PIPERAZINE DERIVATIVES AS TACHYKININ ANTAGONISTS

Abstract: This invention relates to piperazine derivatives of formula (I), wherein each symbol is as defined in the description, and its pharmaceutically acceptable salt, to processes for preparation thereof, to pharmaceutical composition comprising the same, and to use of the same for treating or Tachykinin-mediated diseases in human being or animals.

Description: D E S C R I P T I O N PIPERAZINE DERIVATIVES AS TACHYKININ ANTAGONISTS TECHNICAL FIELD The present invention relates to new piperazme derivatives and a pharmaceutically acceptable salt thereof. More particularly, it relates to new piperazme derivatives and a pharmaceutically acceptable salt thereof which have pharmacological activities such as Tachykm antagonism, especially Substance P antagonism, Neurokmin A antagonism, Neurokmin B antagonism, and the like, to a process for preparation thereof, to a pharmaceutical composition comprising the same, and to a use of the same as a medicament. Accordingly, one object of the present invention is to provide new and useful piperazme derivatives and a pharmaceutically acceptable salt thereof which have pharmacological activities such as Tachykmm antagonism, especially Substance P antagonism, Neurokmin A antagonism, Neurokmin B antagonism, and the like. Another object of the present invention is to provide a process for the preparation of said piperazme derivatives and a salt thereof. A further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said piperazme derivatives and a pharmaceutically acceptable salt thereof. Still further object of the present invention is to provide a use of said piperazme derivatives or a pharmaceutically acceptable salt thereof as Tachykmm antagonist, especially Substance P antagonist, Neurokmin A antagonist or Neurokmin B antagonist, useful for treating or preventing Tachykinin-mediated diseases, for example, respiratory diseases such as asthma, bronchitis, rhinitis, cough, expectoration, and the like; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis, and the like; inflammatory diseases such as rheumatoid arthritis, osteoarthπtis, and the like; pains or aches (e.g., migraine, headache, toothache, cancerous pain, back pain, etc.) , and the like in human being or animals. BACKGROUND ART Some piperazme derivatives having pharmaceutical activities such as Tachykmm antagonism have been known as described m EP 0655442 Al . DISCLOSURE OF INVENTION The object compound of the present invention can be represented by the following general formula (I) : R- wherein Y is bond or lower alkylene, R is aryl which may have suitable substituent (s) , R is aryl or indolyl each of whicn may have suitable substituent (s) , -a R is hydrogen or lower alkyl, R is chloro (lower) alkenyl; chloro (lower) alkynyl; pyridyl (lower) alkylammo (lower) alkyl; pyridyl (lower) alkylammo (lower) alkenyl; N- (lower alkyl ) -N- [pyridyl (lower) alkyl] ammo (lower) - alkyl; tnazcl lammo (lower) alkyi; lower alkoxy (lower) alkylammo ( lower) alkyl; bis [ (lower) al oxy (lower) alkyl] ammo (lower) alkyl; N- (lower alkyl) -N- [ (lower) alkoxy (lower)alkyl]a mo- (lower) al yl; hydroxy (lower) l yl ; lower a1kylsulfonyloxy (lower) alkyl; phenyl (lower) alkyl which may have lower alkanoyl, ammo, lower al anoylammo, di (lowe ) alkylaminocarbonyl or nitre- lower alkoxyphenyl {lower; alkylcaroonyl; lower alkanoylbenzoyl; benzoyl (lowe ) alkyl which has lower alkyl, chlorine or di (lower) alkylammo; benzoyl (lower) alkyl which has halogen and lower alkyl; dihalobenzoyl (lower) alkyl; di (lower) alkylbenzoyl (lower) alkyl; 3- luc obenzoyl (lower) alkyl; 3- (4- luorobenzoyl) propyl; 4, 4-ethylenedιoxy-4- ( -fluorophenyl) utyl; piperazmylcaroonyl (lower) alkyi wnich has cyclopentyl or halopnεnyl; (2-pyrιdyl) (lowe ) alkyl; (3-pyrιdyl) propyl; (3-pyrιdyl) (lower) alkynyl; i idazo] l (lower) alkyl which may have lower alkyl; pyrazolyl {lower) alkyi which may nave lower alkyl; thicmorpholmylcarbonyl (lower) alkyi; (3-azabιcycio[3.2.2]non-3-yl) carbonyl (lower) alkyl; or thienylcarbonyi (lower) alkyl, 1,2,3, 6-tetrahydropyrιdyl (lower) alkyl, 1,2,3, 6-tetrahydropyrιdyi (lower) alkynyl, 1, 2, 3, 4-cetranydroιsoqumoiyl (lower) al yl, 4, 5, 6, 7-tetrahydrothieno [3, 2-c]pyridinyl (lower) alkyl, saturated heterocyclic (lower) alkyl, saturated heterocyclic (lower) alkenyl, saturated heterocyclic (lower) alkynyl, saturated heterocyclicamino (lower) alkyl, saturated heterocyclicamino (lower) alkenyl or saturated heterocyclicamino (lower) alkynyl, each of which may have suitable substituent (s) , and a pharmaceutically acceptable salt thereof. It is to be noted that the object compound (I) may include one or more stereoisomers due to asymmetric carbon atom(s) and double bond, and all of such isomers and a mixture thereof are included within the scope of the present invention. It is further to be noted that isomerization or rearrangement of the object compound (I) may occur due to the effect of the light, acid, base or the like, and the compound obtained as the result of said isomerization or rearrangement is also included within the scope of the present invention. It is also to be noted that the solvating form of the compound (I) (e.g. hydrate, etc.) and any form of the crystal of the compound (I) are included within the scope of the present invention. According to the present invention, the object compound (I) or a salt thereof can be prepared by processes which are illustrated in the following schemes. 'rocess 1 ill) T ^ or i s lεciive deπvat 1 >r a salt thereof a the irr.ino group or a salt thereof process (la) or its reactive derivative a salt thereof at tr. iir.ino group tnereot Process (III) (lb) or its reactive derivative or a salt thereof at the carboxy group cr a salt thereof Process 4 Cc) or lit there or ir a salt thereof process s -; (Ie) o ■ " a or a salt thereof Process 6 R 1 < If > dg) or a salt thereof or a salt thereof Process 7 - (Ig) (Ih) or a salt thereof or a salt thereof wherein Y, -A R 2 , R 3 and R 4 are each as defined above, X is lower alkylene, R is lower alkoxyphenyl (lower) alkyl or lower alkanoylphenyl, R is piperazinyl which has cyclopentyl or halophenyl; or thiomorpholinyl, R is acyloxy, o R is pyridyl (lower) alkylammo; N- (lower alkyl) -N- [pyridyl (lower) alkyl] amino; triazolyla ino; orpholinoamino; lower alkoxy(lower) alkylamino; bis [ (lower) alkoxy (lower) alkyl] amino; N- (lower al yl) -N- [ (lower) alkoxy (lower) alkyl] amino; imidazolyl; pyrazolyl; or 1, 2, 3, β-tetrahydropyridyl, 1,2,3, 4-tetrahydroisoquinolyl, 4, 5, 6, 7-tetrahydrothieno [3, 2-c]pyridinyl or saturated heterocyclic, each of which may have suitable substituent (s) , q R is lower alkanoyl, and W and W 2 are each a leaving group. As to the starting compounds (II) , (III) , (IV) , (V) , (VI) , (VII) and (VIII) , some of them are novel and can be prepared by the procedures described in the Preparations and Examples mentioned later or similar manners thereto. Suitable sains and pharmaceutically acceptable salts of the starting and object compounds are conventional non-toxic salt ana include an acid addition salt such as an organic aci salt (e.g. acetate, triflucroa etate, fumarate, maleate, tartrate, mεthanesulfonate, benzenesulfonate, formate, toluenesuifcnate, etc.) , an inorganic acid salt (e.g. hydrcchioride, hydrobromide, hydroicάide, sulfate, nitrate, phosphate, etc.), or a salt with an ammo acid (e.g. arginine, aspartic acid, glutamic acid, etc.) , or a metal salt such as an alkaii metal salt (e.g. sodium salt, potassium, salt, etc.) and an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.;, a ammonium salt, an organic base salt (e.g. trimethyiamine salt, tnethylaraine salt, pyπdme salt, picoline salt, αicyclohexyiamine salt, N, M' -dibenzyiethyienediamine salt, etc.) , or the like. In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention intends to include within the scope thereof are explained in detail as fo11cws . The term "lower" is intended to mean I to 6, preferably 1 to , carbon atom(s) , unless otherwise indicated. Suitable "lower alkylene" may include straight or branched one having 1 to 6 carbon atom(s) , such as metnylene, ethyiene, trimethylene, propylene, tetramethylene, methylmethylene, methyltrimethylene, hexa ethylene, and the li e, in which the preferred one is met ylene, ethyiene, trimethylene or methylmethylene. Suitable "halogen" and "halogen moiety" in the term "dihalocenzoyl (lower ) alkyl " and "halophenyl" may include fluorine, chlorine, bromine and iodine. Suitable "lower alkyl" and "lower alkyl moiety" in the terms "pyridyl (lowerj alkylamino (lowe ) alkyl", "pyridyl (lower) alkylamino (lower) alkenyl", N- (lower alkyl) -N- [pyridyl (lower) alkyl ] ammo (lowe ) alkyl", "tri zolyl mino (lower) alkyi", "lower al oxy (lower) aIky1amino- i lowe ■ alkyl" , "bis [ t lower) alkoxy (lower) alkyl] amino (lowe ) - alkyi", "N- (lower alkyi) -N- [ (lower) lkoxy ( lower) alkyi amino- (lower) al yl", "hydroxy (lower) lkyl", "lower alkyisuifonyloxy(lower) lkyl", "phenyl (lower) alkyl", "di ( lowe ! al ylaminocarbonyl" , "lower alkoxyphenyl (lower) - alkylcarbonyi", "benzoyl (lowe ) alkyl", "di (lower) alkylamino" , "benzoyl (lower ) alkyl" , "dihaiobεnzoyl (lower) alkyl", "di (lower) alkyibenzoyl (lower) alkyl", "3- luorobe zoyl (lower) lkyl" , "piperazinylcarbonyl (lower) - alkyi", ,; (2-pyridyl) (lower) alkyl", "imidazclyl (lower) alkyl" , "pyrazolyl (lower) al yl", "thiomorpholin 1carbony1 (lower) - al yl", " (3-azabicyclo[3.2.2] non-3-yl) carbcnyl (lower) al yl", "thienylcaroonyl (lower) alkyl", "1,2,3, 6- etrahydropyπdyl (lower) alkyl" , "1,2,5, -te rahydroisoquinolyl (lower; alkyl", "4, 5, 6, 7-tetrahydrothιeno [3, 2-clpyridinyl (lower) alkyl", "saturated heterocyclic (lower) alkyi", "saturated heterocyclicamino (lower) alkyl" and "lower alkoxyphenyl (lower) lkyl" may include straight or branched one having I to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, iscbutyl, pentyi, hexyl and the like, preferably one having 1 to 5 carbon atom(s) . Suitable "lower alkenyl moiety" in the terms "chloro (lower) alkenyl", "pyridyl (lower) alkylamino (lower) - alkenyl", "saturated heterocyclic (lower) alkenyl" and "saturated heterocyclicamino (lower) alkenyl" may include vinyl, 1- (or 2-)propenyl, I- (or 2- or 3-)butenyl, 1- (or 2- or 3- or 4- ,» pentenyl, l-(or 2- or 3- or 4- cr 5-)hexenyl, methyivinyl, ethylvinyi, l-(or 2- or 3-) methyl-1- (cr 2-)- propenyl, l- (or 2- or 3-) ethyl-1- (or 2- J propenyl, I- (or 2- or 3- or 4-)methyl- - (or 2- or 3-)butenyl, and the like, in which more preferable example may be C^ - ^ alkenyl. Suitable "lower alkynyl moiety" the terms "chloro ; lowe j alkynyl", " (3-pyridyl) ( lower) alkynyl", "1,2,3, 6-tetrahydropy idyl (lower) al ynyl", "saturated heterocyclic (lowerj lkynyl" and "saturated heterccyc lcamino (lower) alkynyl" may include ethynyi, l-propynyl, propargyl, 1-methyipropargyl, 1 or 2 or 3- butynyl, 1 cr 2 or 3 or 4-pentynyi, 1 cr 2 cr 3 cr 4 or 5- hexynyi and tne like, in which more preferable example may te C2~Cc, alkynyl. Suitable "aryl" may include phenyl, naphthyi, and the like, in which the preferred one is Cg-C-. Q aryl and the most preferred one is phenyl. Suitable "lower alkanoyl" and "lower alkanoyl moiety" in the terms "lower alkanoyla ino", "lower alkanoylbenzoyl" and "lower alkanoylphenyl" may include formyi, acetyi, propanoyl, butanoyi, 2-methylpropanoyl, pentanoyl, 2, 2-dιmethylproρanoyi, hexanoyl and the like. Suitable "lower alkoxy moiety" in the terms "lower alkoxyphenyl ■ lowe ) aikyicarbonyl" and "lower alkoxyphenyl ( lower) alkyl" may include ethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyioxy, t-pentyioxy, hexyioxy and the like. Suitable "saturated heterocyclic" and "saturated heterocyclic moiety" in the terms "saturated heterocyclic- lowe ) alkyl", "satura ed heteroc clic (lower) alkynyl", "saturated heterocyclicamino (lower) alkyi", "saturated heterocyclicamino (lower) lkenyl" and "saturated heterocyclicamino (lower) alkynyl" may include saturated 3 to 8-membered (more preferably 5 to 7- membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s) , fcr example, pyrrolidinyl, imidazolidmyi, piperidyl, piperazinyl, hexametnylenei mo, etc.; saturated 3 to 8-membereά (more preferably 5 or 6- membered) heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morphci yl, sydnonyl, etc.; saturated 3 to 8-membered (more preferably 5 or 6- me bered) heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolidinyl, thiomorpholmyl, etc.; saturated heterobicyclic group of the formula : I t) ( wherein /, m and n are each integer of 1 to 6 ) ; saturated heterobicyclic group of the formula - (wherein q, r, s and t are each- integer of 1 to 6) ; and the like Suitable "subεtitαent" m the terms "aryl which may have suitable substituent (s) ", "aryl or mdolyl each of which mav have suitable substituent (s) ", "thienylcarbonyl (lower) lkyl, 1,2,3, 6-tetrahydropyrιdyl (lower) alkyl, 1,2,3, 6-tetrahydropyrιdyl (lower) alkynyl, 1,2,3, 4-tetrahydroιsoqumolyl (lower) alkyl, 4,5,6, 7-tetrahydrothιeno [3, 2-c]pyrid yl (lower) alkyl, saturated heterocyclic (lower) alkyi, saturated heterocyclic- (lower) alkenyl, saturated heterocyclic (lower) alkynyl, saturated heterocyclicamino (lower) alkyl, saturated heterocyclicamino (lower) alkenyl or saturated heterocyclicamino (lower) alkynyl, each of which may have suitable substituent (s) " and "1,2, 3, 4-tetrahydroιsoqumolyl, 4, 5, 6, 7-tetrahydrothιero- [3, 2-c]pyridmyl or saturated heterocyclic each of which may have suitable substituent (s) " may include lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, outyl, isobutyl, tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, etc.) , cyclo (lower) alkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), lower alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, tert-butoxy, pentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, etc.), lower alkoxy (lower) alkyl (e.g., methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1-ethoxyethyl, 2-ethoxyethyl, etc.), lower alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, etc.) , lower alkenyl (e.g., vinyl, 1-propenyl, allyl, 1-methylallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, etc.), lower alkynyl (e.g., ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl, etc.), mono (or di or tπ) halo (lower) alkyl (e.g., fluoromethyl, difluoromethyl, tπfluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, 1 or 2-fluoroethyl, 1 or 2-bromoethyl, 1 or 2-chloroethyl, 1, 1-dιfluoroethyl, 2, 2-dιfluoroethyl, etc.), halogen (e.g., chlorine, bromine, fluorine and iodine) , carboxy, protected carboxy, hydroxy, protected hydroxy, aryl (e.g., phenyl, naphthyl, etc.), ar (lower) alkyl such as phenyl (lower) alkyl (e.g., benzyl, phenethyl, phenylpropyl, etc.) , carboxy (lower) alkyl wherein lower alkyl moiety can be referred to the ones as exemplified above, protected carboxy (lower) alkyl wherein lower alkyl moiety can be referred to tne ones as exemplified above, nitro, am o, protected amino, di (lower) alkylamino (e.g., dimethylamino, diethylammo, diisopropylamino, ethylmethylammo, isopropylmethylammo, ethylisopropylam o, etc.), hydroxy (lower) alkyl, protected hydroxy (lower) alkyl, acyl, cyano, oxo, mercapto, lower alkylthio (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.) , lower alkylsuiflnyl (e.g., methylsulfinyl, ethylsulfmyl, propylsulf yl, isopropylsulfinyl, butylsulfinyl, etc.) , im o, morpholmyl (e.g., 2-morpholmyl, 3-morpholmyl, morpholmo) , bivalent group of the formula : and the like. Suitable "leaving group" may include lower alkoxy (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, etc.) , aryloxy (e.g. phenoxy, naphthoxy, etc.) , an acid residue or the like. Suitable "acid residue" may be halogen (e.g. chlorine, bromine, iodine, etc.) , sulfonyloxy (e.g. methylsulfonyloxy, phenylsulfonyloxy, mesitylenesuifonyloxy, toluenesulfonvloxy, etc. ) or the like . Suitable "acyloxy" may include hydroxysulfonyloxy, lower alkylsulfonyloxy (e.g. methylsulfonyloxy, ethylsulfonyloxy, etc.) , phosphonooxy, and the like. Preferreα embodiments of the ooπect compound (I) are as fellows : Y is lower alkylene (more preferably ι -C Δ aikylene, mos t preferably methylene) ; R- is aryl (more preferably ^-C^ Q aryl, most preferably phenyl) which may have 1 to 3 (more preferably 1 cr 2, most preferably 21 suitable substituent (s) [more preferably mono(cr di cr tri) hale ; lower) alkyl (more preferably trihalo (lower) alkyl, most preferably trifluorcmethyi) ] ; R ~ is aryl (more preferably C--C-) Q aryl, most preferably phenyl or naphthyl) or indolyl each of which may ha ve I to ? (more preferably 1 or 2, most preferably 2) suitable substituent (s) [more preferably substituent selected from the group consisting of lower alkyl (more preferably C^ ~C Δ alkyl, most preferably methyl) , lower alkoxy (more preferably C-^-C^ alkoxy, most preferably methoxy) , mono (or di or tri) hale (lower) alkyi (more preferably mono (or di cr tri) halo (C- -C Δ ) alkyl, most preferably trifluoromethyl) and halogen (more preferably chlorine cr fluorine) ] ; R" is nydrogen; and A is chloro (lower) alkenyl (more prererably chloro (Co-C^ ) - alkenyl, most preferably 4-chlcro-2-butenyI) ; chicro (lower) alkynyl (more preferably chloro (C^-C^) - alkynyl, most preferably 4-chiorc-2-butynyl) ; pyridyl (lower) alkylamino (lower) alkyl [more preferably pyridyl (Ci -C Δ ) alkylamino (Cι_-C 4 ) alkyi, most preferably 2- r ! 3-pyridylmethyl) amino] ethyl, 2- [ ( -pyridylmethy1 ) - amino] ethyl or 3- [ (3-pyridylmethyl ) amino] propyl] ; pyridyl \lower) alkylamino (lower } aixenyl (more preferably cyriαyi (C- - Δ ) al ylamino (C -C 4 ) lkenyl, most preferabl 4- [ (3-pyridylmethyl) amino] -2-butenyl) ; - (lov/er alkyl) - - [pyridyl (lower) alkyl] amino (lower) alkyl [more preferably 1>!- ( C ^ -C alkyi) - - [pyridyl (C-, -C Δ ) - alkyi } amino ( C^ -C Δ ) alkyi, more preferably 2- [N-methyl-N- (3-pyridylmethyi) mino] ethyl] ; triazclyla ino (lower) alkyl (more preferably triazolylam o (C 1 -C 4 ) alkyl, most preferably 3- (1,2, 4- triεzoi-3-yiammo ' s propyl) ; lower alkoxy(lower) alkylamino (lower) alkyl (more preferably -C Δ alkoxy (C-^-C^) alkylamino (C- j _-C 4 ) alkyl, most preferably 2- (2-methoxyethyi) aminoethyl) ; bis i lowe ) alkoxy (lower) alkyl] ammo (lowe ) alkyl [more prefer bly bis [ (C 1 -C ώ )al oxy(Cι-C.)alkyl]amino(C 1 -C ! )- alkyl, most preferably 3- (bis (2-metnoxyethyI ; amino - propyl j ; N- (lower alkyl) - - [ (lower) al oxy ( lower) alkyi] amino- (lower) alκyl [more preferably M-tC^-C^ alkyl) - K- (Ci -C Δ ) alkoxy (C- j _-C ) alkyl] amino (C-j -C^ ) alkyl, most prefe ably 2- [N-methyl- - (2-methoxyethyl) amino] ethylj ; hydroxy (lower) lkyl (more preferably hydroxy- !Cι -Z Δ ) alkyi, most preferably hydroxypropyi) ; lov/er alkylsulfonyioxy (lower) alkyl (more preferably C -, . ~C Δ alkylsulfonylcxy(C- -C Δ ) alkyl, most preferably etnylsulfonyloxypropyl) ; phenyl (lower) alkyl (more preferably phenyl !C- F -C j alkyi, most preferably benzyl) which may have lower alkanoyl (more preferably Cι-C alkanoyl, most preferably acetyi) , amino, lower alkanoyiamino (more preferably C--C ! alkanoyiamino, most preferably aeetylam o) , di (lower) alkyiaminocarbonyi (more preferably di(Cι-C^)- alkyiaminocarbonyi, most preferably diethylaminocarbonyl) or nitre- lower alkoxyphenyl (lower) aikylcarbonyi (more preferably C- -C/, alkoxyphenyl (C-, -C 4 ) aikylcarbonyi, most preferably methoxyphenylmethylcarbonyi) ; lower alkanoylbenzoyl (more preferably C ^ - Δ alkanoylbenzoyl, most preferably acetvlbenzovl); 1 D benzoyl (lower) alkyl (more preferably benzoyl ( Z -, -Z Δ ) - alkyl, most preferably benzoyl ethyl) which has lower alkyi (more preferably Cη-C 4 alkyl, most preferably methyl) , chlorine or di (lowe i alkylamino (more preferably di { C 1 - ~C Δ ) alkylamino, most preferably dimetnylamino) ; cεnzoyi ; lower) alkyl (more preferably benzoyl ( C -, -C,. ) - alkyl, most preferably benzoylmethyl) which has halogen (more prεferably fluorine) and lower alkyl (more preferably alkyl, most preferably methyl) ; dihalobenzoyl (lower) alkyl [more preferably cinaiooenzoyi (C- -C 4 ) ai>:v- , most preferably (difluorobenzoyl ) methylj ; di ! lower) alkylbenzoyl (lower) alkyl [more preferably di (C 1 -C 4 ) alkylbenzoyl (C^-C^) lkyl, most preferably dimetnyibenzoyimethyl] ; 3-fiuorobenzoyl (lower) lkyl (more preferably 5- fIuorobenzoyl (C-i -C ) alkyl, most preferably 3- fluorobenzoylmethyi) ; 3- ( -fiuorobenzoyl) propyl; , -ethyienedioxy-4- (4-fiuorophenyl) butyl; oioeraz ylcarbonyl (lower) alkyl (more preferably piperazinylcarbonyl ) alkyl, most preferably piperazinyicarbonylmethyl) which nas cyclopentyl cr halophenyl (more preferably fluorophenyl) ; (2-pyridyl) (lower) alkyl (more preferably (2-pyridylι- (C -C 4 ' al yi, most preferably (2-pyridyl;methyl) ; (3-pyridyl) propyl (more preferably 3- (3-pyridyl) propyl) ; (3-pyridyI) (lower) alkynyl (more preferably (3- pyridyl) ( C- ? -C a ) alkynyl, most preferably 3- (3-pyridyl) -2- propynyl) ; imidazoiyi (lower) lkyl (more preferably imidazolyi- fCi -Z Δ ϊ alkyi, most preferably ' IH-ιmidazol-1-yl )methyl, ( lH-imidazol-2-yl)methyi or (iH-imidazol-4-yl) methyl) which may have lower alkyl (more preferably Cη -C^ alkyl, most oreferabiy methyl) ; pyrazolyl (lower) alkyl (more preferably pyrazolyl ( C - -Z ,-, ) - aik-'i, most preferably (IH-pyrazoi-4-yl)methyl or 3-(lH- pyrazcl-4-yi) propyl) which may nave lower alkyl (more preferably ^ - alkyl, most preferably methyl) ; tniomorpholinyicarbonyl (lower) lkyl (more preferably thiomcrphclinyicarbonyi (Cι_-C 4 ) alkyl, most preferably tniomorphciinylcarbonyimetnyl) ; < 3-azabicycl [3.1.2] non-3-yi , carbcnyl (lower) alkyl more preferably ( 3-azabιcycle [3.2.2 or.