , and 7- ( 4 20 chloro-( Z ) -2 -butenyloxy ) -3,4 -dihydro -1H -quinolin - 2 -one Reference Example 6 ( 1.3 g ) was obtained in the form of a white powder . 1H -NMR (CDC13 ) d ppm : Preparation of 2.62 (2H , t , J = 6.3 Hz) , 2.90 ( 2H , t, J = 6.3 Hz ) , 4.16 (2H , 7-( 4 - chlorobutoxy ) -3 -methyl - 1H - quinolin - 2 -one d , J = 6.3 Hz ) , 4.62 (2H , d , J = 4.6 Hz ) , 5.86-5.90 (2H , m ), 6.31 25 ( 1H , d , J = 2.5 Hz ), 6.54 ( 1H , dd , J = 8.3 Hz, 2.5 Hz) , 7.06 ( 1H , By a similar method as in Reference Example 1 , 7-( 4 d , J = 8.3 Hz ), 7.56 (1H , brs ). chlorobutoxy )-3 -methyl - 1H -quinolin - 2- one in the form of a white powder was prepared from 7 -hydroxy - 3- methyl - 1H Reference Example 10 quinolin - 2 -one using 1 -bromo - 4 - chlorobutane . 1H -NMR (DMSO -do ) d ppm : 30 Preparation of 2 -methyl - 4- ( 2 -oxo - 1,2,3,4 - tetrahyd 1.80-1.95 (4H , m ) , 2.04 (3H , s ) , 3.72 ( 2H , t , J = 6.0 Hz) , roquinolin - 7 -yloxy ) butyric acid methyl ester 4.03 ( 2H , t , J = 6.0 Hz) , 6.75-6.80 (2H , m ), 7.47 (1H , d , J = 8.5 4.98 g of sodium iodide was added to an acetonitrile (70 Hz ), 7.66 (1H , s ) , 11.58 (1H , brs ) . ml) solution of 5 g of 4 -chloro - 2 -methylbutyric acid methyl 35 ester and it was refluxed for 3 hours . Water was added to the Reference Example 7 reaction solution , which was then extracted with dichlo romethane and , after washed with water , dried over magne Preparation of 1-( 4 - chlorobutyl) -1H - quinolin - 2 -one sium sulfate , and the solvent was evaporated under reduced pressure . The residue was added to a mixture of 4.33 g of 0.30 g of sodium hydride ( 60 % oily ) was added to a 40 7 -hydroxy - 3,4 - dihydro - 1H - quinolin - 2 - one , 6.0 g of potas dimethylformamide ( 20 ml) solution of 1.0 g of 1H - quino sium carbonate and dimethylformamide (90 ml) and stirred lin - 2 -one while being stirred under ice - cooling and stirred at at 80 ° C. for 6 hours . Water was added to the reaction room temperature for 0.5 hour, and after that 1.6 ml of solution , which was then extracted with ethyl acetate and , 1 - bromo - 4 - chlorobutane was added and stirred at room after washed with water , dried over magnesium sulfate , and temperature for 14 hours . Water was added to the reaction 45 the solvent was evaporated under reduced pressure . The solution , which was then extracted with ethyl acetate and , residue was purified by silica gel column chromatography after washed with water , dried over magnesium sulfate , and (dichloromethane : methanol = 100 : 3) , and 6.0 g of 2 -methyl the solvent was evaporated under reduced pressure . The 4-( 2 -oxo - 1,2,3,4 -tetrahydroquinolin -7 - yloxy )butyric acid residue was purified by silica gel column chromatography methyl ester was obtained in the form of a yellow oil . (n -hexane :ethyl acetate = 3 :1 ), and 1.02 g of 1-( 4 -chlorobu- 50 1H -NMR (CDC13 ) ppm : tyl) -1H - quinolin - 2 -one was obtained in the form of colorless 1.23 (3H , d , J = 7.1 Hz) , 1.75-1.90 ( 1H , m ), 2.10-2.25 ( 1H , oil . m ), 2.55-2.65 (2H , m ), 2.72 ( 1H , q , J= 7.0 Hz) , 2.80-2.90 1H -NMR ( CDC13 ) d ppm : ( 2H , m ) , 3.68 ( 3H , s ) , 3.95 (2H , t, J = 6.2 Hz) , 6.33 (1H , d , 1.85-2.00 (4H , m ) , 3.60-3.65 ( 2H , m ), 4.35 ( 2H , t, J = 7.0 J = 2.3 Hz) , 6.49 ( 1H , dd , J= 8.3 Hz , 2.21 Hz ), 7.02 ( 1H , d , Hz) , 6.70 ( 1H , d , J = 9.5 Hz ), 7.23 ( 1H , dd, J = 8.6 Hz , 7.5 Hz) , 55 J= 8.3 Hz) , 8.41 (1H , brs ) . 7.38 ( 1H , d , J = 8.9 Hz ), 7.54-7.62 (2H , m ), 7.68 ( 1H , d , J = 9.5 Hz ) . Reference Example 11 Preparation of 7-( 4 - hydroxy - 3 -methylbutoxy )-3,4 Reference Example 8 60 dihydro - 1H -quinolin - 2- one Preparation of 1- ( 5 - chloropentyl) -1H -quinolin - 2 -one 6 g of 2 -methyl - 4-( 2 -oxo - 1,2,3,4 - tetrahydroquinolin - 7 yloxy ) butyric acid methyl ester was added dropwise to a By a similar method as in Reference Example 7 , 1-( 5 tetrahydrofuran (200 ml) suspension of 1.6 g of lithium chloropentyl ) -1H -quinolin -2 - one in the form of colorless oil 65 aluminum hydride while being stirred under ice - cooling and was prepared from 1H -quinolin - 2 -one using 1 - bromo- 5 stirred at the same temperature for 2 hours . While being chloropentane . stirred under ice -cooling , saturated Rochelle salt aqueous US RE48,059 E 23 24 solution was added , which was extracted with diethyl ether added to the reaction solution , which was then extracted and , after washed with water, dried over magnesium sulfate , with ethyl acetate and , after washed with water , dried over and the solvent was evaporated under reduced pressure . The magnesium sulfate , and the solvent was evaporated under residue was purified by silica gel column chromatography reduced pressure . The residue was purified by silica gel (dichloromethane :methanol =40 : 1 ) , and 2.8 g of 7-( 4 - hy- 5 column chromatography (dichloromethane : methanol = 50 : 1) , droxy -3 -methylbutoxy ) -3,4 -dihydro -1H - quinolin - 2 -one was and 7-( 4 -chlorobutoxy ) -4 -methyl - 3,4 -dihydro - 1H - quinolin obtained in the form of a yellow oil . 2 -one (0.29 g ) was obtained in the form of a white powder . H -NMR (CDC1z ) 8 ppm : H -NMR (DMSO -d .) 8 ppm : 0.99 (3H , d , J = 6.5 Hz) , 1.60-2.05 ( 3H , m ) , 2.60-2.65 ( 2H , 1.28 ( 3H , d , J = 7.0 Hz ), 1.85-2.05 (4H , m ), 2.35-2.45 ( 1H , m ), 2.85-2.95 (2H , m ), 3.55 (2H , t, J= 5.3 Hz) , 3.95-4.10 10 Hzm ); ) ,2,65-2.75 3.97 (2H ,( t1H, J= , 6.0m ), Hz 3.00-3.15 ), 6.32 ( 1H (1H , ,d m, J) =, 2.53.62 Hz (2H ), 6.55 ,t , 1–6.0( 1H , ( 2H , m ), 6.38 ( 1H , d , J = 2.5 Hz ), 6.53 ( 1H , dd, J = 8.3 Hz , 2.4 dd , J= 8.5 Hz, 2.5 Hz) , 7.08 (1H , d , J = 8.5 Hz) , 7.96 ( 1H , brs ). Hz ), 7.04 (1H , d , J = 8.3 Hz ) , 8.59 (1H , brs ) . Reference Example 15 Reference Example 12 15 Preparation of 7- [2- ( 2 - chloroethoxy ) ethoxy ] -3,4 Preparation of methanesulfonic acid 2 -methyl - 4-( 2 dihydro - 1H - quinolin - 2 -one oxo - 1,2,3,4 -tetrahydroquinolin - 7 -yloxy )butyl ester A mixture of 7.0 g of 7 -hydroxy -3,4 -dihydro - 1H -quino Methanesulfonyl chloride ( 1.0 ml) was added to a dichlo lin - 2 - one , 7.1 g of potassium carbonate , 30 ml of bis - 2 romethane (80 ml) solution of 2.8 g of 7- ( 4- hydroxy -3- 20 chloroethyl ether and 400 mlof acetonitrile was refluxed for 2 days. Water was added to the reaction solution , which was methyl butoxy ) -3,4 -dihydro -1H -quinolin - 2 - one and 2.4 ml then extracted with dichloromethane and , after washed with of triethylamine while being stirred under ice - cooling and water, dried over magnesium sulfate , and the solvent was stirred at room temperature overnight. Water was added to evaporated under reduced pressure. The residue was purified the reaction solution , which was then extracted with dichlo by silica gel column chromatography (dichloromethane : romethane and , after washed with water, dried over magne 25 methanol= 40 : 1 ) , and 8.3 g of 7- [2- ( 2 - chloroethoxy ) ethoxyl sium sulfate , and the solvent was evaporated under reduced 3,4 -dihydro -1H -quinolin - 2 - one was obtained in the form of pressure . The residue was purified by silica gel column a white powder . chromatography ( dichloromethane: methanol = 30 : 1 ), and 1H -NMR ( CDC13 ) d ppm : methanesulfonic acid 2 -methyl - 4- ( 2 -oxo - 1,2,3,4 - tetrahydro 2.61 (2H , t , J = 7.4 Hz) , 2.90 ( 2H , t, J = 7.4 Hz ) , 3.66 (2H , quinolin - 7 - yloxy )butyl ester ( 2.8 g ) was obtained in the 30 t, J = 5.8 Hz ), 3.74-3.88 (4H , m ) , 4.11 (2H , t , J = 4.7 Hz) , 6.36 form of a green powder. (1H , d , J = 2.2 Hz) , 6.54 ( 1H , dd , J = 8.3 Hz , 2.2 Hz ) , 7.05 ( 1H , 1H -NMR (CDC1z ) 8 ppm : d , J = 8.3 Hz) , 8.01 ( 1H , m ) . 1.07 ( 3H , d , J = 6.8 Hz ), 1.60-1.80 (1H , m ), 1.90-2.00 ( 1H , m ), 2.15-2.25 ( 1H , m ), 2.50-2.65 ( 2H , m ) , 2.90 ( 2H , t , J = 7.3 Reference Example 16 Hz ), 3.95-4.10 ( 2H , m ), 4.10-4.20 ( 2H , m ), 6.33 ( 1H , d , 35 J = 2.5 Hz ), 6.51 (1H , dd , J = 8.3 Hz, 2.5 Hz) , 7.05 ( 1H , d , Preparation of J = 8.3 Hz) , 8.16 ( 1H , brs ). 6-( 3 -chloropropoxy ) -3,4 - dihydro - 1H - quinolin - 2 -one Reference Example 13 By a similar method as in Reference Example 9 , 6-( 3 40 chloropropoxy) -3,4 -dihydro - 1H -quinolin - 2 -one in the form Preparation of 7-( 4 -bromo- ( E )-2 -butenyloxy )-3,4 of a white powder was prepared from 6 -hydroxy - 3,4 -di dihydro -1H - quinolin - 2 -one hydro - 1H -quinolin - 2 -one using 1 -bromo - 3 - chloropropane . H -NMR ( CDC13 ) è ppm : By a similar method as in Reference Example 9, 7- ( 4 2.15-2.35 ( 2H , m ), 2.55-2.65 (2H , m ), 2.90-3.00 (2H , m ), bromo-( E )-2 -butenyloxy ) -3,4 -dihydro -1H - quinolin - 2 - one 45 3.50-3.80 ( 2H , m ), 4.00-4.10 (2H , m ) , 6.73 (3H , brs ) , 8.68 in the form of a white powder was prepared from 7 -hydroxy (1H , brs ). 3,4 -dihydro - 1H -quinolin - 2 -one using trans - 1,4 - dibromo - 2 Reference Example 17 butene . H -NMR (CDC1z ) 8 ppm : Preparation of 2.61 (2H , t, J = 7.5 Hz) , 2.89 (2H , t , J = 7.5 Hz) , 3.98 ( 2H , 50 6-( 4 -bromobutoxy ) -3,4 -dihydro -1H - quinolin - 2 - one d , J = 7.0 Hz) , 4.51 (2H , d , J = 4.8 Hz) , 5.90-6.10 ( 2H , m ) , 6.43 ( 1H , d , J = 2.1 Hz ), 6.51 ( 1H , dd , J = 8.2 Hz , 2.1 Hz ), 7.03 ( 1H , By a similar method as in Reference Example 9 , 6-( 4 d , J = 8.2 Hz) , 9.35 ( 1H , brs ) . bromobutoxy ) -3,4 - dihydro - 1H - quinolin - 2- one in the form a white powder was prepared from 6 -hydroxy -3,4 -di Reference Example 14 55 hydro - 1H - quinolin - 2 -one using 1,4 - dibromobutane . 1H -NMR (DMSO - d ) 8 ppm : Preparation of 7-( 4 - chlorobutoxy ) -4 -methyl - 3,4 1.75-1.85 (2H , m ), 1.90-2.00 ( 2H , m ), 2.30-2.45 ( 2H , m ), dihydro - 1H - quinolin - 2 -one 2.75-2.85 (2H , m ), 3.58 ( 2H , t, J= 6.5 Hz ), 3.91 (2H , t, J = 6.5 Hz ) , 6.70-6.80 (3H , m ), 9.88 (1H , brs) . Boron tribromide ( 1 M dichloromethane solution , 6.2 ml) 60 was added to a dichloromethane solution (5 ml) of 0.54 g of Reference Example 18 7 -methoxy - 4 -methyl - 3,4 - dihydro - 1H -quinolin - 2 - one while being stirred under ice - cooling and 0.23 g of precipitated Preparation of crude crystals were separated by filtration . 0.2 g of potas 1- ( 5 - chloropentyl) -3,4 -dihydro - 1H -quinolin - 2 -one sium carbonate and 0.45 ml of 1 -bromo - 4 -chlorobutane 65 were added to an acetonitrile (2.5 ml) -water (2.5 ml) solu By a similar method as in Reference Example 7 , 1- ( 5 tion of the crude crystals and refluxed for 6 hours . Water was chloropentyl) -3,4 -dihydro - 1H -quinolin - 2 - one in the form of US RE48,059 E 25 26 colorless oil was prepared from 3,4 -dihydro - 1H -quinolin -2 Reference Example 23 one using 1 -bromo - 5 - chloropentane. H -NMR (CDC1z ) 8 ppm : Preparation of 7- (4 - chlorobutoxy )-3,4 -dihydro - 2H 1.45-1.60 ( 2H , m ), 1.60-1.75 (2H , m ), 1.75-1.90 (2H , m ), isoquinolin - 1 -one 2.60-2.70 ( 2H , m ), 2.85-2.95 (2H , m ) , 3.54 ( 2H , d , J = 6.6 5 By a similar method as in Reference Example 9 , 7- (4 Hz ) , 3.59 (2H , d , J = 7.7 Hz) , 6.76-7.04 (2H , m ) , 7.15-7.29 chlorobutoxy ) -3,4 - dihydro - 2H - isoquinolin - 1 - one in the ( 2H , m ). form of a white powder was prepared from 7 -hydroxy -3,4 dihydro - 2H - isoquinolin - 1 -one using 1 -bromo - 4 -chlorobu Reference Example 19 tane . 10 H -NMR ( CDC13 ) d ppm : Preparation of 2-( 5 - chloropentyl) -3,4 -dihydro - 2H 1.93-2.00 (4H , m ), 2.88-2.96 ( 2H , m ), 3.51-3.58 ( 2H , m ), isoquinolin - 1 -one 3.62 (2H , t, J = 6.2 Hz) , 4.05 (2H , t , J = 5.7 Hz ) , 6.25 (1H , s ), 7.00 ( 1H , dd , J = 8.3 Hz, 2.7 Hz) , 7.13 ( 1H , d , J = 8.3 Hz ) , 7.57 By a similar method as in Reference Example 7 , 2-( 5 ( 1H , d , J = 2.7 Hz ). chloropentyl) -3,4 -dihydro - 2H -isoquinolin -1 -one in the form 15 of brown oil was prepared from 3,4 -dihydro - 2H - isoquino Reference Example 24 lin - 1 -one using 1 -bromo - 5 -chloropentane . H -NMR (CDC13 ) d ppm : Preparation of 1.50-2.00 ( 6H , m ), 2.99 ( 2H , t, J = 6.6 Hz ), 3.52-3.60 (6H , 20 2- ( 4 - chlorobutyl) -2H -isoquinolin -1 - one m ) , 7.17 ( 1H , d , J = 7.3 Hz ) , 7.31-7.44 (2H , m ), 8.07 (1H , dd , By a similar method as in Reference Example 7 , 2-( 4 J = 1.3 Hz, 7.5 Hz ). chlorobutyl) -2H - isoquinolin - 1 -one in the form of a yellow oil was prepared from 2H - isoquinolin - 1 -one using 1 -bromo Reference Example 20 4 -chlorobutane . 25 1H -NMR ( CDC13 ) è ppm : Preparation of 7-( 3 - chloropropoxy ) -3,4 - dihydro - 2H 1.80-2.00 (4H , m ), 3.59 (2H , t, J =6.3 Hz) , 4.05 (2H , t, isoquinolin - 1 -one J = 7.0 Hz ), 6.51 (1H , d , J = 7.4 Hz ), 7.05 (1H , d , J = 7.4 Hz) , By a similar method as in Reference Example 9 , 7-( 3 7.46-7.52 (2H , m ), 7.63 ( 1H , m ) , 8.42 ( 1H , d , J = 8.1 Hz) . chloropropoxy ) -3,4 - dihydro -2H - isoquinolin - 1 - one in the 30 Reference Example 25 form of brown oil was prepared from 7 -hydroxy - 3,4 - di hydro -2H - isoquinolin - 1- one using 1- bromo - 3 -chloropro Preparation of pane . 7-( 3 - chloropropoxy )-2H - isoquinolin - 1 -one H -NMR (CDC13 ) d ppm : 2.20-2.40 ( 2H , m ), 2.90-3.00 ( 2H , m ), 3.50-3.80 (4H , m ) , 35 By a similar method as in Reference Example 9 , 7-( 3 4.15-4.20 ( 4H , m ) , 6.48 (1H , brs ), 7.01 ( 1H , dd, J = 4.0 Hz , chloropropoxy ) -2H -isoquinolin - 1 - one in the form of a white 1.5 Hz) , 7.13 (1H , d , J = 4.0 Hz) , 7.59 ( 1H , d , J = 1.4 Hz) . powder was prepared from 7 -hydroxy -2H -isoquinolin -1 -one using 1 -bromo - 3 - chloropropane. Reference Example 21 H -NMR ( CDC13) o ppm : 40 2.30 (2H , quint, J= 6.1 Hz ), 3.78 (2H , t, J = 6.4 Hz ), 4.28 Preparation of 7 -hydroxy - 2 -methyl - 3,4 -dihydro - 2H (2H , t, J = 5.9 Hz ) , 6.54 ( 1H , d , J = 7.1 Hz) , 7.06 (1H , d , J = 6.6 isoquinolin - 1 -one Hz ) , 7.29 ( 1H , dd , J = 8.7 Hz, 2.7 Hz ) , 7.51 ( 1H , d , J = 8.7 Hz ), 7.82 ( 1H , d , J = 2.7 Hz) , 10.64 (1H , s ) . By a similar method as in Reference Example 4 , 7 -hy droxy - 2 -methyl - 3,4 - dihydro - 2H - isoquinolin - 1 -one in the 45 Reference Example 26 form of a brown powder was prepared from 7 -methoxy - 2 methyl- 3,4 - dihydro - 2H - isoquinolin - 1 -one . Preparation of H -NMR (DMSO -d .) 8 ppm : 7-( 3 - chloropropoxy ) -2 - ethyl - 2H - isoquinolin - 1 -one 2.84 ( 2H , t , J = 6.5 Hz) , 3.01 (3H , s ), 3.47 ( 2H , t , J = 6.6 Hz ) , 6.85 ( 1H , dd , J = 8.1 Hz, 2.5 Hz) , 7.08 ( 1H , d , J = 8.1 Hz ), 7.29 50 By a similar method as in Reference Example 7,7-( 3 ( 1H , d , J = 2.5 Hz ) , 9.49 (1H , s ) . chloropropoxy ) -2 -ethyl - 2H - isoquinolin - 1 -one in the form of a colorless oil was prepared from 7-( 3 - chloropropoxy ) -2H Reference Example 22 isoquinolin - 1 -one using ethyl iodide. 1H -NMR (CDC13 ) d ppm : Preparation of 7-( 4 - chlorobutoxy )-2 -methyl - 3,4 55 1.38 (3H , t, J= 7.2 Hz ) , 2.29 (2H , quint, J = 6.1 Hz ), 3.76 dihydro -2H - isoquinolin - 1- one (2H , t, J= 6.4 Hz ), 4.07 (2H , q , J = 7.2 Hz) , 4.25 (2H , d , J = 5.8 Hz) , 6.48 ( 1H , d , J = 7.3 Hz ) , 6.98 ( 1H , d , J = 7.3 Hz) , 7.23 By a similar method as in Reference Example 9,7-( 4 ( 1H , dd , J = 8.7 Hz , 2.7 Hz ), 7.44 ( 1H , d , J = 8.7 Hz ), 7.85 ( 1H , chlorobutoxy ) -2 -methyl - 3,4 -dihydro - 2H - isoquinolin - 1 -one d , J = 2.6 Hz ) . in the form of a brown oil was prepared from 7 -hydroxy- 60 2 -methyl - 3,4 -dihydro - 2H - isoquinolin -1 -one using 1- bromo Reference Example 27 4 -chlorobutane . 1H -NMR (CDC13 ) d ppm : Preparation of 1.90-2.00 (4H , m ) , 2.93 (2H , t, J = 6.8 Hz ), 3.15 (3H , s ), 2- (4 -chlorobutyl ) -7 -methoxy -2H - isoquinolin - 1 -one 3.45-3.65 ( 4H , m ), 4.04 ( 2H , t , J = 5.8 Hz ), 6.95 ( 1H , dd , 65 J = 8.3 Hz , 2.5 Hz) , 7.07 ( 1H , d , J = 8.3 Hz ), 7.59 ( 1H , d , J = 2.5 By a similar method as in Reference Example 7 , 2-( 4 Hz) . chlorobutyl) -7 -methoxy -2H - isoquinolin - 1- one in the form US RE48,059 E 27 28 of colorless oil was prepared from 7 -methoxy - 2H - isoquino H -NMR (DMSO -do ) 8 ppm : lin - 1 - one using 1 -bromo - 4 - chlorobutane . 3.25-3.35 (8H , m ), 6.94 ( 1H , d , J = 7.6 Hz) , 7.30 ( 1H , dd , 1H -NMR (CDC1z ) 8 ppm : J = 7.8 Hz , 7.8 Hz ) , 7.51 ( 1H , d , J = 5.5 Hz) , 7.68 ( 1H , d , J = 8.1 1.64-2.00 (4H , m ) , 3.59 (2H , t , J = 6.3 Hz) , 3.93 (3H , s ), Hz ), 7.73 (1H , d , J = 5.5 Hz) , 9.35 (2H , brs ). 4.06 ( 2H , t , J = 6.9 Hz) , 6.49 ( 1H , d , J = 7.3 Hz) , 6.96 (1H , d , 5 J = 7.3 Hz ), 7.25 (1H , dd , J = 8.6 Hz , 2.7 Hz) , 7.45 ( 1H , d , Reference Example 31 J= 8.7 Hz ), 7.83 (1H , d , J = 2.7 Hz ). Preparation of tert -butyl 4 -benzo [ b ]thiophen -4 -yl - 3 methylpiperazin - 1 -carboxylate Reference Example 28 10 In the same manner as in Reference Example 30 , tert butyl 4 - benzo [ b ] thiophen -4 -yl - 3 -methylpiperazin - 1- car Preparation of boxylate was prepared from tert -butyl 3 -methylpiperazin - 1 6-( 3 -chloropropoxy ) -2H - isoquinolin -1 -one carboxylate and 4 -bromobenzo [b ] thiophene . By a similar method as in Reference Example 9 , 6-( 3- 15 H -NMR ( CDC13 ) è ppm : chloropropoxy) -2H -isoquinolin - 1 - one in the form of a pale 1.85-1.95 ( 3H , m ), 1.50 ( 9H , s ), 2.8-2.9 ( 1H , m ) , 3.15 yellow powder was prepared from 6 -hydroxy - 2H - isoquino 3.35 (2H , m ), 3.4-3.5 ( 1H , m ) , 3.5-3.65 (1H , m ) , 3.65-3.7 lin - 1- one using 1 -bromo - 3 - chloropropane . (1H , m ) , 3.7-3.9 ( 1H , m ), 6.98 ( 1H , d , J = 7.5 Hz) , 7.29 (1H , 1H -NMR (CDC13 ) 8 ppm : dd , J = 8 , 8 Hz ) , 7.38 (1H , d , J = 5.5 Hz ), 7.61 (1H , d , J = 8 Hz) . 2.30 (2H , quint, J = 6.0 Hz ), 3.78 ( 2H , t , J =6.2 Hz ) , 4.24 20 Reference Example 32 (2H , t, J = 5.9 Hz) , 6.46 ( 1H , d , J = 7.2 Hz) , 6.93 ( 1H , d , J = 2.4 Hz ), 7.05-7.12 (2H , m ) , 8.33 ( 1H , d , J = 8.9 Hz ), 10.33 ( 1H , Preparation of 1 -benzo [ b ] thiophen - 4 -yl - 2 -methyl s ) . piperazine dihydrochloride Reference Example 29 25 A solution of 1.22 g (3.7 mmol) of tert- butyl 4 -benzo [ b ] thiophen -4 -yl - 3 -methylpiperazin - 1 -carboxylate in methyl Preparation of 7- ( 3 - chloropropoxy ) -2 -methyl -3,4 ene chloride ( 12 ml) was added to trifluoroacetic acid (6 ml) , and the mixture was stirred at room temperature for 1 hour. dihydro - 2H - isoquinolin - 1 -one The reaction mixture was concentrated under reduced pres 30 sure , then an aqueous solution of 5 % potassium carbonate By a similar method as in Reference Example 9 , 7-( 3 was added to the residue and the resulting mixture was chloropropoxy ) -2 -methyl - 3,4 - dihydro - 2H - isoquinolin - 1 extracted with methylene chloride. The organic phase was one in the form of a brown powder was prepared from dried over magnesium sulfate and concentrated under 7 -hydroxy - 2 -methyl -3,4 -dihydro -2H -isoquinolin - 1 -one reduced pressure . Concentrated hydrochloric acid ( 6 ml) and using 1 -bromo - 3 - chloropropane. 35 methanol ( 10 ml) were added to the residue and the resulting ' H -NMR (CDC13 ) & ppm : mixture was concentrated under reduced pressure . The resi 2.15-2.35 ( 2H , m ), 2.85-3.00 (2H , m ), 3.15 ( 3H , s ) , due was recrystallized from acetonitrile to obtain 1 -benzo 3.50-3.80 (4H , m ), 4.10-4.20 ( 2H , m ) , 6.96 ( 1H , dd , J = 8.3 [ b ]thiophen -4 - yl- 2- methylpiperazine dihydrochloride (0.98 Hz, 2.7 Hz) , 7.08 ( 1H , d , J = 8.3 Hz) , 7.62 ( 1H , d , J = 2.7 Hz) . g ) as light brown powder. 40 H -NMR (DMSO -do ) è ppm : Reference Example 30 0.92 (3H , d , J = 6.5 Hz) , 2.8-3.6 (6H , m ), 3.6-4.0 ( 1H , m ) , 5.3-6.8 ( 1H , m ), 7.20 ( 1H , br) , 7.38 ( 1H , dd , J = 8 , 8 Hz ) , Preparation of 1 -benzo [b ] thiophen - 4 -yl - piperazine 7.5-8.0 (3H , m ) , 9.4-10.1 (2H , m ) . hydrochloride 45 Reference Example 33 A mixture of 14.4 g of 4 - bromobenzo [ b ] thiophene , 29.8 g Preparation of 1 - benzo [ b ] thiophen - 4 -yl - 3 -methyl of piperazine anhydride, 9.3 g of sodium t- butoxide , 0.65 g piperazine dihydrochloride of ( R ) - ( + )- 2,2 '- bis ( diphenylphosphino ) -1,1 '- binaphthyl (BI NAP ), 0.63 g of dipalladium tris (dibenzylideneacetone ) and 50 In the same manner as in Reference Example 30 , 1 -benzo 250 ml of toluene was refluxed for 1 hour under nitrogen [b ] thiophen - 4 - yl- 3 -methylpiperazine dihydrochloride was atmosphere . Water was poured to the reaction solution , prepared from 2 -methylpiperazine and 4 -bromobenzo [b ] which was then extracted with ethyl acetate and , after thiophene . washed with water , dried over magnesium sulfate , and the 1H -NMR (DMSO - d ) d ppm : solvent was evaporated under reduced pressure . The residue was purified by silica gel column chromatography (dichlo 55 1.34 ( 3H , d , J = 6.5 Hz) , 2.85-2.95 ( 1H , m ) , 3.05-3.15 (1H , romethane: methanol : 25 % ammonia water = 100 : 10 : 1 ), and m ) , 3.2-3.6 (6H , m ) , 6.97 ( 1H , d , J = 7.5 Hz) , 7.31 (1H , dd , 9.5 g of 1 -benzo [ b ]thiophen - 4 - yl- piperazine in the form of J = 8 , 8 Hz) , 7.54 (1H , d, J = 5.5 Hz) , 7.69 ( 1H , d , J= 8 Hz ), yellow oil was obtained . 7.75 ( 1H , d , J = 5.5 Hz) , 9.2-9.3 ( 1H , m ), 9.64 ( 1H , br) . 3.7 ml of concentrated hydrochloric acid was added to a 60 Reference Example 34 methanol solution of 9.5 g of 1- benzo [ b ] thiophen - 4 -yl piperazine , and the solvent was evaporated under reduced Preparation of ethyl 3-( 4 -benzo [ b ] thiophen - 4 -yl pressure . Ethyl acetate was added to the residue and pre piperazin - 1 - yl) propionate cipitated crystals were filtrated and recrystallized from methanol and 1 -benzo [b ] thiophen - 4 - yl- piperazine hydro- 65 5.05 g (19.8 mmol) of 1- Benzo [b ] thiophen - 4 -yl -pipera chloride was obtained as colorless needle - like crystals . zine hydrochloride was added to an aqueous solution of Melting point 276-280 ° C. sodium hydroxide , and the mixture was extracted with US RE48,059 E 29 30 methylene chloride . The organic phase was dried over extracted with methylene chloride . The organic phase was magnesium sulfate and concentrated under reduced pres dried over magnesium sulfate and concentrated under sure . The residue was dissolved in 50 ml of ethanol and ethyl reduced pressure . The residue was purified by silica gel column chromatography (n -hexane : ethyl acetate = 2: 1 -1: 1 ), reactionacrylate (mixture 2.44 ml , was 21.8 refluxedmmol) wasfor added4 hours thereto . The , thenreaction the 5 then concentrated under reduced pressure to obtain 4-( 4 mixture was cooled to room temperature and concentrated benzo [ b ] thiophen - 4 - yl- piperazin - 1 -yl )butane - 1 - ol (6.65 g ) under reduced pressure. Isopropyl ether was added to the as colorless oil . residue to filter out insoluble matters . The insoluble matters Reference Example 38 were washed with isopropyl ether and dried to obtain ethyl 3-( 4 -benzo [b ]thiophen - 4 -yl - piperazin - 1 - yl ) propionate ( 5.26 10 Preparation of 1 -benzo [ b ] thiophen - 4 -yl - 4-( 3 -chloro g ) as white powder. propyl )piperazine Reference Example 35 3.56 g ( 12.9 mmol) of 3-( 4 -Benzo [b ]thiophen - 4 -yl - piper azin - 1 - yl) propan - 1 - ol was suspended in 30 ml ofmethylene Preparation of 3-( 4 -benzo [b ]thiophen - 4 - yl- pipera 15 chloride , and carbon tetrachloride (30 ml) and triphenyl zine- 1 - yl) propan - 1 - ol phosphine (4.06 g , 15.5 mmol ) were added thereto followed by stirring under reflux for 3 hours . The reaction mixture Lithium aluminum hydride ( 1.18 g , 24.8 mmol) was was cooled to room temperature , then methanol and meth added to a solution of 5.26 g ( 16.5 mmol ) of ethyl 3-( 4 ylene chloride were added thereto so as to make the mixture benzo[ b ] thiophen -4 -yl - piperazin - 1 - yl ) propionate in tetrahy- 20 uniform . Silica gel ( 30 g ) was added to the uniform solution , drofuran (55 ml) with cooling in an ice -bath , followed by and the solvent was evaporated under reduced pressure. The stirring at room temperature for 4 hours . Water ( 1.2 ml) , residue was purified by silica gel column chromatography 15 % sodium hydroxide aqueous solution ( 1.2 ml) , and water ( silica gel : 300 g , n -hexane : ethyl acetate = 2 : 1 ) , then concen ( 3.6 ml) were added to the reaction mixture in this order with trated under reduced pressure to obtain 1 -benzo [b ] thiophen stirring at room temperature . Insoluble matters were 25 4 -yl - 4- ( 3 - chloropropyl )piperazine (2.36 g ) as colorless oil . removed by filtration , and the filtrate was concentrated H -NMR ( CDC13 ) è ppm : under reduced pressure . The residue was purified by silica 1.95-2.10 ( 2H , m ), 2.60 (2H , t , J = 7.2 Hz) , 2.65-2.75 ( 4H , gel column chromatography ( n -hexane : ethyl acetate = 3 : m ), 3.15-3.25 (4H , m ), 3.65 (2H , t, J = 6.6 Hz) , 6.89 ( 1H , dd , 2 - ethyl acetate ) , then concentrated and dried under J = 7.6 , 0.7 Hz ), 7.27 ( 1H , dd , J = 7.9 , 7.8 Hz ) , 7.38 ( 1H , d , reduced pressure to obtain 3- (4 -benzo [b ]thiophen - 4 - yl- pip- 30 J = 5.6 Hz) , 7.41 (1H , d , J = 5.7 Hz ), 7.55 ( 1H , d , J = 8.0 Hz ) erazin - 1 - yl) propane - 1 -ol ( 0.23 g ) as white powder. 1H -NMR (CDC13 ) d ppm : Example 1 1.75-1.85 ( 2H , m ), 2.74 (2H , t , J = 5.8 Hz) , 2.75-2.85 (4H , m ) , 3.15-3.25 (4H , m ), 3.85 (2H , t, J = 5.3 Hz ), 5.19 (1H , brs ) , Preparation of 7- [4- ( 4 - benzo [ b ] thiophen - 4 -yl -piper 6.88 (1H , d , J = 7.6 Hz ) , 7.27 ( 1H , dd , J = 7.9 , 7.8 Hz ) , 7.39 35 azin - 1 -yl )butoxy ] -1H - quinolin - 2 -one ( 2H , s ), 7.56 (1H , d , J = 8.0 Hz ). A mixture of 9.0 g of 7-( 4 -chlorobutoxy ) -1H - quinolin - 2 Reference Example 36 one , 10 g of 1 -benzo [ b ] thiophene- 4 - yl- piperazine hydro chloride , 14 g of potassium carbonate , 6 g of sodium iodide Preparation of 4-( 4 -benzo [ b ] thiophen - 4 -yl - piper 40 and 90 ml of dimethylformamide was stirred for 2 hours at azin - 1 -yl ) butyl acetate 80 ° C. Water was added to the reaction solution and pre cipitated crystals were separated by filtration . The crystals 1.0 g ( 3.9 mmol) of 1 -Benzo [b ] thiophen -4 - yl- piperazine were dissolved in a mixed solvent of dichloromethane and hydrochloride was suspended in 20 ml of dimethylforma methanol, dried over magnesium sulfate , and the solvent mide (DMF ), and potassium carbonate ( 1.3 g, 9.4 mmol) and 45 was evaporated under reduced pressure . The residue was 4 -bromobutyl acetate (0.7 ml, 4.8 mmol) were added thereto purified by silica gel column chromatography (dichlo followed by stirring at 80 ° C. for 6 hours. The reaction romethane: methanol = 100 : 3 ). Recrystallized from ethanol, mixture was cooled to room temperature, then water was 13.6 g of 7-[ 4- ( 4 -benzo [ b ]thiophen - 4 -yl - piperazin - 1 -yl ) bu added thereto and the resulting mixture was extracted with toxy -] - 1H -quinolin -2 -one in the form of a white powder was ethyl acetate . The organic phase was washed with water , 50 obtained . dried over magnesium sulfate , and concentrated under Melting point 183.5-184.5 ° C. reduced pressure. The residue was purified by silica gel H -NMR (DMSO -d ) d ppm : column chromatography ( methylene chloride :methanol = 30 : 1.6-1.75 ( 2H , m ) , 1.75-1.9 ( 2H , m ) , 2.44 (2H , t , J = 7 Hz) , 1 ) , then concentrated under reduced pressure to obtain 2.5-2.8 (4H , m ) , 2.9-3.2 (4H , m ) , 4.06 (2H , t , J = 6.5 Hz) , 6.30 4-( 4 - benzo [b ] thiophen -4 -yl - piperazin - 1 - yl) butyl acetate 55 (1H , d , J = 9.5 Hz) , 6.75-6.85 ( 2H , m ) , 6.88 (1H , d , J = 7.5 Hz) , ( 0.72 g ) as light yellow oil . 7.27 ( 1H , dd , J = 8 Hz , 8 Hz) , 7.40 ( 1H , d , J = 5.5 Hz) , 7.55 ( 1H , d , J = 9.5 Hz ), 7.61 ( 1H , d , J = 8 Hz ), 7.69 (1H , d , J = 5.5 Reference Example 37 Hz) , 7.80 ( 1H , d , J = 9.5 Hz ), 11.59 ( 1H , bs ) . Preparation of 4- (4 -benzo [b ]thiophen -4 -yl - piper 60 Example 2 azin - 1 -yl ) butan - 1 -ol Preparation of 3-[ 2-( 4 - benzo [ b ] thiophen - 4 - yl- piper Potassium carbonate (3.87 g , 28 mmol) was added to a azin - 1- yl) ethoxy ] -1H -quinolin -2 -one solution of 7.76 g (23.3 mmol) of butyl 4-( 4 -benzo [b ] thiophen - 4 - yl- piperazin - 1 -yl ) acetate in 90 % methanol ( 150 65 By a similar method as in Example 1 , 3- [2- ( 4 - benzo [ b ] ml) followed by stirring at room temperature for 2 hours . thiophen - 4 - yl -piperazin - 1 -yl ) ethoxy ] -1H -quinolin - 2 -one Water was added thereto and the reaction mixture was was prepared from 3-( 2 -bromoethoxy ) -1H - quinolin - 2 -one . US RE48,059 E 31 32 White Powder ( Chloroform ) Hz, 8 Hz ), 7.40 ( 1H , d , J = 5.5 Hz) , 7.48 (1H , d , J = 8.5 Hz) , Melting point 201.9-204.5 ° C. 7.61 ( 1H , d , J = 8 Hz) , 7.65-7.7 ( 2H , m ) , 11.57 ( 1H , bs ) . 1H -NMR (CDC12 ) d ppm : Example 6 2.90-2.95 ( 4H , m ), 3.10 ( 2H , t , J = 5.9 Hz ) , 3.23-3.27 (4H , 5 m ), 4.30 (2H , t, J = 5.9 Hz) , 6.90 ( 1H , d , J = 7.7 Hz) , 7.08 ( 1H , Preparation of 7-[ 4- ( 4 -benzo [b ]thiophen - 4 - yl- piper s ), 7.15-7.32 (2H , m ), 7.37-7.41 ( 4H , m ), 7.47-7.49 ( 1H , m ) , azin - 1 -yl )butoxy ] -3 -methyl - 1H -quinolin - 2 -one 7.55 (1H , d , J = 8.1 Hz ), 11.33 (1H , br) . By a similar method as in Example 1 , 7- [ 4-( 4 -benzo [b ] thiophen - 4 -yl -piperazin - 1 - yl) butoxy - ] - 3 -methyl - 1H -quino Example 3 10 lin - 2 - one was prepared from 7-( 4 -chlorobutoxy )-3 -methyl 1H - quinolin - 2 -one . White Powder (Ethyl Acetate ) Preparation of 7- ( 3-( 4 -benzo [ b ] thiophen - 4 - yl- piper Melting point 197-199° C. azin - 1 - yl) propoxy ] -4 -methyl - 1H - quinolin - 2 - one H -NMR (DMSO - d ) 8 ppm : 15 1.6-1.7 ( 2H , m ) , 1.75-1.9 (2H , m ) , 2.04 (3H , s ), 2.44 (2H , By a similar method as in Example 1 , 7- (3- ( 4 - benzo [b ] t, J = 7 Hz) , 2.55-2.7 (4H , m ), 3.0-3.15 (4H , m ) , 4.04 (2H , t, thiophen - 4 - yl- piperazin - 1 - yl) propoxy ] -4 -methyl - 1H - quino J = 6.5 Hz) , 6.75-6.85 ( 2H , m ) , 6.88 ( 1H , d , J = 7.5 Hz) , 7.27 lin - 2 - one was prepared from 7-( 3 - chloropropoxy ) -4 -methyl (1H , dd , J= 8 Hz , 8 Hz ) , 7.40 ( 1H , d , J= 5.5 Hz ), 7.47 ( 1H , d , 1H - quinolin - 2 - one . J = 8.5 Hz) , 7.61 ( 1H , d, J = 8 Hz ), 7.65-7.75 (2H , m ) , 11.59 Slightly Brown Powder (Ethyl Acetate ) 20 (1H , bs ) . Melting point 202-208 ° C. ' H -NMR (DMSO -d ) d ppm : Example 7 1.95-2.0 (2H , m ), 2.37 (3H , s ), 2.55 (2H , t , J = 7 Hz) , Preparation of 7-( 3- ( 4 - benzo [b ] thiophen - 4 -yl - piper 2.6-2.7 (4H , m ) , 3.05-3.2 (4H , m ), 4.09 (2H , t, J = 6.5 Hz) , 25 azin -1 -yl ) propoxy ]-1H - quinolin - 2- one 6.21 ( 1H , bs ) , 6.8-6.85 (2H , m ) , 6.90 ( 1H , d , J = 7.5 Hz) , 7.28 ( 1H , dd , J = 8 Hz, 8 Hz) , 7.41 (1H , d , J = 5.5 Hz) , 7.6-7.7 (2H , By a similar method as in Example 1 , 7-( 3- ( 4 -benzo [ b ] m ) , 7.69 ( 1H , d , J = 5.5 Hz) , 11.41 ( 1H , bs) . thiophen -4 -yl - piperazin - 1 -yl ) propoxy )-1H -quinolin - 2 -one was prepared from 7-( 3 - chloropropoxy) -1H -quinolin -2 -one . Example 4 30 White Powder ( Ethyl Acetate - Diethyl Ether ) Melting point 204-207 ° C. H -NMR (DMSO -d ) d ppm : Preparation of 7- [4- ( 4 -benzo [b ] thiophen - 4 -yl - piper 1.97 (2H , t , J = 6.8 Hz) , 2.50-2.60 ( 2H , m ), 2.60-2.65 (4H , azin - 1- yl )butoxy ] -4 -methyl - 1H -quinolin -2 -one m ), 3.05-3.10 (4H , m ), 4.08 ( 2H , t , J = 6.4 Hz) , 6.29 (1H , d , 35 J = 9.5 Hz) , 6.75-6.85 ( 2H , m ) , 6.90 (1H , d , J = 7.7 Hz) , By a similar method as in Example 1 , 7-[ 4- ( 4 - benzo [ b ] 7.25-7.30 ( 1H , m ), 7.40 (1H , d , J = 5.6 Hz ), 7.55 (1H , d , J = 8.4 thiophen - 4 - yl- piperazin - 1 -yl ) butoxy ] -4 -methyl - 1H -quino Hz ), 7.60-7.65 ( 1H , m ), 7.69 (1H , d , J = 5.5 Hz ), 7.80 ( 1H , d , lin - 2 -one was prepared from 7- ( 4 - chlorobutoxy ) -4 -methyl J = 9.5 Hz) , 11.57 ( 1H , s ) . 1H - quinolin -2 -one . White Powder (Ethyl Acetate ) 40 Example 8 Melting point 164-168 ° C. Preparation of 1- [4- ( 4 - benzo [ b ]thiophen - 4 - yl- piper H -NMR (DMSO - d ) 8 ppm : azin - 1 -yl ) butyl ] -1H -quinolin - 2 - one hydrochloride 1.6-1.7 ( 2H , m ) , 1.75-1.85 ( 2H , m ), 2.37 (3H , s ) , 2.44 45 By a similar method as in Example 1 , 1- [ 4-( 4 -benzo [ b ] ( 2H , t , J = 7 Hz) , 2.55-2.7 (4H , m ) , 3.0-3.2 (4H , m ), 4.0-4.15 thiophen - 4 - yl- piperazin -1 -yl ) butyl ] -1H - quinolin -2 -one was ( 2H , m ) , 6.20 (1H , bs ) , 6.8-6.85 (2H , m ) , 6.88 ( 1H , d , J = 7.5 prepared from 1- ( 4 - chlorobutyl ) -1H -quinolin - 2 - one, and Hz) , 7.27 ( 1H , dd , J = 8 Hz, 8 Hz) , 7.40 (1H , d , J = 5.5 Hz) , after it was made into an ethanol solution , 1N hydrochloric 7.6-7.7 (2H , m ) , 7.69 (1H , d , J = 5.5 Hz) , 11.42 (1H , bs ) . acid ethanol solution was added thereto , precipitated crystals 50 were separated by filtration , and thereby 1- [ 4- ( 4 -benzo [b ] Example 5 thiophen - 4 - yl -piperazin - 1 -yl ) butyl ]-1H - quinolin - 2 - one hydrochloride was obtained in the form of a white powder . Preparation of 7-( 3-( 4 - benzo [ b ] thiophen - 4 - yl- piper Melting point 282.0 ° C. (decomposed ) azin - 1- yl) propoxy ] -3 -methyl - 1H - quinolin -2 -one 1H -NMR (DMSO -do ) d ppm : 55 1.60-2.00 ( 4H , m ) , 3.10-3.40 (6H , m ), 3.50-3.60 (4H , m ) , 4.31 ( 2H , t , J = 7.4 Hz) , 6.63 ( 1H , d , J = 9.4 Hz) , 6.96 ( 1H , d , By a similar method as in Example 1 , 7- (3- (4 -benzo [b ] J = 7.6 Hz ), 7.24-7.35 (2H , m ), 7.48 ( 1H , d , J = 5.4 Hz) , thiophen - 4 - yl- piperazin - 1 - yl) propoxy ] -3 -methyl - 1H - quino 7.59-7.78 ( 5H , m ), 7.93 ( 1H , d , J = 9.5 Hz ), 10.00-10.20 ( 1H , lin -2 -one was prepared from 7-( 3 - chloropropoxy ) -3 -methyl m ). 1H - quinolin - 2 -one . 60 White Powder (Ethyl Acetate ) Example 9 Melting point 185-187 ° C. Preparation of 1- [5- (4 - benzo [b ] thiophen -4 - yl- piper H -NMR (DMSO - d ) • ppm : azin - 1- yl ) pentyl ]-1H -quinolin -2 -one hydrochloride 1.9-2.0 (2H , m ) , 2.04 (3H , s ) , 2.55 (2H , t , J = 7 Hz) , 65 2.6-2.75 (4H , m ) , 3.0-3.2 (4H , m ) , 4.07 (2H , t , J = 6.5 Hz) , By a similar method as in Example 1 , 1- [5- ( 4 -benzo [ b ] 6.75-6.85 ( 2H , m ), 6.90 ( 1H , d , J = 7.5 Hz ) , 7.28 ( 1H , dd , J = 8 thiophen - 4 -yl - piperazin - 1 - yl) pentyl] -1H - quinolin - 2 - one US RE48,059 E 33 34 was prepared from 1- (5 -chloropentyl ) -1H -quinolin - 2 -one , Melting point 237-239 ° C. and after it was made into an ethanol solution , 1N hydro 1H -NMR (DMSO -do ) è ppm : chloric acid ethanol solution was added thereto , precipitated 1.75-1.85 ( 2H , m ), 1.85-2.0 (2H , m ), 2.42 (2H , t, J= 7.5 crystals were separated by filtration , and thereby 1- [5- ( 4 Hz ) , 2.79 (2H , t, J = 7.5 Hz) , 3.15-3.5 ( 6H , m ) , 3.5-3.7 (4H , benzo [ b ] thiophen -4 - yl- piperazin - 1 -yl ) pentyl] -1H - quinolin 5 m ) , 3.96 (2H , t , J = 6 Hz ), 6.46 ( 1H , d , J = 2.5 Hz ), 6.5-6.55 2 -one hydrochloride was obtained in the form of a white ( 1H , m ), 6.97 ( 1H , d , J = 7.5 Hz ), 7.07 ( 1H , d , J= 8.5 Hz ), 7.32 powder. ( 1H , dd , J = 8 Hz, 8 Hz ) , 7.50 ( 1H , d , J = 5.5 Hz ), 7.71 ( 1H , d , Melting point 225.0-227.0 ° C. J = 8 Hz) , 7.77 ( 1H , d , J = 5.5 Hz ) , 10.03 ( 1H , s ) , 10.65 ( 1H , 1H -NMR (DMSO -d ) 8 ppm : br ). 1.35-1.50 (2H , m ) , 1.60-1.80 ( 4H , m ), 3.10-3.30 (6H , m ) , 10 3.50-3.60 (4H , m ) , 4.27 (2H , t, J = 7.4 Hz) , 6.61 ( 1H , d , J = 9.5 Example 13 Hz) , 6.96 ( 1H , d , J = 7.5 Hz) , 7.20-7.34 (2H , m ) , 7.47 ( 1H , d , J = 5.5 Hz) , 7.61-7.77 ( 5H , m ) , 7.91 ( 1H , d , J = 9.5 Hz) , Preparation of 7-[ 4- ( 4 -benzo [ b ]thiophen - 4 - yl- piper 10.30-10.50 ( 1H , m ). 15 azin - 1- yl) -( Z )-2 -butenyloxy ] -3,4 -dihydro - 1H - quino Example 10 lin - 2 - one Preparation of 7-[ 3-( 4 - benzo [ b ] thiophen - 4 - yl- piper By a similar method as in Example 1, 7- [4- (4 -benzo [b ] azin - 1 - yl) propoxy ] -3,4 - dihydro - 1H - quinolin - 2 - one thiophen - 4 - yl -piperazin - 1 -yl ) - ( Z ) -2 -butenyloxy ] -3,4 - di 20 hydro - 1H - quinolin -2 -one was prepared from 7-( 4 -chloro By a similar method as in Example 1, 7-( 3- ( 4 -benzo [ b ] (Z ) -2 -butenyloxy )-3,4 -dihydro - 1H -quinolin -2 -one . thiophen -4 - yl- piperazin - 1- yl ) propoxy ] -3,4 - dihydro -1H -qui White Powder (Methanol ) nolin - 2 -one was prepared from 7- (3 - chloropropoxy )-3,4 Melting point 68-70° C. dihydro - 1H - quinolin - 2- one . H -NMR (DMSO -d ) 8 ppm : White Powder (Methanol ) 25 2.42 (2H , t, J = 7.5 Hz) , 2.64 (4H , br ), 2.79 (2H , t , J = 7.5 Melting point 163-165° C. Hz ), 2.9-3.25 (6H , m ) , 4.61 (2H , d , J = 3 Hz) , 5.65-5.9 ( 2H , 1H -NMR (DMSO -d ) 8 ppm : m ) , 6.48 ( 1H , d , J = 2.5 Hz) , 6.54 (1H , dd , J = 2.5 , 8.5 Hz) , 1.8-2.0 (2H , m ) , 2.41 (2H , t , J = 7.5 Hz) , 2.45-2.6 ( 2H , m ), 6.89 ( 1H , d , J = 7.5 Hz) , 7.06 ( 1H , d , J = 8.5 Hz ) , 7.27 ( 1H , dd , 2.6-2.7 (4H , m ), 2.78 ( 2H , t, J = 7.5 Hz ), 2.95-3.2 (4H , m ), J = 8 Hz, 8 Hz) , 7.40 (1H , d , J= 5.5 Hz) , 7.61 (1H , d , J = 8 Hz) , 3.97 ( 2H , t , J = 6.3 Hz ) , 6.46 ( 1H , d , J = 2.3 Hz) , 6.50 ( 1H , dd , 30 7.69 (1H , d , J = 5.5 Hz ) , 10.01 ( 1H , bs ) . J = 2.4 Hz , 8.2 Hz) , 6.90 (1H , d , J = 7.6 Hz) , 7.04 ( 1H , d , J = 8.2 Hz) , 7.27 ( 1H , dd , J = 7.8 Hz, 7.8 Hz) , 7.40 (1H , d , J = 5.6 Hz ) , Example 14 7.61 (1H , d , J = 8.0 Hz) , 7.69 ( 1H , d , J = 5.5 Hz) , 9.97 ( 1H , bs ) . Preparation of 7- [4- ( 4 -benzo [ b ]thiophen - 4 -yl -piper Example 11 35 azin - 1 - yl) -3 -methylbutoxy ]-3,4 -dihydro - 1H - quino lin -2 -one hydrochloride Preparation of 7-[ 4- ( 4 -benzo [b ] thiophen -4 -yl -piper azin - 1- yl) butoxy ] -3,4 -dihydro -1H - quinolin - 2 -one By a similar method as in Example 1 , 7- [4- ( 4 -benzo [b ] thiophen -4 - yl -piperazin - 1 -yl ) -3 -methylbutoxy ] -3,4 -di By a similar method as in Example 1, 7-[ 4- ( 4 -benzo [b ] 40 hydro -1H -quinolin -2 -one was prepared from methanesulfo thiophen -4 -yl - piperazin - 1 -yl ) butoxy ] -3,4 - dihydro - 1H - qui nic acid 2 -methyl - 4- ( 2 -oxo - 1,2,3,4 - tetrahydroquinolin - 7 nolin -2 - one was prepared from 7- (4 - chlorobutoxy) -3,4 -di yloxy )butyl ester , and after it was made into a methanol hydro - 1H -quinolin - 2 -one . solution , 0.5N hydrochloric acid methanol solution was White Powder (Methanol ) added thereto , precipitated crystals were separated by filtra Melting point 147-148 ° C. 45 tion , recrystallized from isopropyl alcohol and thereby 7-[ 4 1H -NMR (DMSO - d ) 8 ppm : ( 4 -benzo [b ] thiophen -4 -yl - piperazin - 1 -yl ) -3 -methylbutoxyl 1.55-1.65 (2H , m ), 1.65-1.8 ( 2H , m ) , 2.35-2.5 (4H , m ), 3,4 -dihydro -1H -quinolin - 2 - one hydrochloride was obtained 2.55-2.7 (4H , m ) , 2.78 (2H , t, J = 7.5 Hz ) , 3.0-3.15 (4H , m ) , in the form of a slightly yellow powder . 