-3-yl ) carbcnyl : - ^) - alkyl, most preferably (3-azabicyclo [3.2.2 } non-3- yl: careonylmethyl) ; or thienyicarbonyi ( lower) alkyl (more preferably thiεnyicaroonyl (C- -C 4 ) lkyi, most preferably tnienylcarbonylmethyl) , I, 2, 3, 6-tetrahydropyridyl- (lower) lkyl (more preferably 1, 2, 3, 6-tetrahydropyridyl- ;c- -C Δ ) lkyi, most preferably 3- (1,2, 3, 6- tetrahyαropyrιdin-1-yl) propyl > , 1,2,3, 6-tetrahydropyridyl (lower; lkynyl (more preferably I, 2, 3, 6-tetrahydropyridyl (C^-C^) lkynyl, most preferably -- - [1, 2, 3, 6-tetrahydropyrιdin-l-yl; -2-butynyl) , 1, 2, 3, -tetrahydroisoquinoiyl (lower) alkyl i ore prefer bly 1, 2, 3, -tetrahydreιscquιnolyl ( Z ^ -Z ) alkyi, most preferably I, 2, 3, -tεtrahydroιsoquinciylpropyl j , 4,5,6,7-tetrahydrothiene[3,2-c]pyridinyl(lower) alkyl (more preferably 4, 5, 6, -r.etrahyάrocnιeno [3, 2-c] - pyriαinyl (C-| -C 4 ) alkyi, most preferably -. , 5, 6, 7- etrahycrothienc [3, 2-cj pyridinylpropyl ) , saturated heterocyclic (lower) alkyl (mere preferably saturated heterocyclic [ -Z j alkyl, more preferably saturated heterocyclicethyi or saturated heterocyclicpropyl, most preferably saturated heterocyclicpropyl; , saturated neterocyclic (lower; alkenyl (more preferably saturated heterocyclic (C-)-C 4 , alkenyl, most preferably saturated hεterccyclicbutenyi ) , saturated heterocyclic (lower) alkynyl (more preferably saturated heterocyclic (C^-C- ) alkynyl, most preferably saturated heterocyclicbutynyl or saturatea heterocyclicpentynyl, , saturated heterocyclicamino (lower; alkyl (more preferably saturated heterocyclicamino (C η -C , ; alkyl, most prererably saturated neterocyciicam opropyl) ,, saturated heterocyclicamino (lower) alkenyl (more preferably saturated heterocyclicamino (Co-d ) alkenyl, most preferably saturated neterocyclicaminobutenyi ) or saturated heterocyclicamino ;lower' alkynyl (mere preferably saturated heterocyclicamino (C -Ccj alkynyl, most preferably saturated heterecyclicaminobutynyl < [wherein "saturated heterocyclic moiety" is saturated 3 to -membεred (more preferably 5 to -membered) heteromonocyclic group containing 1 to 4 (more preferably 1 or 2) nitrogen atom(s) (more preferably pyrrciidinyl, piperidyl, piperazinyl or hεxamεthyleneimino, most preferably piperidyl) ; saturated 2 to 8-membered (more preferably 5 to 7- emxiered) heteromonocyclic group containing I or 2 (more preferably 1) oxygen atom(s) and I to 3 (more preferably 1) nitrogen atom(sj (more preferably morpholinyl or hcmomorpholinyl, most preferably morpholinyl) ; saturated 3 to 8-membered (more preferably 5 or 6- me bered) heteromonocyclic group containing 1 or 2 (more preferably 1) sulfur atom(s) and I to 3 (more preferably I) nitrogen atom(s) (more preferably thiomorpnolir.yl) ; or saturated heterocyclic group of the formula : (wnerein r , s ana art eaci as define above) ,mcre preferably 3-azabιcycio [3.2.2] non-3-yl) ] , eacn of which may have 1 to 3 (more preferably 1 or 2) suitable substituen (s) [more preferably substituent sεiεcted from tne group consisting of cycle ( lower) alkyi (more preferably cyclchexyl) , lower alkanoyl (more preferably Cη-C, alkanoyl, most preferably acetvl), lower alkvl ;more preferably C-^-C^ alkyl, most preferably methyl) , mono (or di or tri) halo (lower) lkyl (more preferably monohaio (C^-C 4 ) alkyl, most preferably fluoromethyl) , lower alkoxy (more preferably alkoxy, most preferably methoxy-) , lowεr alκoxy !lower) alkyl (more preferably alkoxy (C τ -C 4 ) alkyi, most preferably methoxymethyl) , halogen (more preferably chlorine) , aryl (more preferably phenyl' , cyano, oxo and bivalent group More preferred embodiments cf the obiect compound (I) are as follows : Y is lower alkyiene (more preferably Z Λ -C Δ alkylene, most preferably methylene) ; - ' -,-n υ R 1 ' is pnenyl which may nave 1 or z mcno(cr αi or tri) halo- dower) alkyl [more preferably bis ; rihalo (lower) alkyl) - phenyl, most preferably bis (trifluoromethyl) phenyl] ; R 2 = phenyl which may have 1 or 2 suitable substituent ( s ) selected from the group consisting of lower alkyi, lower alkoxy, mono (or a: or tri) halo (lower) alkyl and halogen u [more prεferably di (lower) iκylpnenyi, ,lower) lkoxyphenyl, [trinaio (lower) alkyl ]phenvl, [ lower) alkyi j halophenyl , haiophenyl or dihaiophenyl, meet preferably dimethylpnenyi, ethoxyphenyi, ■ rifiucrometnyi) pnenyi, methyifiuerophenyl, : _ucropnenyl cr dirluorcchlc: len l], naphthyl O 1" mαoiVi ; : 3 is nydrcgen; and Δ is morpholinyl (lowe ) alkyl which may have 1 or 2 lov/er alkyl (more preferably methyl, , hcmcmerphoimyl (lower; alkyl, thiomcrpholinyl (lower) alkyl, ,-hexamεthyler.eimmo) (lower) alky_ , ' 3-azabicycio [ 3.2.2] non-3-yl , (lower; alkyl, piperazinyl (lower; alkyl which may have phenyl or cyclo ( lower) alkyl (more preferably piperazinyl (lower) alkyl wnich nas phenyl or cyclohexyl), morpholinyl (lower) alkenyl which may have I or 2 lower alkyl (more preferably methyl), morpholinyl (lower) alkynyl whicn may have a substituent selected from the group consisting of lower alkyi 'mere preferably methyl), lower amox ( lower } alkyl (more preferably methoxymethyl , and mono; or αi or t i) halo ( lower; alkyi (more preferably fluoromethyl; , thiomorpholinyl ( lower) alkenyl , thiemorphoimyi (lower) alkynyl, pyrrolidinyi (lower) alkynyl which may have lower alkoxy ( lower) alkyl (more preferably methoxymethyl) . piperazinyl ( lower) alkynyl whicn may have cycle ( ower) alkyi (more prererably cyclohexyl) , morpholinylammo ( lower; al yi, marohoimylamino (lower) alkenyl, morpholinylammo (lower) alkynyl, cr piperidyl dower) alkyi which nay nave 1 or 2 suitable substituent (s; selected from the group consisting of bivalent group of the formula : f T" ]j , phenyl, cvano, lower alkanoyl, lower alkoxy, pipεndmyl, and oxo [more prefεrably [spiro [mαan-1, 4 ' -pipeπdme] -1 ' -yl] (lower) - alkvl, piperidyl (lower) alkyl which has phenyl, acetyi, ethoxy, piperioino or oxo, or piperidyl (lower, alkyl which has pheny- and cyano] . The Processes 1 to 7 for preparing tne object compound (I) of tne present invention are explained in detail m the folio Jinσ. f ee?" Tne object compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at tne irnmo group or a salt thereof with the compound (IV) or a salt thereof. Su_table reactive derivative at the irnmo group of the compound (I may include Schiff's case type immo or its tautomeric enamme type isomer formed by the reaction of the compoαrd (ID with a carbonyl compound sucn as aldehyde, ketone or the like; a silyi derivative formed by the reaction of the compound 'ID witn a siiyl compound such as bis (trimethylsilyl) acetamioe, mono (tπmethylsilyl, acetamide, bis (trimetnylsilyl) urea or the like; a derivative formed by reaction of the compound 'ID with phosphorus trichloride or pnosgene and tne like. Tne reaction is usually carried cut a conventional solvent such as water, alcohol [ε.g. mεthanol, εthanoi, etc.], acetonε, dioxene, acetonitrile, chloroform, methylene chloride, ethyiene chloride, tetrahydrofuran, ethyl acetate, N, N-αimethylformamide, pyridme or any other organic solvent which does not adversely influence the reaction. These conventional solvents may also be used m a mixture with water . Tne reaction may also bε cameo out the presence of an inorganic cr organic base such as alkali metal carbonate, alkali metal bicarbonate, tri dower; aikylamme, pyridme, \< τ - (lower) alkyimorpholine, , -dι dower; aikyibenzylamme, or the like. The reaction temperature is net critical, and the reaction is usually carried cut under cooling to heating. Process 2 The ccxεct compound da or a salt thereof can be prepared by reacting the compound (V, cr its reactive derivative at the carboxy group or a salt thereof with the compound (II) or its reactive derivative at the i ino group cr a salt thereof. Suitable reactive derivative at tne carboxy group of the compound (V 1 may include an acid haiide, an acid anhydride, an activated amide, an activated ester, and the like. The suitable example of the reactive derivative may be an acid chloride; acid azide; a mixed acid anhydride with 'id such as substituted phosphoric acid [e.g. dialkyiphospheric acid, phenylphosphoric acid, dipnenyiphosphoric acid, dibenzylphosphcric acid, haiogenated phosphoric acid, etc.j, diai yiphosphorous acid, lower alkanesuifonic acid [e.g. methanesuifonic acid, ethanesulfor.ie acid, etc.], sulfurous acid, thiosuifuric acid, sulfuric acid,, aliphatic carboxylic acid [e.g. acetic acid, propionic acid, butyric acid, isobutyric acid, pivaiic acid, valeric acid, isovaleric acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] or aromaticcarboxylic acid [e.g. benzoic acid, etc.] ; a symmetrical and anhydride; an activated amide with imidazoie, 4-substituted imidazole, aimethylpyrazole, triazolε or tetrazoie; or an activated ester [e.g. cyano ethyl ester, methoxymethyl ester, dimethyiiminomethyi [ (CH- 7 ~ =CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2, 4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, esyj-phenyl ester, phenylazopnenyl ester, phenyl thioester, p-nitrophenyl thioester, p-cresyi thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.], cr an ester with a N-hydroxy compound [e.g. X, rP-dimetr.ylhydroxylamme, l-nydroxy-2- (IH) -pyridone, h ' -hydroxysucc imide, N-hydrcxyphchalimide, 1-hydroxy-1H- benzetrlazele, etc.], ana the like. Zheεe reactive derivatives can optionally be selectee from them according to the kind of the compound (V) to be used. Zh reaction is usually carried cut in a conventional solvent such as water, alcohol [e.g. etnanoI, ethanol, etc.], acetone, dioxane, acetonitriie, chloroform, methylene chloride, ethyiene chloride, tetrahydrofuran, ethyl acetate, M,N-dimethyiformamide, pyridine cr any other organic solvent ;h. noes not adversely influence the reaction. These conventional solvents may also be used in a mixture with wa er . In this reaction, when the compound (V) is used in a free acid form or a salt thereof, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,K τ ' -dichiorohexylcarbodiimide; N-cyclohexyi-M' -morpholmoethy1carbodiimide; N-cycionexyl-N' - ( -diethyiammocycIohexyi) carbodiimide; N, ' -diethylcarbodiimide; N, M' - iisopropylcarbodiimide; M-ethyl- ' - (3-dimethyl minopropyl) carbodiimide; pentamethyieneketene-N-cyclohexyliminε; diphenyl eter.e-N-cyciohexyli me; ethoxyacetylene; 1-aikcxy-l-chlorcethylene; trialkyl phosphite; ethyl pclyphosphate; isopropyl polyphosphate; phosphorus cxychioride (phosphoryl chlcride) ; phosphorus trichloride; diphenyi phosphorviazide; thienyi chloride; oxalvl chloride; lower alkyi naloformafe [e.g. ethyl chiorofor ate, isopropyl chloroformatε, etc . ] ; triphenylphcsphine; 2-echyl-7- hydrcxybenzisoxazoliu salt; 2-ethyI-5- (m-sulfophenyl) - isoxazoiium hydroxide intramolecular salt; 1- tp-enlorooenzenesulfonyloxy ) -6-ch-oro-lH-benzotrιazoIe; 2-cnlcrc-. -methyipyridiniuir iodide; 1- (r-dimetnylammopropyl) -3-ethylcaroocιimide nyoroch orice; so-caliec. vilsmeier reagent prepared by tne reaction of N, - direthylformamide w-.tr. thιon _ cnioriαe, phosgene, trιcn_erometnyl chiorefor ate, phosphorus oxychloride, e:c; cr tne like. The reaction may also be carried cut the presence of a: in o rganic cr organic base suer. a- email metal carbonate, alkaii metal bicarbonate, tri :lowerj cdkvlamine, pyridme, X 1 - (lower; aI yimorpholme, H, N-di , lov/er' alkylbenzylam e, or me reaction temperature is net crιtιca_, ana the 'eaeticn is usually carried out under cooling to warming :ocess s The object compound (Ibi or a salt thereof can bε prepared by reacting the compound (III or its reactive derivative at tne carboxy group or a salt thereof with tne compound ( VI " or a salt thereof. Tne reaction mode and reaction conditions of this reaction are to oe referred to fnose as explained m Precess Process 4 Tne object compound (Id) or a salt thereof can be prepared by subjecting the cempound 'le 1 or a salt thereof t an acyiation reaction. Tne reaction can oe carried cut m the manner disclosed cess e Tne compound (le) or a salt thereon can oe prepared by reacting tne compound (Id, cr a salt thereof with tne compound (VII) or a salt thereof. This reaction is usually carried out in a solvent such as water, alcohol (e.g., ethanol, ethanol, etc.), benzene, X, X-dimefhylformamide, tetranydrofuran, toluene, methyiene chloride, ethyiene dichlorice, chloroform, dioxane, acetcnitriie, diethyl ether or any other solvents which do net adversely affect the reaction, or the mixture thereof. The reaction temperature is not critical and the reaction is usually carried out under cooling to heating. Zr. reaction may be also carried cut the presence cf :; inorganic or an organic base such as alkali metal (e.g., sodium, potassium, etc.) , alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.) , alkali metal hydrogencarbonate (e.g., sodium hydrogencarbonate, potassium hyercgencarbenate, etc.), alkali metal carbonate 'e.g., sodium caroonate, potassium carbonate, etc.), tri (lower) alkylam e (e.g., trimethyla ine, triethyiamine, diisopropyiethylamine, etc.), alkaii metal hydride (e.g., sodium, hydride, etc.), alkali metal (lower) alkoxide (e.g. sodium methcxide, sodium etnoxide, etc.) , pyridinε, lutidine, picoime, dimethylammopyridme, N- (lower) alkylmcrphoime, N, -di (lower) alkyibenzyiamine, N, M-αi (lowεr) aIkyIan line or the like. nen the basε and/or the starting compound are in liquid, they can be used also as a solvent. Process 6 The object compound (Ig) or a salt thereof can be prepared by subjecting the compound [If) or a salt thereof to a reduction reaction. Zr ' .e reaction can be carried out m the manner disclosed in Example 29 mentioned later cr similar manners thereto. Process 7 The object compound (Ih) or a salt thereof can be prepared by subjecting the compound (Ig) or a salt thereof to 20 aeyiaticr. reaction. Tne reaction can be carried out the manner disclosed m Ξxamp-e Id mentioned later cr similar manners thereto. 5 Th ^ object compound (I and a pharmaceutically acceptac-e salt thereof have Pharmacological activities such as Tacnv in antagonism, especia.r Substance P antagonism, Xeuro iinm X antagonism or Neurokm Ξ antagonism, and therefore ar÷ useful fcr treating er preventing Tαchyκ.nιn- I meα_ated diseases, partιcular_y Substance P-meoiated diseases, fcr example, respiratory diseases such as asthma, bronchitis 'e.g. chronic bronchitis, acute bronchitis end diffuse pannroncmolitis, etc.,, rnmιt-.≤, coαph, expecrorat-_t, and the like; 5 ophthalmic diseases such as con unct v_tιs, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis, and the like; inflammatory diseases suen as rheumatoid arthritis, 0 osteoarthritis, and tne like; pains or aches (e.g. migraine, headache, cluster heaαacne, tcethacne, cancerous pam, back pair., neuralgia, etc.; ; and the like. Further, it is expected tnat the object compound (I and 5 a pharmaceut-cally acceptable: salt thereof cf the present invention are useful for treating cr preventing ophthalmic diseases such as glaucoma, uveitis, and tne like; gastrointestinal diseases such as α cer, ulcerative colitis, irritable bo^el syndrome, food allergy, and the like; 0 inflammatory diseases such as nepnritis, anc tne lκe; circulatory diseases such as hypertension, angina pectoris, cardiac failure, thrombosis, Raynaud's disease, and tne like; epilepsy; spastic paralysis; pollakiuria; cystitis; bladder detrusor hyperreflexia; irinary incontinence; Parkinson 5 diseases; dementia; AIDS related dementia; Alzheimer's disεases; Town's syndrome; Huntmgtond chorea; carcmoid syndrome; disorders related to immune enhancement or suppression; disorders caused by Helicocacter pylon or another sciral urease-pcsitive gram-negative bacterium; sunburn; angiogenesis or diseases caused oy angiogenesis; and ne like. It is furthermore expected that tne object compound (I j ane a pharmaceutically acceptable salt thereof cf the present inventlor are useful for treating or preventing chronic obstructive pulmonary αiseases, particularly chronic pulmonary emphysema; iritis; proliferative vitreoretmopatny; psoriasis; inflammatory intestinal diseases, particularly Tronn's diseases; hepatitis; superficial pam on congelation, curn, herpes zoster or diabetic neuropathy; tenalgia attended to yper.ipiαe ia; postoperative neuroma, particularly cf mastectomy; vuivar vestibuiitis; hemediaiysis-associateo -tch ng; lichen pianus; laryngopharyngitis; bronchiectasis; coniosis; whooping cough; pulmonary tuberculosis; cystie fibrcsis; emesis; mental diseases, particularly anxiety, depression, dysthymic disorders and schizophrenia; demyelmatmα diseases such as mumipie sclerosis ana amyotrophic lateral sclerosis; attenuat_on of morpnmε withdrawal; oedema, such as oedema caused by thermal m ury; small cell carcinomas, particularly snail cell lung cancer 'SCLC) ; nypersensitivit disorders sucn as poison ivy; fibrcsmc ana collagen diseases such as scleroderma and eosmophilic fascioliasis; reflex sympathetic dystropny such as shoulder/hand syndrome; addiction disorders such as alcoholism; stress related somatic disorders; rneumatic diseases such as f brositis; and tne like. Furthermore, the object compound (I) and a pharmaceutically acceptable salt thereof of tne present invention are Central Nervous System (CNS) oenetrant. For therapeutic purpose, the compound (I) and a pharmaceutically acceptable salt thereof of the present invention can be used a form of pharmaceutical preparation containing one of said compound, as an active ingredient, m admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral, external including topical, enternal, intravenous, intramuscular, naiant, nasal, mtraarticula , mtraspmal, transtracheal or transocular administration. The pharmaceutical preparations may oe solid, semi-solid or solutions such as capsules, tablets, pellets, dragees, powcerr, granules, suppositories, ointments, creams, lotions, mnaiant;., injections, cataplasms, geis, tapes, eye droos, solution, syrups, aerosols, suspension, emulsion, or tna like. If desired, there may be included m tnese preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives. While tne dosage of the compound (I) will vary depending upon the age and condition of a patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mq, 500 mg and 1000 mg of tne compound (li may be effεctrve for treating Tachykmm-mediated diseases such as asthma and tne like. In general, amounts between 0.1 mg/booy and about 1,000 mg/body ma be administered per day. _n oroer to snow tne utility of the object compound (I) and a pharmaceutically acceptable salt thereof, tne pnar acologicai test data of some representativε compourds of tne present invention is shown in tne following. A. Evaluation cf NK-) antagonist transport efficiency tc the cental nervous system using a h-N -, rεceptor binding assay L - Test Method (1) Administration of test compound and extraction of thε compound from brain Male SL rats were given an i.v. injection of a solution containing a test compound (1 mg/kg) . 