3.93 ( 2H , t , J = 6.4 Hz ) , 6.44 ( 1H , d , J = 2.5 Hz) , 6.49 (1H , dd , Melting point 217-219 ° C. (decomposed ) J = 2.5 Hz, 8.3 Hz ), 6.89 ( 1H , d , J = 7.5 Hz) , 7.04 ( 1H , d , J = 8.3 50 H - NMR (DMSO -do ) è ppm : Hz) , 7.27 ( 1H , dd , J = 7.8 Hz, 7.8 Hz ), 7.35-7.45 ( 1H , m ) , 1.12 (3H , d , J = 6.5 Hz) , 1.55-1.7 (1H , m ), 1.9-2.05 ( 1H , 7.61 ( 1H , d , J = 8.1 Hz) , 7.68 (1H , d , J = 5.6 Hz) , 9.97 (1H , bs ). m ), 2.2-2.3 (1H , m ), 2.41 (2H , t , J = 7.5 Hz) , 2.79 (2H , t , J = 7.5 Hz ), 3.05-3.15 ( 1H , m ), 3.15-3.25 (1H , m ), 3.25-3.45 Example 12 (4H , m ), 3.45-3.55 (2H , m ) , 3.55-3.7 (2H , m ), 3.9-4.1 ( 2H , 55 m ), 6.49 (1H , d, J= 2.5 Hz ), 6.54 ( 1H , dd , J= 2.5 Hz , 8.5 Hz ), Preparation of 7-[ 4- ( 4 -benzo [b ] thiophen -4 - yl -piper 6.97 ( 1H , d , J = 7.5 Hz ), 7.06 (1H , d , J= 8.5 Hz) , 7.33 ( 1H , dd , azin - 1 - yl) butoxy ] -3,4 - dihydro - 1H - quinolin - 2 - one J = 8 Hz , 8 Hz ), 7.49 ( 1H , d , J = 5.5 Hz ) , 7.70 (1H , d , J = 8 Hz) , hydrochloride 7.77 ( 1H , d , J = 5.5 Hz ), 10.03 ( 1H , bs ), 10.66 ( 1H , br ). IN hydrochloric acid ethanol solution was added to an 60 Example 15 ethanol solution of 7-[ 4- (4 -benzo [ b ] thiophen - 4 - yl- piper azin - 1- yl ) butoxy ]-3,4 -dihydro - 1H - quinolin - 2 -one prepared Preparation of 7-[ 4-( 4 -benzo [ b ] thiophen - 4 - yl- piper in Example 11 , and precipitated crystals were filtrated and azin - 1 - yl) - ( E ) -2 -butenyloxy ] -3,4 - dihydro - 1H - quino recrystallized from 90 % aqueous ethanol and 7-[ 4-( 4 -benzo lin - 2 - one [ b ] thiophen - 4 -yl -piperazin - 1 - yl) butoxy ] -3,4 - dihydro - 1H 65 quinolin - 2 -one hydrochloride was obtained as slightly By a similar method as in Example 1 , 7-[ 4- ( 4 -benzo [ b ] brown needle - like crystals . thiophen - 4 -yl -piperazin - 1 - yl) - ( E ) -2 - butenyloxy ] -3,4 - di US RE48,059 E 35 36 hydro - 1H - quinolin - 2 -one was prepared from 7-( 4 - bromo being stirred under ice -cooling and stirred at room tempera ( E )-2 - butenyloxy )-3,4 - dihydro - 1H - quinolin -2 - one. ture for 1 hour, and after that 0.07 ml ofmethyl iodide was White Powder (Dichloromethane -Diisopropyl Ether) added and stirred at room temperature for 1 hour. Water was Melting point 147.8-149.7 ° C. added to the reaction solution , which was then extracted 1H -NMR (CDC13 ) d ppm : 5 with ethyl acetate and , after washed with water , dried over 2.61 (2H , t, J= 7.5 Hz) , 2.65-2.75 (4H , m ), 2.90 ( 2H , t, magnesium sulfate , and the solvent was evaporated under J = 7.5 Hz ), 3.1-3.2 (6H , m ), 4.52 (2H , d , J = 4.3 Hz) , 5.9-6.0 reduced pressure . The residue was purified by silica gel ( 2H , m ), 6.31 ( 1H , d , J = 2.3 Hz ) , 6.55 ( 1H , dd , J = 8.3 Hz , 2.3 column chromatography (dichloromethane :methanol = 30 : 1 ) . Hz ), 6.90 ( 1H , d , J = 7.6 Hz) , 7.05 (1H , d , J= 8.3 Hz) , 7.27 The solvent was evaporated under reduced pressure and ( 1H , m ), 7.37-7.41 ( 2H , m ) , 7.53-7.60 (2H , m ) . 10 0.5N hydrochloric acid ethanol solution was added thereto , precipitated crystals were separated by filtration , and Example 16 thereby 0.15 g of 7-[ 4- (4 -benzo [ b ]thiophen - 4 -yl - piperazin 1 -yl ) butoxy ]-1 - methyl - 3,4 - dihydro -1H - quinolin - 2 -one Preparation of 7- [4- ( 4 -benzo [ b ]thiophen - 4 - yl- piper hydrochloride was obtained in the form of a slightly yellow azin - 1 -yl ) butoxy ]-4 -methyl - 3,4 -dihydro - 1H - quino 15 powder. lin - 2 - one Melting point 275.6-277.6 ° C. By a similar method as in Example 1 , 7- [4- ( 4 -benzo [ b ] 1H -NMR (DMSO - d ) d ppm : thiophen - 4 - yl- piperazin - 1 - yl) butoxy ] -4 -methyl - 3,4 - di 1.70-1.94 (4H , m ) , 2.48-2.52 (2H , m ), 2.77 (2H , t , J = 7.2 hydro -1H - quinolin - 2 -one was prepared from 7-( 4 - chlorobu- 20 Hz) , 3.15-3.30 ( 9H , m ) , 3.52-3.63 (4H , m ), 4.03 (2H , t, toxy )-4 -methyl - 3,4 -dihydro -1H -quinolin - 2 - one. J = 6.0 Hz ), 6.58-6.63 (2H , m ), 6.96 ( 1H , d , J = 7.5 Hz ), 7.11 White Powder (Methanol ) ( 1H , d , J = 8.1 Hz) , 7.31 (1H , dd , J = 7.8 Hz , 7.8 Hz ) , 7.48 ( 1H , Melting point 112-115º C. d , J = 5.5 Hz) , 7.69 ( 1H , d , J = 8.0 Hz) , 7.75 ( 1H , d , J = 5.5 Hz ) , 1H -NMR (DMSO -D ) & ppm : 10.61 ( 1H , br ). 1.14 (3H , d , J = 7 Hz) , 1.55-1.7 (2H , m ) , 1.7-1.8 (2H , m ) , 25 2.19 ( 1H , dd , J = 7 , 16 Hz ), 2.43 (2H , t , J = 7 Hz) , 2.5-2.7 (5H , Example 19 m ) , 2.9-3.0 (1H , m ), 3.0-3.1 (4H , m ) , 3.94 (2H , t , J = 6.5 Hz) , 6.45 ( 1H , d , J = 2.5 Hz) , 6.53 ( 1H , dd , J = 2.5 , 8.5 Hz) , 6.89 Preparation of 6-( 3-( 4 -benzo [b ] thiophen - 4 - yl- piper ( 1H , d , J = 7.5 Hz ) , 7.07 ( 1H , d , J= 8.5 Hz) , 7.27 (1H , dd , J= 8 azin - 1 -yl ) propoxy ] -3,4 -dihydro - 1H - quinolin -2 -one Hz, 8 Hz) , 7.39 ( 1H , d , J = 5.5 Hz ), 7.61 (1H , d , J = 8 Hz ) , 7.69 30 hydrochloride ( 1H , d , J = 5.5 Hz ), 9.98 ( 1H , bs) . By a similar method as in Example 1 , 6-[ 3- ( 4 -benzo [ b ] Example 17 thiophen - 4 - yl- piperazin - 1 - yl) propoxy ] -3,4 - dihydro - 1H - qui nolin -2 -one was prepared from 6-( 3 - chloropropoxy ) -3,4 Preparation of 7-{ 2- [ 2- ( 4 - benzo [ b ] thiophen - 4 - yl 35 dihydro - 1H - quinolin - 2 - one , and after it was made into a piperazin -1 -yl ) ethoxyJethoxy } -3,4 -dihydro - 1H - qui methanol solution , 0.5N hydrochloric acid methanol solu nolin - 2 -one dihydrochloride tion was added thereto , precipitated crystals were separated by filtration , recrystallized from a mixed solvent of ethyl By a similar method as in Example 1 , 7- { 2- [ 2-( 4 -benzo acetate -diethyl ether and thereby 6-[ 3- ( 4 -benzo [ b ]thiophen [b ]thiophen -4 - yl- piperazin - 1- yl) ethoxyJethoxy } -3,4 - di 40 4 -yl - piperazin - 1 - yl) propoxy ] -3,4 -dihydro - 1H -quinolin - 2 hydro - 1H -quinolin - 2 -one was prepared from 7-[ 2- ( 2 - chlo one hydrochloride was obtained in the form of a white roethoxy ) ethoxy ]-3,4 -dihydro -1H -quinolin - 2 -one , and after powder. it was made into an ethanol solution , IN hydrochloric acid Melting point 231-234° C. ethanol solution was added thereto , precipitated crystals H -NMR ( DMSO -do ) d ppm : were separated by filtration , recrystallized from isopropyl 45 2.20-2.30 ( 2H , m ), 2.35-2.45 ( 2H , m ), 2.83 (2H , t, J= 7.5 alcohol- diisopropyl ether and thereby 7- {2- [ 2- (4 -benzo [ b ] Hz) , 3.20-3.70 (10H , m ), 4.02 ( 2H , t, J = 5.9 Hz) , 6.70-6.85 thiophen - 4 - yl- piperazin - 1- yl) ethoxyJethoxy } -3,4 - dihydro (3H , m ) , 6.96 ( 1H , d , J = 7.6 Hz ) , 7.31 ( 1H , dd, J = 7.9 Hz , 7.9 1H - quinolin - 2 - one dihydrochloride was obtained in the Hz ), 7.48 ( 1H , d , J= 5.6 Hz) , 7.69 (1H , d , J= 8.1 Hz) , 7.76 form of a white powder. ( 1H , d , J = 5.5 Hz) , 9.93 ( 1H , brs ) , 10.90 (1H , brs ) . Melting point 172.3-177.2 ° C. 50 1H -NMR (CDC13 ) d ppm : Example 20 2.53 (2H , t , J = 7.5 Hz) , 2.80 ( 2H , t, J = 7.5 Hz ) , 3.40 (2H , m ), 3.54-3.59 ( 2H , m ), 3.79-3.94 (6H , m ), 4.16-4.30 (6H , Preparation of 6-[ 4- ( 4 -benzo [ b ] thiophen - 4 - yl- piper m ) , 6.50-6.53 (2H , m ), 7.01 (1H , d , J = 8.0 Hz ) , 7.36 ( 1H , dd , azin - 1 - yl) butoxy ] -3,4 -dihydro - 1H -quinolin - 2 -one J = 8 Hz, 8 Hz ), 7.53-7.62 (2H , m ), 7.82 (1H , d , J = 8.0 Hz) , 55 By a similar method as in Example 1, 6-[ 4- ( 4 -benzo [ b ] 7.91 ( 1H , m ) , 8.02 ( 1H , brs ), 13.31 ( 1H , brs ). thiophen - 4 - yl- piperazin - 1 - yl) butoxy ] -3,4 - dihydro - 1H - qui Example 18 nolin - 2 -one was prepared from 6-( 4 -bromobutoxy ) -3,4 - di hydro - 1H - quinolin - 2 -one . Preparation of 7- [4- (4 -benzo [b ] thiophen -4 -yl - piper 60 White Powder ( Ethyl Acetate - Diethyl Ether ) azin - 1 -yl )butoxy ]-1 -methyl - 3,4 -dihydro - 1H - quino Melting point 175-178 ° C. lin - 2 - one hydrochloride H -NMR (CDC13 ) ppm : 1.65-1.90 ( 4H , m ), 2.52 (2H , t , J = 7.3 Hz) , 2.55-2.65 ( 2H , 48 mg of sodium hydride (60 % oily ) was added to a m ) , 2.65-2.75 (4H , m ) , 2.94 ( 2H , t , J = 7.5 Hz) , 3.15-3.25 solution of 0.40 g of 7-[ 4-( 4 -benzo [b ] thiophen -4 -yl - piper- 65 (4H , m ), 3.90-4.00 (2H , m ), 6.65-6.75 (3H , m ), 6.89 (1H , dd , azin - 1 -yl )butoxy ] -3,4 -dihydro - 1H - quinolin - 2 -one in dim J = 0.7 Hz, 7.6 Hz) , 7.27 ( 1H , dd , J = 7.9 Hz, 7.9 Hz) , ethylformamide (5 ml) and tetrahydrofuran ( 5 ml) while 7.35-7.45 ( 2H , m ), 7.55 ( 1H , d , J = 8.0 Hz) , 8.02 (1H , brs ). US RE48,059 E 37 38 Example 21 1H -NMR (DMSO -d ) d ppm : 1.6-1.9 (4H , m ), 2.98-3.60 ( 16H , m ) , 6.98 (1H , d , J = 7.7 Preparation of 1- [4- ( 4 - benzo [b ] thiophen - 4 -yl - piper Hz ) , 7.30-7.38 (3H , m ), 7.46-7.51 (2H , m ), 7.71 (1H , d , azin - 1 -yl )butyl ] -3,4 -dihydro - 1H -quinolin - 2 -one J = 8.2 Hz) , 7.77 ( 1H , d , J = 5.5 Hz ) , 7.89 ( 1H , d , J = 7.7 Hz ) , hydrochloride 5 10.10 (1H , brs ). By a similar method as in Example 1 , 1-[ 4-( 4 -benzo [b ] Example 24 thiophen - 4 - yl - piperazin - 1 - yl) butyl] -3,4 -dihydro - 1H -quino lin - 2 - one was prepared from 1- (4 - chlorobutyl) -3,4 -dihydro 1H -quinolin - 2 -one , and after it was made into an ethanol 10 Preparation of 2- [5- ( 4 - benzo [ b ] thiophen - 4 -yl -piper solution , 1N hydrochloric acid ethanol solution was added azin - 1- yl ) pentyl ] -3,4 -dihydro - 2H - isoquinolin -1 -one thereto , precipitated crystals were separated by filtration and thereby 1-[ 4-( 4 -benzo [ b ]thiophen - 4 - yl- piperazin - 1 - yl) bu By a similar method as in Example 1 , 2- [5- ( 4 -benzo [ b ] tyl] -3,4 -dihydro - 1H - quinolin - 2 -one hydrochloride was thiophen - 4 - yl -piperazin - 1 -yl ) pentyl] -3,4 -dihydro -2H - iso obtained in the form of a white powder . 15 quinolin -1 -one was prepared from 2-5 - chloropentyl) -3,4 Melting point 257.0-259.0 ° C. dihydro -2H - isoquinolin -1 -one . H -NMR (DMSO -d ) 8 ppm : White Powder (Ethyl Acetate - Diisopropyl Ether ) 1.60-1.80 (4H , m ), 2.54 (2H , t, J = 8.3 Hz) , 2.87 ( 2H , t, Melting point 91.8-93.3 ° C. J= 7.9 Hz ), 3.10-3.30 (6H , m ), 3.50-3.60 (4H , m ), 3.95 (2H , 20 H -NMR ( CDC13 ) d ppm : t , J = 7.0 Hz) , 6.94-7.04 ( 2H , m ), 7.14-7.35 (4H , m ) , 7.48 1.32-1.37 (2H , m ), 1.56-1.64 (4H , m ), 2.38 (2H , t , J = 7.6 ( 1H , d , J= 5.6 Hz) , 7.70 (1H , d , J = 8.0 Hz ), 7.76 (1H , d , J= 5.6 Hz) , 2.62 (4H , m ), 2.92 (2H , t , J = 6.5 Hz) , 3.09-3.11 (4H , m ) , Hz) , 10.00-10.20 ( 1H , m ). 3.47-3.55 (4H , m ) , 6.81 ( 1H , d , J = 7.5 Hz) , 7.08-7.11 (2H , m ), 7.17-7.35 (4H , m ), 7.47 ( 1H , d, J = 8.0 Hz ), 8.01 ( 1H , dd , Example 22 25 J = 7.5 Hz, 1.4 Hz) . Preparation of 1-[ 5- ( 4 -benzo [ b ] thiophen - 4 -yl - piper Example 25 azin - 1- yl ) pentyl ] -3,4 -dihydro - 1H -quinolin - 2 -one hydrochloride Preparation of 6- [ 3- ( 4 - benzo [ b ] thiophen - 4 -yl - piper 30 azin - 1- yl ) propoxy ] -3,4 -dihydro -2H - isoquinolin - 1 By a similar method as in Example 1 , 1- [ 5- ( 4 -benzo [ b ] one thiophen - 4 - yl- piperazin - 1 - yl) pentyl ]-3,4 -dihydro - 1H - qui nolin - 2 -one was prepared from 1- (5 - chloropentyl ) -3,4 -di hydro - 1H -quinolin - 2 -one , and after it was made into an By a similar method as in Example 1 , 6-( 3-( 4 -benzo [ b ] ethanol solution , IN hydrochloric acid ethanol solution was 35 thiophen - 4 - yl -piperazin - 1 -yl ) propoxy ] -3,4 -dihydro - 2H - iso added thereto , precipitated crystals were separated by filtra quinolin -1 - one was prepared from 6-( 3 - chloropropoxy ) -3,4 tion and thereby 1- [5- (4 -benzo [b ]thiophen -4 - yl -piperazin - 1 dihydro - 2H - isoquinolin - 1- one . yl) pentyl ] -3,4 - dihydro - 1H -quinolin - 2 - one hydrochloride White Powder (Ethyl Acetate -Diethyl Ether ) was obtained . Melting point 203-205º C. Melting point 242.0-244.0 ° C. 40 H -NMR ( CDC13 ) d ppm : 1H -NMR (DMSO -do ) è ppm : 2.00-2.10 (2H , m ) , 2.60-2.70 (2H , m ), 2.74 (4H , brs ) , 2.96 1.30-1.45 ( 2H , m ) , 1.50-1.65 (2H , m ) , 1.70-1.85 (2H , m ) , (2H , t, J = 6.5 Hz) , 3.20 (4H , brs ), 3.50-3.60 (2H , m ), 4.11 2.53 ( 2H , t, J = 8.2 Hz ), 2.85 ( 2H , t , J = 8.0 Hz ) , 3.10-3.30 (6H , ( 2H , t , J = 6.3 Hz) , 6.09 ( 1H , brs) , 6.73 (1H , s ), 6.85-6.95 m ) , 3.50-3.60 (4H , m ), 3.91 (2H , t , J = 7.3 Hz) , 6.94-7.03 45 ( 2H , m ) , 7.25-7.30 ( 1H , m ) , 7.35-7.45 ( 2H , m ), 7.55 ( 1H , d , ( 2H , m ), 7.13-7.34 (4H , m ), 7.47 ( 1H , d , J = 5.6 Hz ), 7.69 J = 8.1 Hz ) , 8.01 ( 1H , d , J = 8.6 Hz ) . (1H , d , J = 8.0 Hz ) , 7.76 ( 1H , d , J = 5.5 Hz ), 10.30-10.50 (1H , m ) . Example 26 Example 23 50 Preparation of 6- [3- (4 - benzo [b ] thiophen -4 - yl- piper azin - 1 - yl) propoxy ] -2 -methyl - 3,4 - dihydro - 2H - isoqui Preparation of 2-[ 4- ( 4 - benzo [ b ] thiophen - 4 - yl- piper nolin - 1 -one azin - 1 -yl )butyl ] -3,4 - dihydro -2H - isoquinolin - 1 -one hydrochloride 55 By a similar method as in Example 18, 6-[ 3- ( 4 -benzo [ b ] thiophen -4 - yl- piperazin - 1- yl ) propoxy ] -2 -methyl - 3,4 -di By a similar method as in Example 1 , 2-[ 4- ( 4 - benzo [ b ] hydro -2H - isoquinolin - 1 -one was prepared from 6- [3- (4 thiophen - 4 - yl - piperazin - 1 - yl) butyl ] -3,4 - dihydro - 2H - isoqui benzo [ b ] thiophen - 4 - yl- piperazin - 1 -yl ) propoxy ] -3,4 nolin - 1 -one was prepared from 2-( 4 - chlorobutyl ) -3,4 - di dihydro -2H - isoquinolin - 1 -one using methyl iodide . hydro - 2H - isoquinolin - 1 -one , and after it was made into an 60 ethanol solution , 1N hydrochloric acid ethanol solution was White Powder (Ethyl Acetate -Diethyl Ether ) added thereto , precipitated crystals were separated by filtra Melting point 110-113 ° C. tion , recrystallized from a mixed solvent of isopropyl alco H -NMR ( CDC13 ) d ppm : hol- ethanol and thereby 2- [4- ( 4 - benzo [ b ] thiophen - 4 - yl- pip 2.05 (2H , t , J = 6.9 Hz) , 2.65 ( 2H , t , J = 7.3 Hz ) , 2.74 (4H , erazin - 1 - yl) butyl ] -3,4 - dihydro - 2H - isoquinolin - 1 - one 65 brs ) , 2.97 ( 2H , t , J = 6.7 Hz) , 3.14 (3H , s ), 3.21 (4H , brs ) , 3.54 hydrochloride was obtained . ( 2H , t , J = 6.7 Hz) , 4.11 (2H , t, J = 6.4 Hz) , 6.68 ( 1H , s ) , 6.86 Melting point 257.5-265.5º C. ( 1H , dd , J = 2.3 Hz, 8.6 Hz ) , 6.91 (1H , d , J = 7.7 Hz) , 7.25-7.30 US RE48,059 E 39 40 ( 1H , m ) , 7.40 (1H , d , J = 5.5 Hz) , 7.42 ( 1H , d , J = 5.5 Hz ) , 7.56 Example 30 ( 1H , d , J = 7.9 Hz ) , 8.03 ( 1H , d , J = 8.6 Hz) . Preparation of 7- (3- (4 - benzo [b ] thiophen -4 - yl- piper Example 27 azin - 1 - yl )propoxy ] -2 -methyl -3,4 - dihydro - 2H - isoqui 5 nolin - 1 -one hydrochloride Preparation of 6-( 3- ( 4 -benzo [b ] thiophen -4 -yl - piper azin - 1 - yl) propoxy ) -2 - ethyl- 3,4 - dihydro - 2H - isoqui After 7-[ 3- (4 -benzo [b ] thiophen - 4 -yl - piperazin - 1- yl ) nolin - 1 - one propoxy ] -2 -methyl - 3,4 -dihydro -2H - isoquinolin - 1- one was By a similar method as in Example 18 , 6-( 3- (4 - benzo [b ] 10 madesolution into was an addedethanol thereto solution , precipitated , 1N hydrochloric crystals acid were ethanol sepa thiophen - 4 - yl- piperazin - 1 -yl ) propoxy ] -2 - ethyl- 3,4 -dihydro rated by filtration , recrystallized from ethanol and thereby 2H -isoquinolin - 1 -one was prepared from 6- (3- ( 4 - benzo [ b ] 7-[ 3- ( 4 -benzo [ b ]thiophen - 4 - yl- piperazin - 1 - yl) propoxy ]-2 thiophen - 4 -yl - piperazin - 1 -yl ) propoxy ] -3,4 - dihydro - 2H methyl- 34 -dihydro - 2H - isoquinolin - 1 -one hydrochloride isoquinolin - 1 -one using ethyl iodide . was obtained in the form of a white powder . White Powder ( Ethyl Acetate- Diethyl Ether) 15 Melting point 229-233 ° C. Melting point 128-131 ° C. H -NMR (DMSO -d ) ppm : H -NMR (CDC13 ) è ppm : 2.20-2.30 (2H , m ), 2.89 (2H , t, J = 6.7 Hz) , 3.01 ( 3H , s) , 1.21 ( 3H , t , J = 7.2 Hz) , 2.05 (2H , t, J = 6.9 Hz) , 2.65 (2H , 3.21 ( 2H , t , J = 6.9 Hz) , 3.30-3.60 ( 8H , m ) , 3.60-3.70 ( 2H , t , J = 7.3 Hz ), 2.74 (4H , brs ), 2.96 (2H , t, J =6.6 Hz ), 3.21 (4H , 20 m ), 4.11 (2H , t, J = 6.0 Hz ), 6.97 (1H , d , J = 7.7 Hz ), 7.06 (1H , brs ), 3.54 (2H , t, J = 6.7 Hz) , 3.62 (2H , q , J = 7.2 Hz) , 4.11 dd , J = 2.8 Hz, 8.3 Hz ), 7.22 ( 1H , d , J = 7.9 Hz) , 7.31 ( 1H , dd , ( 2H , t , J = 6.3 Hz) , 6.68 ( 1H , d , J = 1.7 Hz ) , 6.86 (1H , dd , J = 2.3 J = 7.8 Hz , 7.8 Hz) , 7.41 (1H , d , J = 2.7 Hz) , 7.49 ( 1H , d , J = 5.5 Hz, 8.2 Hz) , 6.91 ( 1H , d , J = 7.7 Hz) , 7.25-7.30 ( 1H , m ), 7.40 Hz ), 7.69 (1H , d , J = 8.1 Hz ), 7.76 ( 1H , d , J = 5.5 Hz) , 10.70 ( 1H , d , J = 5.5 Hz) , 7.42 ( 1H , d , J = 5.5 Hz) , 7.56 (1H , d , J = 7.8 (1H , brs ) . Hz) , 8.03 ( 1H , d , J = 8.6 Hz ) . 25 Example 31 Example 28 Preparation of 7-( 3-( 4 -benzo [ b ] thiophen - 4 - yl- piper Preparation of 7- (3- ( 4 -benzo [ b ] thiophen - 4 -yl -piper azin - 1 - yl) propoxy ] -2 - ethyl- 3,4 - dihydro - 2H - isoqui azin - 1- yl ) propoxy ] -3,4 -dihydro -2H -isoquinolin -1 30 nolin - 1 - one dihydrochloride one By a similar method as in Example 18 , 7-( 3-( 4 -benzo [ b ] By a similar method as in Example 1, 7-[ 3-( 4 -benzo [b ] thiophen - 4- yl- piperazin -1 -yl ) propoxy ) -2 - ethyl - 3,4 - dihydro thiophen - 4 - yl- piperazin - 1 - yl) propoxy ] -3,4 -dihydro - 2H - iso 2H - isoquinolin - 1 -one was prepared from 7-( 3- ( 4 - benzo [b ] quinolin - 1 - one was prepared from 7- ( 3 - chloropropoxy )-3,4- 35 thiophen -4 - yl -piperazin - 1 - yl) propoxy ]-3,4 - dihydro - 2H dihydro -2H -isoquinolin -1 - one. isoquinolin - 1| -one using ethyl iodide, and after it was made into a methanol solution , 0.5N hydrochloric acid methanol White Powder ( Ethyl Acetate- Diethyl Ether) solution was added thereto , precipitated crystals were sepa Melting point 176-179 ° C. rated by filtration , recrystallized from a mixed solvent of H -NMR (CDC1z ) ppm : 40 methanol- ethyl acetate and thereby 7-[ 3- ( 4 -benzo [b ] thio 2.00-2.10 (2H , m ) , 2.64 (2H , t , J = 7.3 Hz) , 2.73 ( 4H , brs ) , phen -4 -yl - piperazin -1 - yl )propoxy )-2 -ethyl - 3,4 -dihydro -2H 2.94 ( 2H , t , J = 6.6 Hz ), 3.20 (4H , brs ), 3.50-3.60 (2H , m ) , isoquinolin - 1 -one dihydrochloride was obtained in the form 4.12 ( 2H , t , J = 6.3 Hz ), 5.92 ( 1H , brs) , 6.90 ( 1H , d , J = 7.7 of a white powder. Hz ) , 7.03 ( 1H , dd , J = 2.8 Hz , 8.3 Hz ) , 7.13 ( 1H , d , J = 8.3 Hz ) , Melting point 210-213 ° C. 7.25-7.30 ( 1H , m ), 7.39 (1H , d , J = 5.5 Hz) , 7.42 (1H , d , J = 5.5 45 1H -NMR ( DMSO - d ) d ppm : Hz) , 7.55 ( 1H , d , J = 8.1 Hz) , 7.62 ( 1H , d , J = 2.7 Hz ). 