5 Min later the animals were anesthetized by ether, blεd and perfused through the aorta ascencens with 20 ml of saline. The brain was rapidly removed, weighed and homogenized in 4 vol. ice-cold distilled water by using Polytoron (KINEMATICA) . To extract tne test compound, 500 μi of the homogenate, 100 μl of methanol, 500 μi of C.l N NaOH and 4 ml of ethyl acetate were mixed by shaking for 10 min at room temperature. The organic phase (2.5 ml! was recovered by centnfugation at 3,000 rpm for 10 mm, dried and dissolved dimethyl suifoxide. (2) h-NK- | receptor binding assay (a) Cruoe CHO cell membrane preparation CHO cells permanently expressing h-NK-. receptors were harvested and homogenized with a Dcuncε homogεnizer at 4°C m a buffer (0.25 M sucrose, 25 mM Tπs-HCl (pH 7.4) , 10 mM MgCl-j, 1 mM EDTA, 5 μg/ml p-APMSF) . The homogenate was centrifuged (500 x g, 10 mm) , and the pellet was resuspended m the same buffer, homogenized, and centrifuged. The two supernatants werε combined and centrifuged (100,000 x g, 1 hour) . The crude cell membranes thus isolated were resuspended in a buffer (25 mM Tris-KCl (pH 7.4) , 10 mM MgCi 2 , 1 mM EDTA, 5 μg/ml p-APMSF) and stored at -80°C until use. (b) i-BH-Substance P binding to the prepared membrane Cell membranes (6 μg/ml) were incubated with ± -d ' -BK- Substance ? (0.1 nM) with or without the extracted compounds m 0.25 ml of a medium (50 mM Tris-KCl (pK 7.4) , 5 M MnCl , 20 μg/mi c.nymos atin, 40 μg/ml bacitracm, 4 μg/mi leupeptm, 5 μg/ml p-APMSF, 200 ug/ml BSAϊ at 22° for 90 mm. At the end of the incubation period, the contents were quickly filtered tnrough a Blue Mat 11740 filter (pretreated with 0.1 polyethylenimme for 3 hours prior to use) by using SKATRON Ceil harvester. The filter was then washed with a washing buffer (50 mM Tris-KCl (pH d4 ; , 5 mM MnCi 7 ) . The radioactivi y was counted by s g an auto gamma counter v ackard RIA3TA? 542CA . Ail data presented are specific binding defined as that displaceable by 3 μM ur.laoeled Substance P. [II] Test Pesuit All of the following Test Compounds showed more than 80 mn_bitιcn rate of I-3H-Substan.ee P binding to h- K^ receptors at the dose of I mg/kg. Test Compounds : The object compounds of the Examples 7, 11, 12, 22, 23, 24- (2) , 26, 35, 3D, 37-(2;, (4) , (5) , (6) , (8), 44-(d , d', d), (5) , (7) , 46, 47, 51, 52-d, , 53-(lj, 54, 55, 58, 59-(i), (3) , 62-(l) , 67-(4), (5, , (6), (7) , (13) , 71, 72, 73, 74, 75, " d, 77, 81, 82-{l) , 82-(4), 82- (5) , 82-'7), 82-(8, , 82-(9) , 82-(10) , 82- (12) , 84- (I l and 86 3. Emesis in the ferret [I] Test Method Individually housed adult male ferrets (Marshall Farms, 1.4 to 2.2 kg) werε given an i.p. injection of a solution ccntatmmg a test compound. 30 Mm later the emetic responses (retching and vomiting) were induced by administration of mtra-gastπc copper εulfate (40 mg/kg/ml) ano observed ror the next 30 mm. The timing ana number of retches and vomits observed were reccrded for each animal. An moιv_deul an.iral was tested with at least 10 days between experiments . [II Test Result All cf tne following Test Compounds snowed 100' 1 inhibition rate of emes-s in the ferret at the dose of 3.2 anα/c: 1' " c/ kg. Test compounds : The object compounds of the Examples 11, 22, 22, 24- (2) and 37- (5), (6) The following Preparations and Examples are given for the purpose cf illustrating this invention. (to be continued on the next pagξ Example 1 A mixture of (2R) -1- [3, 5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-yimethyi) piperazine (5 g) and 3-bromoproρanol (1.68 g) in N,N-dimethylformamide (40 ml) was heated at 60°C m the presencε of potassium carbonate (4.55 g) . After 9 hours, the reaction mixture was poured into water (400 mi) and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium suifate. After evaporation of the solvent, the obtained residue was purified by column chrcmatography en sidica gel using dichloromethane- methanol (30 ) as an eluent to give (2R)-l-[3,5- ois (trifluoromethyl) benzoyl j -4- ( -hydroxypropyl > -2- (IH- doi- 3-yimetnyi) piperazme (5.36 g, as a powαer. IP. (Neat) : 3600-3100, 1625, 1275, 1170, 1123, 898 cm -1 MR (DMS0-d 6 , δ) : 1.6-5.0 (16K, mj ; 6.6-8.2 (8H, ) ; 10.34 (IE, s ) MA-SS : 514 (M-d) , 454 Example 2 Zhe following compound was obtained according to a similar manner to that of Example 1. (2R)-I-[3,5-3is (trifluoromethyl) benzoyl } -2- (3, 4- dimethylbenzyl) -4- (3-hydroxypropyi) piperazine IR (Nujcl) : 3400 (br) , 3000-2700, 1625, 1430, 1270.. 1120 cm -1 NMR (DMS0-d 6 , δj : 1.55-1.75 (2H, m) ; 2.05-..9 (19H, m) ; 6.5-8.2 ( 6H, ) MASS : 503 (M+l) Example 3 A mixture of (2R! -1- [3, 5-ois (trifluoromethyl > benzoyj j -2- (lPX-indoi-3-yimethvl ! piperazine (C.3 g) , 2-bromc-4'- chioroacetcpnenone (0.2 g,ι and potassium carbonate (0.16 g) m N,N-oimethylformamide (5 ml) was stirred at room temperature for 1 hour and 20 minutes. The reaction mixture was poured into water (20 ml) and extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. After evaporation cf the solvent, tne obtained residue was purified by column chromatography on silica gel using toluene-ethyl acetate { Δ . : I ) as an εluent. Practices containing objective compound were collected and concentrated under recucec pressure. Tne obtained product was dissolved m ethyl acetate, treated idth 4N hydrogen chloride m ethyl acetate solution ane then evaporated under reducεd pressure. Tne residue was triturated with n-hexanε to give (2R; -1- [3, 5-bιs (trifiuoromefnyl)benzoyl] -4- (4- chioropnenylcarbonyimethyl) -2- (lK-mdol-3-ylmethyl) piperazine nydrcchloride (0.31 g) as a powder. mp : 140°C (dec.) [α]f j C : -22.6 3 (C=0.5, MeOK) I? (XXα oi, : 3500-3100, 2700-2150, 1690, 1635, 1275, 1100 c " ' MF (TMSO-d 6 , δ) : 2.9-5.3 dlH, m) ; 6.4-8.3 (12H, m) ; 10.7-11.05 (2H, m) MASS : 608 (M+l) (free) Example 4 The following compound was obtained according to a similar manner to that of Example 3. (2Ri-i-[3,5-Bιs (trifluoromethyl) benzoyl] -4- ( 5-chioro-2- thienyl ) carbonylmethyl] -2- (lH-mool-3-ylmethyl) piperazine nydroch1cridε [α]§° : -55.2° (C=0.5, MeOH) IR (Neat) : 2^00-3100, 2700-2150, 1635, 1415, 1275, 1130 cm ~ - NMR (DM3ϋ-d 6 , δ) : 3.0-5.2 (IIH, m) ; 6.8-8.3 (10K, m) ; 1C.9 ~ (IH, s) MASS : 651 (M+l) (free), 614 Examplε 5 A mixture of (2R) -1- [3, 5-bis (trifluoromethyl) benzoyl] -2- (IH-indol-3-ylmethyl) piperazine (C.3 g) , 2-bromo-3'- fiuorcacetophenone (0.19 g; and potassium carbonate (0.16 g) m N, X τ -d-umethylformamide (5 ml; was stirred at room temperature fcr 1 hour and 20 minutes. The reaction mixture was poured into water (20 ml; and extracted with etnyl acetate. The organic layer was washed with water and dried over magnesium sulfate. After evaporation of the solvent, the resulting residue was purified by column chromatography on. silica gel using toiuene-etnyi aeetate (2d) as an eluent. The obtained product was dissolved in ethyl acetate (2 ml) and treated with 4M hydrogen chloride ethyl acetate solution (164 μl) . The resulting precipitate was collected by filtration and dried at 50 C C for 5 hours tc give (2R) -1- [3, 5-bis (trifluoromethyl) benzoyl 1 -4- (3- fluorcphenyicaroonylmethyl) -2- (IK-indol-3-ylmethyl) piperazine hydrochioride (C.2 g) as a powder, mp : 195"C (deed IP (Nujci) : 3200, 2650-2200, 1695, 1655, 1270, 1125 cm-- NMR (DM50-d , δ) : 3.3-5.3 (11H, ) ; 6.6-8.3 (12K, ml ; J 0.8-11.4 (2H, m) MASS : 592 (M+l) (free) Anal. Calcd. for C^ Q .hd^FdN & HCi : C 57.38; H 4. CI; N 6.69 Found : C 57.23; H 3.79; N 6.49 Example 6 The following compounds were obtained according to a similar manner to that of Example 5. (1 ) (2R) -1- [3, 5-3is (trifluoromethyl) benzoyl] -4- (3, 4- difluorophenylcarbonylmethyl) -2- ( lH-indoi-3- yimethyi) piperazine hydrochlorice o : 171°C (dec.) [ ]? 0 : -31.6° (C=0.5, MeOH) IP (Nujcl) : 3550-3100, 2650-2150, 1690, 1640, 1510, 1275, 1130 cm -1 NMP (DMSG-d 6 , δ) : 3.0-5.3 (IIH, ) ; 7.6-8.3 (11H, m) ; 10.7-11.o (2H, m; MASS : 610 (M lj (free) Anal. Calcd. for C3 Q H23FgX C2-HCl : C 55.78; H 3.74; N 6.50 Found : C 55.54; H 3.72; N 6. 1 (2 i (2R) -1- :[3, 5-Bi (trifluoromethyl) benzoyl j -2- ( lH-mdol-3- yi etnyl) -4- (4-methylphenyicarbonylmethyi) piperazine hydrochloride mp : 2C2°C (dec.) IR (Nujcl) : 3550-3100, 2650-2150, 1690, 1640, 1280, 1175, 1125 cm-- NMR (DMSO-d 6 , δ) : 2.43 (3H, s) ; 3.1-5.3 (IIH, m) ; 6.8-8.3 (12H, ) ; 10.8-11.2 (2H, m; MASS : 537 (M+l) (free) d) (2?0-l-[3,5-3is (trifluoromethyl)benzo lϊ -4- (3, 4- dimetnyiphεnylcarbonyimethyi; -2- (lH-indol-3- yimefnyi) piperazine hydrochloride p : lc6°C (dec.) L ' α] __ 5 : -36.3° (C=0.5, MeOH) IP. (Nujcl) : 3600-315C, 2700-2300, 1685, 1635, 1275, 1130 c "1 NMR dMSO-d δ , δ) : 2.34 (6H, s) ; 3.2-5.3 (IIH, ) ; 6.6-8.3 (UK, m) ; 10.6-11.2 (2H, m) MASS : 601 (M-l (free) Anal. Calcd. for C32H2 F fe I\ τ 3 0 9 -HCI-l .1H ? 0 : C 58.42; H 4.93; N 6.39 Found : C 58.46; H 4.90; N 6.27 (4; (2R)-l-ι3,5-3is (trifluoromethyl) benzoyl] -4- d-fluoro-3- methylphenylcarbonyl ethyl) -2- (lH-mαol-3- ylmethyi) piperazme hydrochicriαe ; } 5- : -28.8° [Z=0.5, MeOH, I? (Nujcl) : 3600-3100, 2700-2200, 1685, 1635, 12 5, 1130 cm -1 NMR (PMSO-dg, δ) : 2.34 (3H, ε) ; 3.1-5.3 (IIH, ) ; c .6-8.3 d1K, ' ; 1 .7-11.2 ( H, , MASS : 606 (M-d ) (free) Example n A mixture of (2R) -1- [3, 5-oιs (trifluorometnyl) benzoyl -2- ( lH-ιnccl-3-yimethyl! piperazme (228 mg; , l- 4- dromcmethyij phenyl] ethanonε (107 mg) and potassium carbonate '42 mg) acetcnitrile (2 mi) was refiuxed for 4.5 hours. After cooling, the mixture was evaporated in vacuo. Ethyl acetate and wafer were addεa to the residue and the organic layer was separatee, washed with brine, dried over magnesium suifate, and evaporated m vacuo. Tne residue was purified by column cnromatography on s lica gel with a mixture of dichlcrometnane and metnanci as an eluent to give (2R>-4-'4- acet lbenzyl) -1- [3, 5-bis ( rifluoromethyl) benzoyl] -2- (1H- inαoi-3-yimethyij piperazine (0.30 g; . To a solution cf this piperazine (0.30 g) m ethyl acetate was added 4N hydrogen, chloride m etnyi acetate solution. d.13 ml) and tne whole was evaporated m vacuo. Tne residue was triturated with a mixture of ethyl acetate and ether to give (2R)-4-(4- acetyioer.zyi ■ -1- [3, 5-bis (trifluorometnyl) oenzoyi] -2- { 1H- ihdcI-3-yimethyl; piperazme hydrochloride (283.3 mg) as a powder . mo : if2d (dec.) [α] 0 -30.0° (C=0.27, MeOH) 3350, 1675, 1655, 1635, 1610, 1275 c 1 'CDC1 δ) : 2.36-5.60 (IIH, m) ; 6.10-9.30 (13H, m) ; 12.90 (IH, or s) MASS : 588 (M) (free) Example « A mixture of (2R) -1- [2, 5-bis (trif uoromethyl) benzoyl] -2- ( IH-mooI-3-ylmetnyI) piperazme (0.3 ς) , 2-bromo-4'- dimethylammoacetophenone (0.2 g) and potassium carbonate (0.16 gι in N, -dimethylformamide ml; was stirred at room temperature fcr 2 Incurs. The reaction mixture was poured into 'water (20 ml) and extracted with ethyl acetate. The organic layer was washed with water and dried over magnesium suifate. After evaporation cf the solvent, the resulting residue was purified by column chromatography on silica gel using tcluenε-ethyl acetate (2d) as an eluent . Fractions containing objective compound were coliectεd and evaporated under reduced pressure to give (2R)-l-[3,5- bis (trifluoromethyl)benzoyl]-4-(4-dimechyiarιmophenyI- carbonyimethyl) -2- (lH-indol-3-yimεthyl) piperazine (0.26 g) . mp : 185°C (dec. ) [cx]g C : -44.6° (C=0.5, MeOH) I ΪNu oi) : 3300, 1650, 1590, 1290-1150 cm -1 NMR (DMSO-d 6 , δ) : 2.05-4.9 (IIH, m) ; 3.03 (6H, sj ; 3.2 (12H, ) ; 10.80 (IH, s) MAS! Examp e 9 A mixture cf (2R) -1- jd, 5-bis (trifluoromethyl) benzoyl] -2- (3, -dichicrobenzyl) piperazine hydrochloride (200 mg) , 4-nιtrobenzyi chloride (158 mg) and triethylamine (268 μl) in netrahydrcfuran (5 mi) was refiuxed overnight. After cooling, tne precipitates were filtered off and the filtrate was evaporated vacuo. The residue was purified by column J 8 chromatography en silica gel with a mixture of toluene and ethyl acetate as an eluent to give (2R)-l-[3,5- bis (trifluoromethyl)benzoyi -2- (3, -dichiorobenzyl) -4- (4- nitrobenzyl ) piperazme (169.8 mg) . I? (Neat; : 3100-2750, 1770, 1730, 1635, 1520, 1440, 1340, 1275, 1130 cm -1 NMR (CMSO-d-, δ, : 2.1C-5.4G (IIH, m) ; 6.85-8.20 (10H, ) Example 10 The following compound was obtained according tc a similar manner tc that of Example 5. (2R)-l-[3,.5-Bis (trifluoromethyl) benzoyl] -2- (3, 4- di ethylbenzyl) -4- (4-nitrobenzyl) piperazme IR (Neat) : 3100-2750, 1633, 1515, 1430, 1340, 1275, NMR (DMSO-d 6 , δ) : 2.00-4.85 (17H, m) ; 50-3.10 (10H, m) MASS 580 [M÷l. Example 11 To a mixture of (2R) -1- [3, 5-bis (trifluorometnyl ) - benzoyl] -2- (3, 4-dimethylbenzyi) piperazine (0.25 g) and 4- acetyioenzoic acid (0.09 g) m dichlorom.ethane (3 ml) was adoed triethyiamine tθ.2 ml) at room temperature. 2-Chioro- l-methylpyridinmm iodide (0.1" g) was added, and the mixture was stirred at room temperature for 2.5 hours. The resulting mixture was concentrated under reduced pressure and the residue was oartitior.ee between εtnyi acetate ana water. The organic layer was washed with aqueous sodium bicarbonate solution anc cried over magnesium suifate. After evaporation cf the solvent, the residue was purified by column chromatocraonv using ethyl acetate - n-hexane (Id) as an eluent tc afford (2R) -4- ( -acetyibenzoyi) -1- [3, 5- bis (trifluoromethyl) benzoyl] -2- (3, 4-dimethylbenzyl) piperazinε d.31 g) . NMR (DMSC-dc, δ) : 1.9-2.4 (3H, m) ; 2.5-5.2 (10H, m) ; 6.4-8.2 (10K, m) MASS : 5 1 (Mr1) Example 12 To a mixture of (2R) -1- [3, 5-bis (trifluoromethyl) - benzoyl] -2- (3, -dicnlerobenzyl) piperazme hydrochloride (200 mg, and 4-acetyIbenzoic acid (57 mg) in dichloromethane (5 ml) was added triethyiamine (l " i ui ) at room temperature. 2- Chiorc-1-mεthyloyridinιum iodide (107 mg; was added, and the mixture was stirred at room temperature for 1.5 hours. The resulting mixture was washed successively with aqueous 0. IN hydrogen chloride solution, aqueous saturated sodium hydrogen carbonate solution and brine, and dried over magnesium suifate. After evaporation of the solvent, the residue was purified by column chromatography using toluene-ethyl acetate dd) as an eluent to give (2P) -4- !4-acetyIbenzoyl -1- [3, 5- bis ( rifluoromethyl) benzoyl1 -2- (3, -dichlorobenzyl)piperazine d53 mg) . d]2.° : 11.2" (C=0.5, MeOH) IR (Neat) : 3100-2850, 1685. 1630, 1440, 1275, 1130 cm ""1 NMR (2MSO-d 6 , δ) : 2.15-5.15 (9H, m) ; 2.62 (3H, s) ; 6.P-8.3 (10K, m) MASS : 633 (M+2) , 631 .deal. Calcd. for C 29 H 22 F 6 Ci 2 N 2 C 3 : C 55.17; H 3.51; N 4.44 Found : C 55.22; H 3.53; N 4.28 Ex mple ' : 5 (2R; -1- [2, 5-Bis (trifluoromethyl;benzoyl] -2- (3, 4- dimethylbenzyi) piperazine fumarate (785 mg) was added to a mixture of 2N sodium hydroxide solution (5 ml) and ethyl acetatε. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give (2R) -1- [3, 5-bis (trifluoromethyl) benzoyl] -2- (3,4- dimethylbenzyl; piperazine . A solution of this piperazine in N, N-dimethyiformamide (7 ml) was added to a mixture of 2- acetylbenzcic acid (230 mg) , 1- (3-cimethyiammoprepyi) -3- ethylcarbcdii ide hydrochloride (295 mg; and 1- hydroxybenzotriazoie (208 mgϊ in N,X-dimethyiformamide (3 ml) and the whole was stirred at room temperature overnight. The mixture was poured into a saturated sodium hydrogen carbonate solution '7 ml) and the resulting precipitates were fiiterεd off. The filtrate was evaporated vacuo tc give (2R)-4-(2- acetyloenzeyi) -_- [3, 3-bis (trifluorome hyl ) benzoyl] -2- , 4- dimethylbenzyl) piperazine (0.45 g) as a powder, mp : 82-85°C [ ] ^ 9 : -22.7° (C=0.32, MeOH) IR ;CH 2 C1 9 , : 1750, 1635, 1615 cm " : NMR (CDC1 3 , δ) : 1.75-5.40 (I8H, m) ; 6.40-3.10 (1OH, m) MASS : 591 (M) Example 14 Tne following compound was obtained according to a similar manner to that of Example 13. (2R, -4 - ■ 3-Acetvlbenzovl ; -1- [3, 5-bis drifluoromethyl ) - benzoyl ] -2- (3, 4-dimethylbenzyl ) piperazine mp : 155.5-157d ' α -χ : 5 - 8 ° !C=0.26 / MeOH ) IR (Nujol) : 1683, 1630 cm -1 NMR (CDCI3, δ) : 2.05-2.32 (6H, ) ; 2.63 (3H, s); 2.70-5.40 (9H, ) ; 6.40-8.15 (10H, m) MASS : 592 (M-l) Example 15 To a stirred mixture cf (2R)-I-[3,5- bis (trifluoromethyl) benzoyl] -2- (lK-indoi-3-ylme hyi ) - piperazine (250 mg) , 2-methcxyphenylacetic acid (92 mg) and i-nydroxynenzotriazole (75 mg) m dichlorom.ethane (8 ml) was added 1- (3-dimethyiammopropyl) -3-etnyicarbodiimide hydrochloride (105 mg) at room temperature. After 3 hours, tnε react!en mixture was poured into aqueous sodium bicarbonate solution and extracted with dichlorcmethane. The extract was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel using ethyl acetate - n-nexane (id.5) as an eluent to give (2R)-l-[3,5- bis (trifluoromethyl)benzoyij-2-(lH-indoi-3-yimethyl) -4- (2- methoxyphenyimethylcarbonyl) piperazine (290 mg) as a powder. NMR dM50-d 6 , δ) : 2.6-5.0 (14H, m) ; 6.4-8.2 (12H, ) ; 10.8 (IH, m) MASS : 604 (M+I ) Example 16 The following compounds were obtained according to a similar manner tc tnat of Example 15. ( 1) (2R) -4- (3-Acetyibenzoyl) -I- [3, 5-bis (trifluoromethyl) - benzoyl] -2- (lH-indol-3-yimethyl) piperazine mp : 136-187.5d r „. : " > 4.2- (C=0.29, MeOH) IR (Nujoi: : 2260, 1690, 1638, 1600, 1275 cm -1 NMR (CDC1 3 , δ) : 1.55-5.46 (12H, m) ; 6.55-8.50 (13H, rr.) MASS : 602 (M) (2) (2R) -4- (2-Acetvlbenzovl) -1- [3, 5-bis (trifluoromethyl) cenzoyi] -2- (lH-indoi-3-yimethyl) piperazinε mo : 190-192d 28 C=0.28, MeOH) IR (Nujol) : 3300, 2700, 1750, 1720, 1635, 1630, 1275 cm -1 NMR (CDC1 3 , δ) : 1.46-5.45 (12H, m) ; 6.54-3.25 (13H, m) MASS : 602 (M) Example d To a stirred mixture on (2R)-i-[3, 3- bis ;trifluoromethyl)benzoyl]-4- (carbo ym.ethyl) -2- ( lH-mdoi-3- yimethyi ) piperazine (0.4 g) and tniomorpholme (0.08 g) in- dry N, N-dimethylformamide (4 ml) were added I- (3- dimethyiaminopropyl) -3-ethylcarbooiimιde hydrochloride (0.16 g, and 1-hydrcxybenzctriazole (0.12 g) at room temperature. After 3 hours, the reaction mixture was poured into aσueous sodium bicarbonate solution (40 ml) and the resulting precipitate was collected by filtration. The crude product obtained was purified by column chromatography on silica gel using tciuene-ethyl acetate (Id) as an eluent to give (2R)- l- 3,5-bιs(trifluoromethyl) benzoyl ] -2- ( lH-indol-3-ylmethyl) - 4- (thiomorpholmocarbcnylmethyi) piperazme (0.42 g) . α] f d : -10.0° (C=0.5, MeOH) IR (Neat) : 3650-3100, 1634, 1274, 1170, 1122, 898 cm -1 NMR dMSO-d.-, δ) : 2.00-5.00 (19H, m) ; 6.60-3.20 (8H, s) MASS : 599 (M-l) Example 8 The following compound was obtained according to a similar manner tc that cf Example id (2R)-l-'[3,5-Bis (trifluoromethyl) benzoylj-4-[ { - i - ) -1-piper zinyl) carbonylmeth y lj -2- (lH-indol-3- ylmetnyl) piperazine hydrochloride mo : 133d (dec.) IR (Nujod : 3600-3100, 2650-2150, 1680-1580, 1510, 1275, 1133 cm -1 NMR (DMSO-d 6 , δ) : 3.05-5.15 (19H, m) ; 6.6-8.3 (12H, rX ; 10.40 (2H, br s) ; 11.02 (IH, s) Example 15 To a stirred mixture of (2R)-l- 3,5- bis (trifluoromethyl) benzoyl] -4- (carboxymethyi) -2- (lH-mdoi-3- yimetnvl i Piperazine (200 mg) and 4-cyciopentylpiperazine (60 m l in dry M, N-dimεtnyiformamide (5 ml/ were added l-(3- dimethvdaminopropyl) -3-ethyicarbodiιmide hydrochloride (82 mg and 1 -hydroκybenzotriazoie (58 mg) at room temperature. After 7 hours, the reaction mixture was poured into water (30 ml) and extracted with ethyl acetate. The extract was washed with water and dried over magnesium suifate. After evaporation cf the solvent, the residue was purified by column cnrcmatography on silica gel using dichloromethane- methanol (10:1) as an eluent and then treated with 4N hydrogen chioride m εthyi acetate solution (80 μl) to give (2R) -1- [3, 3-bis (trifluoromethyl) benzoyl] -4- ' {4-cyclopentyl-1- eiperazmyl) carbonylmethyl] -2- (lH-indol-3-ylmethyi) piperazine hydrochlorice (140 mg) . mp : 270 β C (dec.) [α j z : -24.2° (C=0d, MeOH) IR (Nujcl) : 3270, 2430-2150, 1630, 1275, 1180, 112r cm. ^ NMR (BMSO-d~, δ) : 1.45-5.0 (28H, m) , 6.55-8.25 (8H, m) ; 10.90 (IH, s) ; 11.21 (2H, br s) 'J3"-J / ~ £- C 5 ^d H 5.58; N 10.21 bound : C 57.91; H 5.64; N 10.18 Exampl e 2 X. solution cf methanesuifonyl chloride (id g) in dichiorometnane (4 mi) was added tc a stirred solution of (2R) -1- [3, 5-bis (trifluoromethyl) benzoyl] -4- (3-hydroxypropyl) - 9. ( lH-mdcl-3-yimethyl ; piperazine (4.99 g) and triethvlamine (1.1 g) m dichiorometnane (50 mi) at ice-bath temperature over a 20-m.mute period. After being stirred at tne same temperature for 1 hour, the reaction mixture was diluted with dichlcrometnane (50 ml) and then washed with water and aqueous sodium bicarbonate solution. The dichiorometnane layer was dried over magnesium suifate and concentratεd under reduced pressure. The residuε was purifiεd by column cnrcmatography on. silica gel using dicnloromethane-metnanol (30 d) as an eluent to give (2R)-l-d,5- bis (trifluorome hyl/benzoyl] -2- (lH-indol-3-ylmethyi ) -4- (3- methylsulfonyloxypropyl) piperazine (4.31 g) as a powder. MASS : 592 (M-d) Example 21 The following compound was obtained according tc a similar manner to that cf Example 20. (2R) -1- [3, 5-Bis (trifluoromethyl) benzoyl] -2- (3, 4- dimethyibenzyi) -4- (3-methylsulfonyloxypropyl) piperazine IR (Nujoi) : 2950-2700, 1035,. 1430, 1350, 12^5, 1165, 1125 cm-- NMR (CMSO-d^, δ) : 1.8-4.95 '19H, n) ; 3.19 (3H, s) ; 4.31 [2H, t, J=ό.2Hz) ; 6.95-8.2 (6H, m) MASS : 581 (M-l) Example 22 A mixture cf (2R) -1- [3, 5-bis (trifluoromethyl) benzoyl J -2- (lH-mdoi-3-yimethyl) -4- (3-methylsulfonyloxypropyl) piperazine (0.2 g; , 3-azabicyclc [3.2.2] nonane (0.05 g) and triethvlamine (0.09 mi) in N, N-dimethylformamide (1 mi) was heated at 80 c After 6 hours, the reaction mixture was pourec into water (10 -1 ) Λ:nd the resulting precipitate wai lollected bv filtration. The crude product was dissolved in ethanol (2 mi) and then treated with 17.61 hydrogen chloride ethanol solution (0.3 ml) to give (2R) -4- [3- (3-azabicyclo [3.2.2]non- 3-yl) propyl ] -I- d, 5-bis (trifluorometnyl) benzoyl1-2- ( IH-mdol- S-ylmetnyi) piperazme dihydrochioricε (0.12 g ( as a powder. p : 194-202°C [α]fd : -6.0° (C=0.2, MeOH) I? (Nujol; : 3600-3100, 2750-2000, 1680-1550, 1275, 1172, 1126, 900 err -1 NM? (DMSO-d-, δ) : 1.50-5.20 (29H, m) ; 6.60-8.25 (6H, .) ; 9.80 (IK, b: b I 1 96 (IH, s) ; II .60 (IH, br Example 23 A mixture of (2R) -1- [ 3, 5-bis (trifluoromethyl) benzoyl] -2- ;lH-indol-3-ylmethyl) -4- ( 3-methylsulfonyloxypropyl) piperazine (0.2 g) , tniom.orpholine (C.042 g) and triethvlamine (0.09 mi) m dry acetcnitrile (2 ml) was stirred at 90°C fcr 15 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and water. Zhe organic layer was washed with brine and dried over magnesium suifate. After evaporation of tne solvent, the residue was purified by column chromatography on silica gel using ethyl acetate-methanol (10:1) as an eluent to give (2R) -1- ] 2, 5-bis (trifluorometnyl) benzoyl] -2- ( IH- doi- 3-ylm.ethyi; -4- (3-thiomcrpholmopropyl) piperaz e. The product obtained was dissolved in ethanol and treated with 17.5 " hydrogen chloride in ethanol solution to give (2R)-1- [3, 5-bis (trifluoromethyl) benzoyl] -2- (lH-mdoi-3-yimethyI ) -4- (3-thιcmorphcimopropyl; piperazine dihydrochloride (0.19 g) as a powder. [α] 2 ) 0 : -4.5° (C=0.5, MeOH) IR (Nujol) : 3650-3050, 2750-1980, 1635, 1274, 1170, o 1123, 900 cm -1 NMR (DMSO-d 6 , δ) : 2.20-2.20 (23H, m) ; 6.50-8.25 (8H, ) ; 10.96 (IH, s) ; 11.00-11.90 (2H, m) MASS : 599 (M÷I) (free) (2R ) -4- ( 3-Thιomorpholinopropyl ) -I- [3, 5-bis (trifluoro¬ metnyl; benzoyl] -2- (lH-ιndoi-3-yimetnyl ; piperazine dimaieate p : 110-115d [oXd, 1 : -14.2° (C=0.25, MeOHX IR (Nujcl) : 3350, 2720, 1690, 1620, 1605, 1280, 1130 cm - : NMR OM30-c 6 , δ) : 1.70-5.12 (23H, ) , 6.14 [ An , s) , 6.55-3.32 (8H, m) , 10.90 (IH, s) Example 24 The following compounds were obtained according to a similar manner to that of Example 23. (11 (2R) -l- 3, 5-Bis ( trifluoromethyl ) benzoyl j -2- ( lH-indol-3- ylmetnyi ) -4- ( 3-morpholinoprooyi ) piperazme dihydrochloride mp : 26£°C (dec. ) [α. Tj : -6.0° (C=0.5, MeOH) IR (Nujol) : 3650-3100, 2750-2200, 1655, 1275, 1120 cm -1 NMR (DMSC-d 6 , δ) : 2.2-2.45 (2H, m) ; 3.0-5.25 (21H, mi ; 6.55-8.25 (8H, ) ; 10.96 (IH, s) ; 11.1-12.85 (2H, m; MASS : 583 (M- ) (free) Anal. Caico. fcr C gH-^FgN^O-^dHCl-0.4H 7 0 : C 52.56; K 5.29; N 8.45 Found : C 22.54; H 5.33; N 3.25 (2) (2R) -1- [3, 5-Bis (trifluoromethyl) benzoyl] -2- (3, 4- dimethylbenzyl) -4- (3-thiomorpholmopropyl) piperazine 1 dihydrochlcride mp : 272°C (dec.) [α]^ 1 : -11.6° (C=0.5, MeOH) IR (Nujol) : 3650-3100, 2750-2650, 1635, 1270, 1120 cm -1 NMR (DMSO-c c , δ) : 2.1-2.5 (8H, ) ; 2.7-5.2 (21H, m) ; c . 6 - 8 . 25 ( 6H , m ) ; 1 1 . 15- 11 X 5 ( 2H , r.X MAS S : 588 (M÷ I ; ( f ree ) Examp l e 25 A mixture of (2R) -1- [3, 5-bis (trifluoromethyl) benzoyl] -2- ( lH-indol-3-yImethyi) -4- (3-methylsulfonyloxypropyl) piperazine (200 mg 1 ' and 1 , 2, 3, 4-tetrahydroιsoquincline (90 mg) in methanel (3 mi) was stirred for 1.5 hours at reflux temperature. The reaction mixture was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel using ethyl acetate-methanol (10:1) as an eluent to give (2R) -1- [3, 5-bis (trifluoromethyl) - benzoyl] -2- (lH-indol-3-ylmethyl) -4- [3- [1,2,3,4- tetrahydrcisoGuinolm-2-yi]propyl]piperazine (I6 ~ mg) as a oewder. [dig 0 : -9.6° (C-O , MeOH) I? (Neat) : 3260, 1630, 1430, 1380, 1350, 1270 cm " NMR (DMSO-d 6 , δ) : 1.60-4.93 (21H, m) ; 6.60-8.3^ (12H, m) ; 10.85 (IH, s) MASS : 629 (M÷I) Example 26 The following compound was obtained according to a similar manner to that of Example 25. (2R)-i-[3,5-Bis (trifluoromethyl) benzoyl) -2- (lK-indoi-3- yimεthyi) -4- [3- (4, 5, 6, 7-tetrahydrothieno [3, 2-c] pyridin-5- yi) propyl]piperazine ^J 8 : -9-°° (C=0.5, MeOH) IR (Neat) : 3260, 1630, 1430, 1350, 1275 cm "1 NMR (DMSO-d , δ) : 1.55-4.97 (21H, m) ; 6.30-8.24 10K, ml 10.85 (IH, MASS 635 (M-l) Lxa o- A mixture cf (2R) -1- [3, 5-bis (trifluorometnyl) benzoyl] -2- ! lH-indol-3-yimεthyi) -4- (3-metnyis i onyloxypropyl; piperazine (150 mc) and 4-cyano-4-phenyipiperιdme nydrochicride i mg) methanoi (5 ml) was stirree at reflux temperature m the presence cf sodium carbonate (100 mg) . After 2 hours, the reaction mixture was evaporated under reduced pressure. The residue was extracted with ethyl acetate and the extract was concentrated under reduced pressure. The residuε was purified by column, chromatography on. silica gel using ethyl acetate-methanoi (10:1) as an eluent to give (2R)-l-[3,5- bis (trifluoromethyl) benzoyl] -4- [3- (4-cyano-4- phenylpiperidino)propylj -2- (lH-indoI-3-ylmethyl)piperazine (89 mg) as a powder. [ j , 0 : -19.2° (C=0.5, MeOH) NMR (DMSO-d ό , δ) : 1.52-4.96 (23H, m) ; 6.60-8.26 (13H, m; ; 1 .85 (IH, s) MASS : 682 (M+l) A mixture cf (2R) -I- [3, 5-ois (trifluoromethyl) benzoyl] -2 (lH-mdol-3-ylmethyi) -4- ( 3-methylsuifonyloxypropyl ) pipera nε ddO mg) and spiro [indan-1, 4 ' -piperidine] (70 mg) in acetonitriie (3 ml) was refiuxed for 1.5 hours. The reactior mixture was evaporated under reduced pressure and then the residue was purified by column chromatography on. silica gel using dichloromethane-methanol (1 :1) as an eluent to give (2R)-l-[3,5-bis (trifluoromethyl) benzoyl ] -4- [3- (spiro [indan- 1,4' -piperidine] -l'-yl)propyi]-2- (IH-indol-3- ylmetnyi) piperazine (208 mg) as a powder. IR (Neat) : 3260, 1630, 1435, 1380, 1350, 1275 cm -1 NMR (DMSO-d j r, δ; : 1.45-5.00 (27H, m) ; 6.62-8.23 (12H, m) ; 10.88 (IH, s) MASS : 683 (M-l) Example 29 A mixture of (2R) -1- [3, 5-bis (trifluoromethyl) benzoyl] -2- V J, -dichicrobenzylj -4- (4-nitrobenzyl)piperazine (157 mg) , ammonium chloride (15.7 mg) and iron powder (157 mg) in a mixture of ethanol (5 ml) and watεr d.25 ml) was refluxed for 1.5 hours. After cooling, the precipitates were filtered off and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on siiica gel with a mixture of toluene and ethyl acetate as an eiuεnt to givε (2R) -4- (4-aminobenzyl ) -1- [3, 5-bis (trifluoromethyl) benzoyl] -2- (3, 4-dιchlcrocenzyi) piperazine (128.4 mg) . IR (Neat) : 3350, 2970-2700, 1630, 1515, 1460, 1430, 1275, 1130 cm -1 NMR (DMΞO-d.-, δ) : 1.95-5.05 (13H, m) ; 6.50-3.25 (10H, m) MASS : 592 (M+2) , 590 (M) Example 30 The following compound was obtained according to a similar manner tc that of Example 29. (2R) -4- ( 4-Ammobenzyl) -I- [3, 5-bis (trifluoromethyl ) - benzoyl5 -2- (3, 4-dιmethyibenzyl) piperazine IR (Neat) : 3450, 3300, 3100-2650, 1625, 1515, 1435, 1275, 1125 cm -1 NMR (DMSO-d,r, δ) : 1.90-4.80 (17H, m; ; 4.98 (2H, s) ; 6.40-3.20 (10H, ) MASS : 550 (M+l) Example 31 Piridine (23 μl) and acetyl chloride (16 μl) were successively added tc a solution of [2P ) -4- ( -aminobenzyl ) -1 r - 5-bis (trifluoromethyl)benzoyl ] -2- d, 4-dιchlorobenz 11 - piperazine (113 mg) and the whole was stirred at room temperature for 1.5 hours. The mixture was poured into water and tne separated oil was extracted with ethyl acetate. The extract was washed with water, dried ever magnesium suifate and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of toluene and etnyi acetate as an eluent to give (2R)-4-(4- acetylammobenzyl) -I- [3, 5-bis (trifluoromethyl)benzoyl]-2- (3, 4-dichlorobenzyl) piperazine (98.3 mg) . The obtained piperazme was dissolved in ethyl acetate. 4N Hydrogen chloride in ethyl acetate solution (43 μl) was added to the solution and the mixture was evaporated in vacuo. The residue was triturated with n-hexane to give (2R)-4-(4- acetylamincbenzyl) -1- [3, 5-bis (trifluoromethyl)benzoyl]-2- (3, 4-dichlorcbenzyi) piperazine hydrochloride (92 mg) . [ ]f 0 : -11.8° (C=0.5, MeOH) IP (Neat) : 3600-3150, 2750-2100, 1635, 1600, 1525, 1415, 1270, 1130 cm -1 NMR (DMSO-d 6 , δ) : 2.07 (3H, s J ; 2.85-5.15 (IIH, m) ; 6.80-8.30 (10H, m) ; 10.13 (IH, s) MASS : 632 (M+l) (freei Example 32 The following compound was obtained according to a similar manner to that of Example 31. (2R) -4- (4-Acetylaminobεnzyi) -1- [3, 5- bis (trifluoromethyl) benzoyl] -2- (3, 4-dimethylbenzyl) piperazine hydrochloride [α] n 5 : -23.2° (C=0.5, MeOH) IR (Nujol) : 3650-3100, 2750-2100, 1640, 1600, 1530, 1275, 1170, 1130 cm -1 NMR dMS0-d 6 , δ) : 1.95-2.10 (9H, m) ; 2.80-5.05 (IIH, ) ; 6.50-3.30 (I0H, m) ; 10. I "7 (IK, s) ; 11.00-11.40 (IH, m) MASS : 592 (M÷l) (free) Example ?3 (2Ri -1- (3, 5-Bis (trifluoromethyl) benzoyl] -2- (lH-indol-3- yimethyi) -4- ;thiomorpholinocarbonyimethyi) piperazine was converted to the corresponding hydrochloride by treatment with I 7 .6 ' hydrogen chloride m ethanol solution. IP (Nujol; : 3650-3100, 2750-1980, 1638, 1276, 1171, 1129, 900 cιr. ~ - NMR (DMSO-dg, ό) : 2.55-5.15 (I9H, m) ; 6.60-8.25 (8H, m) ; 10.99 (IH, s) MASS : 599 (M+l) (free) Preparation 1 A mixture of formaldehyde (37' ~ m water, 20.7 ml) and morpholine (17.1 ml) was adjusted to pH 3.5 witn diluted suifuric acid. Propargyl alcohol (10 g), potassium iodide (0.3 g; , ana copper (II) suifate (0.14 g) were added to the solution and the whole was stirred at 95°C for 6 hours. After cooling, the insoluble material was removed by filtration and the pH of the filtrate was adjusted to 9 with 24 sodium hydroxide solution. Brine (100 ml) was added to the solution and the solution was extracted with a mixture of ethyl acetate and ethanol (10:1) eight times and then with n-butanol six times. The combined extract was dried over magnesium suifate and evaporated in vacuo. The residue was distilled m reduced pressure to give 4-morpholino-2-butyn-I- ol (14.03 g) . op : 124-131°C IP (Neat) : 3350, 2850, 1105, 1000 cm "] NMR (CDCI3, δ; : 2.18 (IH, br s , 2.57 (4H, t, J=4.7Hz) , 3.31 (2H, t, J=i.9Hz), 3.75 (4H, t, J=4.7Hz), 4.30 (2H, t, J=I.9Hz) MASS : 156 (M +l) Preparation ? The following compound was obtained according to a similar manner to that of Preparation 1 with the exception of purification by column cnromatograpny on silica gel using a mixture cf ethyl acetate and ethanol (30:1) as an eluent instead of distillation m reduced pressurε. 4-Th1emcrpholmo-2-butyn.-1-cl IP (Meat) : 3350, 2900, 2800, 1420, 1330, 1115, 1100 cm -1 NMR (CDCI3, δ) : 1.93 (IH, br s) , 2.65-2.90 (8K, m) , 3.32 , 2ή ' , t, 0=1.9Hz), 4.31 (2K, t, J=1.9Hz MASS : 172 (M +1) Preparation 3 Tr.ior-.yl chloride (2.1 ml) was added to a solution of 4- morpnolιnc-2-butyn-l-cl (1.47 1 _n dichiorometnane (10 ml) witn ice oatn cooling. After stirring for 0.5 nour, the solution was evaporated m vacuo. The residue was triturated with ethyl acetate to give 4-norohol_.nc-2-butynyi chloride hydrochlorice (1.91 g) . mp : I62-165°C IR (Nujcl) : 2640, 2510, 2450,- 2353 cm -1 NMP (DMS0-d 6 , δ ) : 3.31 (4H, or ≤ , 3.92 (4H, br s) , 4.21 (2H, t, J=1.9Hz), 4.5 " ' (2H, t, J=1.9Hz) , 12.23 MAS 4 (M) (free; Preparation 4 The following compound was obtained according to similar manner to that of Preparation 3. 4-Thιomcrchoimo-2-butynyi chloride hydrochloride mp : 185-lo7°C IR (Nujcl) : 2600, 2450, 2380, 1260, 1260, 1160, 915 cm - λ NMR (DMSC-dc, C ) : 2.58-4.00 (8H, ; , 4.21 (2H, t, J-d. Hz) , 4.53 (2H, t, J=2.0Hz), 12.08 (IH, br s) MASS : 193 (M) (free) Preparation 5 X. mixture cf 4-chioro-l- (4-fluorophenyl-1-butanone (500 mg) , etnylene glycci (247 mg) and catalytic amount of p- toiuenesulfonie acid .onohydrate m benzene (5 ml) was refiuxed fcr 20 nours with continuous removal of water using Dean-Stark apparatus. After cooling, the solution was washed successively with IN NaOH solution and brine, dried over magnesium suifate, and evaporated m vacuo to give 4-chioro- 1- ( -fluorcphenyl) -1-butanone cyclic ethyiene acetal (613.2 mg) as an cii . IR (Neat; : 2950, 2870, 1600, 1500, 1220, 1030 cm "1 NMR (DMΞO-d 6 , c) : 1.60-1. oO (2H, ; , 1.90-2.00 (2H, m) , 3.61 (2H, t, J=6.5Hz; , 3X0-4.10 (4K, ! , 7.10- 7.50 (4H, ) SS : 245 (M+l) , 209 Example 3^ A mixture of (2R) -1- [3, 5-bis (trifluoromethyl) benzoyl] -2- d-naphthyimethyi) piperazme (l.C g; and 3-bromopropancl (330 mg) m N, N-dimethylformamide (2.5 mi) was stirreo at room. temperature in the presence of powdered potassium caroonate (444 g) . After 17 hours, the reaction mixture was diluted with ethyl acetate (30 ml) and then washed successively with water and brine, and dried over magnesium suifate. Evaporation cf the solvent m vacuo gave (2R)-l-[3,5- bis (trifluoromethyl) benzoyl] -4- (3-hydroxypropyl) -2- (2- naphthyimethyi)piperazine (1.19 g; . IR xNeat) : 3425, 1635, 1430, 1340, 1275, 1170, 1130 cm -1 NMR (CDCI 3 , δ) : 1.50-5.28 (lόH, ) , 7.40-7.93 (10H, m) MASS : 525 (M-rl) Example 33 A mixture cf (2R) -1- [2, 5-bis (trifluoromethyl ) benzoyl] -2- d-naphthylmethyi ) piperazine (200 mg) and 1- (4-ch!orc-2- butynyl ) morphoiine hydrochloride (95 mg) in N,N- dimethylformamide (0.5 ml) was stirred at room temperature in the presence of powdered potassium carbonate (177 mg) . After 17 hours, the reaction mixture was diluted with ethyl acεtatε (30 ml) and then washed successively with water and brine, and dried ever magnesium suifate. After evaporation of the solvent in vacuo, the resulting residue was purified by column chromatography on. silica gel using ethyl acetatε as an eluent. Tne product obtained was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate solution tc give (2R) -1- [2, 5-bis (trifluoromethyl) benzoyl] -4- (4-morphoiino-2-butynyl) -2- (2-naphtnyimethyl) piperazine dihydrochlcπαe (257 mg) . ι] 21 •?ι D [C=0. MeOH) IR (Nujcl) : 3350, 2550, 1630, 1275 cm -1 NMR (DMSO-d 6 , δ) : 2.80-5.31 (21H, m) , 7.0-8.28 (10H, ) MASS : 604 (M+l) (free) Example 3 A mixture cf (2R) - 1 - [3, 5-bis (trifluoromethyl) benzoyl ] -2- ( , 4-dichlorobenzyl)piperazine hydrochloride (150 mg) and 1- (4-chIoro-2-butynyi)morphoiine hydrochloride (63 mg) in ,N-dimethylformamide (0.5 mi) was stirred at room temperature m the presence cf oowoered potassium carbonate (160 mg) . After 17 hours, the reaction mixture was diluted with ethyl acetate (30 ml) and then washed successively with water and erme, and dried over magnesium suifate. After evaporation of the solvent in vacuo, the resulting residue was purified by column chromatography en silica gel using a mixture of ethyl acetate and methanoi '10:1) as an eluent to give (2R) -1- [3, 5-bis (trifluoromethyl) benzoyl] -2- (3, 4- dichlcrobenzyl) -4- (4-morphoiino-2-butynyl) piperazme . The product obtained was dissolved in ethyl acetatε and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-i-[3,5-bis (trifluoromethyl)benzoyi]-2-(3,4- dichicrobenzyi) -4- ( -mcrphoimo-2-butynyl)piperazine dihydrochloriαe (155 mg) . IR (Neat) : 3400, 2350, 1640, 1425, 1275 cm -1 NMR (DMSO-d 6 , δ) : 2.91-5.20 (2IH, m) , 7.0-8.26 (6H, m) MA.SS : 522 (M-l) (free) Example 37 The following compounds were obtained according to a similar manner to that of Example 7. (1; (2R) -4- (4-Morpholmo-2-bUtynyl) -I- [3, 5- bis (trifluoromethyl) benzoyl] -2- ( lH-indoi-3-yimethyl) - piperazine dihydrochioride mp : 165-169°C [ a ] ^ 1 : -0.4° (C-0.25, MeOH; IR (Nujol) : 3350, 2550, 2320, 1635, 1550, 1270, 1120 cm -1 NMR (DMSO-d 6 , δ) : 2.80-5.25 (21H, ) , 6.56-8.30 (8H, m) , 10. 6 (1H, s) MASS : 593 (M) (free) (2; (2R; -4- (4-Mcrph.ciino-2-butyr.yI) -1- [ 3, 5- bis (trifluoromethyl) benzoy dimethylbenzyl) piperazine dihydrochioride mp : 155-162°C ( ]^ 1 : -11.5° (C=0.2β, MeOH) IR (Nujol) : 3350, 2650, 2300, 1655, 1640, 1275, I120 cm -1 NMR (DMSO-dg, δ) : 2.02-2.30 (7H, ) , 2.64-5.30 (20H, ) , 6.60-8.30 (6H, ) MASS : 582 (M) dree) (3) (2R) -4- (4-Thiomorphoiin.o-2-butynyi) -1- : 3, 5- bi s ( rifluoromethyl) benzoyl ] -2- (3, 4-dιmethylbenzyi) - piperazine dihydrochioride mp : I62-170d [αj^ 2 : -9.4° (C=0.27, MeOH) IR (Nujol) 3350, 2650, 2320 d, 1640, 127.' 1125 :m NMR (DMSO-dc, 2.04-2.35 (7H, m) , 2.65-5.25 (20H, ra; , 6.57-8.28 (6H, ) MASS : 598 (M) (free) (4 ; (2R) -4- (4-Thiomorpholir.o-2-butynyI) -I- [3, 5- bi≤ (trifluoromethyl) benzoylj -2- (lH-mdol-3- yimethyi) piperazine dihydrochioride mp : 166-1 "7 0°C [α] 2 : -1.5° (C=9.26, MeOH; IP (Nujol) : 3350, 2650, 2300, 1635, 1275, 1125 cm "1 NMR (DMSC-d 6 , δ) : 2.53-5.30 (21H, m) , 6.54-8.30 (8H, m) , 10.93 (IK, br s;, 12.10 (2H, br s) MASS : 609 (M) (free) 5; (2R; -4- (2-Morphoiinoethyl) -1- [3, 5-bis (trifluoromethyl) benzoyl ] -2- (3, 4-dimethylbenzyl) piperazine dihydrochioride mp : 223-228d [α] 2 - 2 : -13.0 D ;C=0.2S, MeOH) : (Nujcl) 3350, 2550, 1630, 1450, 1275, 1120 cm -1 NMR { DMS O-d f- , δ) 1.95- !5 (27H, ) , 6.50-8.32 (6H, j , 10.80-11.90 (2H, br ) MASS : 558 (M) (free) ( ; (2R ' -4- (2-Thiomcrpholinoethyl ) -1- [ 3, 5- bi≤ (trifluoromethyl ) benzoyl] -2- ( lH-indoi-3- vimetnvl ; piperazine dihydrochioride mo : -. /'.- brY .. ~3> y9 ,, πMceuO;H: /) IR (Nujol) : 3350, 2600, 1640, 1275, 1125 cm " NMR (TM30-d 6 , δi : 2.60-5.30 (21H, m) , 6.50-8.30 (8H, ; , 10.96 (IH, s) , II.10-12.10 (2H, br ) MASS : 585 (M) (free ) l i (2R ) -4- (2-Morpholinoethyl) -1- [3, 5- bis (trifluoromethyl) benzoyl ] -2- ( iK-indol-3- ylmethyl) piperaz e dihydrochioride mp : 170-17β°C α] 2 , 8 - 5 : -3.0° (C=0.30, MeOH) IR (Nujol) : 3350, 2570, 1640, 1275, 1125 cm ""1 NMR (DMSO-d , 5) : 2.60-5.30 ;21K, mj , 6.55-8.40 (8H, ) , 10.95 (IH, s) , 11.10-12.04 (2H, br ) MASS : 569 (M) (free> (8 i (2R) -4- i 2-Thιomorphoiinoεthyl) -1- [3, 5- bis (trifluoromethyl) benzoyl ] -2- (3, 4-dimethylbenzyl) - piperazine dihydrochioride mp : 261.5°C [α]?, 8 "" : -1.9° (C=0.29, DMF) IR (Nujcl) : 3350, 2350, 1640, 1275, 1130 cm "1 NMR (DMSO-d 6 , δ; : 2.0C-5.30 (27H, m) , 6.60-8.30 (6H, m> , 10.60-12.00 (2H, br m) MASS : 5 (M) (free) 5 ^ Exampl e 38 A mixture of (2R) -1- [3, 5-bis (trifluoromethyl ) benzoyl] -2 ( lH-mdoI-3-ylmethyl) piperazme (3O0> mg) , 4-chloro-i- (4- fiuorophenyi) -I-butanone cyclic ethyiene acetal (161 mg; , potassium carbonate (182 mg) , and potassium iodide (109 mgi m acetonitriie (10 mi' was refluxed for 20 hours. After cooling, tne insoluble material was removed by filtration anc the filtrate was evaporated m vacuo. The residue was purified ry column chromatography en silica gel ιtn a mixture cf toluene ana ethyl acetate as an eluent to give (2R) -4- [4, 4-etnyleneαιoxy-4- (4-fiuorophenyi)butylj-l-[3,5- bis (trifluoromethyl)benzoyl]-2-(lH-mcoI-3- ylmethyl) iperazme as a powder. This compound was furtner Π vι tieα by washing with diiscpropyi ether. mp : 145-146d IP (Nujol) : 3200, 1620, 1600, 1275, 1120 cm "1 NMR (CMSO-o G , δ) : 1.35-1.55 (2H, m) , 1.80-4.90 (I7H, ) , 6.55-8.20 (12H, m) , 10.67 (IH, br s; MASS : 664 (M- ) Exa o1e 39 To a stirred mixture of (2R)-l-[3,5- bis (trifluoromethyl)oenzoyi]-4- (carboxymethy_ ) -2- (IH-mcol-3- yimethyl) piperazme ιC.2 g) and 3-azabιcycio [3.2.2] nonane (0.05 gι in dry N, N-dimethylformamide (2 ml) were added I- (3- dimethyiammopropyl ) -3-ethylcarbcαnm de hyαrocnloride (0.082 g; and 1-hydroxybenzotrιazole (0.053 g) at room temperature. After 6 hours, the reaction mixture was poured into aqueous sodium bicarbonate solution (20 ml) anc the resulting precipitate was collected by filtration. The crude product obtained was purified by column chromatography on silica gel using toluene-ethyl acetate { 1 : 2 ) as an eluent and treatεd with 17.6 hyαrogen chloride etnanoi solution to give (2R ) -4-[ (3-azabιcycio[3.2.2] non-3-yl) carbonylmethyl] -1- [3, 5- bis (trifluoromethyl)oenzcyl -2-( lH-mdol-3- G ylmethyl ) piperazme hydrochloride (0.2 g) as a white powder. α: -, (C=0.5, MeOH^ (R (Nujol) 3650-3100, 2750-2000, 1637, 127* /i 1130, 900 cm "1 NMR (DMSO-d 6 , δ) : 1.50-1.75 (8H, m) , 2.07 (2H, br s) , 3.15-5.10 (15H, m) , 6.60-8.25 (8H, ) , 10.15 (IH, tr s) , 11.00 (IH, s) LASS : 621 (M+l) (free Exampm 40 To a stirred mixture of (2R)-l-[3,5- bis ( rifluorometnyl)benzoyl]-4- (4-carooxyoenzyl)-2- (IH-mdoi- 3-ylmetnylj piperazme d50 mg and αietnylamme hydrochloride (28 mg; m ory dicnloromethane (5 ml ι were added a solution of 1- (3-oιmethyiammopropyl) -3-ethyicamodiimιde (40 mg) dichioro ethane (1 ml) and 1-hydroxybenzotrιazole (34 mg) at room temperature. After 5 hours, tne reaction mixture was poured into aqueous sodium bicarbonate solution (20 il) . The organic layer was separated and washed with brine and dried over magnesium suifate. The cruce product ootamed was purified by column, chromatography en silica gel using ethyl acetate - n-hexane (4:1) to givε (2R,-l-[3,5- bis (trifluoromethyl) benzoyl : -4- [4- (N,N-αiethylammocarbonyl) - benzyl] -2- ( lH-mdoi-3-yimethyl) piperazme (107 mg) as a powder. [α]^ 1 : -40.3° (C=0.5, MeOH) IR (Neat) : 3250, 1620, 1430, 1275, 1130 cm -1 NMR (CDC1 3 , δ) : 1.1C-5.0C (25H, m) , 6.40-8.00 (8H, m) , 9.14 (IH, s, MASS : 645 (M-rl) Example 41 Tc a stirred mixture of (2R)-I-[3,5- bis (trifluoromethyl) benzoyl] -4- (3-hyoroxypropyl) -2- (2- naphtnyimethyl ; piperaz e d.l g 1 and triethvlamine (425 mg) in dicnloromethane (10 ml) was added dropwise methanesuifonyl chloride (252 mg) at ice-bath tempεraturε. After 2 hours, the reaction m.ixture was washεd with water and then dried over magnesium suifate. After evaporation cf the solvent, the resulting residue was cnromatographed or. silica gel using etnyl acetate as an eluent to give (2R) -1- [3, 5- bis (trifluoromethyl) benzoyl] -2- (2-naphtnylmethyl ) -4- (3- mathylsulfonyloxypropyl) piperazine (988 mg) . IR .XNeat) : 1635, 1430, 1350, 1280, 1X0, 1130 cr. "1 NMR (CDC1 3 , δ) : 1.59 (3H, s) , 1.90-5.28 (15H, m) , 7.40-7.90 (10H, rr.) MASS : 603 (M+i) r-x mole t ? The tcllowing compounds were obtained according to a similar manner to that of Example 41. (1) (2R)-l-[3, 5-Bιs (trifluoromethyl) benzoyl] -2- (3, 4- dichlcrobenzyl) -4- (3-methylsulfonyloxypropyl) piperazine IR (Neat) : 1630, 1470, 1430, 1340, 1270 c "1 NMR (CDCI3, δ) : 1.55-5.14 (I5K, m) , 3.04 (3H, s) , (2) (2R) -1- [3, 5-Bιs (trifluoromethyl) benzoyl] -2- (2- naphtnyimethyl) -4- (2-methylsulfonyloxyethyl(piperazine