1.09 (3H , t , J = 7.1 Hz ) , 2.20-2.30 (2H , m ), 2.87 (2H , t , J = 6.5 Hz) , 3.20-3.70 ( 14H , m ) , 4.11 ( 2H , t, J = 5.9 Hz) , 6.96 Example 29 (1H , d , J = 7.7 Hz) , 7.00-7.10 (1H , m ), 7.22 (1H , d , J = 8.3 Hz) , 7.25-7.35 ( 1H , m ), 7.41 (1H , d , J = 2.7 Hz) , 7.48 (1H , d , J = 5.5 Preparation of 7- (3- ( 4 -benzo [b ]thiophen - 4 - yl -piper 50 Hz ), 7.69 ( 1H , d , J= 7.7 Hz) , 7.76 ( 1H , d , J = 5.5 Hz ), 11.08 azin - 1 -yl ) propoxyl- 2 -methyl - 3,4 - dihydro - 2H - isoqui ( 1H , brs ) . nolin - 1 - one Example 32 By a similar method as in Example 18 , 7- [ 3- ( 4 -benzo [ b ] thiophen - 4 - yl -piperazin - 1 - yl )propoxy ]-2 -methyl - 3,4 -di 55 Preparation of 7-[ 4- ( 4 -benzo [ b ] thiophen - 4 - yl- piper hydro - 2H - isoquinolin - 1 -one was prepared from 7-( 3-( 4 azin - 1 - yl) butoxy ) -2- methyl -3,4 - dihydro - 2H - isoqui benzo [b ]thiophen -4 - yl -piperazin - 1- yl ) propoxy ]-3,4 nolin - 1- one hydrochloride dihydro - 2H - isoquinolin - 1 -one using methyl iodide . White Powder ( Ethanol) By a similar method as in Example 1 , 7-[ 4- ( 4 -benzo [ b ] Melting point 115-117 ° C. 60 thiophen - 4 -yl - piperazin - 1 -yl ) butoxy ] -2 -methyl - 3,4 -di H -NMR (CDCI ) : ppm : hydro - 2H - isoquinolin - 1 -one was prepared from 7-( 4 - chlo 1.95-2.10 ( 2H , m ), 2.64 (2H , t , J = 7.3 Hz) , 2.70-2.80 (4H , robutoxy ) -2 -methyl - 3,4 - dihydro - 2H - isoquinolin - 1 - one , and m ) , 2.94 (2H , t , J = 6.7 Hz) , 3.10-3.25 (4H , m ) , 3.16 ( 3H , s ) , after it was made into a methanol solution , 0.5N hydrochlo 2.54 (2H , t, J = 6.7 Hz) , 4.11 (2H , t, J= 6.5 Hz) , 6.90 (1H , d , ric acid methanol solution was added thereto , precipitated J = 7.0 Hz ) , 6.98 ( 1H , dd , J = 2.7 Hz, 8.3 Hz) , 7.08 ( 1H , d , 65 crystals were separated by filtration , recrystallized from a J = 8.3 Hz) , 7.28 (1H , dd , J= 7.9 Hz, 7.9 Hz ), 7.35-7.45 ( 2H , mixed solvent ofmethanol - ethyl acetate and thereby 7-[ 4 m ), 7.55 ( 1H , d , J = 8.1 Hz ) , 7.63 (1H , d , J = 2.6 Hz ). ( 4 - benzo [ b ] thiophen - 4 - yl- piperazin - 1 - yl) butoxy ] -2 -methyl US RE48,059 E 41 42 3,4 - dihydro - 2H - isoquinolin - 1 -one hydrochloride was 6.9 Hz) , 7.26 ( 1H , d , J = 7.9 Hz) , 7.33 ( 1H , dd , J = 8.8 Hz, 2.8 obtained in the form of a white powder . Hz) , 7.41 ( 1H , d , J = 5.5 Hz) , 7.59-7.63 (3H , m ) , 7.69 ( 1H , d , Melting point 213-218 ° C. J = 5.5 Hz ) , 11.21 ( 1H , d , J = 4.9 Hz ). H -NMR (DMSO - d ) ppm : 1.70-2.00 (4H , m ), 2.88 (2H , t , J = 6.6 Hz ), 3.01 (3H , s ), 5 Example 36 3.10-3.70 ( 12H , m ) , 4.03 ( 2H , t , J = 5.8 Hz) , 6.95 ( 1H , d , J = 7.5 Hz) , 7.04 (1H , dd , J = 2.8 Hz, 8.5 Hz ), 7.20 (1H , d , Preparation of 7- [3- (4 -benzo [b ]thiophen - 4 - yl- piper J = 8.4 Hz ) , 7.31 (1H , dd , J = 7.8 Hz , 7.8 Hz) , 7.39 ( 1H , d , azin - 1 - yl) propoxyl - 2 -methyl - 2H - isoquinolin - 1 - one J = 2.7 Hz) , 7.48 (1H , d , J = 5.7 Hz) , 7.69 ( 1H , d , J = 8.1 Hz ) , hydrochloride 7.75 ( 1H , d , J = 5.5 Hz) , 10.71 ( 1H , brs ) . 10 By a similar method as in Example 18 , 7- [3- (4 -benzo [b ] Example 33 thiophen - 4 - yl- piperazin - 1 - yl) propoxy ]-2 -methyl - 2H - iso quinolin - 1 -one was prepared from 7- [3- ( 4 - benzo [ b ] thio Preparation of 7- [4- ( 4 -benzo [ b ]thiophen - 4 - yl- piper phen - 4 -yl -piperazin - 1 - yl ) propoxy ] -2H - isoquinolin - 1 - one azin - 1- yl ) butoxy ] -3,4 -dihydro -2H - isoquinolin - 1 -one 15 using methyl iodide, and after it was made into an ethyl hydrochloride acetate solution , 1N hydrochloric acid ethanol solution was added thereto , precipitated crystals were separated by filtra By a similar method as in Example 1 , 7- [4- ( 4 -benzo [ b ] tion , recrystallized from ethyl acetate and thereby 7- [3- ( 4 thiophen - 4 - yl- piperazin - 1 -yl ) butoxy ] -3,4 -dihydro -2H - iso benzo [b ] thiophen -4 -yl - piperazin - 1 -yl ) propoxy ] -2 -methyl quinolin - 1- one was prepared from 7-( 4 - chlorobutoxy ) -3,4- 20 2H - isoquinolin - 1 -one hydrochloride was obtained in the dihydro -2H -isoquinolin - 1 -one , and after it was made into an form of a white powder . ethyl acetate solution , 1N hydrochloric acid ethanol solution Melting point 227.6-230.2 ° C. was added thereto , precipitated crystals were separated by H -NMR (DMSO -do ) d ppm : filtration , recrystallized from ethyl acetate and thereby 7- [4 2.31 (2H , quint, J= 7.0 Hz) , 3.20-3.40 (6H , m ), 3.52 (3H , (4 -benzo [b ] thiophen -4 - yl - piperazin - 1- yl) butoxy ]-3,4 -di 25 s ), 3.54-3.70 (4H , m ), 4.23 (2H , t, J= 5.8 Hz) , 6.60 ( 1H , d , hydro -2H - isoquinolin - 1 -one hydrochloride was obtained in J = 7.3 Hz ), 6.99 ( 1H , d , J= 7.7 Hz) , 7.30-7.38 (3H , m ), 7.51 the form of a white powder . (1H , d , J = 5.6 Hz) , 7.63-7.73 (3H , m ), 7.78 (1H , d , J = 5.5 Hz) , Melting point 223.8-226.8 ° C. 10.88 ( 1H , s ). H -NMR (DMSO -do ) d ppm : 1.81-1.93 (4H , m ), 2.83 ( 2H , t , J = 6.5 Hz) , 3.16-3.32 (8H , 30 Example 37 m ), 3.43-3.64 (4H , m ), 4.06 (2H , t , J = 5.9 Hz) , 6.97 ( 1H , d , J = 7.6 Hz) , 7.07 (1H , dd , J = 8.3 Hz , 2.7 Hz) , 7.24 ( 1H , d , Preparation of 7- [3- ( 4 - benzo [ b ] thiophen - 4 -yl -piper J= 7.7 Hz ), 7.32 (1H , dd , J = 7.9 Hz , 7.9 Hz) , 7.39 ( 1H , d , azin - 1 - yl) propoxy ] -2 - ethyl- 2H -isoquinolin - 1 -one J= 2.7 Hz) , 7.50 ( 1H , d , J= 5.6 Hz ), 7.71 ( 1H , d , J= 8.0 Hz ), hydrochloride 7.77 ( 1H , d , J = 5.5 Hz) , 7.95 ( 1H , s ), 10.62 ( 1H , s ). 35 By a similar method as in Example 1 , 7-( 3- ( 4 -benzo [ b ] Example 34 thiophen - 4 - yl -piperazin - 1 - yl ) propoxy ]-2 - ethyl- 2H -isoqui nolin - 1- one was prepared from 7-( 3 - chloropropoxy ) -2 Preparation of 2-[ 4- ( 4 -benzo [b ] thiophen -4 -yl - piper ethyl- 2H -isoquinolin - 1 -one , and after it was made into an azin - 1 -yl )butyl ] -2H - isoquinolin - 1 -one 40 ethyl acetate solution , 1N hydrochloric acid ethanol solution was added thereto , precipitated crystals were separated by By a similar method as in Example 1 , 2-[ 4-( 4 -benzo [ b ] filtration , recrystallized from ethyl acetate and thereby 7-[ 3 thiophen - 4 - yl -piperazin - 1 -yl ) butyl] -2H - isoquinolin - 1 -one ( 4 -benzo [ b ] thiophen - 4 -yl - piperazin - 1 -yl )propoxy ] -2 - ethyl was prepared from 2-( 4 -chlorobutyl ) -2H - isoquinolin - 1 -one . 2H - isoquinolin - 1 -one hydrochloride was obtained in the Pale Brown Powder (Ethyl Acetate -Diisopropyl Ether ) 45 form of a white powder. Melting point 141.1-142.7 ° C. Melting point 229.9-231.2 ° C. 1H -NMR (CDC13 ) & ppm : H -NMR (DMSO - d ) d ppm : 1.62 (2H , m ), 1.87 (2H , m ) , 2.50 (2H , t , J = 7.4 Hz ) , 1.25 (3H , t, J = 7.1 Hz ) , 2.29 (2H , brs ) , 3.14-3.49 (6H , m ), 2.66-2.71 (4H , m ), 3.16-3.19 (4H , m ), 4.06 (2H , t, J= 7.2 3.56-3.72 (4H , m ) , 4.00 (2H , q , J = 7.2 Hz) , 4.23 (2H , t, J = 5.9 Hz ) , 6.50 ( 1H , d , J = 7.3 Hz ), 6.89 ( 1H , d , J = 7.7 Hz) , 7.08 50 Hz) , 6.62 (1H , d , J = 7.3 Hz) , 6.99 (1H , d , J = 7.6 Hz) , ( 1H , d , J = 7.3 Hz) , 7.24-7.65 (7H , m ), 8.44 ( 1H , d , J= 7.9 Hz) . 7.27-7.39 (3H , m ), 7.51 (1H , d , J = 5.6 Hz) , 7.62-7.73 ( 3H , m ), 7.78 ( 1H , d , J= 5.5 Hz) , 10.38 (1H , s ). Example 35 Example 38 Preparation of 7-( 3-( 4 -benzo [ b ] thiophen - 4 - yl- piper 55 azin -1 -yl ) propoxyl- 2H - isoquinolin -1 -one Preparation of 2- [4- (4 - benzo [b ] thiophen -4 - yl- piper azin - 1- yl ) butyl ] -7 -methoxy -2H - isoquinolin - 1 -one By a similar method as in Example 1, 7-( 3-( 4- benzo [b ] hydrochloride thiophen -4 - yl- piperazin - 1 -yl ) propoxy ] -2H - isoquinolin - 1 one was prepared from 7- ( 3 -chloropropoxy ) -2H - isoquino- 60 By a similar method as in Example 1, 2- [4- (4 -benzo [b ] lin - 1 -one . thiophen -4 - yl- piperazin - 1- yl ) butyl ] -7 -methoxy -2H - isoqui White Powder (Ethyl Acetate ) nolin - 1 - one was prepared from 2- ( 4 -chlorobutyl ) -7 Melting point 220.1-222.5 ° C. methoxy -2H - isoquinolin - 1 - one, and after it was made into H -NMR (DMSO - d ) d ppm : an ethyl acetate solution , IN hydrochloric acid ethanol 1.99 (2H , quint, J= 6.6 Hz) , 2.57 (2H , t, J = 7.0 Hz ), 2.66 65 solution was added thereto , precipitated crystals were sepa ( 4H , brs ), 3.09 (4H , brs ), 4.16 ( 2H , t, J = 6.3 Hz) , 6.52 ( 1H , rated by filtration , recrystallized from ethyl acetate and d , J = 7.1 Hz ), 6.90 (1H , d , J = 7.4 Hz) , 7.04 ( 1H , dd , J = 6.9 Hz, thereby 2-[ 4-( 4 - benzo [ b ] thiophen - 4 - yl- piperazin - 1 - yl) bu US RE48,059 E 43 44 tyl ]-7 -methoxy - 2H -isoquinolin - 1 -one hydrochloride was added thereto , precipitated crystals were separated by filtra obtained in the form of a white powder . tion , recrystallized from ethyl acetate and thereby 6- (3- ( 4 Melting point 243.5-245.6 ° C. benzo [b ] thiophen -4 -yl - piperazin - 1- yl ) propoxy )-2 - methyl 1H - NMR (DMSO -d ) 8 ppm : 2H - isoquinolin - 1 -one hydrochloride was obtained in the 1.78 (4H , brs ), 3.10-3.28 (6H , m ), 3.56 (4H , t, J= 9.6 Hz ), 5 form of a white powder. 3.87 ( 3H , s ), 4.04 ( 2H , t, J = 5.3 Hz) , 6.64 ( 1H , d , J = 7.3 Hz ) , Melting point 241.4-244.8 ° C. 6.96 (1H , d , J = 7.6 Hz) , 7.30 ( 1H , d , J = 8.0 Hz ), 7.34 (1H , dd , H -NMR (DMSO -do ) d ppm : J = 8.6 Hz, 2.9 Hz) , 7.41 ( 1H , d , J= 7.3 Hz) , 7.49 ( 1H , d , J = 5.6 2.31 ( 2H , t , J = 7.6 Hz) , 3.46 (3H , s ) , 3.19-3.70 ( 10H , m ) , Hz ), 7.63 (1H , d , J = 8.6 Hz) , 7.69 ( 1H , dd , J = 8.0 Hz, 8.0 Hz) , 4.24 ( 2H , t , J = 5.9 Hz) , 6.54 (1H , d , J = 7.4 Hz) , 6.99 ( 1H , d , 7.77 ( 1H , d , J = 5.5 Hz) , 10.60 ( 1H , s ) . 10 J = 7.6 Hz ), 7.10 (1H , dd , J = 8.8 Hz, 2.4 Hz ), 7.15 ( 1H , d , J = 2.3 Hz) , 7.33 ( 1H , dd , J = 7.9 Hz , 7.9 Hz ), 7.45 ( 1H , d , Example 39 J = 7.1 Hz ), 7.51 (1H , d , J = 5.5 Hz ), 7.71 (1H , d , J = 8.0 Hz) , 7.78 ( 1H , d , J = 5.5 Hz ) , 8.14 ( 1H , d , J = 8.8 Hz) , 10.86 ( 1H , Preparation of 2- [4- ( 4 -benzo [ b ]thiophen - 4 - yl- piper s ). azin -1 -yl ) butyl] -7 - hydroxy -2H - isoquinolin - 1 -one 15 hydrobromide Example 42 Boron tribromide (2M dichloromethane solution , 1.0 ml) Preparation of 7-[ 4- (4 -benzo [b ] thiophen - 4 -yl - piper was added to a dichloromethane (50 ml) solution of 2-[ 4 azin - 1 - yl) butoxy ] -1H - quinolin - 2 -one hydrochloride (4 - benzo [b ] thiophen -4 - yl- piperazin - 1- yl ) butyl ] -7 -methoxy- 20 2H - isoquinolin - 1 -one (0.16 g ) while being stirred under IN hydrochloric acid aqueous solution was added to a ice - cooling and stirred at room temperature for 3 days. Water solution of 7-[ 4-( 4 -benzo [ b ] thiophen - 4 -yl - piperazin - 1 -yl ) was added to the reaction solution , which was then stirred at butoxyl- 1H - quinolin -2 -one in methanol and dichlorometh room temperature for 0.5 hour . Precipitated crystals were ane and the solvent was evaporated under reduced pressure . separated by filtration , recrystallized from ethyl acetate and 25 The residue was recrystallized from 70 % ethanol and thereby 2-[ 4- ( 4 -benzo [b ] thiophen - 4 - yl- piperazin - 1 -yl ) bu thereby 7-[ 4- ( 4 -benzo [b ] thiophen - 4 -yl -piperazin - 1- yl) bu tyl] -7 - hydroxy - 2H - isoquinolin - 1 - one hydrobromide (0.13 toxy ] -1H - quinolin - 2 -one hydrochloride was obtained in the g ) was obtained in the form of a white powder. form of a white powder . Melting point 273.6-275.7 ° C. Melting point 238-241° C. H -NMR (DMSO -d ) 8 ppm : 30 H -NMR (DMSO -d ) ppm : 1.75 (4H , brs ), 3.08 ( 2H , t , J = 11.1 Hz ), 3.16-3.28 (4H , m ) , 1.80-2.00 (4H , m ), 3.20-3.45 (6H , m ), 3.50-3.60 (4H , m ), 3.59 (2H , t, J = 10.5 Hz ) , 4.01 ( 2H , brs ), 6.58 (1H , d , J = 7.3 4.06 (2H , t, J = 5.6 Hz) , 6.28 ( 1H , d , J = 9.5 Hz ) , 6.75-6.85 Hz) , 6.97 ( 1H , d , J= 7.5 Hz ), 7.19 ( 1H , dd , J = 8.6 Hz , 2.6 Hz ), ( 2H , m ), 6.95 ( 1H , d , J = 7.5 Hz) , 7.30 (1H , dd , J = 7.8 Hz, 7.8 7.29-7.36 (2H , m ) , 7.49-7.65 (3H , m ), 7.71 ( 1H , d , J = 8.0 Hz ), 7.47 ( 1H , d , J = 5.7 Hz) , 7.56 (1H , d , J = 8.4 Hz ), 7.68 Hz ) , 7.78 ( 1H , d , J = 5.5 Hz ) , 9.50 ( 1H , brs ), 9.95 ( 1H , s ) . 35 ( 1H , d , J = 8.1 Hz) , 7.70-7.85 ( 2H , m ) , 10.92 ( 1H , brs ), 11.61 Example 40 (1H , brs ) . Example 43 Preparation of 6- ( 3-( 4 - benzo [b ] thiophen - 4 - yl- piper azin - 1 -yl ) propoxyl - 2H - isoquinolin - 1 -one 40 Preparation of 7-[ 4- ( 4 -benzo [ b ] thiophen - 4 - yl- piper azin - 1 - yl) butoxy ] -1H - quinolin - 2 - one sulfate By a similar method as in Example 1 , 6-[ 3- ( 4 -benzo [ b ] thiophen - 4 - yl - piperazin - 1 - yl) propoxy ] -2H -isoquinolin - 1 Dilute sulphuric acid was added to a solution of 7-[ 4- ( 4 one was prepared from 6 -chloropropoxy -2H - isoquinolin - 1 benzo [b ] thiophen -4 - yl -piperazin - 1 -yl ) butoxy ]-1H - quinolin one . 45 2 - one in methanol and dichloromethane and the solvent was White Powder (Ethyl Acetate ) evaporated under reduced pressure . The residue was recrys Melting point 228.8-230.7 ° C. tallized from 60 % ethanol and thereby 7- [4- ( 4 -benzo [ b ] H - NMR (DMSO -d ) 8 ppm : thiophen -4 - yl- piperazin - 1- yl ) butoxy ]-1H - quinolin - 2 -one 1.98 (2H , quint, J = 6.7 Hz) , 2.56 ( 2H , t, J = 7.0 Hz) , 2.65 sulfate was obtained in the form of a white powder . (4H , brs ), 3.09 (4H , brs ), 4.17 (2H , t, J= 6.3 Hz ), 6.47 (1H , 50 Melting point 248-251 ° C. d , J = 7.1 Hz) , 6.90 ( 1H , d , J = 7.6 Hz) , 7.05 (1H , dd , J = 8.8 Hz , H -NMR (DMSO - d ) 8 ppm : 2.4 Hz) , 7.10-7.15 (2H , m ), 7.28 ( 1H , d , J= 7.8 Hz) , 7.41 1.80-1.95 (4H , m ) , 2.50-4.00 ( 10H , m ) , 4.00-4.10 ( 2H , (1H , d , J = 5.5 Hz) , 7.62 ( 1H , d , J = 8.0 Hz) , 7.70 ( 1H , d , J = 5.5 m ) , 6.30 ( 1H , d , J = 8.2 Hz) , 6.75-6.85 (2H , m ) , 6.97 (1H , d , Hz ), 8.07 (1H , d , J = 8.8 Hz ) , 11.03 ( 1H , s ) . J = 7.6 Hz ), 7.31 (1H , dd , J = 7.8 Hz, 7.8 Hz ), 7.49 ( 1H , d , 55 J = 5.6 Hz) , 7.55-7.60 ( 1H , m ), 7.70 (1H , d , J = 8.0 Hz ) , Example 41 7.75-7.85 ( 2H , m ) , 9.25-9.75 ( 1H , br) , 11.62 ( 1H , brs ). Preparation of 6- (3- ( 4 -benzo [ b ] thiophen - 4 -yl -piper Example 44 azin - 1 -yl ) propoxy ]-2 -methyl - 2H - isoquinolin - 1- one hydrochloride 60 Preparation of 7- [4- (4 - benzo [b ] thiophen -4 - yl- piper azin - 1 -yl ) butoxy ) -1H - quinolin - 2 -one maleate By a similar method as in Example 18 , 6-( 3-( 4 -benzo [b ] thiophen - 4 -yl - piperazin - 1 -yl ) propoxy ) -2 -methyl -2H - iso A methanol solution of maleic acid was added to a quinolin - 1 -one was prepared from 6-( 3-( 4 -benzo [ b ] thio solution of 7-[ 4- ( 4 - benzo [b ] thiophen - 4 -yl - piperazin - 1 -yl ) phen -4 -yl - piperazin - 1 -yl ) propoxy ] -2H - isoquinolin - 1 -one 65 butoxy ] -1H -quinolin - 2 -one in methanol and dichlorometh using methyl iodide , and after it was made into an ethyl ane and the solvent was evaporated under reduced pressure . acetate solution , IN hydrochloric acid ethanol solution was The residue was recrystallized from 80 % ethanol and US RE48,059 E 45 46 thereby 7- [ 4-( 4 -benzo [ b ]thiophen - 4 - yl - piperazin - 1 - yl ) bu H -NMR (DMSO -d ) d ppm : toxy ] -1H - quinolin - 2 -one maleate was obtained in the form 1.73-2.00 ( 4H , m ), 2.28 ( 3H , s ), 3.07 (2H , J= 11.0 Hz) , of a white powder. Melting point 181.6-182.8 ° C. 3.23-3.43 (4H , m ), 3.62 (4H , t, J = 15.0 Hz ), 4.09 (2H , t, 1H -NMR (DMSO -do ) d ppm : J = 7.1 Hz) , 6.31 ( 1H , dd , J = 9.5 Hz, 2.3 Hz ), 6.80 ( 1H , s ), 1.87 (2H , brs) , 3.26-3.47 ( 10H , m ) , 4.10 ( 2H , s) , 6.07 (2H , 5 6.84 ( 1H , d , J = 2.3 Hz ), 6.98 ( 1H , d , J= 7.5 Hz ) , 7.11 (2H , d , s ), 6.33 ( 1H , d , J = 9.5 Hz) , 6.82-6.84 ( 2H , m ) , 6.99 (1H , d , J = 8.0 Hz) , 7.33 ( 1H , dd , J = 7.5 Hz , 7.5 Hz) , 7.46-7.52 (3H , J = 7.6 Hz ) , 7.33 ( 1H , d , J = 7.8 Hz ) , 7.51 (1H , d , J = 5.5 Hz) , m ), 7.58 ( 1H , d , J = 9.5 Hz) , 7.72 ( 1H , d , J = 7.5 Hz ) , 7.78 ( 1H , 7.59 (1H , d , J = 9.3 Hz ), 7.70-7.85 (3H , m ), 11.65 ( 1H , s) . d , J = 11.3 Hz ) , 7.81 ( 1H , d , J = 9.5 Hz ) , 9.31-9.49 (1H , m ) , 11.54-11.63 ( 1H , m ). Example 45 10 Example 48 Preparation of 7-[ 4- ( 4 -benzo [b ] thiophen - 4 -yl - piper azin - 1 -yl ) butoxy )-1H -quinolin - 2 -one fumarate Preparation of 7- [3- ( 4 -benzo [ b ]thiophen - 4 - yl- piper azin - 1- yl) propoxy ] -2- methyl -3,4 - dihydro - 2H - isoqui Fumaric acid was added to a solution of 7-[ 4- ( 4 -benzo 15 [ b ] thiophen - 4 - yl- piperazin - 1 - yl) butoxy ] -1H - quinolin - 2 - one nolin - 1 -one sulfate in methanol and dichloromethane and the solvent was evaporated under reduced pressure . The residue was recrys Dilute sulphuric acid was added to a solution of 7-( 3- ( 4 tallized from ethanol and thereby 7- [4- ( 4 -benzo [ b ]thiophen benzo [b ] thiophen -4 -yl - piperazin - 1 -yl ) propoxy )-2 - methyl 4 -yl - piperazin -1 - yl) butoxyl - 1H -quinolin -2 - one fumarate 20 3,4 - dihydro - 2H -isoquinolin - 1 - one in ethanol and dichlo was obtained in the form of a white powder . romethane and the solvent was evaporated under reduced Melting point 209-211 ° C. pressure . The residue was recrystallized from 85 % ethanol H -NMR (DMSO -do ) è ppm : and thereby 7-[ 3- ( 4 -benzo [b ] thiophen -4 -yl - piperazin - 1 -yl ) 1.60-1.90 ( 4H , m ), 2.47-2.50 ( 2H , m ), 2.60-2.75 (4H , m ), propoxy ] -2 -methyl - 3,4 - dihydro - 2H -isoquinolin - 1 - one sul 3.00-3.15 (4H , m ), 4.05 (2H , t , J = 6.3 Hz ), 6.28 (1H , d , J = 9.4 25 fate was obtained in the form of a white powder . Hz) , 6.60 ( 2H , s ) , 6.76-6.82 ( 2H , m ), 6.88 ( 1H , d , J = 7.4 Hz) , Melting point 222-224 ° C. 7.26 ( 1H , dd , J = 7.9 Hz, 7.8 Hz) , 7.39 ( 1H , d , J = 5.9 Hz) , 7.54 H -NMR ( DMSO -do ) d ppm : ( 1H , d , J = 9.4 Hz ) , 7.61 ( 1H , d , J = 8.0 Hz ) , 7.69 (1H , d , J = 5.5 2.10-2.30 (2H , m ) , 2.91 (2H , t , J = 6.6 Hz) , 3.03 (3H , s ), Hz) , 7.79 (1H , d , J = 9.5 Hz) , 11.58 (1H , brs ) . 3.05-4.00 (12H , m ) , 4.13 (2H , t , J = 5.9 Hz) , 6.99 (1H , d , 30 J = 7.5 Hz ) , 7.09 ( 1H , dd , J = 2.7 Hz, 8.3 Hz) , 7.24 ( 1H , d , Example 46 J = 8.4 Hz ), 7.33 ( 1H , dd , J = 7.8 Hz , 7.8 Hz ), 7.44 (1H , d , J = 2.7 Hz ) , 7.51 ( 1H , d , J = 5.5 Hz ), 7.72 (1H , d , J = 8.1 Hz) , Preparation of 7-[ 4- ( 4 -benzo [b ] thiophen - 4 -yl - piper 7.78 ( 1H , d , J = 5.5 Hz) , 9.00-10.05 ( 1H , br) . azin - 1 - yl )butoxyl - 1H -quinolin - 2 -one citrate 35 Example 49 Citric acid was added to a solution of 7- [4- ( 4 -benzo [ b ] thiophen -4 - yl- piperazin - 1- yl) butoxy )-1H - quinolin - 2 -one in Preparation of 7-( 3- ( 4 - benzo [ b ] thiophen - 4 - yl- piper methanol and dichloromethane and the solvent was evapo azin - 1 - yl) propoxyl - 2 - methyl- 3,4 - dihydro - 2H - isoqui rated under reduced pressure . The residue was recrystallized nolin - 1 -one fumarate from 50 % ethanol and thereby 7-[ 4-( 4 -benzo [b ] thiophen -4- 40 yl- piperazin - 1 - yl) butoxy ]-1H -quinolin -2 -one citrate was Fumaric acid was added to an ethanol solution of 7- [ 3 obtained in the form of a white powder . ( 4 -benzo [b ] thiophen -4 -yl - piperazin - 1 -yl ) propoxy ) -2 Melting point 183-185 ° C. methyl- 3,4 - dihydro - 2H -isoquinolin - 1- one and the solvent H -NMR (DMSO - d ) 8 ppm : was evaporated under reduced pressure . The residue was 1.50-2.00 (4H , m ), 2.58 (2H , s ), 2.62 (2H , s) , 2.75-2.85 45 recrystallized from 70 % ethanol and thereby 7-( 3- ( 4 - benzo ( 2H , m ) , 2.95-3.05 (4H , m ) , 3.10-3.20 (4H , m ), 4.05 (2H , t , [b ]thiophen -4 - yl - piperazin - 1 - yl) propoxy )-2 -methyl - 3,4 -di J = 5.3 Hz) , 6.28 (1H , d , J = 9.4 Hz) , 6.75-6.85 ( 2H , m ), 6.90 hydro - 2H - isoquinolin - 1- one fumarate was obtained in the ( 1H , d , J = 7.6 Hz ) , 7.27 ( 1H , dd , J = 7.9 Hz, 7.9 Hz) , 7.42 ( 1H , form of a pale yellow powder . d , J = 5.5 Hz ), 7.55 ( 1H , d , J = 9.3 Hz) , 7.64 ( 1H , d , J = 8.0 Hz) , Melting point 149-151° C. 7.71 ( 1H , d , J = 5.5 Hz) , 7.79 ( 1H , d , J = 9.5 Hz ) , 11.59 (1H , 50 H -NMR (DMSO - d ) 8 ppm : brs ) . 