IR (Neat) : 1635, 1430, 1350, 1275, 1170, 1125 cm -1 Example 4.3 A mixture of (2R) -1 -[ 3, 5-bis (trifluoromethyl ) benzoyl ] -2- .d-naphthylmethyi) -4- (3-methylsulfonyloxypropyl ) piperazine (250 mg) , tnicmorpholme (43 mg) and triethyiamine (46 mg) m dry methane! (5 mi) was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel using ethyl acetate as an eluent. The product obtained was dissolved in ethyl acetate and treated with 4N hydrogen chloride ethyl acetate solution tc give (2R) -1- [3, 5-bis (trifluoromethyl) benzoyl] -2- (2-naphthylmethyl) -4- (3- thicmorphoiinopropyl ) piperazine dihydrochioride (195 mg) . [a] 2 : -22.0° (C=0.5, MeOH) IR (Nu oi) : 3400, 2500, 1640, 1275, 1170, 1130 cm "1 NMR ;CDCI 3 , δ) : 1.50-5.69 (23H, mi , 7.34-7.93 (10H, ) MASS : 610 (M+i) (free ) Example 44 The following compounds were obtained according to a similar manner to that of Example 43. ( 1 ) (2R) -1- [3, 5-Bis (trifluoromethyl) benzoyl] -2- (2- naphtnyimethyi) -4- (2-mcrpholmoetnyl) piperazine dihydrochioride t α] 2 , 3 : -25.2° (C=C5, MeOH) IR (Nujcl) : 3400, 2510, 2425, 1635, 1425, 1275, 1170, 1130 cm -_ NMR (DMSO-d 6 , δ) : 2.88-5.31 (21H, m) , t.07-8.24 (1GH, m) MASS : 580 ( -d) (freε) (2) (2R)-l-[3,5-Bis (trifluoromethyl) benzoyl ] -2- (2- naphtnyimethyi) -4- (2-thiomorphclinoethyl ) piperazine dihydrochioride [α] j 2 : -23.7" (C=0.5, MeOH) IP (Nujol) : 2350, 1640, 1270, 1180 cm "1 NMR (DMSO-d 6 , δ) : 2.80-5.31 (2IK, m) , 7.03-8.20 (10K, m) MASS : 596 (M+l) (free) (3) (2R) -I- id, 5-Bis (trifluoromethyl) benzoyl] -2- (lH-mdol-3- yimetnyi ) -4- [ 3- ( -oxopiperidmo) propyl ] piperazine ^D : -19.0° (C=0.5, MeOH) IR (Nujol) : 3270, 1720, 1625, 1430, 1340, 1275, 1125 cm "1 NMP (CXCI 3 , δ; : I.66-5.20 (23H, m) , 6.69-8.28 (8H, ) (4 ^ '2P'-l-d,5-Bιs .trifluorome hyl ιbenzoyij-2-(3,4- dichlcrobenzyi) -4- (3-thιomorpnolmopropyl) piperaz e dmycrochloride tα]χ 8 : ^ 2.2° (C=0.5, MeOH^ IR (Nujol) : 3400, 2400, 1650, 1280 err "1 NMR dMSG-c 6 , δ- : 2.10-5.20 (23H, m) , o.92-8.32 (6H, m) , 11.12-11.72 (2H, m) MASS : 623 (M-rl, (free) (5) (2R) -1- [3, 5-Bis (trifluoromethyl) benzoyl] -2- (3, 4- dicolorober.zyl) -4- (3-morphoimopropyl) piperazme dihydrochioride [α] 1 , 9 : -2.3° (C=0.5, MeOH) IR (Nujcl) : 3400, 2550, 2450, 1650, 1280 cm "1 NMP (DMSO-d 6 , δ) : 2.10-5.20 (23H, m) , 6.94-8.34 (6H, m) , _1.C3--1.76 (2H, ) MASS : 612 (M- ) (free; (6) (2R ) -4- [ 3- ( 4-Acεtylpιperidιno) propyl] -1- [3, 5- bis ( trifluoromethyl ) benzoyl ] -2- ( lH-indol-3- yimethyi ^ piperazme dihydrochioride L ' α]§° -7.2' (C=0 MeOH) -ι IR -'Nujol) : 3300, 2600, 1700, 1630, 1275 cm - NMR (DMSC-d 6 , δ) : 1.67-5.24 (24H, m) , 2.16 (3H, s) , 6.62-8.28 (8H, ) , 10.95 (IH, s) MASS : 623 (M-l) (free) (7 ) (2R) -4- [3- dhiazolιdm-3-yl) propyl 1 -I- [3, 5- cisi trifluoromethyl ) benzoyl ] -2- ( lH-mdoI-3- yimethyl ) piperazme dihydrochioride α] 25 d=0.5, -OH) IR (Nujol) : 3600-3100, 2700-2250, 1660-1580, 1270, 1120 cm "1 NMR (DMSO-d 6 , δ) : 2.2C-2.40 (2H, m) , 3.00-5.20 (19H, m) , 6.40-8.25 (8H, ) , 10.97 (IH, m) , 11.20-11.90 (2H, rr.) MASS : 585 (M-d) (free 1 d * i2R) -4- [3- (4-Phenyl-l-pipεrazmyl) propyl] -1- [3, 5- bis ttrifluoromethyl ) benzoyl] -2- (lK-indoi-3- ylmethyi) piperazine trihydrochloride [α] 2 , 5 : -=.0° (C=0.5, MeOH) I )Nujcl> : 3600-3100, 2750-2300, 1630, 1275, 1120 cmd 1 NMR (DMSO-d 6 , δ) : 2.05-2.45 (2H, m) , 3.05-5.20 (21H, m; , 6.60-8.05 (13K, m) , 10.97 (IH, s) , 11.00-11.85 (3H, ) MASS : 658 (M+l) (free) (9) (2R)-4-[3- ( -Cyclohexyl-1-piperazinyl) propyl] -1- [3, 5- bis (trifluoromethyl) benzoyl ] -2- ( lH-mdol-3- ylmetnyl ) piperazine trihydrochloride mp : 250°C (dec. ) [α]§ 5 : -7.8° (C=0.5, MeOH) IR (Nujol) : 3600-3100, 2650-2200, 1640-1600, 1370, 1270, 1120 cm "1 NMR (DMSO-d e , δ; : 1.00-2.40 (IIH, ) . 3.00-5.30 (23H, , , 6.60-8.30 (8K, rr; , 10.9 "1 (IH, s), 11.30-12.30 (3H, m) MASS : 664 (M-d) (free) Examp e 45 .A mixture of (2R) -I- [3, 5-bis (trifluoromethyl) benzoyl] -2- ( lH-indoi-3-yimethyl) -4- (2-methyisuifcnyioxyethyl) piperazine (200 mg! , 4-aminomorphciine (36 mg) and triethvlamine (52 mg) in dry metnanol (5 mi) was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic layer was washed with brine and dried over magnesium suifate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and methanoi (10:1) as an eluent to afford (2R)-1- [3, 5-bis itrifluoromethyl) benzoyl ] -2- lK-indol-3-yimethyl ) -4- [2- (morpholinoammo) ethyl]piperazine (55 mg) . iα]j 2 : -16.2° (C=0.5, MeOH) IR (Nujol) : 3300, 1615, 1275 c "1 NMR (DMSO-d 6 , δ) : 2.14-5.10 (21H, m) , 6.0-8.26 (8H, m) , 10.91 (IH, s) MASS : 584 (M+l) Example 46 A mixture of (2R) -1- [3, 5-bis (trifluoromethyl) benzoyl] -2- (lK-indol-3-ylmethyl) -4- (3-methylsulfonyloxypropyl) piperazine (ICC mg) and 4-phenylpiperιdme (60 mg) in acetonitriie (3 mi) was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography on siiica gel using ethyl acεtate-methanol (5:1) as an eluent to give (2R)-1- [3, 5-bis (trifluoromethyl) benzoyl] -2- (lH-indoi-3-ylmethyl) -4- [3- (4-pnenylpiperιdino) propyl]piperazine (90 mg) . [α.§° : -24.6° (C=1.0, MeOK) (Neat) 3250, 1630, 1430, 1275, 1130 cm " NMP (DMSC-d 6 , δ) : 1.52-4.93 (24K, m) , 6.60-8.28 (13H, m; , .0.87 S / MASS : 657 (M-d) Example 47 A solution of (2R) -2- (3, 4-dichiorobenzyl) -1- [3, 5- bis (trifluoromethyl) benzoyl] -4- (2-hydroxyethyl) piperazme (50 t o mg) in ethyl acetate (3 mi) was treated with 4N hydrogen chloride in ethyl acetate solution (0.2 ml) and the resulting mixture was concentrated in vacuo to give (2R)-2-(3,4- dichiorobenzyl ) -1- [3, 5-bis (trifluoromethyl)benzoyl]-4-(2- hydroxyethyi) piperazine hydrochloride (45 mg) as a powder. IR (Neat 1 . : 3260, 2550, 1640, 1425, 1275 cm "1 NMP (DMSO-d 6 , δ) : 2.60-5.53 (13H, m) , 6.91-8.32 (6H, m) , 10.96 (IH, br s; iMASS : 530 (M+l) (free) 1 0 Example 8 The following compounds were obtained according to a similar manner to that of Example 47. I D (2R) -4- (4-Ammobenzyl) -1- [3, 5-bis (trifluoromethyl ) - benzoyl] -2- (3, 4-dimethylbenzyl; piperazine dihydrochioride mp : 179°C (dec.) [α j y -16.6° (C=0.5, MeOH) 20 (P. (Nujol) : 3400-3050, 2650-2300, 1660-1580, 1275, 1125 cm " NMI dMSO-d 6 , δ) .00-2.20 (6H, m) , 2.80-5.05 (UK, m) , 6.45-3.25 (10H, rr.) , 11.40-11.90 (2H, m) MASS : 550 (M+l) (free) -D '? (2R) -4- ( -Nitrobenzyl) -1- [3, 5-bis (trifluoromethyl ) - benzoyl] -2- (3, 4-dimethyibenzyi ) piperazine dihydrochioride p : 140°C (dec.) 30 fair) 3 : -18. ° (C=0.5, MeOH) IR (Nujcl) : 3600-3200, 2650-2200, 1640, 1520, 1350, 1275, 1130 c ~ - NMR (DMSO-d 6 , δ, : 2.00-2.20 (6H, m) , 2.80-5.00 (IIH, ) , 6.50-8. 0 (10H, ) 5 MASS : 580 (M+l) (free) oo Example 49 To a solution of (2R) -4- [ , -ethylenedioxy-4- (4- fiuorophenyi) butyl] -1- [3, 5-bis (trifluoromethyl)benzoyl j -2- (lK-indoi-3-ylmethyl) piperazine (210 mg) in ethyl acetate was added 4N hydrogen chloride in ethyl acetate solution (0.5 ml) and the whole was stirred at room temperature for 23 hours. The solution was evaporated m vacuo. The residue was triturated with a mixture of ethyl acetate and diisopropyl ether tc givε (2R V -4- [ - (4-fiuorophenyi) -4-oxobutyl] -1- [3, 5- bis ( rifluoromethyl)benzoyl] -2- (lK-indol-3- ylmethyi) piperazme hydrochloride (183.7 mg) . mp : 61°C (dec.) [α] 2 ' : -14.2° (C=0.5, MeOH) I? (Nujol) : 3400-3150, 2650-2300, 1675, 1635, 1595, 1280-1250, 1275, 1125 crn -1 NMR (DMSO-d 6 , δ) : 2.00-2.25 (2H, m) , 3.05-5.20 (13H, m) , 6.55-8.25 (12K, m) , 10.95 (IH, s), 11.10-11.50 (IH, ) MASS : 620 (M-d) (free) Preparation 6 Tetrahyorofuran (15 ml) was added to 700 solution of sodium bis (2-methoxyethoxy) aluminum hydride in toluene (49.7 g) under an atmosphere of nitrogen and then cooled. A solution of 4-morpholιno-2-butyn-l-ol (3.0 g) in tetrahydrofuran (15 ml) was added dropwise maintaining the reaction temperature 4-5°C. After being stirred for 10 minutes, the reaction mixture was allowed tc warm to room temperature. After 1 hour, water (6 mi) and 100 aqueous sodium hydroxide solution (4.5 ml) were added cautiously and then filtered. The filtrate was dried over potassium carbonate and concentrated under reduced pressure to give an oily product, which was purified by column chromatography on silica gel using ethyl acetate-methanol (5:1) to afford (E)- 4-morpholino-2-buten-l-ol (1.03 g) . IP (Neat) : 3350, 1450, 1110, 990, 855 cm "1 NMR (CDCI 3 , δ) : 2.48 (4H, t, J=4.7Hz), 2.77 (IH, s) , 3.02 (2H, d, J=5.4Hz), 3.73 (4H, t, J=4.7Hz) , 4.15 (2K, d, J=4.0Hz), 5.64-5.96 (2K, m) MASS : 158 (M+l) Preparation 7 Ihionyi chloride (0.96 ml) was added dropwise to a solution of (E) -4-morphoiino-2-buten-l-ol (1.03 g) in dichlorom.ethane (10 ml) at ice-bath temperature. After 3 hours, the reaction mixture was evaporated under reduced pressure and the resulting residue was triturated with ethyl acetate to give (E) -4-morpholino-2-butenyl chloride hydrochloride (0.98 g) . p : 155-160°C IR (Nujol) : 2750-2700, 1275, 1255, 1120, 1078, 1065, 975 cm ~ - NMR (DMSO-d 6 , δ) : 2.80-3.55 (4H, m) , 3.64-4.10 (6H, ) , 4.26 (2H, d, J=5.7Hz), 5.90-6.25 (2H, ) , 11.82 (IH, br s) MASS : 176 (M) (free) Example 50 A mixture of (2R) -1- [3, 5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) piperazine (0.20 g) , 5-morpholino-3- pentynyi chloride hydrochloride (0.175 g) , potassium carbonate (0.303 g) and potassium iodide (10 mg) in dry acetonitrile (4 ml) was stirred under reflux for 60 hours. After removal of the solvent, the resulting residue was dissolved with ethyl acetate. The solution was washed with brine, dried over magnesium suifate and evaporated under reduced pressure. The residue was purified by column chromatography on siiica gel using toluene - ethyl acetate (1:2) as eluent and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-l-[3,5- bis (trifluoromethyl) benzoyl ] -2- ( lH-indol-3-ylmethyl ) -4- (5- morpheiino-3-pentynyi) piperazine dihydrochioride (0.174 g) . [ ]?l : -19.5° (C=0.5, MeOH) IR 'Nujol) : 3600-3150, 2700-2300, 1640, 1280, 1170, 1185 cm ~ - MMR dMSC-d 6 , δ; : 2.90-5.50 (23H, rr.) , 6.80-8.30 (3H, rr., , 10.95 (IH, s) , 11.79 (2H, br s) MASS (APCd : 603 (M+2) , 6C (M-rl) (free) Anal. Calcd. for C^ F oFddOo^HCi-I .5E 0 : C 52.70, H 5.26, N 7.93 Found : C 52.72, H 5.54, N 7.60 Example 51 To a mixture of (2R) -1- 3, 5-bis (tri luoromethyl) - benzoyl] -2- (3, 4-dιmεthyibenzyl) piperazme (0.2 g) , 1-methyi- 4-formyi-lH-pyrazole (50 mg) , and sodium triacetoxyborc- hydride (131 mg) in dicnloromethane (2 ml) was added one drop of acetic acid. After being stirred at room temperature overnight, the solution was evaporatεo undεr rεduced pressure. The resulting residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried over magnesium suifate and evaporated under reduced pressure. Tne rεsidue was puri-fied by column chromatography on silica gel using ethyl acetate- methane! as eluent and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R) -1- [3, 5-bis (trifiuorc- mεtnyi) benzoyl ] -2- (3, -dimeth Ibenzyl ■ -4- [ (I-methyl-lH- pyrazel-4-yl )methyl]piperazine hydrochloride (97 mg) . mp : 243-244°C IR (Nujol) : 3350, 2750-2000, 1655, 1635, 1275, 1165, 1130 cm " - NMR IDMSO-o e , δ) : 1.97-2.26 (7H, ) , 2.78-5.10 (13H, m.; , 6.50-8.30 (8H, rr.) , 11.24-11.74 (IH, br m) MASS (APCI) : 539 (M+l; (free) by Anal. Caicd. for C^-yHdgFgNXO-HCiX . H ? o 52.00, H 5.56, N 8.98 unc 51.82, H 5.15, N 8.99 The roliowmg compounds were obtained according tc a similar manner to that of Example 51. (1) d? v -l-[3, 5-3is(trifiuorcmethn d benzoyl ] -2- [3, 4- dimethylbenzyl ; -4- [ ( I-methyi-iH-ιmιdazol-4-yl ) methyl piperazme dihydrochioride [α] 2 : -11.80° (C=0.5, MeOH) IR (Neat) : 3350, 2550, 1640, 1430, 1275, 1170, 1130 cm "1 NMR (DMSO-d 6 , δ) : 2.07 (3H, s) , 2.17 (3H, s) , 2.72- 5.10 (UK, m) , 3.88 (3K, s) , 6.60-9.08 (8H, m ) MASS : 539 (M-1 ) (free) (2) (2R)-l-[2, 5-Bis (trifluoromethyl) benzoyl] -2- (3, - dimetnyibenzyl ) -4- [ ( i-methyi-lH-ιmidazoi-2-yl) methyl ] piperazine dihydrochioride [α]j§ 5 : -12.10° (C=C5, MeOH) IR (Neat) : 3350, 2500, 1640, 1430, 1280, 1175, 1130 cm "1 NMR (DMSO-d 6 , δ) : 2.07 (3H, s) , 2.16 (3H, s) , 2.53- 5.14 (IIH, rr.) , 3.94 (3H, s; , 6.47-8.26 (8H, rr.) MASS : 539 (M-l) (free) Example 53 The following compounds v/ere obtained according to a similar manner to that of Example 43. (1) (2R) -1- [3, 5-3is (trifluoromethyl) benzoyl] -2- (3, 4- dimethyibenzyi ) -4- ( 3-morpholinopropy!) piperazine dihydrochioride -.o !20-230°C [α]f, ~ - : -17.3° (C=0.3, MeOH) I? (Nujol) : 3350, 2650, 1655, 1635, 1620, 1445, 1370, 1270 cm "1 NMR d.MSO-d 6 , c) : 1.92-5.22 (29H, m) , 6.56-8.23 (6H, m) , 11.43 (2H, br s) MASS (AFCI; : 572 (M+l) (free* Anal. Calcd. for : C 34.04, H 5.79, N 6.52 Found : C 53.72, H 5.80, N 6.29 (2) (2R! -4- [2- ■N,N-Bis (2-me noxyetnyl) ammo] ethyl]-!- [3, 5- bis \trifluoromethyl) benzoyl1 -2- , -dimethylbenzyl) - piperazme dihydrochioride [α] 2 , 2 : -9.6° (C=0.5, MeOH) IR [Nujol, : 3350, 2650, 1655, 1635, 1620, 1445, 1370, 1270 cm "1 NMR dMSO-d 6 , δ) : 1.92-2.22 d7H, m) , 3.32 (6H, s) , 6.56-8.26 dH, m) MASS (APCI, : 604 (M-d) (frεε) .deal. Calcd. for C3 Q H.3QFg 3O3-2HCld.6K2O : C 21.08, H 6.32, N 5.96 Found : C 51.06, H 6.40, N 6.14 d) (2R)-l-d,5-3ιs(trifluoromethyl) benzoyl] -2- (lH-indci-3- yimethy!) -4- [3- (1,2, 3, 6-tetrahydrcpyridm-l-yl) propyl] - piperazine dihydrochioride p : >2C0d (αϊ 2 , 3 : -2.30° (C=0.5, MeOH) IR (Nujcl, : 3530-3300, 2700-2400, 1530 cm "1 NMR ;3M30-d 6 , δ) : 2.20-4.20 (2IH, m) , 5.72 (IK, c, 0-11.2Hz), 5.93 (IH, d, J=10.2Hz), 6.55-8.23 (8K, m ; , 10.95 (IK, br s) MASS (APCI) : 579 (M+l) (free) .anal . Calcd. for C 30 H3 7 F 6 N 4 O-2HCl-2K 2 C : 01 C 52.41, H 5.57, S.15 Found : C 52.02, H 5 7, N 7X2 (4) (2?0-4- -( 3-AzabicycIo [3.2.2]ncn-3-yl)propylj-l-[3,5- his (trifluoromethyl)benzoyl] -2- (3, 4-dichlorobenzyi) - piperazine dihydrochioride mp : 15CXC 'dec; ,αjχ 5 - : : -2.90° (C-0.5, MeOH ' . IF. (Nu^el; : 3500-3100, 2700-2400, 1630 cm ": NMR (DMS0-d 6 , δ) : 1.60-2.90 (29H, m) , 6.90-8.30 (6H, m) MASS (APCI : 652 (M+2d 650 (M-d) (free^ Anal. Calcd. for C -, H -Cl F r rN-,0-2HCl-H 0 : C 50.22, H 5.30, X 5.67 Found : C 50.25, H 5.60, N 5.32 (5) (2R) -1- [3, r-Bis (trifluoromethyl) benzoyl] -2- (3, 4- dichlorobenzyl) -4- [3- (4, 1 '-bipiperιdιn-1-yl) propyl ι - pioerazme crihydrechicridε np : 200d [α] 8 - : -3.40° (C=0.5, MaOK) IR (Nu θl) : 3300, 2700-2400, 1630, 1450 cm -1 NMR (FMSO-dg, δ) : I.60-3.90 (34H, rX , 6.90-0.30 (OH, m) MASS (FAB) : 693 (M-d) , 695 dree) Anal. Caicd. for C 33 H 40 Cl2F g ,O-3HCl : 0 49.36, K 5.40, N 6.96 Found : C 49. S 1 , H 5.75, N 6.7 Example 54 A solution cf (2R) -1- [ 3, 5-bis ( rif iuorometnyl ) benzoyl ] - 2- ( 3, 4-dιrτιethyibenzyl ) -4- (4-morpholmo-2-butynyl ) piperazine (141 mg) in methanol (10 ml) was hyorogenated over 10^ Pd-C (50 mg) at room temperature under 2-3 atoms. After removal of the catalyst by filtration, the filtrate was concentrated under reduced pressure. Che residue was purified by column chromatography on siiica gel using dichloromethane-methano! as eluent and treated with 4M hydrogen chloride in ethvi acetate solution to give (2R) -1- [3, 5-bis (trifluoromethyl) - oenzoyi i -2- , 4 -dimethylbenzyl ) -4- (4-mcrphoiιnobutyi ) - piperazine dihydrochioride (106 mg) . mo : 279°C - - "3 .α j fd -13.5° (C=0.5 MeOH) : (Nutcd : 3300, 2700-2400, 1645, 1500, 1445, 1370, 1270, 1170 cm -1 NMR (DMSO-d β , δ) : _ . / I S _ = . -. I T -, U m) , 6.56-3.26 (6H, 1.00-11.40 (2K, ) MASS (APCI) : 5S6 (M+l) (free) The following compound was obtained according tc a simiiar manner to that of Example 54. (2R) -1- , 5-Bis (trifluoromethyl)benzoylj -2- (lH-indol-3- ylinethy1) -4- (5-morpholinopentyl(piperazme dihydrochioride [ ] b : -6.10° {C=0.5, MeOH) IR (Neat) : 3400-3200, 2700-2400, 1640, 1430 cm -1 NMR (DMSO-d ? , δ) : i.50-5.20 (27H, m) , 6.60-8.30 (8H, ) , 10.80-11.50 (3H, m) MASS : 611 (M+l) (free) Anal. Calcd. for C 31 H 3 gF 6 N 4 0 9 -2HCid .3H 2 0 : C 52.67, H 5.79, N 7.92 Found : 0 52.66, H 6.13, N X " c Example 56 A. solution of (2R) -1- [3, 5-bis (trifluoromethyl) benzoylj - 2- (3, -dimethylbenzyl) -4- (5-morphoiino-3-pentynyl) piperazine (200 mg i was treated with 4N hydrogen chloride in ethyl acetate solution to give (2R', -1- [3, 5-bis (trifluoromethyl ) - benzoyl . -2- (3, 4-dimethylbenzyi) -4- ( 5-morphoiino-3-pentynyl) - piperazine dihydrochioride. fαj , 1 : -25.2° (C=0.5, MeOH') IP (Neat, : 3700-3100, 2920, 2750-2250, 1635, 1500, 1430, 1275, 11 " d, 1120 cm ~ - NMR dMSO-d 6 , δ; : 2.05-2.20 (6H, m) , 2.75-5.15 (23H, , 6.65-8.28 (6H, r) , 11.60-12.20 (2H, ) 596 (M+l ; (free) ;=lee. c - C 31 H 35 6^3°2- 2 C .5H 2 0 : 0 53.53, H 5.60, N 6.04 _ouno 0 53.47, H 6.14, N 5.91 ι n Example / d?j -1- , 5-3ιs (trifluorome hyl > be zoyl] -2- (3, 4- dimεthylbεr.zyl) piperaz e fu arate (9.13 g was treated with aqueous 10 scdiuir hydroxide solution (65 ml) ana dichroromethane (65 ml 1 . The organic layer was separated, 15 washed v/itn brme, cried over magnesium suifate and evaporated under reduced pressure. A mixture of (2R)-l-jd,5- ois (t ifluorome hyl)benzoyll-2-(3, 4-dimethylbenzyl) piperazine obtained by the above procedure, potassium carbonate (3.60 g) and 1, -dιchicrc-2-butyne (1.9 ml) m N, N-dimethylformamide 20 ( ~ d rr.l) was stirred for 4.5 hours at room temperature. The mixture was poured into water (360 ml' and extracted with ethyl aeetate. The extract was washed with brmε, dπεd ever .magnesium suifate anc evaporated under reduced pressure. The residue was purified by column chromatography cn siiica 25 gel using tcluεne-etnyl acetatε as eluent to give (2R1-1- d, 5-ois ' i luorometnyl) oenzcyl] -2- (3, -dimethylbenzyl) -4- d-chiere-2-butynyl) piperazme (4.S6 g, . I? (Meat) : 1706, 1635, 1503, 1275, 1125 cm -1 NMR (CDCI 5 , δ) : 2.05-5.20 (19K, ) , 6.60-7.64 (6K, rX 30 MASS (APCI) : 531 (M+l) Example 56 A mixture cf (2R) -1- [ 3 , 5-biε (trifluoromethyl) benzoyl] -2- (3, 4-dimεtnylbεnzyl) -4- (4-chloro-2-butynyl) piperazme (0.49 d g 3-methyιmorpholmε hyarocr.ioride (0.15 g) , potassium carbonate (0.29 g) and potassium iodide (10 mg) in dry N,N- di εthyiformamide (5 ml) was stirred fcr 5 hours at room temperature. The mixture was poured into water and extracted with ethyl acetatε. The extract was washed with brine, dried over magnesium suifate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using ethyl acetate as eluent ana treated with 4N hydrogen chicride m ethyi acetate solution to give (2R,ι-l- [3 , 5-bis (trifluoromethyl) enzoyl] -2- 3, -dimethylbenzyl; -4- [4- d-methyimorpholino) -2-butynyl 1 piperazine dihydrochioride (0.28 ) . mp : 150-160d [αj , S - : -5.71° (C=1.0, MeOH) IR (Nujol) : 3300, 2700-2400, 1650, 1430 cm -1 X0MR (DMSO-d 6 , 5) : 1.20-3.22 (29H, ) , 6.60-8.20 (6K, m) , 12.20-12.40 (2H, m) MASS (A-FCI) : 596 (M+l) (free) .Anal. Calcd. for C 31 K 35 F 6 3 G 2 -2HC1-I .7H 2 0 : C 53.25, H 5.82, N 6.01 Found : C 53.28, H 5.97, N 5.80 Example 59 The following compounds were obtained according to a similar manner to that of Example 58. (2R) -1- d, 5-Bis (trifluoromethyl; benzoyl • -2- ( 3, - dimethyibenzyl) -4- [4- (2-methoxymethylmorphoiino) -2- butynyl] piperazine dihydrochioride p : 150-165°C IR (Nujol! : 2300, 27CC-24C0, 1640, 1430 cm -1 NMR (DM50-d 6 , δ) : 2.00-5.22 (28H, m) , 3.25 (3H, 6.50-8.20 (6H, ) , 12.20-12.40 (2H, ) MASS (A.PCI) : 626 (M+l) (free) Ana!. Calcd. for C 32 K 37 FgN 3 0 3 -2HC!-H 2 0 : C 53.64, K 5.77, N 5.86 Found : C 53.60, H 5.94, N 5.67 (2 ; (2R) -1- d, 5-Bis (trifluoromethyl) benzoyl ] -2- ( 3, - dim.etnyibenzyi ) -4- [4- (2-f luorometnylmorphoiino) -2- butynyi j piperazine dihydrochioride mp : 175-180d [αj? 5 - 4 : -8.75° (C=0.7, MeOK) IR (Nujbl; : 3300, 2700-2400, 1635, 1500 cm -1 NMR (DMSO-d 6 , δ) : 2.00-5.22 (28H, m) , 6.50-8.20 (6H, ) MASS (APCI) : 614 (M+l) (free) Anal. Calcd. for C 21 H 3 ,F 7 3 0 2 -2HC1-H 2 0 : C 52.85, H 5.44, N 5.96 Found : C 52.82, K 5.45, N 5.74 (3) (2R) -1- , 5-3is (trifluoromethyl) benzoyl] -2- (3, 4- dimethylbenzyl) -4- [4- (3, 3-dimethyimorpholino) -2- butynyl ] piperazine dihydrochioride mp : 1S0-190 C C IR (Nujol) : 3300, 2700-2400, 1635 cd 1 NMR (DMSO-d^, δ) : 1.30-1.40 (6H, ) , 2.0C-5.22 (25H, m) , 6.60-8.20 (6K, m) , 12.05-12.20 (2H, m) MASS (APCI) : 610 (M+1H) (free) Anal. Calcd. for C 32 K3 7 F 6 3 θ2-2KCl-2.5H 9 C : C 52.82, H 6.09, N 5.68 Found : C 52.84, H 5.89, N 5.78 (4) !2R;-l-ιd,5-3is(trifluoromethyl ) benzoyl 1 -2- (3, 4- dimethyibenzy!)-4-[4-( (2S) -2-methoxymethylpyrrolidino) - 2-butynyl1 piperazine dihydrochioride mp : 1 5-197°C 'oXig 8 - : -19.79 : (C=0 , MeOK) IR (Nujol) : 3450, 2700-2400, 1640, 1450 cm -1 NMR ;DMSO-d fi , δ) : 2.00-5.22 (23H, ' , 3.32 (3H, s) , c.50-6.20 (6H, ni , 11.50-11.70 (2H, m) MASS (A.PCI) : 610 (M-rl (free) for C3 2 H 3 - 7 F 6 N 3 0 ? -2HCidH 2 0 : C 53.49, H 6.03, N 5.35 Found : C 53.66, K 5.73, N 5.82 ■ ^ > - ' - d .5-Bis (tri: .uorerrethyl ' benzoyl " ' -2- (3, 4- dimetnylbεnzyl ) - 4 - [ 4 - { 3-methoxymetr.ylmorpholmo) -2- butynyl iperazine dihydrochioride 10 np : 1 0-155°C Lot] J 8 - 4 : -7.22° (C=0.63, MeOH) IR 'N'lhod : 3300, 2700-2400, 1635, 1440 cm "* NMR (TMS0-d , 6) : 2.00-5.22 (28H, .) , 3.32 (3H, s) , 6.50-3.20 (6K, ) 15 MASS (APCI) : 626 (M+l) (free) Anal. Calcd. for C 3? h 7 F 6 3 θ3-2HC! : C 52.32, H 5.90, N 5.72 Found : C 52.33, H 6.11, N 5.43 20 Example 60 .A mixture cf (2R) -1- [ 3 , 5-bis (trifluoromethyl)benzoyl] -2- d, 4-dιmεtnylbenzyl) piperazine (0.38 g) , potassium carbonate (0.42 ς) , 3- d-pyridyl) -2-propynyl chloride hydrochloride (1.9 ml) and small amount cf potassium iodide in N,N- 25 dimethylformamide (10 ml) was stirred for 2 hours at 40°C. The m.ixture was pouree into water anc extracted with ethyl acetatε. Tne extract was washed with brine, dried over magnesium suifate and evaporated under reduced pressure. Zhe residue was purified by column enrematcgraphy on silica gel ^ using etnyl acetate as eluent and treated with 4N hydrogen chloride m ethyl acetate solution to give (2R)-l-[3,5- bis ( trifluoromethyl) benzoyl] -2- (3, -dimefhyiJeenz i) -4- [3- (3- pyridv-.) -2-propynyl]piperaz e dmydrccnloride (0.26 g) . mp : 1 0-150d αjg 8 - : -10.13° (C=0.S, MeOH) IR (Nu;jθij : 3300, 2700-2400, I63C, 1450 cm _1 NMR (DMSO-o 6 , δ) : 2.00-5.22 <17H, m) , o.50-8.20 (8H, m) , c .70-6.85 (2H, ) MASS XAPCI) : 560 (M+l (free ) Anal. Calcd. for C^F^FgN^C HCl .8H 9 0 : C 52.76, H 5.11, N 6.15 Found : 2 52.74, H 4.26, N 6.05 Exam le 61 A mixture cf (2R! -]- d, 5-brs (trifluorometnyl ) benzoyl] -4- L (E) -4-chiorc-2-butenyl] -2- (2-naphtnyimethyi; piperazme (300 g) , thicmerpholmε (0.054 ml- ana pcwdεrεd potassium carbonate (100 g) m dry acetonitriie (3 mi) was heated at 50°C fcr 1 - hours. Aodition.al potassium carbonate (100 mg) anc thiomorphoime (0.054 ml, were aoaed and then the resulting mixture was further heated at the same temperature. .After 2 hours, the reaction mixture was cooled and then fiitered. Tne filtrate was concentrated under reduced pressurε and tne resulting residue was purified by column chromatography on silica gel using a mixture of dicnloromethane and methanol (40:1) . Tne obtained product was d_ssolved in ethyl acetate and treated with 4N nyαrogen chloride in etnyl acetate (0.6 ml ι to give (2R)-l-[3,5- bi≤ (trifluoromethyl) benzoyl] -2- (2-naphthylmethyl) -4- ( (E) -4- tnιomcrphclmo-2-butenyl) piperaz e dihydrochlcrioe (190 mgd p : >230°C ϊαj f , 0 -- : -14.50" (C=0.5, MeOH) IR (Nujcl) : 3650-3100, 2410, 1640, 1274, 1130 cm -1 NXIP (DMSO-d 6 , δ) : 2.55-5.30 (21H, ml , 6.00-6.30 (2H, m) , 7.00-3.20 10H) MASS : 622 (M-d I (free) Example 62 The following compounds were obtained according to a simiiar manner to tnat of Examoie 61. 76 (1) ;2R)-I-d,5-3is(trifluoromethyl )benzoyl]-2-(2- naph hyimethyl) -4- [ (Ξ) -4-morpholmo-2-butenyl] piperazine dihydrochioride mp : 230d ! ] ]2 6 - ; : -16.60° (C=0.5, MeOH) I? (Nu:o_., : 3600-3100, 2450, 1639, 1273, 1130 cm -1 NMR dMSO-o 6 , δ) : 2.30-3.30 (21H, m;, 6.10-6.30 (2H, m; , 7.00-3.25 (10H, m; MASS : 60o (M-d; (free) ) (2R) -1- , 5-Bιs [trifluoromethyl, oenzoyl] -2- (3, 4- dimet-hylbenzyl) -4- [ (E) -4-thιomorphoiino-2- butεnvi ioioεrazinε dihydrochioride IR (Nnjci^ : 5603-3100, 2450, 1642, 1274, 1130 cm -1 NMR (TMSO-d f -, δ) : 2.10-5.10 (27K, ml, 5.90-6.30 (2H, m/ , c . cD- ( 3K r ^ (2K, s), 8.05 (. s) MASS 600 (M-d) (free) Example 63 -X mixture of (2R) -1- 3, 5-bis (trifluoromethyl)benzoyl] -4- (Ξ) -4-chicro-2-butenyi]-2- (3,.4-dιmethylbenzyi) piperazine (450 mg) , 3, 3-dimethyimorphoiinε hydrochloride (130 mg) and powdered potassium carbonate (350 mg) m dry acetonitrile (5 mi, was heated at reflux temperature for 3 hours. A.dditionai potassiu earbonate (350 mg) and 3, 3-dimethyimorphoiine hydrochloride (130 mg) were added and then the resulting mixture was further heated at reflux temperature. After 6 hours, the reaction mixture was cooleo and then filtered. The filtrate was concentrated under reducεd pressure and the resulting residue was purified by column chromatography on silica gel using a mixture cf dichiorometnane and metnanol (50:1; . The obtained product was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate ^ solution tc give (2R) -1- [3, 5-bis (trifluoromethyl) enzoyl] ;3, -dimethylbenzyl) -4-[ (E)-4-(3, 3-dimethylmorpholino) -2- butenyi ]piperaz e dihydrochioride (370 mg) . p : >23G°C IR (Nutci) : 3400, 2450, 1639, 1274, 1130 cm "1 NMR (DMSO-c 6 , δ) : 1.34-1.40 (6H, m) , 2.10-2.18 (6K, m) , 2. " 0-5.20 (19H, m) , 6.10-6.30 (2H, ) , 6.65- 2H, MASS : 612 (M+l) (free) Example 6- A mixture of (2R) -1- 3, 5-bis ( rifluoromethyl; benzoyl -2- (3, 4-dimεthyibenzyl) piperazine (1.0 g) , (E) -1, 4-dιchloro-2- butene (0.31 ml) and powdered potassium carbonate (0.4 g) in- dry acetonitriiε (10 ml) was hεated at 50°C. After 4 hours, the reaction m.ixture was cooled and then filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography on siiica ge! using a mixture of toluene and ethyl acetate ( 4 : 1 ) te give (2R) -1- [2, 5-bis (trifluoromethyl) benzoyl] -2- (3, - dimethyibenzy!) -4- (E) -4-chloro-2-butenyl]piperazine (0.53 g) IR (Neat) : 3460, 1638, 1272, 1125, 900 cm ~: NMR (CDCI 3 , δ) : 2.00-5.20 (19H, ) , 5.75-6.00 (2H, ) , 6.60-8.00 (6H, m) MASS : 533 (M+l) Example 65 The following compound was obtained according to a similar manner to that of Example 64. (2R)-i- 3,5-Bis (trifluoromethyl) benzoyl] -2- (2- r.aphthylrr.ethyi) -4- [ (E) -4-chicro-2-butenyl]piperazine IR (Neat) : 1637, 1273, 1128, 900 cm "1 30 NMR (C CI3, δ) : 2.05-5.20 (I3H, ) , 5.30-6.00 (2H, m) , 7.10-8.10 (10H, m) MASS : 555 (M+l) Examp e 66 .A mixture of (2R) -I- [3, 5-bis (trifluoromethyl ) benzoyl] -2- (iK-mdol-2-yimethyI) -4- (3-methylsulfonyloxypropyl/piperazine (150 mg) , 4-ammomorphoime (36 mg) and triethvlamine (52 mg) m dry methancl (5 ml) was refluxed for 2 hours. The reaction mixture was concentrated unoεr reduced pressurε and the resulting residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic layer was washed with brine and drier; over magnesium suifate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and metnanoi (10:1) tc afford an oily product, which was treated with 4N hydrogen chloride in ethyl acetatε solution (0.5 mi) to give (2R) -1- [3, 5-bis (trifluoromethyl) - benzoyl -2- ' IK-indol-3-ylme nyI, -4- [5- (morpholinoamino) - propyl] piperazme dihydrochioride (53 mg) . ]O ]P, 3 : -3.60° (C=0.5, MeOK) IR XNu:cl) : 3300, 2500, 1630, 1420, 1275 cm "1 NMR (DMSO-d 6 , δ) : 2.00-5.24 (23K, ) , 6.60-8.23 (8H, m) , 10.94 (IH, s) , 11.50 (IH, br s) MASS : 598 (M+l) (free) Example 67 One icllowing compounds were obtained according to a similar manner to that of Example 66 . (1 ) (2R) -1- 3, 5-3is (trifluoromethyl) benzoyl ] -2- (lK-indcI-3- yimetnyi) -4- [ 2 - (cis-2, 6-dimethyimorpholino) ethyl ] - piperazine dihydrochioride ]^ C : -2.60 c (C=0.5, MeOH) IR (Nu-od : 3350, 2600, 1640, 1280, 1175, 1130 cm -1 NMR (DMSO-d 6 , δ) : 1-55 (6H, , , 2.52-5.20 (19H, m) , 6.60-3.24 (8H, ) .. 10.95 (IH, s) MASS : 597 (M-d) (free' 5 (2) (2R)-l-d,5-Bis( rif luorometnyl , benzoyl ] -2- (lH-indol-3- yimet.Vv 1 ' -4- [3- ( cis-2 , 6-αimεthyImcrphol o) propyl ] - piperazine dihydrochioride I? ^ci : 3350, 2600, 16<d, 1280 crd IC NMR (DMSO-d 6 , δ) : 1.20 (6H, ) , 2.C8-5.20 (21H, m) , 6.63-3.33 (8H, rr.) , 10.94 [IK, s) MASS : 611 (M-l) (free' (3) (2R) -1- [3, 5-Bιs (trifluoromethyl ) benzoyl] -2- (3,4- 5 dim.etnylbenzyl ) -4- [2- (1-imidazolyl , ethyl] piperazme dihydrochioride IR (Nujol , : 3350, 2700, 2575, 1640, 1430, 1280, 1170, 1130 cm -1 0 NMR (TMSO-d 6/ C) : 2.04-5.20 (12K, ) , 2.09 (3K, s] , 2.16 (3K, s) , 6.55-8.22 (8H, m) , 9.29 (IK, s) (4) (2R)-l- 3,5-3is (trifluoromethyl) benzoyl ] -2- ( 3, 4- 5 dimethylbenzyl —4 — [3— (morpholmoaminc ) propyl j piperazine dihydrochioride ;α]^ C : -14.10° (C=0.5, MeOH) I? XNujol) : 2350, 2550, 1640, 1430, 1280 cm -1 NMR (BMSC-dg, δ) : 1.97-5.14 (23H, rr.) , 2.10 (3H, S) , 0 2.18 (3H, s) , 6.64-8.24 (6 , m) , 10.92 (IK, br s) MASS : 58 ~ > (M+l) (free) (5) (2R)-i-d,5-Bιε (trifluoromethyl) benzoyl ] -2- ( 3, 4- dimethylben.zyl ) -4- [2- (3-pyridyimethyiammo) ethyl ] - 5 Piperazme trihydrochloride ■ αl 2i 3.5( :C=0.5, MeOH) (Nu-icl 3400, 2600, 1640, 1430, 1280, 1170, NMR 'DMSO-dg, δ) : 2.0^-5.20 (13K, ) , 2.10 (3K, s) , 2.16 (3H, s) , 4.50 (2H, s;, 6.60-9.09 (10H, m) , 10.22 dK, tr s) MASS : 572 (M-d (free; d) (2R)-i-]3,5-3is trifluoromethyl ; benzoyl _ • -2- (3, 4- dimethylbenzyl' -4- (2-homomorpnclmcεthyl) iperazine dihydrochioride αd : -9.9C 3 (C=0.5, MeOH) IR (Nujol) : 34CO, 260c, 24.50, 1640, 1430, 1280 n ' 1 NMR (EMSO-d 6 , δ) : 2.04-5.17 (23H, m) , 2.10 (3H, s), 2.16 (3H, s), 6.62-6.26 (6K, l MASS : 572 (M-d) (free) (7) (2R)-l- 2,5-3is( rifluoromethyl) benzoylj -2- (3, 4- dimethylbenzyl! -4- (3-homomorpholinopropyl) piper zme dihydrochioride 1CX5 9 : -10.0° (C=0.5, MeOK) IR (Nujol) : 3400, 2600, 1635, 1430, 1280 cm -1 NMR (DMSO-d 6 , δ, : 2.73-5.20 (25K, ) , 2.10 (3K, s), 2.16 (3H, S), 6.62-6.24 (6H, m) MASS : 586 (Mτl) (free) (6i !2R;-1- ]3,5-3IS (trifluoromethyl)benzcyl] -2- (lH-mdol-3- Ime hyl) -4- (3-homomorphoiinopropyl) piperazine dihydrochloride iccjfV : -5.50" (C=0.5, MeOH) IR (Nujol) : 3300, 2650, 1640, 1275 cm "1 NMR dMΞO-d 6 , δ) : 1.90-5.23 (25H, rr.) , 6.62-8.34 (8H, ) , 10.95 (]H, s) M SS : 597 (M+i) (free; (9! dP)-W3,5-Bιs (erifluoromethyl) benzoyl1 -2- (3, 4- dichiorooenzyl ) -4- [3- ( -acetylpιperιdino) propyl ) - piperazme dihydrochlcride fα]g C : 2.20° (C=0.5, MeOH) IR (Nujol) : 3350, 2650, 1700, 1630, 1275 cm -1 XMF (XKSO-dg, δ) : 2.69-5.21 (24H, m) , 2.16 (3H, s) , 6.97-8.30 !6H, m) d.S3 : 552 (M, (free' (10 i (2?i-i-d,5-Bi£! crif_uorcm.et.hyI) benzoyl j -2- ( 3, 4- dimetb.ylber.zyl ) -4- [ 3- ( 4-acetyipιperιdmo 1 propyl ] - piperaz e dihycrochioπce IR (Nujol) : 3425, 3375, 2500, 1705, 1640, 1275 cm ~: NMR (DMSO-d 6 , δ) : 1.67-5.20 (24H, up , 2.16 (6K, sj , 2.2S (3K, s) , 6.62-8.25 (6K, ) , 10.60 (IK, or s), 11.49 (IH, br s) MASS : 612 (M+l) (free) (11, (2R -1- [3, 5-Bιε (trifluoromethyl) benzoyl] -2- (3, 4- dichiercbenzyl; -4- (2-mcroholmcetnyl) piperazme dihydrochioride lαj? C : 6.10" (O0.5, MeOH) IR XXujcl) : 3350, 2600, 1620, 1270 cm -1 XMR d.MSC-d 6 , δ 1 : 2.14-5.16 (21H, m) , 6.93-3.27 ( €H, m) MASS : 593 (M) (free) (12) (2R)-l-d,5-3ιs ; t if luoromethyl ) benzoyl j -2- (IK-mdel-2- yimetnyl) -4- i - ! 4-methoxypιperidino) propyl j piperazme dmydrcchloride LCc d : -6.70° (C=0.5, MeOH; IP (IMUjOi) : 3300, 2550, 1625, 1270 cm -1 MMR (DMS0-d 6 , δ) : 1.57-5.20 (24K, m) , 2.2" (3H, s) , 6.60-S.28 (8H, m) , 10.95 (IK, si MASS : 611 (M+l) (free 1 (13) (2R)-i-[3,5-Bis (trifluoromethyl) benzoyl] -2- (3, 4- dimethylbenzyl ) -4- [2- [N- (2-methoxyethyl ) -N- methyiaminc] ethy ] piperazine dihydrochioride mp : 222°C (dec.) ct] ζ 3 : -12.50° (O0.5, MeOH) IP XNujol) : 3380, 2400, 1644, 1275, 1130 err, "1 NMR ,'DMSO-dg, δ) : 2.0-2.3 (7H, m) , 2.86 (3H, s) , e.33 (3H, s) , 2.3-5.3 (18H, m) , 6.6-8.3 (6K, ) MASS : 560 (M-d) (free) [1'-'.) [2R) - ' .- [ , 5-3is ( trifluoromethyl ;oenzoyl]-2-d,4- di ethylbenzyl) -4- [3- (hexamethyieneimmo) propyl] - piperazine dihydrochioride [ }^° : -11.70° (C=0.5, MeOH) IR /Neat) : 3400, 2600, 1640, 1430, 1280 cd 1 NMR (DMSO-d 6 , δ) : 1.49-5.20 (27H, m) , 2.10 (3H, s) , 2.19 (3H, s) , 6.67-3.23 (6K, ) MASS : 584 (M-d) (free) (15) (2R;-l- 3,5-3is(trifluoromethyl)benzoyl] -2- (3, 4- dime nylbenzyl ) -4- [2- {4-pyrιdyime hyIamino) e hyl ι - piperazine trihydrochloride IR L eac : 3400, 2600, 1640, 1430, 1280, 1175, 1130 cm "1 NMR (DMSO-d 6 , δ) : 2.10 (3K, s) , 2.18 (3H, s) , 2.64- 5.20 (13H, mj , 4.16 (2H, s) , 6.40-8.97 (10H, ) MASS : 579 (M-l; (free) (16) (2R)-l-[2, 5-Bιs (trifluoromethyl) benzoyl] -2- (3, - dimethylbenzyl) -4- [3- (1, 2, 4-trιazol-3- yla ino) propyl] piperazine dihydrochioride fα-lDi : -10.50° (C-0.5, MeOK) I? (Neat) : 3075, 2700, 1675, 1640, 1430, 1280, 1170, 1130 cm -1 NMR dMSO-dg, δ) : 2.05-5.20 (15H, m) , 2.09 (3H, s), 2.16 (3H, s) , 6.60-8.34 (9K, ) MASS : 569 (M-d' (free) Example 68 A mixture of (2R) -1- [3, 5-biε (trifluoromethyl) benzoyl] -2- d-nachfhyim.ethy_ ; piperazme dOO rag, , 4-thiomorρholino-2- butynyi chloride hydrochloride (170 mg) and powdered potassiu carbonate (210 mg) in dry acetonitrile (3 ml) was refluxed fcr 7.5 hours in the presence of potassium iodide ,2C g; . The reaction mixture was cooled and then filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol (50:1) . The obtained product was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate solution (C.6 mi) to give (2R) -1- [3, 5-bis (trifluoromethyl) - benzoyl] -2- (2-naphtnyimethyi; -4- (4-thιomorpholino-2-butynyi) - piperazine dihydrochioride (300 mg) . mp : 152-156°C ccj g 7 : -47.20° (C=0.5, MeOH) IR (Nujol) : 3350, 2500, 1637, 1275, 1125 cm -1 NMR (DMSO-σdc, δ) : 2.70-5.30 (21H, ) , 7.CG-8.20 (10H, m) MASS : 620 (M-d) (free: Example 69 A mixture of (2R) -1- [3, 5-bis (tri luoromethyl) benzoyl] -2- (3, 4-dimethylbenzyl) -4- (4-chloro-2-butynyl) piperazine (200 mg) , 1-cyeIohexylρiperazine (63 mg) and powdered potassium carbonate (210 mg) in dry , -dimethylformamide (2 ml) was stirred for 12 hours at room temperature. Additional i-cyciohexyipiperazine (25 mg) was added and after 2 hours the reaction mixture was poured into water (20 ml) anc extracted with ethyl acetate. The organic layer was wasted wife brine ano dried over magnesium suifate. After evaporation of the solvent, the resulting residue was purified by celumn chromatography cn silica gel using a mixture of cicnlorometnane anc etnanoi (30:1) . Tne obtained product was dissolved m εtnyl acetate ano treated witn 4N nydroge" crdcrice ethyl acetate solution (0.6 ml) to give (2P ) -1- , 5-cis (trifluorometnyl) benzoyr] -2- (3, 4- di ethylDenzyl ι -4- [4- (4-cycIonexyipιperazm-l-yl) -2- butynyl j piperazme trmydrochmride (220 mg) . ^ : _ ~ 5-190°C fα ' - 25,2 : -7.20° (2=0d, MeOH' -R fNu c1) : 3370, 2750-1920, 635, 1276, 1126 c N NMMRR (( MMSSCC--αc 6 - , δδ)) :: 11..0022--5. .20 (36K, ) , b.60-8.30 (6H, m) MAS; 664 ( -rl) (free Example 70 Potassium carbonate (18 "7 mg) and 2- (chloromethyl) - pyridme nyorochloride (81 mg) were added to a solution of (2R) -1- , 5-oιs (trifluoromethyl)benzcyl]-2-(3,4- dimethyloenzyl ) piperazme d00 mg) rr N, N-dimethylformamioe (4 ml' at rooπt temperature with stirring. After 2 nours, tne reacticr. mixture was poured into water (50 ml) and extracted with ethyl acetate. Tne organic layer was washed with water and tr.en dried over magnesium suifate, and evaporated under reduced pressure. The obtained residue was purified by eolum.n cnrom.atography on silica gel using a mixture of ethyl acetate and toluene (1:3) ano treated with 4N hydrogen chioriαe m ethyl acetate solution to afford (2R)-l-[3,5- bis (trifluoromethyl)benzoyl] -2- (3, -dimetnylbenzyl) -4- (2- pyndylmetnyl ) piperazme dihydrochioride (123 mg) . [α]§ 3 : -28.3C 0 d=0.5, MeOK) IR (Nujol) : 3360, 2560, 1640, 1278, 1130 cm -1 NMR (DMSO-α 6 , δ) : 2.0-2.3 dOH, ; , 2.6-5.8 (9H, m) , 6 . 6 - 8 . 7 ( 1 0H , ) MAS S : 53 6 (M+ l ) ( f ree ) Examoie 71 Lindlar catalyst (Pά-CaCC-.-Pb (OAc) 2 ) (40 mg) was added to a solution of (2R) -1- [3, 5-bis (trifluoromethyl) benzoyl] -2- (IK-indol-5-yImethyl) - 4- ( -morpholino-2-butynyl) piperazine in methanol ml; . The mixture was stirred fcr 2 hours under hydrogen at 25°C and then filtered. The filtrate was concentrated under reduced pressure and the resulting residue was chror.atographed cn silica gel with cichiorometnane- methar.ol (20:1) as eluent to give material which on treatment with 4N hydrogen chloride m ethyl acetate solution afforded (2R) -I- [3, 5-bis (trifluoromethyl) benzoyl] -2- (lH-indcl-3- ylmethyl; -4- [ (Z) -4-morpholino-2-butenyl] piperazine dihydrochlcride (104 mg) . IR (Nujol) : 3700-3150, 2750-2300, 1635, 1275, 1170, 1120 cm -1 NMR (DMSO-Qg, δ) : 3.00-4.10 (21H, mX , 6.05-6.35 (2H, , , 6.80-8.10 (8H, m) , 10.72 (IH, ε) MASS : 595 (M-d) (free ' Example 72 The following compound was obtained according to a similar manner to that of Example 71. !2R) -1- , 5-Bis (trifluoromethyl)benzoyi]-2- (3, 4- cimethyibenzyi ) -4- [ (Z ! -4-morpholino-2-butenyl]piperazine dihydrochlcride mp : 243-246°C IR (Nujcl) : 3600-3150, 260C-23C0, 1645, 1275, 1170, 1130 cm "1 NMR (DMSO-d 6 , δ) : 2.10-2.20 (6H, m) , 3.0-4.2 (21H, 38 ) , 6.05-6.35 (2H, m) , 6.30-dlO (3H, m; , 7.60 (2H, s) , 8.09 (IH, s; The NMR spectrum of this compound was measured at 90°C MASS : 584 (M+l) (free) Example 73 X- solution of (2R) -1- [3, 5-bis (trifluoromethyl) benzoyl] - 2- ( lK-indoi-3-ylmethyI i -4- (4-mcrphcImc-2-butynyl) piperazine in methanol (10 ml) was hydrcgenated m the presence of 10. ?d-carbon (50 mg) at room temperature. After completion of the reaction (1 hour and 20 minutes), the reaction mixture was filtered and then chromatographeα on silica gel with dichlorometnane-methanol (20:1) to give material which on treatment with AN hydrogen chloride ethyl acetate solution afforded (2R)-l-[3, 5-bis (trifluoromethyl) benzoyl] -2- (1H- mdoi-3-yimechyi) -4- ( -morpholinobutyl) piperazine dihydrochioride (165.1 mg) . iαjg 1 : -7.10° (C=0.5, MeOH) IR (Nujol) : 3700-3150, 2720-2450, 1635, 1275, 1130- 1080 cm -1 NMR (DMSO-o 6 , δ) : 1.70-2.00 (4K, m) , 2.95-5.20 (21H, ) , 6.60-8.25 (8K, rr.) , 10.95 IIH, s) , 11.10-11.80 MASS : 597 (M+l) (free) Example 7^ The following compound was obtained according to a similar manner to that of Examoie 73. (2R) -1- [2, 5-Bis (trifluoromethyl) benzoyl] -2- (3, 4- dimethylbenzyl) -4- (5-mcrpholinopentyl) piperazine dihydrochlcride mp : 235-238°C [α]§ 2 : -13.90° (C=0.5, MeOK) (Nuj 1) : 3500-3100, 2600, 1630, 1270, 1180-1060 cm " NMR (OMSO-d 6 , δ : 1.2-2.0 (6H, rr.) , 2.0-2.5 (8H, ) , 6-5.2 (19H, m) , 6.6-8.3 (6H, m) , 11.26 (2H, m) MAS 600 (M+l) (free) Example /5 (22 ) -1- [5, 5-3is (trifluoromethyl ' benzoyl ] -2- (3, 4- dimethylbenzyi ) iperazine (200 g; and potassium carbonate (157 mσ) were added to a mixture cf (2.) -4-morpholιno-2- butenyl chicride hydrochloride (105 g) and acetonitriie (3 ml) . The resulting mixture was heated at reflux temperature under stirring. After 16 hours, the reaction mixture was evaporated under reduced pressure and the residue was partitioned between ethyl acetate ano water. The organic phase was separated and washed with brme, and dried over magnesium suifate. The solvent was removed in vacuo to leave an cil which was chromatographed on siiica gel with dichloromethane-methanol (50:1) as eluent to give material whicn en treatment with 4N hydrogen chloride in ethyl acetate solution (0.2 ml) afforded (2R) -1- [3, 5-bis (trifluoromethyl) - benzoyl] -2- (3, 4-dimethylbenzyl) -4- [ (E) -4-morpholino-2- butenyi ] piperazine dihydrochioride (194 mg) . mp : 236-242"C IR (Muπol) : 3350, 2900, 1645, 1275, 1185, 1170, 1135 era "1 NMR (DMSO-d 6 , δ< : 2.16 (3K, s) , 2.20 (3H, s) , 2.60- 4.80 (I9H, m) , 3.91 (4H, t, J=4.8Hz), 6.04-6.40 (2H, ) , 6.74-7.15 (3H, ) , 7.61 (2H, s) , 8.08 (IK, 5! The NMR spectrum cf this compound was measured at 90°C. MASS : 584 (M+l) (free; Example ~ 6 Zr ' .e following compound was obtained according to a similar manner to that of Example 75. (2R) -1- [3, 5-Bis (trifluoromethyl) benzoyl] -2- (lH-indol-3- yimethyl) -4- [ (E) -4-morpholinc-2-buteny ] piperazme dihydrochlcride mo : 123-1 [ ]ξ° : -0.2° (C=3.3, MeOH) IR (Nujol) : 3350, 2750-2000, 1655, 1635, 1275, 1175, 1125 cr. "1 NMR (CMS0-d 6 , δ) : 2.60-5.00 (17H, m) , 3.89 (4H, t, 3=4 .8Hz), 6.00-6.40 (2H, ) , 0.70-7.50 (5H, rr., , 7.30 (2H, s) , 8.03 (IH, s) , 10.74 (IH, ≤) The NMR spectrum of this compound was measured at 90°C. MASS : 595 (Mτl) (free) Example 7 " To a stirred mixture of (2R)-l-(3,5- bis (trifluorometnyl)benzoyI]-2-(IH-mdcI-3-yImethyl) - piperazine (0.2 g) and l-methyl-4-formyl-lH-pyrazole (0.05 g) in dicnloromethane (2 ml) under nitrogen atmosphere was added sodium, triacetoxyborohydride (151 mg) at room temperature. After 4 hours, the reaction mixture v/as evaporated under reduced pressure, and ethyl acetate (20 ml) and aσueous sodium hydrogen carbonate solution (10 ml) were added tc the residue. The organic layer was separated and washed with brine, dried over magnesium suifate and then concentrated under reduced pressure. The resulting residue was purified by column chromatography cn silica gel using a mixture cf ethyl acetate and methanol (50:1) . The obtained product was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate solution tc give (2R)-l-[3,5- ois (tri luoromethyl) benzoyl] -2- ( IH- oI-3-yimethyl ) -4- [ ( I- methyi-IH-pyrazol-4-yI) methyl] piperazine hydrochloride (154 X>.C) . mp : 122-136°C 1 fi r -D 8.50° (C=0.3, MeOK) IR (Nujol) : 3350, 2750-2000, 1655, 1640, 1275, 1175, NMR (DMSO-d 6 , δ) : 2.8C-5.20 (14K, m) , 6.50-8.30 (10H, IΓ. J , 10.90 (IH, s) , 11.40-11.90 (IH, br s) MA.SS : 550 (M+l) (free) Example 78 A mixture of (2R) -1- [ , 5-bis ( rifluoromethyl) benzoyl] -2- (3, 4-dimεthylbenzyl) -4- [2- (methylsulfonyloxy) ethyl] piperazine (200 mg) , 2-ethoxyethyiamine (0.044 ml; and triethvlamine (0.093 ml'ι in acetenitrile (5 ml) was refluxed for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was partitioned between ethyl acetate and aσueous sodium hydrogen carbonate solution. The organic layer was washed with brine and dried over magnesium suifate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel using a mixture cf dicnloromethane and methanol (20:1) to afford an oily product, which was oissdived in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate solution tc give (2R) -1- [3, 5-bis (trifluoromethyl) benzoyl]-2-(2,4- dime hylbenzyl) -4- [2- (2-ethoxyethylamino) ethyl]piperazine dihydrochlcride (64.5 mg) lO ^, 2 : -6.70° (C=0.5, MeOH) IR (Neat) : 3400, 2650, 1640, 1430, 1280, 1170, 1150, 900 cm -1 NMR (DMSO-d 6 , δ) : 1.63 (3H, m) , 2.0-2.30 (6H, m) , 2.6-5.3 (20H, m) , 6.6-8.3 (6K, m) , 9.2-9.6 (IH, br MASS : 560 (M-d) (free) Preparation 8 To a mixture of N- (tert-butylcarbonyl) -4-fluoro-2- phenyiaianme (5.25 g) , N-benzylgiycme oenzyl ester hydrocnioride (5.41 g) and triethvlamine (9.04 ml) in dicnloromethane (50 mi) was added 2-chloro-l-methylpyridinium iodide (5.21 g) at room temperature, and the mixture was stirred for 2.5 hours. The mixture was evaporated under reduced pressure, and the resulting residue was dissolved into ethyl acetate. The ethyl, acetate solution was washed witn diluted hydrochloric acid, saturated sodium hydrogen carbonate aqueous solution and brine successively, and dried over magnesium suifate. After evaporation of the solvent, the resulting residue v/as chroir.atographed on a silica gel using a mixture of toluene and ethyl acetate as an eluent tc give (2R) -N-benzyi-N-benzyloxycarbonylmethyl-2- (tert- butoxycarbonylam o) -3- (4-fiuorophenyi) propanamide (9.62 g) . IR (Nujol) : 3350, 1735, 1680, 1650 cπd 1 NMR (DMSO-d 6 , δ) : 1.24, 1.30 (9H, 2s), 2.70-2.90 (2H, m) , 3.85-4.80 (5H, m) , 5.12 (2K, d, J=3.2Hz), 6.95- 7.45 ;1 H, ) MASS : 521 (M+l) Preparation 9 Tc an ice-cooled solution of (2R) -N-benzyl-N- oenzyloxycarbonylmethyI-2- (tert-butoxycarbonylammo) -3- (4- fiuorophen i ) propanamide (9.48 g) m dichlcromethane (55 ml) was added 4N hydrogen chloride in dioxane solution (54.6 ml) . The mixture was stirred at the same temperature for 15 minutes and at room temperature for one hour. After removal of solvent by evaporation, excess aqueous sodium hydrogen carbonate solution was added to the resulting residue. The mixture was warmed at near 5C°C for several minutes and the resulting precipitates were collected by filtration and washed with water and dried in vacuo to give (3R) -I-benzyl-3- (4-fluorobenzyl) piperazine-2, 5-dιone f5.00 g) . ". Ot 2 ' D ■ 20.30° (C=0.