1.85-2.00 ( 2H , m ) , 2.58 (2H , t, J = 7.2 Hz ) , 2.65-2.75 ( 4H , m ) , 2.88 ( 2H , t , J = 6.7 Hz ) , 3.01 ( 3H , s ), 3.05-3.15 (4H , m ) , Example 47 3.50 (2H , t , J = 6.7 Hz ) , 4.05 ( 2H , t , J = 6.3 Hz ), 6.60 (2H , s ) , 6.89 ( 1H , d , J = 7.6 Hz ) , 7.03 ( 1H , dd , J = 8.3 Hz, 2.7 Hz) , 7.19 Preparation of 7-[ 4-( 4 -benzo [ b ] thiophen - 4 - yl- piper 55 (1H , d , J = 8.3 Hz) , 7.27 ( 1H , dd , J = 7.9 Hz, 7.8 Hz) , 7.38 ( 1H , azin - 1 - yl )butoxyl - 1H -quinolin - 2 -one p - toluenesul d , J = 3.0 Hz) , 7.40 ( 1H , d , J = 5.9 Hz ), 7.61 ( 1H , d , J = 8.0 Hz) , fonate 7.69 ( 1H , d , J = 5.5 Hz) . p - Toluenesulfonic acid monohydrate was added to a solu Example 50 tion of 7-[ 4- ( 4 -benzo [b ] thiophen -4 -yl -piperazin - 1- yl) bu- 60 toxy ]-1H - quinolin - 2 -one in methanol and dichloromethane Preparation of 7- [ 3- ( 4 -benzo [ b ]thiophen - 4 -yl -piper and the solvent was evaporated under reduced pressure . The azin - 1- yl ) propoxy ] -2 -methyl - 3,4 -dihydro -2H -isoqui residue was recrystallized from methanol and thereby 7-[ 4 nolin - 1 - one difumarate ( 4 - benzo [ b ] thiophen - 4 - yl- piperazin - 1 - yl )butoxy ]-1H - qui nolin - 2 - one p -toluenesulfonate was obtained in the form of 65 Fumaric acid was added to an ethanol solution of 7-[ 3 a white powder. ( 4 -benzo [ b ] thiophen - 4 -yl - piperazin - 1 -yl ) propoxy )-2 Melting point 121.0-125.0 ° C. methyl -3,4 - dihydro - 2H - isoquinolin - 1 -one and the solvent US RE48,059 E 47 48 was evaporated under reduced pressure . The residue was Example 53 recrystallized from 90 % ethanol and thereby 7-( 3-( 4 -benzo [ b ] thiophen - 4 - yl- piperazin - 1 - yl) propoxy )-2 -methyl - 3,4 - di Preparation of 7-( 3- ( 4 - benzo [b ] thiophen -4 - yl- piper hydro - 2H - isoquinolin - 1- one difumarate was obtained in the azin - 1 - yl) propoxy ]-2 - methyl - 3,4 - dihydro - 2H - isoqui form of white prism crystal. 5 nolin - 1 -one Melting point 188-189 ° C. By a similar method as in Example 1, 7-( 3- ( 4 -benzo [ b ] ' H -NMR (DMSO -d ) d ppm : thiophen -4 - yl- piperazin - 1- yl ) propoxy ] -2 -methyl - 3,4 -di 1.85-2.00 (2H , m ) , 2.60 (2H , t, J = 7.0 Hz ) , 2.65-2.75 (4H , hydro - 2H - isoquinolin - 1 -one was prepared from 7- ( 3 - chlo m ), 2.88 (2H , t, J = 6.6 Hz) , 3.01 (3H , s ) , 3.00-3.10 (4H , m ) , 10 ropropoxy )-2 - methyl -3,4 - dihydro -2H - isoquinolin - 1 - one . 3.50 (2H , t, J = 6.7 Hz) , 4.05 (2H , t , J = 6.4 Hz ) , 6.61 (4H , s ), White Powder (Ethanol ) 6.90 (1H , d , J = 7.5 Hz) , 7.04 ( 1H , dd , J = 8.2 Hz, 2.8 Hz) , 7.19 Melting point 115-117 ° C. ( 1H , d , J = 8.4 Hz) , 7.27 ( 1H , dd , J = 7.9 Hz , 7.8 Hz) , 7.38 (1H , H -NMR (CDC13 ) è ppm : d , J = 3.0 Hz ), 7.40 ( 1H , d , J = 6.2 Hz ), 7.61 ( 1H , d , J= 8.0 Hz ), 1.95-2.10 ( 2H , m ), 2.64 (2H , t , J = 7.3 Hz) , 2.70-2.80 ( 4H , 7.69 ( 1H , d , J = 5.5 Hz) . 15 m ) , 2.94 (2H , t , J = 6.7 Hz ) , 3.10-3.25 ( 4H , m ), 3.16 (3H , s ) , 2.54 (2H , t , J = 6.7 Hz) , 4.11 ( 2H , t , J = 6.5 Hz) , 6.90 (1H , d , Example 51 J = 7.0 Hz) , 6.98 ( 1H , dd , J = 2.7 Hz, 8.3 Hz ) , 7.08 (1H , d , J = 8.3 Hz) , 7.28 ( 1H , dd , J = 7.9 Hz, 7.9 Hz ) , 7.35-7.45 (2H , Preparation of 7-( 3- (4 -benzo [b ] thiophen - 4 -yl - piper m ), 7.55 ( 1H , d , J = 8.1 Hz) , 7.63 ( 1H , d , = 2.6 Hz ) . azin - 1- yl) propoxy ] -2 -methyl - 3,4 - dihydro - 2H - isoqui 20 nolin - 1 - one maleate Example 54 A methanol solution of maleic acid was added to a Preparation of 7-[ 3- ( 4 -benzo [b ] thiophen - 4 -yl - piper solution of 7-13- ( 4 - benzo [ b ] thiophen - 4 - yl- piperazin - 1 - yl) azin - 1 - yl) propoxy ] -2 -methyl - 3,4 - dihydro - 2H - isoqui propoxyl- 2 -methyl - 3,4 -dihydro - 2H - isoquinolin - 1- one in 25 nolin - 1 -one methanesulfonate methanol and dichloromethane and the solvent was evapo Methanesulfonic acid was added to an ethanol solution of rated under reduced pressure . The residue was recrystallized 7-[ 3- ( 4 -benzo [b ] thiophen - 4 -yl - piperazin - 1 -yl ) propoxy )-2 from ethanol and ethyl acetate and thereby 7-[ 3- (4 -benzo methyl- 3,4 - dihydro - 2H - isoquinolin - 1 - one and the solvent [ b ]thiophen - 4 - yl- piperazin - 1 - yl) propoxy ) -2 -methyl - 3,4 - di 30 was evaporated under reduced pressure . The residue was hydro - 2H - isoquinolin - 1 -one maleate was obtained in the recrystallized from 80 % ethanol and thereby 7-( 3- ( 4 -benzo form of a white powder. [b ] thiophen -4 - yl- piperazin -1 -yl ) propoxyl- 2- methyl - 3,4 -di Melting point 134.6-135.5 ° C. hydro -2H - isoquinolin - 1- one methanesulfonate was obtained H -NMR (DMSO - d ) . ppm : in the form of pale yellow prism crystal. 2.17 ( 2H , brs ), 2.91 (2H , t, J =6.7 Hz ) , 3.03 ( 3H , s ), 3.33 35 Melting point 147-149° C. ( 10H , brs) , 3.52 (2H , t , J = 6.7 Hz) , 4.12 (2H , t, J = 5.9 Hz ) , 1H -NMR (DMSO -do ) d ppm : 6.04 (2H , s ), 6.99 ( 1H , d , J= 7.6 Hz) , 7.07 ( 1H , dd , J = 8.3 Hz, 2.10-2.25 ( 2H , m ) , 2.29 ( 3H , s ) , 2.90 ( 2H , t, J = 6.7 Hz) , 2.6 Hz) , 7.24 (1H , d , J = 8.4 Hz) , 7.32 ( 1H , dd , J = 7.9 Hz, 7.9 3.02 (3H , s ) , 3.05-3.15 ( 2H , m ) , 3.40-3.50 ( 4H , m ) , 3.51 Hz) , 7.43 ( 1H , d , J = 2.6 Hz) , 7.50 (1H , d , J= 5.5 Hz) , 7.71 (2H , t, J= 6.7 Hz ) , 3.55-3.70 (4H , m ), 4.12 (2H , t, J = 6.0 Hz ), ( 1H , d , J = 7.9 Hz ), 7.77 ( 1H , d , J = 5.5 Hz ). 40 6.98 ( 1H , d , J = 7.6 Hz) , 7.06 ( 1H , dd , J = 8.3 Hz, 2.7 Hz ), 7.23 (1H , d , J = 8.4 Hz) , 7.32 ( 1H , dd , J = 7.9 Hz, 7.8 Hz) , 7.43 (1H , Example 52 d , J = 2.7 Hz ) , 7.50 (1H , d , J = 5.5 Hz ) , 7.71 (1H , d , J = 8.1 Hz ), 7.77 (1H , d , J = 5.5 Hz ), 9.40-9.60 ( 1H , m ). Preparation of 7- (3- ( 4 -benzo [ b ] thiophen - 4 -yl -piper 45 Example 55 azin - 1 - yl) propoxy ]-2 - methyl - 3,4 - dihydro - 2H - isoqui nolin - 1 -one p - toluenesulfonate Preparation of 4-[ 3-( 4 -benzo [b ] thiophen - 4 - yl- piper azin - 1- yl) propoxy quinoline hydrochloride p - Toluenesulfonic acid monohydrate was added to a solu tion of 7- [ 3-( 4 -benzo [b ] thiophen - 4 -yl - piperazin - 1 - yl) 50 4 - Chloroquinoline (230 mg, 1.58 mmol ), 3- (4 -benzo [b ] propoxyl- 2 -methyl - 3,4 - dihydro - 2H - isoquinolin - 1 -one in thiophen - 4 -yl - piperazin - 1 -yl ) propan - 1 -ol (310 mg, 1.05 methanol and dichloromethane and the solvent was evapo mmol) , and potassium carbonate (220 mg, 1.6 mmol) were rated under reduced pressure . The residue was recrystallized added to dimethylformamide ( 10 ml) , followed by stirring at from ethanol and ethyl acetate and thereby 7- (3- (4 -benzo 80 ° C. for 5 hours . The reaction mixture was cooled to room [ b ] thiophen - 4 - yl- piperazin - 1 - yl) propoxy ]-2 -methyl - 3,4 -di- 55 temperature , then water was added thereto and the reaction hydro -2H - isoquinolin - 1 -one p - toluenesulfonate was mixture was extracted with ethyl acetate . The organic phase obtained in the form of a white powder . was washed with water , dried over magnesium sulfate , and concentrated under reduced pressure after filtration . The Melting point 173.0-175.5º C. residue was purified by basic silica gel column chromatog 1H -NMR (DMSO -d ) d ppm : 60 raphy ( n - hexane : ethyl acetate = 4 : 1 ) , and concentrated under 2.00-2.33 ( 2H , m ) , 2.28 ( 3H , s ) , 2.91 (2H , t, J = 6.6 Hz ) , reduced pressure . The resulting residue was dissolved in 3.02 ( 3H , s ) , 3.00-3.16 ( 2H , m ), 3.29-3.80 ( 10H , m ), 4.12 ethanol ( 3 ml) , and 1N - HC1 — ethanol solution ( 1 ml) was (2H , t, J = 5.5 Hz) , 6.99 (1H , d , J= 7.9 Hz) , 7.06 ( 1H , d , J= 2.5 added thereto . Insoluble matters produced were filtered out Hz) , 7.11 (2H , d , J = 7.9 Hz ), 7.24 (1H , d , J = 8.0 Hz ), 7.33 and dried to obtain 4- (3- (4 -benzo [b ]thiophen - 4 - yl- piper ( 1H , dd, J = 8.0 Hz, 8.0 Hz) , 7.44 (1H , d , J = 2.5 Hz) , 7.48 (1H , 65 azin - 1 -yl ) propoxy ]quinoline hydrochloride ( 360 mg, yield : d , J = 7.9 Hz) , 7.51 ( 1H , d , J = 5.5 Hz) , 7.72 ( 1H , d , J = 8.0 Hz) , 78 % ) as light yellow powder . 7.82 ( 1H , d , J = 5.5 Hz) , 9.39-9.58 (1H , m ) Melting point: 240-242 ° C. US RE48,059 E 49 50 Example 56 The residue was purified by basic silica gel column chro matography (n -hexane :ethyl acetate = 1 : 1 ) , and concentrated Preparation of 3- (3- (4 -benzo [b ] thiophen -4 -yl -piper under reduced pressure . The resulting residue was dissolved azin - 1- yl ) propoxy ] isoquinoline hydrochloride in ethyl acetate ( 10 ml) , and 1N - HC1 ethanol solution 5 was added thereto . Then , crystals precipitated were filtered 3 -Hydroxyisoquinoline ( 170 mg, 1.17 mmol) , 1 -benzo [ b ] out and dried to obtain 1 - acetyl - 7- [3- ( 4 -benzo [ b ] thiophen thiophen - 4 - yl- 4- ( 3 - chloropropyl) piperazine ( 290 mg, 1.0 4 -yl - piperazin - 1 - yl) propoxy ] -1,2,3,4 - tetrahydroquinoline mmol) , and potassium carbonate (200 mg, 1.45 mmol) were hydrochloride (0.27 q , yield : 52 % ) as white powder . added to dimethylformamide ( 8 ml) , followed by stirring at 80 ° C. for 7 hours . The reaction mixture was cooled to room 10 Melting point: 123.2-124.3 ° C. temperature , then water was added thereto and the reaction mixture was extracted with ethyl acetate . The organic phase Example 59 was washed with water, dried over magnesium sulfate , and concentrated under reduced pressure after filtration . The residue was purified by basic silica gel column chromatog- 15 Preparation of 6-[ 3-( 4 -benzo [b ] thiophen - 4 - yl- piper raphy ( n -hexane : ethyl acetate = 9 : 1 ) , and concentrated under azin -1 -yl ) propoxy ] -1,2,3,4- tetrahydroquinoline reduced pressure . The resulting residue was dissolved in hydrochloride ethanol (2 ml) , and 1N - HCl— ethanol solution (0.5 ml) was added thereto . Insolublematters produced were filtered Lithium aluminum hydride ( 160 mg, 4.2 mmol) was out and dried to obtain 3- [3- ( 4 -benzo [b ] thiophen - 4 -yl - pip- 20 added to a solution of 6-[ 3-( 4 - benzo [b ] thiophen - 4 -yl - piper erazin - 1- yl ) propoxy ] isoquinoline hydrochloride ( 160 mg, azin - 1- yl ) propoxy ] -3,4 -dihydro -1H -quinolin -2 -one ( 1.6 g , yield : 37 % ) as white powder . 3.8 mmol) in tetrahydrofuran (40 ml) , followed by stirring Melting point: 227-229 ° C. under reflux for 1 hour. The reaction mixture was cooled in Example 57 25 an ice -bath , and water (0.16 ml) , 15 % sodium hydroxide aqueous solution (0.16 ml) and water (0.5 ml) were added Preparation of 7- (3- (4 - benzo [b ] thiophen -4 - yl -piper thereto in this order . After stirring the mixture, insoluble azin - 1- yl ) propoxy ] -6 -methoxy - 3,4 -dihydroisoquino matters were removed by filtration and the filtrate was line dihydrochloride concentrated under reduced pressure. The residue was puri 30 fied by basic silica gel column chromatography ( n -hexane : PS - triphenylphosphine (110 mg, 3 mmol/ g ) and dibenzyl ethyl acetate = 1 :1 ), and concentrated under reduced pressure azodicarboxylate (70 mg, 0.3 mmol) were added to a solu to obtain amorphous solid ( 1.4 g ). The amorphous solid tion of 7 - hydroxy -6 -methoxy - 3,4 - dihydroisoquinoline ( 80 obtained (0.6 g ) was dissolved in ethyl acetate ( 15 ml) . mg, 0.45 mmol) and 3- ( 4 -benzo [ b ] thiophen - 4 -yl - piperazin IN - HCl - ethanol solution ( 1.45 ml) was further added 1 -yl ) propan - 1 - ol (83 mg, 0.3 mmol) in tetrahydrofuran ( 1 35 thereto , then crystals precipitated were filtered out and dried ml) , followed by stirring at 50 ° C. for 3 hours . The reaction to obtain 6-( 3- ( 4 - benzo [ b ] thiophen - 4 - yl- piperazin - 1 - yl) mixture was cooled to room temperature and insoluble propoxyl- 1,2,3,4 - tetrahydroquinoline hydrochloride ( 0.55 matters were removed by filtration . The filtrate was concen g ) as white powder. trated under reduced pressure. The residue was purified by Melting point: 123.2-124.3 ° C. basic silica gel column chromatography (n -hexane : ethyl 40 acetate = 1: 1 ), and concentrated under reduced pressure . The resulting residue was dissolved in 2 -propanol , and IN HCl ethanol solution was added thereto . Isopropyl Example 60 ether was further added thereto , then crystals precipitated were filtered out and dried to obtain 7-( 3-( 4 -benzo [ b ] thio- 45 phen - 4 - yl -piperazin - 1 - yl) propoxy ) -6 -methoxy -3,4 -dihy Preparation of 7-( 3- ( 4 -benzo [b ] thiophen - 4 - yl- piper droisoquinoline dihydrochloride (26 mg, yield : 17 % ) as azin - 1 -yl ) propoxy ] -2 -methyl - 1,2,3,4 -tetrahydroqui light yellow powder . noline hydrochloride Melting point: 211.0-213.0 ° C. 50 37 % Formaldehyde aqueous solution ( 0.15 ml, 1.8 Example 58 mmol) , MP- cyanoborohydride ( 2.41 mmol/ g , 0.76 g, 1.8 mmol) and catalytic amount of acetic acid were added to a Preparation of 1 -acetyl - 7-[ 3-( 4 -benzo [ b ] thiophen - 4 solution of 7-( 3-( 4 -benzo [ b ] thiophen - 4 -yl - piperazin - 1 -yl ) yl- piperazin - 1 -yl ) propoxy ]-1,2,3,4 -tetrahydroquino propoxyl- 1,2,3,4 - tetrahydroisoquinoline ( 0.25 g , 0.6 mmol) line hydrochloride 55 in methanol ( 20 ml) , followed by stirring at room tempera ture overnight. The resin was removed by filtration and the Acetic anhydride ( 0.34 ml, 3.6 mmol) and pyridine ( 0.34 filtrate was concentrated under reduced pressure . The resi ml, 4.3 mmol) were added to a solution of 7-[ 3- (4 -benzo [ b ] due was purified by basic silica gel column chromatography thiophen -4 -yl - piperazin - 1 - yl) propoxy ]-1,2,3,4 - tetrahydro (methylene chloride: methanol = 20 : 1 ) , and concentrated quinoline (0.49 g, 1.2 mmol) in methylene chloride ( 10 ml) 60 under reduced pressure. The residue (175 mg) was dissolved with cooling in an ice -bath , followed by stirring at room in ethyl acetate (5 ml) . IN HC1 ethanol solution (0.42 temperature overnight. The reaction mixture was concen ml) was further added thereto , then crystals precipitated were filtered out and dried to obtain 7-( 3- ( 4 - benzo [ b ] thio trated under reduced pressure , and water and ethyl acetate phen - 4 -yl - piperazin - 1 -yl ) propoxy )-2 -methyl - 1,2,3,4 - tetra werethe water added phase to the . Theresidue organic to separate phase was the washedorganic withphase water from , 65 hydroquinoline hydrochloride (103 mg, yield : 37 % ) as white saturated sodium hydrogencarbonate aqueous solution and powder. brine in this order, and concentrated under reduced pressure . Melting point: 260.1-262.8 ° C. US RE48,059 E 51 52 Example 61 were filtered out, washed with water and dried to obtain 4-[ 3- ( 4 -benzo [b ]thiophen - 4- yl- piperazin - 1 - yl )propoxy qui Preparation of 4-( 3- ( 4 -benzo [b ] thiophen - 4 -yl - piper nolin - 2 -carboxylic acid hydrochloride ( 1.43 g, yield : 98 % ) azin -1 -yl ) propoxy ]quinolin -2 - carboxymethylamide as white powder . dihydrochloride 5 Melting point: 235.0 ° C. Example 63 Ethyl 4-[ 3- ( 4 -benzo [b ] thiophen -4 - yl- piperazin - 1 -yl ) propoxyl -quinolin - 2 -carboxylate (0.28 g ) was added to a Preparation of 4-[ 3-( 4 -benzo [b ] thiophen - 4 - yl- piper methanol solution of40 % methylamine ( 10 ml) , followed by azin - 1 - yl) propoxy ] quinolin - 2 - carboxamide stirring at room temperature for two days . The reaction 10 mixture was concentrated under reduced pressure. The resi Triethylamine (0.25 ml, 1.8 mmol) and isobutyl chloro due was purified by basic silica gel column chromatography formate (0.19 ml, 1.4 mmol) were added to a solution (10 ( ethyl acetate :methanol = 11 : 1 ) , and concentrated under ml) of 4-( 3- ( 4 - benzo [b ] thiophen -4 - yl- piperazin - 1- yl ) reduced pressure. The residue ( 166 mg) was dissolved in propoxylquinolin - 2 -carboxylic acid (0.53 g , 1.2 mmol) in ethyl acetate . IN - HCl- ethanol solution (0.7 ml) was 15 acetonitrile with cooling in an ice -bath , followed by stirring at 0 ° C. for 3 hours . 28 % Aqueous ammonia ( 0.15 ml) was further added thereto , then crystals precipitated were filtered added thereto and the reaction mixture was stirred at room out and dried to obtain 4-( 3-( 4 -benzo [ b ] thiophen - 4 - yl- pip temperature for 5 minutes. Ethyl acetate was further added erazin - 1 -yl ) propoxy ] quinolin - 2 - carboxymethylamide dihy thereto , then the reaction mixture was washed with water drochloride (0.17 g , yield : 54 % ) as white powder. and concentrated under reduced pressure . The residue was Melting point: 224.0 ° C. (decomposed ) 20 purified by basic silica gel column chromatography (n -hexane :ethyl acetate = 3: 1) , and concentrated under Example 62 reduced pressure . The residue (0.2 g ) was dissolved and Preparation of 4- [3- ( 4 -benzo [ b ] thiophen - 4 -yl - piper recrystallized from the mixed solvent of ethyl acetate and azin - 1- yl ) propoxylquinolin -2 - carboxylic acid hydro 25 isopropyl ether to obtain 4-( 3-( 4 -benzo [ b ]thiophen - 4 -yl - pip erazin - 1 - yl) propoxy ] -quinolin - 2 - carboxamide (79 mg, chloride yield : 16 % ) as white powder. An aqueous solution of 4N lithium hydroxide ( 3 ml) was Melting point: 153.0-154.5 ° C. added to a methanol solution ( 7 ml) of ethyl 4- (3- ( 4 -benzo Examples 64 to 196 [ b ] thiophen - 4 -yl -piperazin - 1 - yl) propoxy ]-quinolin - 2 - car 30 boxylate ( 1.5 g ) , followed by stirring at room temperature Compounds of Example 64 to 196 shown in the following overnight . Then , water ( 10 ml) and aqueous solution ( 3 ml) Tables 1 to 21 can be prepared in the same manner as in of 4N lithium hydroxide were further added , followed by Example 1 , using corresponding starting materials . In the stirring at 50 ° C. for 11 hours . The reaction mixture was following Tables , compounds with the physical properties , cooled in an ice - bath , and an aqueous solution ( 4 ml) of such as crystalline form , m.p. (melting point ), salt, ' H - NMR 6N - HC1 was added thereto . Then , crystals precipitated and MS (mass spectrum ), were prepared actually . TABLE 1

S

R1-0– (CH2 ) n - N CH3 8 crystalline form ( recrystallization Example No. R1 n solvent) m.p. (° C .) salt 64 3 white powder 125-127 (methanol )

65 4 white powder 217-221 dihydrochloride ( ethanol 2 ethyl acetate ) 66 4 white powder 123-130 ( ethyl acetate ) (decomposed )

N H US RE48,059 E 53 54 TABLE 2

R1—0- (CH2 ) n — N

H3C crystalline form ( recrystallization Example No. R1 n solvent ) m.p. (° C.) salt 67 3 white powder 253-255 hydrochloride ( ethanol) (decomposed )

N H 68 4 white powder 151-153 dihydrochloride ( ethanol- ethyl acetate N acetonitrile )

69 4 white powder 156-159 hydrochloride ( ethanol)

30

TABLE 3

R1 –O– (CH2 ) 3 - N o crystalline form ( recrystallization Example No. R1 solvent) m.p. salt 70 colorless needle 106.0-108.0 ( ethanol )

71 white powder 192.0-194.0 hydrochloride ( ethanol)

72 light yellow powder 240-242 hydrochloride (ethanol )

73 light yellow powder 199.0-201.0 hydrochloride ( ethanol) US RE48,059 E 55 56 TABLE 3 - continued

S R1—0- (CH2 ) 3 —N O crystalline form ( recrystallization Example No. R1 solvent) m.p. salt

74 white powder 233.0-235.0 hydrochloride d ( ethanol ) 75 yellow powder 199.0-204.5 dihydrochloride

76 white solid (ethyl 123.2-124.3 acetate -hexane )

77 white solid 231.3-232.9 hydrochloride ( ethyl acetate )

| CH3

78 white solid 229.6-231.8 hydrochloride ( ethyl acetate )

CH3

79 white powder 237.0-238.5 hydrochloride ( ethyl acetate )

H3C

80 white solid 214.5-216.8 hydrochloride ( ethyl acetate ) HN US RE48,059 E 57 58 TABLE 4

S R1—0– (CH2 ) 3 — N O crystalline form ( recrystallization Example No. R1 solvent) m.p. salt 81 white solid 207.9-208.7 hydrochloride ( ethyl acetate ) H3Cya . 82 light yellow powder 106.0-113.0 ( ethyl acetate -isopropyl ether )

83 white powder 188-190 ( ethyl acetate - ether )

TABLE 5

R1-0– ( CH2) n - N

Example No. R1 n 1H -NMR ( solvent) salt

84 3 1H -NMR (CDC13 ) d ppm : 2.05-2.20 (2H , m ), 2.65-2.77 (6H , m ) , 3.15-3.25 (4H , m ), 4.23 (2H , t , J = 6.3 Hz ) , 6.91 ( 1H , d , J = 7.1 Hz ) , 7.15-7.35 (3H , m ) , 7.35-7.45 (3H , m ), 7.55 ( 1H , d , J = 8.0 Hz ) , 7.70 (1H , d , J 8.9 Hz) , 8.05-8.15 (1H , m ) , 8.83 ( 1H , dd , J = 1.7 , 5.3 Hz ).