δ, MeOH) IR (Nujol) : 3200, 3050, 1665, 1220 cm -1 NMR (DMSC-d , δ) 2.80 (IH, d, J=17.3Hz) , 2.88 (IH, dd, J=I3.7Hz, 4.7Hz) , 3.15 (IH, dd, 3=13.7Hz, bT ' .K, c, J=17.3Kz) , 4.15 (IH, d, r=ι Δ _ 4Hπrz);, 4.26 (IH, m) , 4.63 (IK, d, 0=14.4Hz), c.80-7.40 (9H, rr.) , 8.33 (IH, br s) MASS p eeoa: To an ice-cooled suspension cf lithium aluminum hydride d.2 g) in tetrahyαrcfuran (91 ml) was added ( 3R) -l-benzyl-3- (4-fluorobenzyl ) piperazme-2, 5-dione (4.95 g) by small portions. The mixture was stirred at the same temperature fcr 15 minutes and at room temperature for one hour. After removal of solvent by evaporation, aqueous sodium hydrogen carbonate solution was added to the resulting residue. The mixture was warmed at near 50X2 for several minutes and the resulting precipitates were collected by filtration, washed with water and dried m vacuo to give (3R) -l-benzyl-3- ( - fluorobenzyl ; piperazine (4.63 c) as an oil. I? (Neat) : 3300, 1215 cπd 1 NMR (DMSC-d 6 , δ) : 1.90 (2K, ) , 2.45-2.90 (5H, m) , 2.30-3.45 (4H, ) , 6.95-7.35 (9H, ) MASS : 285 (M+l) Preparation 11 A mixture of (2R) -4-benzyl-i- [3, 5-bis (trifluoromethyl ) - oenzoyl ] -2- (4-fluorobenzyl)piperazme (7.92 g) , ammonium formate (2.38 g; and 10' palladium charcoal (0.79 g) in a mixed solvent of ethanol (80 mi) and water (8 ml) was stirred for 1.5 hours at 60°C under nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through Celit ^ pad. The filtrate was concentrated under reduced pressure and the residue was dissolved into ethyl acetate. The solution was washed with water and crine successively, dried over magnesium suifate, and evaporated under reduced pressure to give (2R)-l-d,5- bis (trifluoromethyl) benzoyl] -2- (4-fluorobenzyl) piperazine (6.04 g, as an oil. [α] 2 ,, 7 ' 5 : -11.70° (C=0.5, MeOH) IR (Neat) : 3300, 1630, 1150 cm -1 NMP dMS -d 6 , δ) : 2.55-2.80 (8H, ) , 4.25 (IH, mi, rd 90-7.52 ( 5H, m) , ~ .64 (IK, br s) , 8.13 (IH, br s) MASS : 435 (M+l) Preparation 12 Ihe following compounds were prepared by a similar manner to that of Preparation 8. ( 1 ) (2R) -N-Benzyl-N-benzyloxycaroonylmethyl-2- (tert- butoxycarbonylamino) -3- (4-methoxyphenyl; propanamide ι ]g 4 - C : +6.60° (C=0.5, MeOH) IR (Neat) : 3300, 1740, 1700, 1650, 1240 cm -1 NMR (DMSO-d 6 , δ) : 1.27, 1.31 (9K, 2s) , 2.76 (2K, ) , 3.69, 3.70 (3H, 2s; , 3.95-4.90 (5H, ) , 5.12 (2H, d, J=4.9Hz) , 6.70-7.36 (14K, m) MASS : 533 (M+l) d) (2R) -X-Benzyl-N-benzyloxycarbonyimetnyl-2- (tert-butoxy- carbonyiamino) -3- ( -trifluoromethylphenyl ) propanamide iα] 2 ; β - : τ9.00° (C=0.5, MeOH) IR (Nujol) : 3350, 1735, 1720, 1670, 1650 cm _ NMR (DMSO-d 6 , δ) : 1.19, 1.27 (9H, 2s), 2.90 (2K, ) , 4.00-4.75 (5H, m) , 5.12 (2K, s), 7.10-7.60 (15H, m) MASS : 571 (M+l) (3) (2R) -N-3enzyl-N-benzyloxycarbonylmethyi-2- (tert- butoxycarbonylammo) -3- ( 1-naphf hyl) propanamide ic]5 7 - 7 : -0.60° (C=0.5, MeOH) IR (Neat) : 3300, 2970, 1740, 1700, 1645 cm "1 NMR (DMSO-d 6 , δ) : 1.18, 1.26 (9H, 2s) , 2.20-3.50 (2K, ) , 3.90-5.20 (7H, ) , 7.10-8.10 (IdH, m) MASS : 553 (Mrl) o Preparation 3 The following compounds were prepared by a similar "-_ r 6 te *-'-άL of Preparation 9. 0 (1; (3R,-l-BenzyI-3-( -metnoxybenzyl)pιperazme-2, 5-dιone 1245 cm "1 NMR ιDMSO-d 6 , 6) : 2.60 (IH, α, J=17.2Hz), 2.80 (IK, dd, J=13.6Kz, 4.7Hr: , ι / 3.09 (IH, dd, 0=13.6Hz, 5 3.8Hz), 3.46 (IH, d, J=l7.2Hz), 3.6 " ? (3K, s) , 4.11 (IH, d, 3=14.4Hz) , 4.22 (IH, br s) , 4.65 (IH, d, J=14.4Hz) , 6.63 (2H, d, J=8.7Hz) , 6.93 (2H, d, J=S.7Hz), 7.10-7.40 ι5H, ; , 3.30 (IH, br s) MASS : 325 (M-rl) (2) (3R)-i-3enzyi-3-(4-trifiuorcmethyibenzyl)piperazme-2, 5- dicne (α] j 6 - δ : -12.0C 1 (C=0.5, MeOH) IR (Nuiol) : 3250, 1680, 1650 cm "1 NMR (BMSO-dg, δ) : 2.85 (IH, d, J=17.4Hzj, 3.00 (IH, dd, J=13.4K∑, 4.8Hz) , 3.25 (IH, dd, J=13.4Hz, 4.4Hz) , 3.59 (IK, d, 0=17.4Hz;, 4.03 (IH, d, J=14.4Hz), 4.35 (IH, br s), 4.74 (IH, d, J=14.4Hz), " 7.00-7.15 (2K, m) , 7.25-7.35 (5H, m) , 7.48 (2K, d, J=8.1Hz), 8.41 (IH, s; MASS : 363 (M+l) {3) (3R) -1-Benzyl-3- (I-naphtnyimethyi) piperazine-2, 5-dιone IP ( uπol) : 3250, 1685, 1655 cm " ' NMR (DMSO-d 6 , δ) : 2.92 (IK, d, 0=17.2Hz) , 3.40-3.65 (3H, m) , 4.31 (3H, s) , 7.03 (2H, m) , 7.29 (5H, m) , 7.54 (2H, m; , 7.82 (IK, dd, J=6.5Hz, 3.0Hz) , 7.94 (IH, m) , 8.14 (IH, m) , 8.31 (IH, d, J=3.0Hz) MASS : 345 (M-rl) Preparation 14 The following compounds were prepared by a similar manner to that of Preparation 10. d) (3R) -i-BenzyI-3- (4-methoxybenzyl) piperazme IR (Neat) : 3250, 1240 cm "1 NMR (DMSO-d 6 , δ) : 1.60-2.00 (4H, ) , 2.40-2.90 (5H, m) , 2.30-3.50 (2H, rr.) , 3.70 (3H, s), 6.81 (2K, d, 0=8.6Hz) , 7.07 (2H, d, J=8.6Hz), 7.15-7.40 (6H, ) MASS : 297 (M-d) (2) (3R)-l-3enzyl-3-(4-trifluoromethvibenzyi) piperazine α]§ 7 - 2 : -5.80° (C=0.5, MeOH) IR (Neat) : 3250, 2925, 2800, 1320 cm -1 NMR dMSO-d 6 , δ) : 1.72 (IH, t, O=10.0Hz), 1.91 (IK, m> , 2.55-2.95 (6H, ) , 3.30-3.50 (3H, m) , 7.15-7.35 (6H, ) , 7.40 (2H, d, 0=8.0Hz) , 7.60 (2H, d, 0=8.0Hz) MASS : 335 (M-rl) I T ) (3R) -1-Benzv) 3- { l-naphthylmethyl)piperazine :αi 27 - 21.80° (C=0.5, MeOH) IR (Neat) : 3300, 3050, 2925, 2800 cm "1 NMR (DMSC-d 6 , δ) : 1.75-2.05 (2H, m) , 2.50-3.60 (9H, ir.) , 7.10-7.65 (9H, m) , 7 (IH, d, J=7.9Hz) , 7.90 (IH, ) , 8.12 (IK, dd, 0=7.1Hz, 2.3Kz) Preparation 15 The following compounds were prepared by a similar 9 " ? manner to that of Preparation 11. (l; (2R)-i-[3,5-Bis (trifluoromethyl ) benzoyl ] -2- (4- metnoxybenzyl) piperazine [ J F . 5 - 1 : -32.60° (C=0.5, MeOH) (Neat) 3300, 1630, 1280 NMR ( MSO-d 6 , c) : 2.40-3.35 (9H, ) , 3.72 (3H, s) , 6.70-8.45 ,' MASS : 447 (M-l; (2) (2R) -1- [3, 5-Bis ;trifluoromethylXbenzoyl] -2- (4- trifluorcmetnyibenzyi) piperazme NMR (DMSO-d 6 , δ) : 2.60-3.70 (9H, m) , 7.15-7.40 (2H, ) , 7.50-7.75 (4H, ) , 8.12 (IH, s) MASS : 485 (M+d (3) (2R)-l-d,5-Bis (trifluoromethyl) benzoyl] -2- (1- naphthyimetnyi) piperazme [ ]2 8 - : : -24.70° (C=0.5, MeOH) IR (Neat; : 3340, 3050, 2950, 2825, 1630 cm "1 NMR (DMSO-d 6 , δ) : 2.50-4.30 (9H, ) , 7.10-8.55 (1CK, m) MASS : 467 (M+l) Preparation 16 A mixture of I-methyi-lK-pyrazole-4-carboxaldehyde (2.0 1 ano triethyl phosphonoacetate (4.52 g) m N,N- dimetnylformamide (20 mi) was stirred under ice-cooiing. After several minutes, sodium hydride d.09 g, 60- m mineral oil) was added tc the mixture, which was stirred for I hour at the same temperature. The resulting mixture was poured into Ice-cater, neutralized with, aqueeus ammonium acetate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium suifate and concentrated under reduced pressure. The resulting residue was chromatographed on a silica gel using a m.ixture of hexane y and etnyl acetate as an eluent to give ethyl (E) -3- d-methyl- lK-pyrazoi-4-yI) acrylate. IR (Nujol) : 2975, 1700, 1635 cm "1 NMR (DMSC-d 6/ δ) : 1.32 (3H, t, 0=7.1Hz) , 4.23 (2K, q, 0=7.1Hz), 6.16 (IH, d, 0=16.0Hz) , 7.54 (IH, s) , 7.55 (IK, d, J=16.0Hz), 7.69 (IH, s) MASS : 181 ;M+1 ; A so.uticn of 2- (Ξ) -3- (l-methyl-lH-pyrazol-4-yl) acrylate (1.04 g) in tetrahydrofuran (50 ml) v/as hyorogenated over 10 " palladium charcoal (0.2 g) at roo temperature at 2 at of hydrogen. After removal of catalyst by filtration through Ceiite^ pac, the filtrate was concentrated under reduced pressure to give ethvl 3- (l-methvl-lK-cvrazoi-4-yi ) - propicnate . IR (Neat) : 2950, 1725 cm "1 NMR (DMS0-d 6 , δ) : 1.24 (3H, t, J=7.1Hz) , 2.50 (2H, t, J=7.5Hz), 2.73 (2H, t, J=7.5Hz) , 3.84 (3H, s;, 4.13 (2K, q, J=7.IHz), 7.18 (IH, s), 7.31 (IH, s) MASS : 183 (M+l) Preparation 18 To an ice-cooled solution of ethyl 3- (1-methyI-lH- pyrazol-4-yI) propionate (1.05 g) in tetrahydrofuran (10 ml; was added lithium aluminum hydride (0.22 g) under nitrogen atmosphere. After the mixture was stirred for 20 minutes, water and 15 sodium hydroxide aσueous solution were added successively to the mixture. The resulting precipitates were filtered off through Celite^ pad and the filtrate was extracted with ethyl acetate. Tne organic layer was washed with ' water, dried over magnesium suifate and concentrated under reduced pressure to give 3- d-methyl-lH-pyrazoI-4-yl) - 1-propanol . IR (Neat) : 3300, 2930 cm "1 NMR (DMS0-d 6 , δ) : 1.87 (2H, ) , 2.55 (2H, t, 0=7.5Kz) , 2.63 (2H, t, 0=6.1Hz) , 3.85 (3H, ε) , 7.16 (IH, s) , 7.31 (IH, ε) MASS : 141 (M-d) c Preparation 19 To a solution of oxalvl chloride (0.361 ml) in dichiorometnane (10 ml) cooled below -65°C with a dry ice- acetone bath, a solution cf dimethyl sulfoxide (C.381 ml) in dicnloromethane (1 ml) was added with efficient stirring over 10 minutes. After 20 minutes oelow -65°C, a solution of 3- ( l-methyI-lH-pyrazol-4-yl, -I-propanoI m dicnloromethane (2 mi; was aαceα to the mixture over 10 minutes below -65°C and the mixture was stirred at the same temperature for 20 minutes and then at -45 - -40 for 20 minutes. After addition of triethvlamine dropwise tc the mixture over 10 minutes followed by stirring for 15 minutes, IN hydrochloric acid solution was added to the mixture. The resulting mixture v/as extracted with a mixture of dicnloromethane and methanoi several times. The extract was concentrated under reduced pressure and the resulting residue was chromatoσrapned on a silica gel using a mixture of dichiorometnane and methanoi as an eluent to give 3-(l- methyl-lH-pyrazoI-4-yI ) -i-propanal . IR (Neat; : 2925, 1720 err. "1 NMR (DMSO-dg, δ) : 2.65-2.90 (4H, ) , 3.86 (3H, s) , 7.17 (IH, s) , 7.32 (IK, s) , 9.80 (IH, s) MASS : 139 (M+l) Example 79 Te a mixture cf 3, 5-bιε (trifluoromethyl) benzoic acid (4.13 g) and pyridme (C.041 ml) in tetranydrofuran (12.5 mi, was added oxaiyl chloride (2.25 g) over 15 minutes at 22-38°C and the mixture was stirred at 55°C for 4 hours. The acid chloride solution obtained above procedure was added to an ice-cooled solution of (3R) -l-benzyl-3- (4-fluorobenzyl) - piperazme (4.51 g) and triethylam e (4.83 g) , dicnloromethane (45 ml) under 5°C for 30 minutes. After being stirred for 2 hours at room temperature, the mixture was washed with water and brine successively, and dried over magnesium suifate. After evaporation of the solvent, the resulting residue was chromatographed on a silica gel using a mixture of toluene and ethyl acetate as an eluent to give (2R) -4-benzyl-l- [3, 5-bis (trifluoromethyl) benzoyl] -2- (4- fluorobenzyl) piperaz e (0.87 g) as a syrup. [α]§ 7 - 5 : -11.50° (0=0.5, MeOH) IR (Neat) : 1740, 1150 cm -1 NMR (DMS0-d 6 , δ) : 2.00-4.40 (IIH, ) , 6.80-7.50 (10H, m) , 7.74 (IH, br s), 8.13 (IH, br) MASS : 525 (M+l) Example 80 The following compounds were prepared by a similar manner to that of Example 79. (1) (2R)-4-Benzyl-l-[3, 5-bis (trifluoromethyl) benzoyl] -2- (4- methoxybenzyl) piperaz e [α]§ 8 - 0 : -21.40° (C=0.5, MeOH) IR (Neat) : 1740, 1640, 1270 cm -1 NMR (DMSO-d 6 , δ) : 1.70-2.40 (3H, m) , 2.60-3.80 (IIH, ) , 6.60-7.60 (10H, m) , 7.65-8.55 (2H, m) MASS : 537 (M+l) (2) (2R)-4-Benzyl-l- [3, 5-bis (trifluoromethyl) benzoyl] -2- (4- trifluoromethylbenzyl) piperazine IR (Neat) : 2950, 2800, 1765, 1740, 1640 cm "1 NMR (DMSO-d 6 , δ) : 1.70-4.30 (IIH, m) , 7.13 (IH, d, J=7.8Hz), 7.20-7.70 (10H, m) , 8.13 (IH, d, J=7.8Hz) MASS : 575 (M+l) (3 , dR) -4-3enzyl-l- [3, 5-bis (trifluoromethyl) benzoyl] -2- ( I- naphtnylmethyi i piperazine lαi 2 , 7 - : : -9.70° (C=0d, MeOK, I? (NUjOi, : 1640 cm " - NX? dM50-d 6 , G) : 2.00-4.40 ;UH, ) , 7.00-8.55 (15H, m) MASS : 557 (M-l) One following compound was prepared by a similar manner ιxa :e dp -l-;2,5-Bιs (trifluoromethyl ) benzoyl] -2- (3, 4- di ethylbenzyl ) -4- [3- (cis-2, 6-oιmethylmorphoiino) propyl ] - piperazme dihydrochioride (α] 2 , 1 - 0 : -11.10° (C=G.5, MeOHX IP 'Neat) : 3400, 2550, 2450, 1640, 1430, 1260, 1175, 1130 cm "1 NMR (DMSO-d 6 , δ) : 1.14 (6H, m) , 2.05-5.24 (19H, ) , 2.10 (3K, s) , 2.18 (3H, sd c.64-8.24 (6H, rr.) MASS : 600 (M+l) (free) Ana_. Calcd. for • 35H ?° C 52.06, H 6.29, N 5.77 Eouno : C 52.08, H 6.44, X ' 5.88 Example 82 The following compounds were obtained according to a similar manner to that of Example 23. (1> ;2R' -1- ' 3, 5-3ιs ( rifluoromethyl) benzoyl] -2- ( 3, - dimetnyibenzyl ) -4- ΪN- (3-pyricyimechyl) -3-ammopropyl ] - p i p erazme trihydrochloride . cc 1 Z r C . ~ Dn =0.25, MeOH) IR (Neat) : 3600-3100, 2800-1950, 1270, 1125 cm " - NMR (DMSO-o-, δ) : 2.09-5.20 (24H, m) , 6.60-9.00 MASS : 559933 ((MMi+l) (free) Anal. Calcd. for C 71 48.10, K 5.86, N 7.2 dund a - - i 02 2P ) -1 - ] 3 , 5-Bιs : trif luorometnyl , oenzcyi . -2- (3, 4- imetnyloenzyl ) -4- (N-rrorphoi o-2-ammoethyl ; piperaz e .myorechlonde 10 a,F, E - f : -26.80° (C = 0.25, MeOK) P (Neat) : 3600-3000, 2800-2000, 1630, 1274, 1120 cm " XMK dMSO-d 6 , δ 2.02-5.20 (26H, , , 6.50- 8.30 (OH, m FA.S S : 73 (M+l) (free; Anal . Cc :c. rcr 28 H 34 F 6 N ; dτ2H0l-9/2H 0-I dCH-dO- C Hc : 1 c. C 46.53, H 6.33, _T 7.48 Found : C 46.64, H 6.23, N 6.67 3) (2R)-l- 3,5-3is ( rifluoromethyl}benzoyl] -2- (3, 4- dimethylbenzyl) -4- (N-morphelmo-4-ammo-2- 20 butynyl) piperazine dihydrochlcride ϊα 28 " G -9.80° (C=0.25, MeOH) IP dead : 3600-3000, 2600-1950, 1630, 1273, 112., cm " NMR dMSO-d 6 , δ) : 2.10-5.20 (28H, ) , 6.20-8.30 (6H, ) MASS : 597 (M+l) (free) lb 1,4) (2R)-l-]3,5-3is( rifluoromethyl) oenzoyi ] -2- (3, 4- dimeth lbenzvl) -4- [N-methvi-X- (3-cyridylmethyi, ■ -2- a moethyi] piperaz e trιhydrocn_crιce [α]^ 8 -^ : -11.80° (C=0.25, MeOH; 30 IP (Nujol) : 3600-3100, 2700-1950, 1630, 1275, 1122 cm " NMR (DMSO-d 6 , δ) : 2.10-5.20 (24H, ; , 6.60-7.80 (6H, ) , 8.10-8.35 (2H, m) , 8.70-6.95 (2H, ) MASS : b93 (M-l) (free, Anal. Calcd. for C 31 H 34 F 6 NdO-3HCl-7/2H 0 : 5 C 48.67, H 5.30, N 7.32 Found : C 48.86, H 5.88, N 6.79 (5) (2R) -1- d, 5-3is (trifluoromethyl) benzoyl] -2- (2, 4- dimetnylbenzyl) -4- [ (E) -N- (3-pyrιdylmethyl) -4-amino-2- outenyl ] piperazme trihydrochloride ;α]g ε - : -10.40 c (C==0.25, MeOH} 600-2100, 2300-1950, 1630, 1274, 1124 cm -1 NM? ddSO-d 6 , δ y : 2.09-5.20 (22H, ,, 66.05-6.25 (2K, 10H, ; MASS : 605 (M+l) (free) Anal. Calcd. for C 47.80, K 19, N 6.97 Founα C 47.81, X i3, N 6. 8 (6) (2R) , 5-Bis ( rifluoromethyl) benzoylj -2- (3, 4- dimethylbenzyl) -4- [ (E) -N-morpholmo-4-amino-2-butenyl] - piperazine dihydrochioride [α]g 8 - 5 : -6.40° (C=0.25, MeOH) IR (Nuuoi) : 3600-3000, 2750-1950, 1620, 1273, 1120 cm " 1 NMR (DMSO-d 6 , δ) : 2.09-: 10 (23H, m) , 5.80-3.30 (8H, m) MASS : 599 (M+l) (free) Anal. Calcd. for C 30 H 36 F 6 N,,O 9 -2HCl-7/2H 2 O C 49.05, H 6.10, N 7.63 Found : C 49.15, H 6.16, N 7.41 1 2?X -1- id, 5-His (trifluoromethyl;benzoyl] -2- (2- naphthyl ethyl) -4- [N- (3-pyridylmethyl) -2- ammoethyl] piperazine trinycrochioride : -11.00° (C==0.25, MeOH) IR (Neat) : 3600-3100, 2800-1950, 1630, 1273, 1120 cm -1 NMR (DMSO-a 6 , δ) :2.5C-5.20 (16K, m; , 7.00-2.00 (14K, ) MASS : 601 (M+i) (free 1 - Anal. Calcd. for C 3 2H3 0 F 6 N 4 O-3HCi- H 2 O : C 49di5, H 5.28, N 7.16 Found : C 49.26, H 5.24, N 6.30 (8) (2R) -1- [3, 5-Bis (trifluoromethyl) benzoyl] -2- (2- naphthyimethyi) -4- (N-morpholmc-2-aminoethyi) piperazine dihydrochlcride [ ]+3 8 - β : -34.80 c (C=0.25, MeOH) IR .'Neat) : 3600-3100, 2800-1950, 1630, 1273, 1120 cm -1 NMR (DMSO-d 6 , δ) :2.50-5.3C (22H, m) , 7.00-8.20 (iOH, m; MASS : 595 (M-d) (free) Anal. Calcd. fcr C 30 H 3 2E 6 N 4 O 2 -2KCi-l1/3H 2 0 : C 49.12, K 5.68, N 7.64 Found : C 49.04, H 5.57, N 7.39 (9 • ;2R)-l-d,5-5is(trifluoromethyl) benzoyl. -2- (2- naphthylmethyl) -4- (N-mcrphoiinc-3-ammopropyi ) piperazine dihydrochlcride ;α]p ( 8 - 6 : -40.10° (C=0.25, MeOH) IR (Nujcl) : 3650-3100, 2800-1970, 1636, 1275, 1123 cm "1 NMR (DMSO-c 6 , δ) : 2.20-5.20 (24H, m) , 7.00-8.20 (1CH, m) , 10.60-11.80 (3H, m) MASS : 610 (M-d) (free) Anal. Calcd. for C 31 H 34 F 6 N 0 2 -2HCl H 2 0 : C 50.62, H 3.75, N 7.62 Found : C 50.72, H 5.58, N 6.99 (10) (2R)-ι-i2,5-Bιs(trifluoromethyl) benzoyl] -2- (2- naphtnyimethyi) -4- [ (E) -N- (3-pyridyimethyi ) -4-amino-2- butenyi] piperazine trihydrochloride fα]§ 3 - 4 : -20.40° (C=0.25, MeOK) IR (Nujcl) : 3650-3100, 2750-1930, 1620, 1272, 1122 cm -1 NMR (DMSO-d 6 , δ) : 3.00-5.30 (16H, m) , 6.00-6.30 (2H, m) , 7.0C-9.10 (14H, m) Anal. Calcd. for C 34 H 32 F β N 4 C HCl-2H 2 0 : C 52.89, K 5.09, N 7.26 Found : C 52.73, H 5.09, N 7.16 - [3, 5-Bιs (trifluorometnyl ) benzoyl] -2- (2 naphthyimethylj -4- [ (E) -N-morphoimo-4-ammo-2 butenyl] piperaz e dihydrochioride 23.5 . (C= Q .25, MeOH) diead 3650-3000, 2750-19 7 C, 1630, 1274 cm -1 NM? (DMSO-dc, δ) 80 ι ι — -\ • * .. (22H, 6.15-6.50 (2H, ) , 7.00-8.25 (10H, m! MASS 621 (M-l) (free' ., 5-Bιs (tr r i ) ι orcmethvl ) :C.ZC -2- (2- nap ntnylmethyl ' -4- [N- ( 2-ρyrιαy_metnyi ) -3- ncpropyl piperazme trmyarcchlcπαe IR (Nujcl) : 3600-3100, 2750-1950, 1630, 1273, 11il cm NMR (2MSC-α 6 , δ) :2.20-5.30 (18H, m) , 7.00-9.10 (14H, ) MAS err irv÷ ' ( tree; β rip :axcc ror ; 33 K 32 F 6 N 4 0-3HC1-1C/3H 9 0 : 50.56, K 5.36, N 7.15 Found : C 50.53, h 5.38, N 0.9' One following compounds were obtained according to a similar manner to that cf Example 35. d i '2R, -1- [3, 5-Ξι≤ (trifluorometnyl ) benzoyl 1 -2- d- napntnylmethyl ) -4- '4-hcmomorpholmo-2-butynyl) piperazme dihyαrochdoride [α]§ - ϋ : -19.80° (C=0.5, MeOH) OR XXeat) : 3400, 2500, 1540, 1430, 1280, 1175, 1120 cm- ~ NMR dMSC-d 6 , δ ' d.95-5.34 (23H, mO, 7.05-8.20 dOH, ) MASS : 618 (M-l, (free, -Ana_ . Caicc. for C 33 H 33 FgN 3 0 7 -2KCl-2.9H 2 0 : C 53.37, H 5.53, X 5.66 Founc : 0 53.33, H 5.47, N 5.67 ι 06 (2 ■ dR^-l- 3,5-3ιs( rifluoromethyl) benzoyl] -2- (3-fl crc-4- methyiDβnzyl ) -4- [ (Ξ) - -morpholino-2-butenyl ]piperazine αihydrcchloriάe ϊotO , 8 - 0 : -4.50" (C=0.5, MeOH) IR (Nujol) : 2400, 1645, 1275, 1125 cm -1 NMR (FMSO-dg, δ) : 2.20 (3H, s, , 2.80-5.20 (21K, rr.) , c.0 -8.20 (OH, m) MASS : 553 (M-rl) (free; .Anal. Calcd. for C 9 K 32 7 N 3 C 2 b2HCl : C 52.74, K 5.10, X τ 6.36 Found : C 52.39, K 5.20, X 6.29 (3) (2R)-l-ι2,5-Bis(trifluoromethyl) oenzoylj -2- (3-flucro-4- methyibenzyi) -4- [ (E) -4-chlorc-2-outenyl] piperazine IR (Neat) : 1640, 1430, 1275, 2130 cm -1 NMR (DMSO-d 6 , δ) : 1.91-4.23 (13H, ) , 5.71-3.20 (8H, rr.) MASS : 53 " ? (M+l) (4) (2R) -I- [3, 5-Bιs (trifluoromethyl) benzoyl] -2- (3,4- dimethylbenzyl) -4- (4-morpnolino-2-butynyi ) piperazme dihydrochioride mp : 9 -I01d NMR (XMSO-α 6 , δ) : 2.0-5.2 (25K, ; , 5.74 (IK, br d) , 5.89 (IK, br d) , 6.6-8.2 (6H, m) MASS : 578 (M-rl) (free) Anal. Calcd. for C 31 H 33 F 6 N 3 0-2HC1-2H 2 0 C 54.22, K 5.73, N 6.12 Found : C 53.99, K 3.83, X 5.93 Example 84 The following compoundε v/ere obtained according to a similar manner to that of Example 50. (1) (2R)-I-d,5~Bis (trifluoromethyl) oenzoylj -2- (4- luorobenzyl) -4- (4-thιomorpholino-2-butynyl) piperazme Id inycrocnioride p : IδC (dec.) ]≠ j b - : -5.00° (C=0.5, MeOH; IR (Nujol l : 3350, 1630, 1125 cn- NMR ( MSC-α-, δ) : 2.60-4.30 (21H, m) , 6.85-7.25 (3H, m) , 7.46 (2H, cr s), 75 dH, br s), 6.16 (IH, d, 0=9.4Hz» MASS : 588 (M+l) (free) -Anal. Caicα. for C-^gK- j gF^N-dS HClO-dO : C 49.56, K 4.75, N 6.19 Found : C 49.47, H 5.13, N 5.93 (2) -I- [ , 5-3ι≤ ( rifluorometnyl j oenzoyi] -2- (4- m tncxybenzyl) -4- (4-tniomcrphcimo-2-butynyi) piperazine dihydrochioride p : 197°C (dec.) - X8 : -8.60° (C=3.5, MeOH) I? (Nu-ci) : 2500, 1640, 1275 cm " x NMR (DMΞO-d 6 , δ) : 2.60-4.70 (24H, ) , 6.70-8.30 (7H, ) MASS : 600 (M-rl) (free) Anal. Calcd. for C 2g H 3 -, F N 3 G 2 S-2HCl-d 3H 0 : C 50.05, H 5.16,. N 6.0 ounα .06, H 5.36, X 5.77 (2R) -1- [2, 5-Bis (trirluoromethyl)benzoyl]-2-(4- -ifruero etϊrviben vl ) — — (4—thic .orohclmo—2— butynyi ) iperazine dihyαrochloriαe mp : 173d (dec . ) 18.0 - X -9.60° (C=0.5, MeOH) IR (Nujcl) : 2400, 1640 cm "1 M1-- -dMSO-dς, δ. : 2.70-5.30 (2IK, ml , 7.22 (IK, d, J-7.7HΣ) , 7.41 (IH, s) , 7.50-7.80 dH, < , 8.18 [IV., d, 0==7.0Hz) MASS : 638 (M+l) (free) Anal. Calco. for C 99 K 28 F 9 N 3 OS-2KCl-l .3H 2 0 : C 47.46, H 4.48, N 5.73 Found : C 4 42, K 4.51, X 5.51 (4) (2P)-l-ι3,5-Bιs (trifluoromethyl) oenzoyl] -2- (1- naphtnyimethyi) -4- ( -thiomorpholmo-2-butynyl ) piperazine dihydrochioride p : 1 1°C (dec. ' ia]t } S ' C : -15.60° (2=0.5, MeOH) IR (Nujcl) : 2500, 1635 cm "1 NMR (DMS0-d 6 , δ) :2.65-4.80 (21H, mj , 7.20-8.60 (10H, m) MASS : 620 (Mτl) (free) Anal. Caicα. for C 32 H 1 F 6 N τ 3 CS-2HCl-0.4 ' ή ? 0 : Z 54.92, H 4.87, N 6.00 Found : C 54.88, H r .04, X 5.65 Example 85 The following compound was obtained according to a similar manner to that of Example 51. (2Rι -1- d, 5-3is (trifluoromethyl) benzoyl . ; -2- (3, 4- dimethyibenzyl ) —4— [3— (l-methyl-iH-pyrazoi-4- yl) propyl ] piperazine hydrochioride p : i£3-165°C ( d - 3 : -19.80° (C==0d, MeOH) 2R XXu oi; : 2550, 1625 cm "1 NMP (DMSO-d 6 , δ) : 1.90-2.25 (6H, m) , br) , 6.65-8.25 (8H, ) Anal. Calcd. fcr C 2g H 32 F 6 NXO-HCl-K 0 : c 56.08, K 5.68, N 9.02 Found : C 56.44, H 5.76, N 8.98 Example 86 The following compound was obtained according to a ι-i;:rj.a: ...c.iz^. :o that cf Examole 61. (2R^ -1- [3, 5-Bis (trifluorometnyl) benzoyl] -2- (lH-ιndol-3- yime hyi) -4- (4- , 3-dιme hylmcrpholιnc) -2-butenyl]piperazine dihydrocnicride Γ.Ό : 21G°C (dec.) " ]? - 4 : -0.63° (C=0.11, MeOH) 2R (Nujcl) : 3660-3300, 2700-2300, 1640, 1445, 1430, 137C, 12d cm -1 NMR (2MSO-d 6 , δ) : 1.30-1.50 (6H, ) , 2.85-5.25 (19H, rr.) , 6.05-6.30 (2H, ) , 6.65-5.25 (8H, ) , 10.97 (IK, br s) , 11.40-12.20 (2K, ) Example 87 The following compound was ootamec according to a similar manner to that cf Example 54. (2R)-l-[3,5-Bis (trifluoromethyl) benzoyl] -2- (3, 4- dimethyibenzyi ) - 4 - [3- (3-pyridyl ■ propyl ] piperazme dinyαrochicrice mp : iό3-163°C [α]t 4 " 7 : -5d7° (C=1.3, MeOH) 2R (Nujol) : 3600-3300, 2700-2300, 1635, 1445, 1430, 1370, 1230 cm "1 NMR (BMSO-d-;, δ) : 1.92-5.22 (29K, m) , 6.56-8.28 (6H, ) , 11.43 (2H, Or s) MASS : 564 (M-l) (free) Anal. Caicc. for C 30 H 3 F 6 N 3 O HCi-2.4KXO : C 53.01, K 5.60, N 6.1b Found : C 53.04, H 5.93, M 5.7 "1