85 4 1H -NMR (DMSO - d6 ) d : 1.90-2.00 (4H , m ) , dihydrochloride 3.25-3.40 (6H , m ) , 3.50-3.65 (4H , m ), 4.20-4.35 (2H , m ) , 6.95 ( 1H , d , J = 7.4 Hz ) , 7.30 (1H , dd , J = 7.9 , 7.9 Hz) , 7.48 ( 1H , d , J = 5.5 Hz ), 7.65-7.80 ( 3H , m ), 7.80-7.95 (2H , m ) , 8.32 ( 1H , d , J = 9.2 Hz) , 9.05-9.20 ( 2H , m ), 11.29 (1H , brs ) . US RE48,059 E 59 60 TABLE 6

S R1 - O- ( CH2) 4 —N O crystalline form ( recrystallization Example No. R1 solvent) m.p. (° C .) salt

86 white powder 239.6-241.5 hydrochloride ( ethyl acetate )

H3C

87 light brown pow 228.3-229.5 hydrochloride der ( ethyl acetate ) N CH3

88 white powder 212.3-214.4 hydrochloride ( ethyl acetate )

89 white powder 232.9-235.1 hydrochloride ( ethyl acetate ) HN

90 white powder 165.8-167.9 hydrochloride ( ethyl acetate ) H3C

91 F white powder 220-225 hydrochloride ( ethanol) HN

92 F white powder 221-224 hydrochloride ( ethanol) H3C

93 white powder 181-183 hydrochloride ( ethanol) US RE48,059 E 61 62 TABLE 7

R1— (CH2 ) n - N O Example No. R1 n 1H -NMR ( solvent ) salt 94 3 1H - NMR (DMSO - d6 ) d : 2.01-212 (2H , m ) , hydrochloride 3.0-3.7 (16H , m ), 6.98 ( 1H , d , J = 7.7 Hz ), 7.29-7.39 ( 3H , m ), 7.47-7.52 ( 2H , m ), 7.70 ( 1H , d , J = 8.0 Hz ), 7.77 ( 1H , d , J = 5.6 Hz ) , 7.89 ( 1H , d , J = 7.7 Hz) , 9.85 ( 1H , br- s )

95 2 1H - NMR (CDC13 ) d : 3.0-4.1 (16H , m ) , 6.94 oxalate ( 1H , d , J 7.4 Hz) , 7.20-7.47 (6H , m ) , 7.64 ( 1H , d , J 8.1 Hz) , 8.04 ( 1H , d , J = 7.4 Hz )

TABLE 8

S

R1 -O- (CH2 ) 3

crystalline form ( recrystallization Example No. R1 solvent) m.p.( ° C.) salt 96 white powder 185.5-190.0 hydrochloride ( ethyl acetate )

97 white powder 134-136 ( ethyl acetate ether )

98 white powder 103-105 ( ethyl acetate ? ether ) 99 white powder 126-128 ( ethyl acetate ago ether ) US RE48,059 E 63 64 TABLE 8 - continued

R1-0— ( CH2) 3– -N O crystalline form ( recrystallization Example No. R1 solvent ) m.p. (° C.) salt 100 white powder 97-99 ( ethyl acetate ether ) H2C

101 brown powder 240-242 hydrochloride (methanol ) ?? .

:O

102 white powder 143-145 ( ethyl acetate ether ) H3C

103 white powder 161-163 ( ethyl acetate ether)

104 white powder 122-124 F ( ethyl acetate F ether) F

TABLE 9

S R1—0— (CH2 ) 4 —N O crystalline form ( recrystallization Example No. R1 solvent ) m.p. (° C.) salt 105 white powder 212.5-216.0 hydrochloride ( ethyl acetate )

N US RE48,059 E 65 66 TABLE 9 - continued

S R1—0- ( CH2) 4 N oo crystalline form ( recrystallization Example No. R1 solvent) m.p. (° C.) salt

106 white powder 224.5-230.0 hydrochloride ( ethyl acetate ) asN

107 white powder 172.0-174.5 hydrochloride ( ethyl acetate )

H2C

108 white powder 196.5-201.5 hydrochloride ( ethyl acetate )

HC so 109 white powder 200.5-205.5 hydrochloride ( ethyl acetate )

H3C

110 white powder 202.5-206.5 hydrochloride ( ethyl acetate )

111 white powder 218.0-223.5 hydrochloride ( ethyl acetate )

N US RE48,059 E 67 68 TABLE 9 - continued

R1 -O- (CH2 ) 4 N

crystalline form ( recrystallization Example No. R1 solvent) m.p. (° C .) salt 112 white powder 125.0-129.0 ( ethyl acetate isopropyl ether)

F F

TABLE 10 TABLE 10 -continued

S 25

R1-0- (CH2 nN) R1—0- (CH2 ) n - 1 N ce 30 o Example No. R1 n MS( M + 1 ) Example No. R1 n MS ( M + 1 ) 113 3 454

118 3 438 35

N

114 501 40 119 3 502

45 Br

115 CH3 3 448

50 120 3 457

116 3 440 NH 55

LZ

60 117 3 434 121 3 420

H CH3 65 US RE48,059 E 69 70 TABLE 11 TABLE 11 - continued

S 5 R1 - O- ( CH2) N — N R1—0- (CH2 ) n — N O Example No. R1 n MS( M + 1 ) Example No. R1 n MS( M + 1 ) 10 129 3 122 3 422 Br

15

123 3 422 TABLE 12 20

R1 -O- (CH2 ) n - N 124 3 499 25 o Example No. R1 n MS ( M + 1 ) 130 Br 3 499 30 Br

125 CI 3 535 N 35

131 3 434 Br

126 3 457 40 ??3

132 3

45 CI

127 H2C . 3 478

50 133 ??3 3 434

N

55

128 3 480

H3C1 134 3 528 60

65 US RE48,059 E 71 72 TABLE 12 - continued TABLE 13 - continued

' S 5 R1 - O- (CH2 ) -N R1-0- (CH2 )n — N c N 8 10 Example Example No. R1 n MS( M + 1 ) No. R1 n MS( M + 1 )

135 3 465 140 ??? 448

15

20

136 3 450 141 3 496

25

H3C1 30 142 3

137 3 462

CH3 N 35 H

40 TABLE 13 143 CH3 3 462

45 R1-0- (CH2 ) -N O

Example 50 144 3 491 No. R1 n MS (M + 1 ) H3C . 138 3 CH3 ' N 55 CH3

2 145 3 60 CH3 139 3 452 OH

65 CH3 US RE48,059 E 73 74 TABLE 14 TABLE 14 - continued

S 5 R1—0- ( CH2) —N a o R1-0- ( CH2) n - N N Example 10 Example No. R1 n MS( M + 1 ) No. R1 n MS( M + 1 ) 153 3 467 146 3 498

15

20 ' N H 154 3 452

147 CH3 25

H3C 30 TABLE 15 148 3 464

CH3 35

R1 - O- ( CH2) n —N

149 Br 3 501 40 Example No. R1 n MS( M + 1 ) 155 3 479

150 H3C . 3 480 45 NH HN CH3 50 N

156 3 151 CH2 3 462 H3C 55

157 3 436 152 3 467 ??3 II 60 N +

65 US RE48,059 E 75 76 TABLE 15 -continued TABLE 16

5 R1—0– ( CH2) n — R1 -O- (CH2 ) n - N o Example MS 10 No. R1 n ( M + 1 ) Example 163 3 491 No. R1 n MS (M + 1 )

158 3 467 15 NH

164 3 494

Z 20 H3C

159 CI 3 525 IZ

25 165 CH2 3

CI 30 Day CH2 166 3 160 3 35 CI N

H3C1 CH3 40 167 ??3 3 | H3C 45 161 O 3 CH3

50 168 H3C CH3 3 479

Br

55

162 3 491 na 169 CH3 3 519 60

65 US RE48,059 E 77 78 TABLE 16 - continued TABLE 17 - continued

5 R1-0– (CH2 ) n— oo R1—0- ( CH2) n — N 10 Example Example MS No. R1 n MS (M + 1 ) No. R1 n ( M + 1 ) 176 2 442 170 3 15

ci

20 177 2 408 CH2

25 NH TABLE 17 178 2 408

30 R1-0– (CH2 ) n O Example 179 5 450 No. R1 n MS( M + 1 ) 35 171 3 479 H3C

CH3 40 180 8 518

172 3 448

45 N CH3 N CH3 CH3 CH3 50 173 2 408 TABLE 18

NH 55 174 2 R1-0- (CH2 ) n —

Example 60 No. R1 n MS( M + 1 )

175 2 406 181 4 471

65 US RE48,059 E 79 80 TABLE 18 - continued TABLE 18 - continued

5 R1—0- (CH2 ) n —N ON R1-0– ( CH2) n — N ? Example Example 10 No. R1 n MS( M + 1 ) No. R1 n MS( M + 1 ) 190 OH 3 438 182 F 4

15

183 4 469

20

H TABLE 19 CI R1 0 OH 184 4 452 25 o N

R1 30 Example No. MS( M + 1 ) 185 CH3 4 448 191 438

35 NH 192 438 186 4 436

40 N

193 436 187 4 436 45 NH

50

188 4 . 434 TABLE 20

R1 - O CH3 S 55

189 -CH3 4 450 Example No. R1 MS ( M + 1 ) 60 194 436 N 65 US RE48,059 E 81 82 TABLE 20 - continued mM KCI, 2 mM CaCl2 , 1 mM MgCl2 , pH 7.4 ) so that the total amount was 200 ul (final dimethylsulfoxide concen tration 1 % ) . The reaction was performed at room tempera R1 - O CH3 ture for 1 hour and terminated by conducting suction filtra 5 tion with a cell harvester on a glass fiber filter plate . The N filter plate made of glass fiber was washed with 50 mM Tris -hydrochloric acid buffer (pH 7.4 ), and after dried , a O microplate liquid scintillation cocktail was added and the Example No. R1 MS( M + 1 ) radioactivity was measured with a microplate scintillation 10 counter . Radioactivity in the presence of 10 uM ( + )- buta 195 436 clamol hydrochloride was assumed as nonspecific binding . IC50 value was calculated from concentration -dependent reaction using a non - linear analysis program . Ki value was calculated from IC50 value using Cheng -Prussoff formula . 196 434 15 The results are shown in the following Table 22 . TABLE 22 Test Compound Ki (nM ) 20 Compound of Example 1 0.2 Compound of Example 3 0.5 Compound of Example 4 0.5 TABLE 21 Compound of Example 5 0.6 Compound of Example 6 0.8 Compound of Example 7 0.5 R1 CH3 ' S 25 Compound of Example 10 0.4 Compound of Example 11 0.1 Compound of Example 12 0.1 Compound of Example 13 2.4 og Compound of Example 14 3.2 Compound of Example 15 0.2 30 Compound of Example 16 0.7 Example No. R1 MS( M + 1 ) Compound of Example 17 2.2 Compound of Example 18 2.6 197 Compound of Example 19 1.2 Compound of Example 20 1.5 Compound of Example 22 4.0 35 Compound of Example 23 0.7 Compound of Example 24 5.0 Compound of Example 26 3.5 N Compound of Example 27 4.9 Compound of Example 28 1.2 Compound of Example 30 0.7 Compound of Example 31 1.4 Pharmacological Test 1 40 Compound of Example 32 1.5 1 ) Dopamine D2 Receptor Binding Assay Compound of Example 33 1.1 The assay was performed according to the method by Compound of Example 34 1.2 Compound of Example 35 1.6 Kohler et al. (Kohler C , Hall H , Ogren S O and Gawell L , Compound of Example 36 1.0 Specific in vitro and in vivo binding of 3H - raclopride . A Compound of Example 37 1.9 potent substituted benzamide drug with high affinity for 45 Compound of Example 38 1.2 dopamine D - 2 receptors in the rat brain . Biochem . Pharma Compound of Example 39 1.2 Compound of Example 40 4.8 col. , 1985 ; 34 : 2251-2259 ) . Compound of Example 41 1.9 Wistar male rats were decapitated , the brain was retrieved Compound of Example 64 3.2 immediately and corpus striatum was taken out . It was Compound of Example 68 1.0 homogenized in 50 mM tris (hydroxymethyl ) aminomethane 50 Compound of Example 69 0.8 Compound of Example 73 4.0 ( Tris ) -hydrochloric acid buffer (pH 7.4 ) of a volume 50 Compound of Example 79 4.7 times of the weight of the tissue using a homogenizer with Compound of Example 80 1.5 a high -speed rotating blade, and centrifuged at 4 ° C., Compound of Example 81 0.8 48,000xg for 10 minutes. The obtained precipitate was Compound of Example 84 2.4 suspended again in the above - described buffer of a volume 55 Compound of Example 85 2.0 Compound of Example 90 0.4 50 times of the weight of the tissue and after incubated at 37° Compound of Example 91 1.4 C. for 10 minutes , centrifuged in the above- described con Compound of Example 92 1.7 dition . The obtained precipitate was suspended in 50 mM Compound of Example 116 4.5 ( Tris )-hydrochloric acid buffer (containing 120 mM NaCl, 5 Compound of Example 117 4.7 Compound of Example 118 3.5 mM KCI, 2 mM CaCl2, 1 mM MgCl2 , pH 7.4 ) of a volume 60 Compound of Example 122 3.3 25 times of the weight of the tissue and preserved by Compound of Example 128 1.3 freezing at -85 ° C. till it was used for binding assay as a Compound of Example 139 0.2 membrane specimen . Compound of Example 155 2.3 Compound of Example 163 2.8 The binding assay was performed using 40 ul of the Compound of Example 184 2.6 membrane specimen , 20 ul of [PH ] -raclopride ( final concen- 65 Compound of Example 185 2.7 tration 1 to 2 nM ) , 20 ul of a test drug and 50 mM Compound of Example 186 2.3 Tris -hydrochloric acid buffer ( containing 120 mM NaCl, 5 US RE48,059 E 83 84 TABLE 22 - continued TABLE 23 - continued Test Compound Ki (nM ) Test Compound Ki (nM ) Compound of Example 188 1.6 Compound of Example 17 2.8 Compound of Example 190 0.8 5 Compound of Example 18 8.0 Compound of Example 19 1.2 Compound of Example 20 3.3 2 ) Serotonin 5 -HT24 Receptor Binding Assay Compound of Example 21 1.0 Compound of Example 22 2.9 The assay was performed according to the method by Compound of Example 23 1.7 Leysen J E et al. (Leysen JE , Niemegeers CJE, Van Nueten 10 Compound of Example 24 2.3 JM and Laduron P M. [3H ] Ketanserin ( R 41 468 ), a Compound of Example 25 4.6 Compound of Example 26 4.4 selective 3H - ligand for serotonin 2 receptor binding sites . Compound of Example 27 4.1 Mol. Pharmacol. , 1982 , 21 : 301-314 ). Compound of Example 28 2.8 Wistar male rats were decapitated , the brain was retrieved Compound of Example 30 2.0 Compound of Example 31 4.5 immediately and frontal cortex was taken out. It was homog- 15 Compound of Example 32 8.6 enized in 0.25 M sucrose of a volume 10 times of the weight Compound of Example 33 6.6 of the tissue using a Teflon glass homogenizer, and centri Compound of Example 34 1.5 fuged at 4 ° C., 1,000xg for 10 minutes. The obtained Compound of Example 35 2.1 Compound of Example 36 2.1 supernatant was transferred to another centrifuge tube and Compound of Example 37 3.1 suspended in 0.25 M sucrose of a volume 5 times of the 20 Compound of Example 38 7.3 weight of the tissue and the precipitate was centrifuged in Compound of Example 39 2.1 Compound of Example 40 5.1 the above -described condition . The obtained supernatant Compound of Example 41 3.2 was combined with the supernatant obtained above and Compound of Example 64 8.2 adjusted to a volume 40 times of theweight of the tissue with Compound of Example 68 7.0 50 mM Tris - hydrochloric acid buffer ( pH 7.4 ) , and centri- 25 Compound of Example 69 6.1 Compound of Example 73 1.3 fuged at 4 ° C., 35,000xg for 10 minutes. The obtained Compound of Example 79 5.5 precipitate was suspended again in the above -described Compound of Example 80 2.5 buffer of a volume 40 times of the weight of the tissue and Compound of Example 81 2.6 centrifuged in the above -described condition . The obtained Compound of Example 84 3.3 Compound of Example 89 3.1 precipitate was suspended in the above -described buffer of 30 Compound of Example 90 5.3 a volume 20 times of the weight of the tissue and preserved Compound of Example 91 6.5 by freezing at -85 ° C. till it was used for binding assay as Compound of Example 92 5.7 a membrane specimen . Compound of Example 116 4.2 Compound of Example 117 1.3 The binding assay was performed using 40 ul of the Compound of Example 118 3.4 membrane specimen, 20 ul of [ H ] -Ketanserin ( final con- 35 Compound of Example 122 2.9 centration 1 to 3 nM ) , 20 ul of a test drug and 50 mM Compound of Example 128 6.3 Tris -hydrochloric acid buffer (pH 7.4 ) so that the total Compound of Example 139 4.0 Compound of Example 155 3.0 amount was 200 ul ( final dimethylsulfoxide concentration Compound of Example 163 7.4 1 % ) . The reaction was performed at 37 ° C. for 20 minutes Compound of Example 184 4.3 and terminated by conducting suction filtration with a cell 40 Compound of Example 185 5.0 harvester on a glass fiber filter plate . Compound of Example 186 8.8 The filter plate made of glass fiber was washed with 50 Compound of Example 188 6.3 mM Tris -hydrochloric acid buffer (pH 7.4 ), and after dried , Compound of Example 190 2.9 a microplate liquid scintillation cocktail was added and the radioactivity was measured with a microplate scintillation 45 3) Adrenalin al Receptor Binding Assay counter . Radioactivity in the presence of 10 uM spiperone The assay was performed according to the method by was assumed as nonspecific binding . Groß G et al. (Groß G , Hanft G and Kolassa N. Urapidil and IC50 value was calculated from concentration -dependent some analogues with hypotensive properties show high reaction using a non - linear analysis program . Ki value was affinities for 5 -hydroxytryptamine ( 5 -HT ) binding sites of calculated from IC50 value using Cheng - Prussoff formula . 50 the 5 -HT1A subtype and for al - adrenoceptor binding sites . The results are shown in the following Table 23 . Naunyn - Schmiedeberg's Arch Pharmacol. , 1987 , 336 : 597 601) . TABLE 23 Wistar male rats were decapitated , the brain was retrieved immediately and cerebral cortex was taken out. It was Test Compound Ki (nM ) 55 homogenized in 50 mM Tris -hydrochloric acid buffer (100 Compound of Example 1 2.3 Compound of Example 2 1.5 mM NaCl, containing 2 mM dihydrogen disodium ethylene Compound of Example 3 2.3 diamine tetraacetate , pH 7.4 ) of a volume 20 times of the Compound of Example 4 4.9 weight of the tissue using a homogenizer with a high - speed Compound of Example 5 6.4 Compound of Example 7 4.0 60 rotating blade , and centrifuged at 4 ° C., 80,000xg for 20 Compound of Example 8 0.6 minutes . The obtained precipitate was suspended in the Compound of Example 9 2.6 above- described buffer of a volume 20 times of the weight Compound of Example 10 3.0 of the tissue and after incubated at 37 ° C. for 10 minutes , Compound of Example 11 5.7 Compound of Example 12 2.1 centrifuged in the above -described condition . The obtained Compound of Example 15 3.3 65 precipitate was suspended again in the above- described Compound of Example 16 7.0 buffer of a volume 20 times of the weight of the tissue and centrifuged in the above -described condition . The obtained US RE48,059 E 85 86 precipitate was suspended in 50 mM (Tris ) -hydrochloric dopamine which was used as a control drug suppressed the acid buffer ( containing 1 mM dihydrogen disodium ethylene quantity of cyclic AMP to about 10 % as the maximum diamine tetraacetate , pH 7.4 ) of a volume 20 times of the activity . weight of the tissue and preserved by freezing at -85 ° C. till It was confirmed that test compounds had partial agonistic it was used for binding assay as membrane specimen . 5 activity for dopamine D , receptor in the above- described The binding assay was performed using 40 ul of the test . membrane specimen , 20 ul of [PH ]-prazosin ( final concen Since the test compounds has partial agonistic activity for tration 0.2 to 0.5 nM ) , 20 ul of a test drug and 50 mM dopamine D2 receptor, they can stabilize dopamine neu Tris -hydrochloric acid buffer (containing 1 mM EDTA , pH rotransmission to a normal condition in a schizophrenia 7.4 ) so that the total amount was 200 ul ( final dimethylsul 10 patient and as a result , exhibit , for example , positive and foxide concentration 1 % ) . The reaction was performed at negative condition improving effect , cognitive impairment 30 ° C. for 45 minutes and terminated by conducting suction improving effect and the other symptom improving effects filtration with a cell harvester on a glass fiber filter plate . without causing side effects . The filter plate made of glass fiber was washed with 50 Pharmacological Test 3 mM Tris -hydrochloric acid buffer (pH 7.4 ) , and after dried , 15 Inhibitory effect on apomorphine- induced stereotyped a microplate liquid scintillation cocktail was added and the behavior in rats radioactivity was measured with a microplate scintillation Wistar rats (male , six -seven weeks old , Japan SLC , Inc. ) counter. Radioactivity in the presence of 10 uM phen were used as test animals . A test compound was suspended tolamine hydrochloride was assumed as nonspecific binding . 20 in 5 % gum arabic /( physiological saline or water ) using an IC50 value was calculated from concentration -dependent agate mortar and was diluted with the same solvent if reaction using a non - linear analysis program . Ki value was necessary . calculated from IC50 value using Cheng -Prussoff formula . Test animals were fasted overnight from the day before . Pharmacological Test 2 Apomorphine (0.7 mg/ kg ) was subcutaneously administered Partial agonistic activity on dopamine D2 receptor using 25 ( 1 ml/ kg ) 1 hour after each test compound was orally D2 receptor expression cells administered ( 5 ml/kg ) . Stereotyped behavior was observed Partial agonistic activity on dopamine D2 receptor was for 1 minute respectively 20 , 30 and 40 minutes after evaluated by quantitatively determining cyclic AMP pro apomorphine injection . The stereotyped behavior of each animal was quantified duction inhibitory effect of a test compound in dopamine D2 30 according to the following condition and score made at three receptor expression cells in which adenosine 3 ', 5 '- cyclic points were summed up and the anti -apomorphine effect was monophosphate ( cyclic AMP) production was induced by evaluated . Six test animals were used for each group . forskolin stimulation . 0 : The appearance of the animals is the same as saline Human recombinant dopamine D2 receptor expressing treated rats ; Chinese hamster ovary / DHFR ( - ) cells were cultured in a 35 1 : Discontinuous sniffing, constant exploratory activity ; culture medium ( Iscove's Modified Dulbecco's Medium 2 : Continuous sniffing, periodic exploratory activity ; ( IMDM culture medium ), 10 % fetal bovine serum , 50 3 : Continuous sniffing, discontinuous biting, gnawing or I.U./ml penicillin , 50 ug /ml streptomycin , 200 ug /ml gene licking . Very brief periods of locomotor activity ; ticin , 0.1 mM sodium hypoxanthine, 16 UM thymidine ) at 4 : Continuous biting , gnawing or licking; no exploratory 37 ° C. and 5 % carbon dioxide condition . Cells were seeded 40 activity . at 104 cells /well on a 96 -well microtiter plate coated with Non -clinical statistical analysis system was used for all poly - L - lysine and grown under the same condition for 2 statistical processing. When the significance probability days. Each well was washed with 100 ul of a culture medium value was lower than 0.05 , it was judged that a significant ( IMDM culture medium , 0.1 mM sodium hypoxanthine , 16 difference existed . The difference of the score between the uM thymidine ). The culture medium was replaced with 50 ul 45 solvent administration group and each test compound of culture medium ( IMDM culture medium , 0.1 % sodium administration group was analyzed using Wilcoxon rank ascorbate , 0.1 mM sodium hypoxanthine , 16 uM thymidine ) sum test or Steel test. In addition , linear regression analysis having dissolved therein 3 uM of a test compound . After was used for calculating 50 % effective dose (95 % confi allowed to incubate at 37 ° C., 5 % carbon dioxide condition dence interval ). for 20 minutes, the culture medium was replaced with 100 50 Since the test compounds showed inhibitory effect for ul of forskolin stimulative culture medium ( IMDM culture apomorphine - induced stereotyped behavior, it was con medium , 0.1 % sodium ascorbate , 0.1 mM sodium hypox firmed that the test compounds have D2 receptor antagonistic anthine , 16 uM thymidine, 10 uM forskolin , 500 UM effect. 3 - isobutyl - 1 -methylxanthine ) having 3 uM of the test com Pharmacological Test 4 pound dissolved therein and allowed to incubate at 37 ° C., 55 Inhibitory effect on (1 ) D - 2,5 -dimethoxy - 4 - iodoamphet 5 % carbon dioxide condition for 10 minutes . After the amine (DOI ) induced head twitch in rats culture medium was removed , 200 ul of Lysis 1B aqueous Wistar rats (male , six - seven weeks old , Japan SLC , Inc.) solution (Amersham Bioscience, reagent attached to cyclic were used as test animals . A test compound was suspended AMP biotrack enzyme immunoassay system ) was dispensed in 5 % gum arabic / (physiological saline or water) using an and shaken for 10 minutes . The aqueous solution of each 60 agate mortar and was diluted with the same solvent if well was used as a sample for measurement. Samples for necessary . measurement quadruply diluted were subjected to measure Test animals were fasted overnight from the day before . ment of the quantity of cyclic AMP using the above DOI ( 5.0 mg/kg ) was subcutaneously administered ( 1 described enzyme immunoassay system . Inhibition ratio of ml/ kg ) 1 hour after each test compound was orally admin the respective test compound was calculated assuming that 65 istered ( 5 ml/ kg ). The number of head twitches was counted the quantity of cyclic AMP of the well to which no test for 10 minutes immediately after DOI injection . Six test compound was added was 100 % . In this empiric test system , animals were used for each group . US RE48,059 E 87 88 Non - clinical statistical analysis was used for all statistical and Microscinto (Perkin - Elmer) was added to the filter and processing . When the significance probability value was remaining radioactivity on the filter was measured . lower than 0.05 , it was judged that a significant difference Serotonin uptake inhibitory activity ( % ) was calculated existed . The difference of the number of head twitches from the radioactivity of total counting as 100 % , of non between the solvent administration group and each test 5 specific counting as 0 % , and of counting obtained with test compound administration group was analyzed using t- test or compound . Dunnett’s test . In addition , linear regression analysis was used for calculating 50 % effective dose (95 % confidence % of inhibition of 5 -HT ( % ) = 100 - [ ( Count obtained interval) . with test compound Nonspecific count ( 0 % Since the test compounds showed inhibitory effect for 10 Uptake )) / ( Total count( 100 % Uptake )-Nonspe DOI- induced head twitch , it was confirmed that the test cific count ( 0 % Uptake )) ]x100 compounds have serotonin 5HT24 receptor antagonistic The results are shown in the next Table 24 . effect . Pharmacological Test 5 TABLE 24 Catalepsy Inducing Effect in Rats 15 Wistar rats (male , six - seven weeks old , Japan SLC , Inc.) Serotonin uptake inhibitory ratio were used as test animals . A test compound was suspended Test compound ( % ) ( 300 nM ) in 5 % gum arabic / ( physiological saline or water ) using an Compound of Example 1 92.4 agate mortar and was diluted with the same solvent if Compound of Example 2 78.8 necessary . 20 Compound of Example 3 84.8 Compound of Example 4 91.0 Test animals were fasted overnight from the day before Compound of Example 5 89.1 observation on catalepsy and ptosis was performed 1 , 2 , 4 , Compound of Example 6 91.3 6 and 8 hours after each test compound was orally admin Compound of Example 7 91.0 istered (5 ml/kg ). Six test animals were used for each group . Compound of Example 8 95.0 Compound of Example 9 97.3 One forepaw of a rat was placed on an edge of a steel 25 Compound of Example 10 92.6 small box ( width : 6.5 cm , depth : 4.0 cm , height : 7.2 cm ) ( an Compound of Example 11 92.5 unnatural pose ) and when the rat maintained the pose for Compound of Example 13 77.0 more than 30 seconds, it was judged that the case was Compound of Example 14 85.2 Compound of Example 15 87.2 catalepsy positive . This observation was performed three Compound of Example 16 86.7 times at each point, and if there was at least one positive 30 Compound of Example 17 86.3 case , it was judged that catalepsy occurred in the individual. Compound of Example 18 91.1 As a result, catalepsy induction effect of a test compound Compound of Example 19 86.3 Compound of Example 20 92.8 was dissociated from inhibitory effect on apomorphine Compound of Example 21 81.4 induced stereotyped behavior , therefore it was suggested Compound of Example 22 90.8 that apprehension for extrapyramidal side effect in clinic 35 Compound of Example 23 95.5 would be low . Compound of Example 24 97.5 Pharmacological Test 6 Compound of Example 25 91.9 Compound of Example 26 92.0 Measurement of Serotonin ( 5 -HT ) Uptake Inhibitory Compound of Example 27 94.0 Activity of a Test Compound by Rat Brain Synaptosome Compound of Example 28 95.3 Wistar male rats were decapitated , the brain was retrieved 40 Compound of Example 30 95.8 Compound of Example 31 96.3 and frontal cortex was dissected out, and it was homog Compound of Example 32 96.9 enized in 0.32 M sucrose solution of a weight 20 times of the Compound of Example 33 94.3 weight of the tissue using a Potter type homogenizer . The Compound of Example 34 94.2 homogenate was centrifuged at 4 ° C., 1,000xg for 10 Compound of Example 35 93.4 Compound of Example 36 97.4 minutes , the obtained supernatant was further centrifuged at 45 Compound of Example 37 97.7 4 ° C., 20,000xg for 20 minutes, and the pellet was sus Compound of Example 38 96.7 pended in an incubation buffer (20 mM Hepes buffer (pH Compound of Example 39 99.2 7.4 ) containing 10 mM glucose , 145 mM sodium chloride, Compound of Example 40 91.6 Compound of Example 41 95.1 4.5 mM potassium chloride, 1.2 mM magnesium chloride, Compound of Example 64 73.0 1.5 mM calcium chloride ), which was used as crude syn- 50 Compound of Example 65 72.9 aptosome fraction . Compound of Example 66 74.1 5 -HT uptake reaction was performed in a volume of 200 Compound of Example 67 93.9 ul using a 96 -well round bottom plate and pargyline ( final Compound of Example 68 95.7 concentration 10 uM ) and sodium ascorbate ( final concen Compound of Example 69 96.3 tration 0.2 mg/ ml ) were contained in the incubation buffer 55 upon reaction and used . Incubation buffer (total counting ), non - labeled 5 -HT ( fi Preparation Examples nal concentration 10 uM , non -specific counting ) and the diluted test compound ( final concentration 300 nM ) were 100 g of a compound of the present invention , 40 of added to each well. One - tenth quantity of the final volume 60 Avicel ( trade name, productof Asahi Chemical Industry Co. , of the synaptosome fraction was added and after preincu Ltd. ), 30 g of corn starch and 2 g of magnesium stearate was bated at 37 ° C. for 10 minutes, tritium labeled 5 -HT solution mixed and polished and tableted with a pestle for glycocalyx ( final concentration 8 nM ) was added and uptake reaction R10 mm . was started at 37 ° C. The uptake time was 10 minutes and The obtained tablet was coated with a film using a film the reaction was terminated by vacuum filtration through a 65 coating agentmade up of 10 g of TC - 5 ( trade name, product 96 -well fiber glass filter paper plate , and after the filter paper of Shin - Etsu Chemical Co., Ltd., hydroxypropyl methylcel was washed with cold normal saline, it was dried enough lulose ), 3 g of polyethylene glycol 6000 , 40 g of castor oil US RE48,059 E 89 90 and an appropriate amount of ethanol to produce a film coated tablet of the above composition . and The invention claimed is : 1. A heterocyclic compound represented by the formula 5 N ( 1 ): (wherein the carbon -carbon - bond R2 10 represents a single bond or a double bond )] or a salt A - N thereof. 2. The heterocyclic compound of the formula ( 1) accord 15 ing to claim 1, wherein the ring Q represents a bicyclic group selected from the group consisting of:

wherein ring Q represented by 20 N represents ( wherein H H

25 -Z --- Y H represents --NH - CH2 _N_CH?, CHÚNH and 30 or CH = N— ; and H the carbon - carbon bond between the 3 -position and 4 -position of the heterocyclic skeleton containing Z and Y represents a single bond or 35 (wherein the carbon -carbon bond a double bond) ; between the 3 -position and 4 -position of the bicyclic the ring Q may have at least one substituent selected heterocyclic skeleton represents a single bond or a from the group consisting of a lower alkyl group , a double bond ); lower alkenyl group , a lower alkynyl group , a 40 the ring Q may have 1 to 3 substituents selected from hydroxy group , a lower alkoxy group , a halogenated the group consisting of a lower alkyl group , a lower lower alkyl group , an aryl group , an aryl lower alkyl alkenyl group , a lower alkynyl group , a hydroxy group , an aryl lower alkoxy group , an arylcarbonyl group , a lower alkoxy group , a halogenated lower group , a lower alkenyloxy group , a lower alkanoyl alkyl group , a phenyl group , a phenyl lower alkyl group , a lower alkanoyloxy group , a cycloalkyl 45 group , a naphthyl lower alkyl group , a phenyl lower group , a cycloalkyl lower alkyl group , a halogen alkoxy group , a naphthyl lower alkoxy group , a atom , a carbamoyl group which may have a lower benzoyl group , a lower alkenyloxy group , a lower alkyl group , a carboxy group , a lower alkoxycarbo alkanoyl group , a lower alkanoyloxy group , a cyclo nyl group , an amino group which may have a lower C3 -C8 alkyl group , a cyclo C3 - C8 alkyl lower alkyl alkanoyl group , a nitro group , a hydroxy lower alkyl 50 group , a halogen atom , a carbamoyl group which group , an amino lower alkyl group which may have may have a lower alkyl group , a caroboxy group , a a lower alkyl group , a thienyl group , a saturated 3- to lower alkoxycarbonyl group , an amino group which 8 -membered heteromonocyclic group containing 1 may have a lower alkanoyl group , a nitro group , a to 2 nitrogen atoms- substituted lower alkyl group 55 hydroxy lower alkyl group , an amino lower alkyl and an oxo group ; group which may have a lower alkyl group , a thienyl group and a saturated 5- to 6 -membered heteromono R , represents a hydrogen atom or a lower alkyl group ; cyclic group containing 1 to 2 nitrogen atoms- sub and stituted lower alkyl group ; and A represents —O - A1- (wherein A , represents an alky A represents —O - A ,- (wherein A , represents a C1- C6 lene group which may be substituted with a hydroxy 60 alkylene group which may be substituted with a group (wherein one oxygen atom may replace a hydroxy group (wherein one oxygen atom may carbon of the alkylene chain ) or a lower alkenylene replace a carbon of the alkylene chain ) ), or a salt group ) or a lower alkylene group ; thereof. provided that when A represents a lower alkylene 65 3. The heterocyclic compound of the formula ( 1) accord group , the ring Q represents a bicyclic group selected ing to claim 2 , wherein the ring Q represents a bicyclic group from the group consisting of: selected from the group consisting of: US RE48,059 E 91 92

and and

N 5 - - H H

the ring Q may have 1 to 3 substituents selected from the (wherein the carbon - carbon bond group consisting of a lower alkyl group , a lower alkenyl 10 between the 3 -position and 4 -position of the bicyclic group, a lower alkynyl group , a hydroxy group , a lower heterocyclic skeleton represents a single bond or a alkoxy group , a halogenated lower alkyl group , a double bond ); phenyl group , a phenyl lower alkyl group , a naphthyl the ring Q may have 1 to 3 substituents thereon selected lower alkyl group , a phenyl lower alkoxy group , a 15 from the group consisting of a lower alkyl group , a naphthyl lower alkoxy group , a benzoyl group , a lower lower alkenyl group , a lower alkynyl group , a alkenyloxy group , a lower alkanoyl group , a lower hydroxy group , a lower alkoxy group , a halogenated alkanoyloxy group , a cyclo C3 - C8 alkyl group, a cyclo lower alkyl group , a phenyl group , a phenyl lower C3 - C8 alkyl lower alkyl group , a halogen atom , a alkyl group , a naphthyl lower alkyl group , a phenyl 20 lower alkoxy group , a naphthyl lower alkoxy group , carbamoyl group which may have a lower alkyl group , a benzoyl group , a lower alkenyloxy group , a lower a carboxy group, a lower alkoxycarbonyl group , an alkanoyl group , a lower alkanoyloxy group, a cyclo amino group which may have a lower alkanoyl group , C3 - C8 alkyl group , a cyclo C3 - C8 alkyl lower alkyl a nitro group , a hydroxy lower alkyl group , an amino group , a halogen atom , a carbamoyl group which lower alkyl group which may have a lower alkyl group , 25 may have a lower alkyl group , a carboxy group , a a phenyl group , a thienyl group and a pyrrolidinyl lower alkoxycarbonyl group , an amino group which lower alkyl group ; and may have a lower alkanoyl group , a nitro group , a hydroxy lower alkyl group , an amino lower alkyl A represents O - A1- ( wherein A , represents a C1 - C6 group which may have a lower alkyl group , a thienyl alkylene group which may be substituted with a 30 group , a pyrrolidinyl lower alkyl group and an oxo hydroxy group (wherein one oxygen atom may replace group ; and a carbon of the alkylene chain )) , or a salt thereof. A represents a lower alkylene group , or a salt thereof. 4. The heterocyclic compound of the formula ( 1) accord 6. The heterocyclic compound of the formula (1 ) accord ing to claim 2 , wherein the ring Q represents a bicyclic group ing to claim 5 , wherein the ring Q represents a bicyclic group selected from the group consisting of: 35 selected from the group consisting of:

and 40 and H H N

( the ring Q may have 1 to 3 substituents selected from the 45 ( wherein the carbon -carbon bond group consisting of a lower alkyl group, a lower alkenyl between the 3 -position and 4 -position of the bicyclic group, a lower alkynyl group , a hydroxy group , a lower heterocyclic skeleton represents a single bond or a alkoxy group , a halogenated lower alkyl group , a double bond ); phenyl group , a phenyl lower alkyl group , a naphthyl 50 the ring Q may have 1 to 3 substituents selected from the group consisting of a lower alkyl group , a lower lower alkyl group , a phenyl lower alkoxy group , a alkenyl group , a lower alkynyl group , a hydroxy naphthyl lower alkoxy group , a benzoyl group , a lower group , a lower alkoxy group , a halogenated lower alkenyloxy group , a lower alkanoyl group , a lower alkyl group , a phenyl group , a phenyl lower alkyl alkanoyloxy group , a cyclo C3 - C8 alkyl group , a cyclo 55 group , a naphthyl lower alkyl group , a phenyl lower C3 -C8 alkyl lower alkyl group , a halogen atom , a alkoxy group , a naphthyl lower alkoxy group , a carbamoyl group which may have a lower alkyl group , benzoyl group , a lower alkenyloxy group , a lower a carboxy group , a lower alkoxycarbonyl group , an alkanoyl group , a lower alkanoyloxy group , a cyclo amino group which may have a lower alkanoyl group , C3 -C8 alkyl group , a cyclo C3 - C8 alkyl lower alkyl 60 group , a halogen atom , a carbamoyl group which a nitro group , a hydroxy lower alkyl group , an amino may have a lower alkyl group , a carboxy group , a lower alkyl group which may have a lower alkyl group , lower alkoxycarbonyl group , an amino group which a thienyl group and a pyrrolidinyl lower alkyl group ) or may have a lower alkanoyl group , a nitro group , a a salt thereof. hydroxy lower alkyl group , an amino lower alkyl 5. The heterocyclic compound of the formula ( 1) accord- 65 group which may have a lower alkyl group , a thienyl ing to claim 1, wherein the ring Q represents a bicyclic group group and a pyrrolidinyl lower alkyl group , or a salt selected from the group consisting of: thereof. US RE48,059 E 93 94 7. The heterocyclic compound of the formula (1 ) accord group , a lower alkanoyloxy group , a cycloalkyl ing to claim 3 selected from the group consisting of : group , a cycloalkyl lower alkyl group , a halogen ( 1 ) 7- [4- ( 4 - benzo [ b ] thiophen - 4 - yl- piperazin - 1 -yl ) bu atom , a carbamoyl group which may have a lower toxy ]-1H - quinolin -2 -one , alkyl group , a carboxy group , a lower alkoxycarbo ( 2 ) 7-[ 3- ( 4 -benzo [b ] thiophen -4 -yl - piperazin - 1 -yl ) 5 nyl group , an amino group which may have a lower propoxy ]-1H - quinolin - 2 - one , alkanoyl group , a nitro group , a hydroxy lower alkyl (3 ) 7-[ 3- ( 4 -benzo [ b ] thiophen - 4 - yl- piperazin - 1 - yl) group , an amino lower alkyl group which may have propoxy ] -3,4 -dihydro - 1H - quinolin -2 -one , a lower alkyl group , a thienyl group , a saturated 3- to 7-[ 4- ( 4 -benzo [ b ] thiophen - 4 - yl- piperazin - 1 - yl) bu 8 -membered heteromonocyclic group containing 1 toxy ] -3,4 -dihydro -1H -quinolin - 2- one , 10 to 2 nitrogen atoms- substituted lower alkyl group ( 5 ) 7-[ 4- ( 4 -benzo [ b ]thiophen - 4 - yl - piperazin - 1 -yl ) bu and an oxo group ; toxy ]-1 - methyl - 3,4 - dihydro - 1H -quinolin - 2 -one and R2 represents a hydrogen atom or a lower alkyl group ; (6 ) 6-[ 3- ( 4 - benzo [b ]thiophen - 4 -yl - piperazin - 1 - yl ) and propoxy ] -3,4- dihydro - 1H - quinolin - 2 -one ; A represents O - A , - (wherein A , represents an alky or a salt thereof. 15 lene group which may be substituted with a hydroxy 8. The heterocyclic compound of the formula (1 ) accord group (wherein one oxygen atom may replace a ing to claim 4 selected from the group consisting of: carbon of the alkylene chain ) or a lower alkenylene ( 1 ) 7- (3- ( 4 -benzo [ b ] thiophen - 4 -yl - piperazin - 1 -yl ) group ) or a lower alkylene group ; propoxy ] -3,4 -dihydro -2H - isoquinolin - 1 -one provided that when A represents a lower alkylene ( 2 ) 7- (3- ( 4 -benzo [b ] thiophen -4 - yl- piperazin - 1 - yl) 20 group , the ring Q represents a bicyclic group selected propoxy ] -2 -methyl - 3,4 -dihydro - 2H - isoquinolin - 1 -one , from the group consisting of: ( 3 ) 7- [4- ( 4 -benzo [ b ] thiophen - 4 - yl- piperazin - 1 -yl ) bu toxyl- 2 -methyl - 3,4 - dihydro - 2H -isoquinolin - 1 -one , ( 4 ) 7- [4- ( 4 -benzo [b ] thiophen - 4 - yl- piperazin - 1 - yl) bu toxy ] -3,4 -dihydro -2H - isoquinoline- 1 -one , 25 ( 5 ) 7-( 3- ( 4 -benzo [ b ]thiophen - 4 -yl - piperazin - 1 - yl) and propoxyl -2H - isoquinolin - 1 -one and N (6 ) 7-[ 3- ( 4 - benzo [ b ]thiophen - 4 - yl -piperazin - 1 - yl) propoxy ]-2 -methyl - 2H - isoquinolin -1 -one ; 30 ? or a salt thereof. 9. A process for producing a heterocyclic compound (wherein the carbon - carbon bond represented by the formula ( 1) : represents a single bond or a double bond ) ] or a salt thereof, (1 ) 35 characterized by comprising a reaction of a compound R2 represented by the formula : ( 0 ) A 40 -A - X

( wherein the ring Q and A are the same as defined above , [wherein ring Q represented by and X ,1 represents a halogen atom or a group which 45 causes a substitution reaction the same as in a halogen atom ) or a salt thereof with a compound represented by the formula : represents (wherein 50 R2 -Z --- Y HN

represents --NH - CH2 . -N = CH , CH2 - NH or — CH = N ; and 55 ög the carbon - carbon bond between the 3 -position and 4 - position of the heterocyclic ( wherein R , is the sameas defined above ) or a salt thereof. skeleton containing Z and Y represents a single bond or 10. The heterocyclic compound according to claim 3 , a double bond ) ; 60 wherein Q may have 1 substituent, which is a lower alkyl the ring Q may have at least one substituent selected group , R , represents a hydrogen , and A , represents a C1- C6 from the group consisting of a lower alkyl group , a alkylene group (wherein one oxygen atom may replace a lower alkenyl group , a lower alkynyl group , a carbon of the alkylene chain ). hydroxy group , a lower alkoxy group , a halogenated 11. The heterocyclic compound according to claim 4 , lower alkyl group , an aryl group , an aryl lower alkyl 65 wherein may have 1 substituent, which is lower alkyl group , an aryl lower alkoxy group , an arylcarbonyl group , R , represents a hydrogen , and A , represents a C1- C6 group , a lower alkenyloxy group , a lower alkanoyl alkylene group . US RE48,059 E 95 96 12. The heterocyclic compound according to claim 7 , which is 7- [4- ( 4 -benzo [ b ] thiophen -4 - yl -piperazin - 1 - yl) bu toxy ]-1H - quinolin - 2 - one or a salt thereof. 13. The heterocyclic compound according to claim 12, which is 7- [ 4-( 4 -benzo [ b ]thiophen -4 -yl - piperazin - 1 -yl ) bu- 5 toxy ) -1H -quinolin - 2 -one . 14. The process according to claim 9 , wherein the process produces 7- [4- ( 4 - benzo [ b ] thiophen - 4 - yl - piperazin - 1 - yl) bu toxyl- 1 H - quinolin - 2 - one or a salt thereof. 15. The process according to claim 14 , wherein the 10 process produces 7- [ 4-( 4 -benzo [ b ] thiophen - 4 - yl- piperazin 1 -yl ) butoxy ] -1H - quinolin - 2 -one .