Claims: C L A I M A compound of the formula wherein 1 is bond or lower alkylene, P 1 is aryl which may have suitable substituent (s) , P 2 is aryl or mdolyl each of which may have suitable substituent (s) , is hydrogen or lower alkyl, P is chloro (lower) alkenyl; ?', chloro (lower) alkynyl; pyridyl (lower) alkylamino (lower) alkyl; yridyl (lower) al ylamino (lower) alkenyl; N- ', lower alkyl) -N- [pyridyl (lower) alkyl] amino- (lower) alkyi; tπazolylammo (lower) alkyl; lower alicoxy (lower) alκylammo (lower) alkyl; bis [ (lower) alkoxy(lower) alkyl] ammo (lower) alkyl; N- (lower alkyl) -N- [ (lower) al oxy (lower) alkylj amino- (lower) alkyl; o hyαroxy (lower) al yl; lower alkylsulfonyloxy (lower) alkyl; nenyl (lower) alkyl which may have lower alkanoyl, ammo, lower alkanoyiamino, di (lower) alkylam ccarbonyl or nitro; lower alkoxyphenyl (lower; alKylcarbonyl; lower alkanoylbenzoyl; benzoyl (lower) alkyl which has lower alkyl, chlorine or di (lower) alkylamino; benzoyl (lower) alkyl which has halogen and lower alkyl; dihalobenzoyl (lower) alkyl; di (lower) alkylbenzoyl (lower) alkyl; 3-fIuorobenzoyl (lower) alkyl; 3- (4-fluorobenzoyl) propyl; 4, 4-ethylenedιoxy-4- (4-fIuorophenyi)butyl; piperaz ylcarbonyl (lower) alkyl which has cyclopentyl or halophenyl; (2-pyrιdyl) (lower) alkyl; (3-pyridyl) propyl; (3-pyrιdyl) (lower) alkynyl; lmidazolyl (lower) alkyl which may have lower alkyl; pyrazolyl (lower) alkyl which may have lower alkyl; thiomorphol ylcarbonyl (lower) alkyl; (3-azabιcyclo[3.2.2]non-3-yl) carbonyl (lower) alkyl; or thienylcarbonyl (lower) alkyl, 1,2,3, 6-tetrahydropyrιdyl (lower) alkyl, 1, 2, 3, 6-tetrahydropyrιdyl (lower) alkynyl, 1,2,3, -tetrahydroιsoquιnolyl (lower) alkyl, 4,5,6, 7-tetrahydrothιeno [3, 2-c]pyridmyl (lower) - alkyl, saturated heterocyclic (lower) alkyl, saturated heterocyclic (lower) alkenyl, saturated heterocyclic (lower) alkynyl, saturated heterocyclicamino (lower) alkyl, saturated heterocyclicamino (lower) alkenyl or saturated heterocyclicamino (lower) alkynyl, each of which may have suitable substituent (s) , and a pharmaceutically acceptable salt thereof. The compound of claim 1, in which Y is lower alkylene, R is ; CC QQ --C -I^ Q O aarryyll wwhhich may have 1 to 3 mono (or di or tri) halo (lower) alkyl, R ~ is Cg-C-^ Q aryl or mdolyl, each of which may have 1 to 3 suitable substituent (s) selected from the group consisting of lower alkyl, lower alkoxy, mono (or di or tri) halo (lower) alkyl and halogen, 3 R is hydrogen, and R 4 is chloro (lower) alkenyl; chloro (lower) alkynyl; pyridyl (lower) alkylamino (lower) alkyl; pyridyl (lower) alkylamino (lower) alkenyl; N- (lower alkyl) -N- [pyridyl (lower) alkyl] ammo- dower) alkyl; triazolylammo (lower) alkyl; lower alkoxy (lower) alkylamino (lower) alkyl; bis [ (lower) alkoxy (lower) alkyl] am o (lower) alkyl; N- (lower alkyl) -N- [ (lower) alkoxy(lower) alkyl] a mo- (lower) alkyl; hydroxy (lower) alkyl; lower alkylsulfonyloxy (lower) al yl; phenyl (lowe ) alkyl which may have lower alkanoyl, am o, lower alkanoyiamino, di (lower) alkylam ocarbonyl or nitro; lower alkoxyphenyl (lower) aikylcarbonyi; lower alkanoylbenzoyl; benzoyl (lower) alkyl which has lower alkyl, chlorine or di (lower) alkylamino; benzoyl (lower) alkyl which has halogen and lower alkyl; dihalobenzoyl (lower) alkyl; di (lower) alkylbenzoyl (lower) alkyl; 3-fIuorobenzoyl (lower) alkyl; 3- (4-fIuorobenzoyl) propyl; 4, 4-ethylenedιoxy-4- ( -fIuorophenyi)butyl; piperazinylcarbonyl (lower) alkyl which has cyclopentyl or halophenyl; (2-pyridyl) (lower) alkyl; (3-pyridyl) propyl; (3-pyridyl) (lower) alkynyl; lmidazolyl (lower) alkyl which may have lower alkyl; pyrazolyl (lower) alkyl which may have lower alkyl; thiomorpholmylcarbonyl (lower) alkyl; (3-azabιcyclo [3. 2 . 2 ] non-3-yl) carbonyl (lower) alkyl; or thienylcarbonyl (lower) alkyl, 1,2,3, 6-tetrahydropyrιdyl (lower) alkyl, 1,2,3, 6-tetrahydropyrιdyl (lower) alkynyl, 1,2,3, 4-tetrahydroιsoqumolyl (lower) alkyl, 4,5,6,7- tetrahydrothieno [3, 2-c]pyridmyl (lower) alkyl, saturated heterocyclic (lower) alkyl, saturated heterocyclic (lower) alkenyl, saturated heterocyclic (lower) alkynyl, saturated heterocyclicamino (lower) alkyi, saturated heterocyclicamino (lower) alkenyl or saturated heterocyclicamino (lower) alkynyl [wherein "saturated heterocyclic moiety" is saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) ; saturated 3 to 8-membered heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atom(s); saturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s) ; or saturated heterocyclic group of the formula : (wherein q, r, s and t are each integer of 1 to 6) ] , each of which may have 1 to 3 suitable substituent (s) selected from the group consisting of cyclo (lower) alkyl, lower alkanoyl, lower alkyl, mono (or di or tri) halo (lower) alkyl, lower alkoxy, lower alkoxy (lower) alkyl, halogen, g-C 10 aryl, cyano, oxo and bivalent group of the formula : The compound of claim 2, which Y is lower alkylene, R 1 is phenyl which may have 1 or 2 mono (or di or tri) halo (lower) alkyl, o R^ is phenyl, naphthyl or mdolyl, each of which may have 1 or 2 suitable substituent (s) selected from the group consisting of lower alkyl, lower alkoxy, mono (or di or tri) halo (lower) alkyl and halogen, R J is hydrogen, and R is chloro (lower) alkenyl; chloro (lower) alkynyl; pyridyl (lower) alkylamino (lower) alkyl; pyridyl (lower) alkylamino (lower) alkenyl; N- (lower alkyl) -N- [pyridyl (lower) alkyl] ammo- dower) alkyl; triazolylam o (lower) alkyl; lower alkoxy(lower) alkylamino (lower) alkyl; bis [ (lower) alkoxy (lower) alkyl] ammo (lower) alkyl; N- (lower alkyl) -N- [ (lower) alkoxy (lower) alkyl] ammo- dower) alkyl; hydroxy(lower) alkyl; lower alkylsulfonyloxy (lower) alkyl; phenyl (lower) alkyl which may have lower alkanoyl, ammo, lower alkanoyiamino, di (lower) alkylammocarbonyl or nitro; lower alkoxyphenyl (lower) aikylcarbonyi; lower alkanoylbenzoyl; benzoyl (lower) alkyl which has lower alkyl, chlorine or di (lower) alkylamino; benzoyl (lower) alkyl which has halogen and lower alkyl; dihalobenzoyl (lower) alkyl; di (lower) alkylbenzoyl (lower) alkyl; 3-fIuorobenzoyl (lower) alkyl; 3- (4-fIuorobenzoyl) propyl; 4, 4-ethylenedιoxy-4- (4-fIuorophenyi)butyl; piperaz ylcarbonyl (lower) alkyl which has cyclopentyl or halophenyl; (2-pyπdyl) (lower) alkyl; (3-pyrιdyl)propyl; (3-pyrιdyl) (lower) alkynyl; l idazolyl (lower) alkyl which may have lower alkyl; pyrazolyl (lower) alkyl which may have lower alkyl; thiomorphol ylcarbonyl (lower) alkyl; (3-azabιcyclo[3.2.2]non-3-yl) carbonyl (lower) alkyl; or thienylcarbonyl (lower) alkyl, 1,2,3, 6-tetrahydropyrιdyl (lower) alkyl, 1, 2, 3, 6-tetrahydropyrιdyl (lower) alkynyl, 1,2,3, 4-tetrahydroιsoqumolyl (lower) alkyl, 4,5,6, 7- tetrahydrothieno [3, 2-c]pyridmyl (lower) alkyl, saturated heterocyclic (lower) alkyl, saturated heterocyclic (lower) alkenyl, saturated heterocyclic (lower) alkynyl, saturated heterocyclicamino (lower) alkyl, saturated heterocyclicamino (lower) lkenyl or saturated heterocyclicamino (lower) alkynyl [wherein "saturated heterocyclic moiety" is pyrrolid yl, piperidyl, piperazinyl, hexamethyleneimmo, morpholinyl, homomorphol yl, thiomorpholmyl or 3-azabιcyclo [3.2.2] non-3-yl] , each of which may have 1 or 2 suitable substituent (s) selected from the group consisting of cyclo (lower) alkyl, lower alkanoyl, lower alkyl, mono (or di or tri) halo (lower) alkyl, lower alkoxy, lower alkoxy (lower) alkyl, halogen, phenyl, cyano, oxo and bivalent group of the formula : The compound of claim 3, m which Y is lower alkylene, R is phenyl which may have 1 or 2 mono (or di or tri) halo (lower) lkyl, R^ is phenyl which may have 1 or 2 suitable substituent (s) selected from the group consisting of lower alkyl, lower alkoxy, mono (or di or tri) halo (lower) alkyl and halogen, naphthyl or mdolyl, -3 R J is hydrogen, and R 4 is (2-pyrιdyl) (lower) alkyl; (3-pyrιdyl) propyl; (3-pyrιdyl) (lower) alkynyl; lmidazolyl (lower) alkyl which may have lower alkyl; pyrazolyl (lower) alkyl which may have lower alkyl; pyridyl (lower) alkylamino (lower) alkyl; pyridyl (lower) alkylamino (lower) alkenyl; N- (lower al yl) -N- [pyridyl (lower) alkyl] ammo- dower) alkyl; triazolylammo (lower) alkyl; lower alkoxy (lower) alkylamino (lower) alkyl; bi s [ (lower) alkoxy (lower) al yl] ammo (lower) alkyl; N- (lower alkyl) -N- [ (lower) alkoxy (lower) alkyl] - amino (lower) alkyi; 1,2, 3, 6-tetrahydropyrιdyl (lower) alkyl; 1,2,3, 6-tetrahydropyridyi (lower) alkynyl; 1,2,3, 4-tetrahydroisoquinoiyl (lower) alkyl; or 4,5,6, 7-retrahydrothieno [3, 2-c]pyridinyl (lower) - alkyl . 5. The compound of claim 3, in which Y is lower alkylene, P. 1 is ohenyl whicn may have 1 or 2 mono (or di or tri) halo (lower) lkyl, R- is phenyl which may have 1 or 2 suitable .substituent (s) selected from the group consisting cf lower alkyl, lower alkoxy, mono (or di or tri ) halo (lower) alkyl and halogen, naphthyl or indolyi, R J is hydrogen, and R is morpholinyl (lower) al yi wmch may have 1 or 2 lower alkyl; homomorphciinyl (lower) lkyl; r.hiomorphoimyl (lower) alkyi; (hexamethyieneim o) (lower) alkyl; ( 3-azabicyclo [3.2.2]non-3-yi) (lower) alkyl; piperazinyl (lower) alkyl which may have phenyl or cycio (lower) alkyl; morpholinyl (lower) alkenyl which may have 1 or 2 lower alkyl; morpholinyl (lower) alkynyl which may have 1 or 2 lower alkyl, lower alkoxy ower) alkyi or mono (or di cr tri) halo (lower) alkyl; fhiomorpholinyl (lower) al enyl; thiomorpholinyl (lower) alkynyl; pyrrolidinyl (lower) lkynyl which may have lower alkoxy (lower) alkyl; piperazinyl (lower) alkynyl which may have cyclo- (lower) alkyl; morpholmyla mo (lower) alkyl; morpholmylammo (lower) alkenyl; morpholmylammo (lower) alkynyl; [spiro [mdan-1, 4 ' -piperidine] -1 ' -yl] (lower) alkyl; piperidyl (lower) alkyl which has phenyl, lower alkoxy, lower alkanoyl, piperidyl or oxo; or piperidyl (lower) alkyl which has phenyl and cyano. 6. The compound of claim 5, m which Y is lower alkylene, R 1 is phenyl which may have 1 or 2 mono (or di or tri)- halo (lower) alkyl, R^ is phenyl which may have 1 or 2 suitable substituent (s) selected from the group consisting of lower alkyl, lower alkoxy, mono (or di or tri) halo (lower) alkyl and halogen, naphthyl or mdolyl, R is hydrogen, and R is morpholinyl (lower) alkyl which may have 1 or 2 methyl; homomorpholmyl (lower) alkyl; thiomorphol yl (lower) alkyl; (hexamethyleneimmo) (lower) alkyl; {3-azabιcyclo[3.2.2] non-3-yl) (lower) alkyl; piperazinyl (lower) alkyl which has phenyl or cyclohexyl; morpholinyl (lower) alkenyl which may have 1 or 2 methyl; morpholinyl (lower) alkynyl which may have 1 or 2 methyl, methoxymethyl or fluoromethyl; thiomorpholmyl (lower) alkenyl; thiomorpholmyl (lower) alkynyl; pyrrolidinyl (lower) lkynyl which may have methoxymethyl; piperazinyl (lower) alkynyl which may have cyclohexyl; morpholmylammo (lower) alkyl; morpholmylammo (lower) alkenyl; morpholmylammo (lower) alkynyl; [spiro [ιndan-1, ' -piperidine] -1 ' -yl] (lower) alkyl; piperidyl (lower) alkyl which has phenyl, methoxy, acetyl, piperidyl or oxo; or piperidyl (lower) alkyl which has phenyl and cyano. 7. The compound of claim 6, m which Y is methylene, R 1 is bis (trifluoromethyl) phenyl, R is phenyl or naphthyl, each of which may have 1 or 2 suitable substituent (s) selected from the group consisting of methyl, methoxy, trifluoromethyl and fluorine, or mdolyl, R is hydrogen, and R is thiomorpholmyl (C-^-C^) alkyl; morpholinyl ) alkenyl which may have 1 or 2 methyl; morpholinyl (C2-C5) alkynyl which may have 1 or 2 methyl, methoxymethyl or fluoromethyl; or morpholmylammo (C-^-C^) alkyl . 8. The compound of claim 7, which is selected from the group consisting of (1) (2R) -1- [3, 5-Bιs ( trif luoromethyl) benzoyl] -2- (1H- ιndol-3-ylmethyl) -4- ( 3-thιomorpholmopropyl ) - piperaz e, \2) (2R)-l-[3, 5-Bιs (trif luoromethyl) benzoyl] -4- (4- morpholmo-2-butynyl) -2- (2-naphthylmethyl) - piperaz e, (3) (2R)-4- (4-Morpholmo-2-butynyl)-l-[3,5- bis (trifluoromethyl) benzoyl] -2- (3, 4- dimethylbenzyl) piperazme, (4) (2R)-l-[3, 5-Bιs (trifluoromethyl) benzoyl] -2- (3, 4- dimethylbenzyl) -4- [3- (morpholmoammo)propyl] - piperazine and (5) (2R)-l-[3,5-Bιs (trifluoromethyl)benzoyl] -2- (3, 4- dimethylbenzyl) -4- [ (E) - -morpholmo-2-butenyl] - piperazme, or a pharmaceutically acceptable salt thereof. 9. A process for the preparation of compound of the following general formula : R wherein Y is bond or lower alkylene, R 1 is aryl which may have suitable substituent (s) , 9 R is aryl or mdolyl each of which may have suitable substituent (s) , Fd is hydrogen or lower alkyl, R is chloro (lower) alkenyl; chloro (lower) alkynyl; pyridyl (lower) alkylamino (lower) alkyl; pyridyl (lower) alkylamino (lower) alkenyl; N- (lower alkyl) -N- [pyridyl (lower) alkyl] ammo- (lower) alkyi; triazoiylammo (lower) alkyi; lower alkoxy (lower) al ylamino (lower) alkyl; bis [ (lower) alkoxy (lower) al yl] ammo (lower) alkyl; X- (lower al yl) -N- [ (lower) al oxy (lower) alkyl] a mo- (lower) alkyl; hydroxy (lower) al yl; lower alkylsulfonyloxy (lower) alkyl; phenyl (lower ' alkyi which may have lower alkanoyl, ammo, lower alkanoyiamino, di (lower) alkyla inocarbonyl or nitro; lower alkoxyphenyl (lower) aikylcarbonyi; icwer alkanoylbenzoyl; benzoyl (lower) alkyl which has lower alkyl, chlorine cr di (lower) alkylamino; benzoyl (lower) alkyl which nas halogen and lower alkyi; dihalobenzoyl (lower) lkyl; αi (lower) al ylbenzoyl (lower) alkyl; 3-fiuorobenzoyl (lower) alkyl; 3- ( 4- fiuorobenzoyl) propyl; 4, 4-ethyienedιoxy-4- ( -fluorcpnenyl) butyl; piperazinylcarbonyi (lower) alkyl which has cyclopentyl or halophenyl; (2-pyndyl) ( lower) alkyl; (3-pyridyl) propyl; (3-pyrιdyl) (lower) alkynyl; i idazolyl (lower) lkyi which may have lower alkyl; pyrazolyl (lower) alkyl which may have lower alkyl; thiomorphoi ylcarbonyl (lower) alkyl; (3-azabιcyclo[3.2.2] non-3-yl ■ carbonyl (lower) alkyi; o; thienylcarbonyl (lower) lkyl, 1, 2, 3, 6-tetrahydropyridyl (lower) alkyi, 1,2,3, 6-tetrahydropyridyl (lower) alkynyl, 1,2,3, 4-tetrahydroιsoqumolyl (lower) alkvl, 4, 5, 6, 7-tetrahydrothιeno [3, 2-c]pyridmyl (lower) - alkyl, saturated heterocyclic (lower) alkyl, saturated heterocyclic (lower) alkenyl, saturated heterocyclic (lower) alkynyl, saturated heterocyclicamino (lower) alkyl, saturated heterocyclicamino (lower) alkenyl or saturated heterocyclicamino (lower) alkynyl, each of which may have suitable substituent (s) , or a salt thereof, which comprises (1) reacting a compound of the formula or its reactive derivative at the irnmo group or a salt thereof with a compound of the formula W 1 -R- or a salt thereof to provide a compound of the formula : cr a salt thereof, in the above formulas, Y, R 1 , R , R and R are each as defined above, and W-, is a leaving group, or (2) reacting a compound of the formula : or its reactive derivative at the imino group or a salt thereof with a compound of the formula or its reactive derivative at the carboxy group or a salt thereof to provide a compound of the formula R 1 or a salt thereof, m the above formulas, Y, R 1 , P, 2 and R J are each as defined above, and is lower alkoxyphenyl ( lower) alkyl or lower alkanoylphenyl, or (3) reacting a compound of the formula or its reactive derivative at the carboxy group or c salt thereof with a compound of the formula H-? 0 salt thereof to provide a compound of the formula or a salt thereof, in the above formulas, -ι O -j Y, R-, R- and R" are each as denned above, X is lower alkylene, and P is piperazinyl which has cyclopentyl or halophenyl; cr thiomorpholmyl, or iecting a compound of the formula or a salt thereof to an acylation reaction to provide a comoounα of the formula : or a salt thereof, the aoove formulas, X, Y, R ~ , P- and R are each as defined above, and is acyloxy, or 5) reacting a compound of the formula >r a salt thereof with a compound of tne formula H-R or a salt thereof to provide a compound of the formul; or a salt thereof, m the above formulas, X, Y, R are each as defined above, and p R is pyridyl (lower) alkylamino; N- (lower alkyl) -N- [pyridyl (lower) alkyl] ammo; triazolyla mo; morpholmoammo; lower alkoxy(lower) alkylamino; bis [ (lower) alkoxy(lower) alkyl] ammo; N- (lower alkyl) -N- [ (lower) alkoxy(lower) alkyl] ammo; lmidazolyl; pyrazolyl; or 1,2,3, 6-tetrahydropyrιdyl, 1,2,3, 4-tetrahydroιsoqumolyl, 4,5,6, 7-tetrahydrothιeno [3, 2-c]pyrιdmyl or saturated heterocyclic, each of which may have suitable substituent (s) , or subjecting a compound of the formula or a salt thereof to a reduction reaction to provide a comoound of the formula : or a salt thereof, in the above formulas, X, X, ?X, R- and P are each as defined above, or .arfing a compound of the formula or a salt thereof with a compound of the formula or a salt thereof to provide a compound of the formula or a salt tnereof, m the above formulas, X, Y, P 1-, R- and R3 are each as defined above, Xd is a leaving group, and - Rd is r-ower al1 1kanoyl1. 10. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a pharmaceutically acceptaoie salt thereof m admixture with pharmaceutically acceptable carriers. 11. A use of a compound of claim 1 as a medicament. 12. A nethoα for treating or preventing Tachykmm-meαiated diseases which comprises administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof to human being or animals. 13. A compound of claim 1 for use as a medicament. 14. Use of a compound of claim 1 for manufacture of a medicament for treating or preventing Tachykmm- mediated diseases.

Inventors: IGARI NORIHIRO, KONISHI NOBUKIYO, MANABE TAKASHI, MATSUDA HIROSHI, MATSUO MASAAKI, SHIGENAGA SHINJI, TAKE KAZUHIKO, TERASAKA TADASHI, IGARI, NORIHIRO, KONISHI, NOBUKIYO, MANABE, TAKASHI, MATSUDA, HIROSHI, MATSUO, MASAAKI, SHIGENAGA, SHINJI, TAKE, KAZUHIKO, TERASAKA, TADASHI
Applicants: FUJISAWA PHARMACEUTICAL CO, IGARI NORIHIRO, KONISHI NOBUKIYO, MANABE TAKASHI, MATSUDA HIROSHI, MATSUO MASAAKI, SHIGENAGA SHINJI, TAKE KAZUHIKO, TERASAKA TADASHI, FUJISAWA PHARMACEUTICAL CO., LTD., IGARI, NORIHIRO, KONISHI, NOBUKIYO, MANABE, TAKASHI, MATSUDA, HIROSHI, MATSUO, MASAAKI, SHIGENAGA, SHINJI, TAKE, KAZUHIKO, TERASAKA, TADASHI
Application year: 1996
Main classification: C07D241
IPC codes: A61K31, A61P1, A61P25, A61P43, C07D241, C07D401, C07D403, C07D405, C07D413, C07D417, C07D495