MXPA98004887A - Piperazine derivatives as taquicin antagonists - Google Patents

Abstract

This invention relates to piperidine derivatives of the formula (I), wherein each symbol is as defined in the description, and its pharmaceutically acceptable salt, to processes for the preparation thereof, to pharmaceutical compositions comprising the same, and to the use thereof to treat Tachykinin-mediated diseases in humans or animals

Description

DERIVATIVES OF P1PERAZINE AS TAQÜICININ ANTAGONISTS TECHNICAL FIELD The present invention relates to novel piperazine derivatives and a pharmaceutically acceptable salt thereof. More particularly, it relates to novel piperazine derivatives and a pharmaceutically acceptable salt thereof, which have pharmacological activities such as Tachykinin antagonism, especially Substance P antagonism, Neurocycin A antagonism, Neurocyanin B antagonism, and the like, for a process for the preparation thereof, for a pharmaceutical composition comprising the same, and for a use thereof as a medicament. Accordingly, an object of the present invention is to provide novel and useful piperazine derivatives and a pharmaceutically acceptable salt thereof, which have pharmacological activities such as Tachykinin antagonism, especially Substance P antagonism, Neurocynin A antagonism, antagonism of Neurocinin B, and the like.

Another object of the present invention is to provide a process for the preparation of the piperazine derivatives and a salt thereof. A further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, the piperazine derivatives and a pharmaceutically acceptable salt thereof. Yet a further object of the present invention is to provide a use of the piperazine derivatives or a pharmaceutically acceptable salt thereof as a Tachykinin antagonist, especially Substance P antagonist, Neurocyanin A antagonist or Neurocyanin B antagonist, useful for treating or prevent Tachykinin-mediated diseases, for example, respiratory diseases such as asthma, bronchitis, rhinitis, cough, expectoration, and the like; ophthalmic diseases such as conjunctivitis, spring 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, osteoarthritis, and the like; pain or discomfort (eg, migraine, headache, tooth pain, cancerous pain, back pain, etc.) and the like in humans or animals.

ANTECEDENTS OF THE TECHNIQUE Some piperazine derivatives having pharmaceutical activities such as antagonism of Tachykinin have been known as described in EP 655442 Al.

DESCRIPTION OF THE INVENTION The compound object of the present invention can be represented by the following general formula (I): wherein Y is a bond or lower alkylene, -sj »" R1 is aryl, which may have suitable substituent or substituents, R2 is aryl or indolyl each of which may have suitable substituent or substituents, R3 is hydrogen or lower alkyl, R 4 is lower chloroalkenyl, lower chloroalkynyl, lower pyridylalkylamino-lower alkyl, lower pyridylalkylamino-lower alkenyl, N- (lower alkyl) -N- [pyridylamino lower] -aminoalkyl lower, lower laminoalkyl triazole, lower alkoxy -alkyl lower-lower alkyl, bis [lower alkoxy-lower alkyl] aminoalkyl lower, N- (lower alkyl) -N- [lower alkoxy-lower alkyl] lower aminoalkyl, lower hydroxyalkyl, lower alkylsulphonyloxy-lower alkyl lower phenylalkyl which may have lower alkanoyl, amino, lower alkanoylamino, dialkyl laminocarboni lower or nitro, lower alkoxy lower alkylcarbonyl; oi lbenzoi the lower; benzoi lalqui the lower which has lower alkyl, chloro or lower dialkylamino; lower benzoylalkyl which has halogen and lower alkyl; dihalobenzo lalqui lower; lqui lbenzoi lower alkyl lower alkyl; 3- f luorobenzoi lalqui the lower; 3- (4-fluorobenzoyl) propyl; 4,4-ethyl-endioxy-4- (4-fluorophenyl) butyl; piperazini lcarboni lalqui the lower one which has cyclopentyl or halophenyl; (2-pyridi 1) lower alkyl; (3-pyridyl) pro ilo; (3-pyridyl) lower alkynyl; imidazole and the lower alkyl which may have lower alkyl; . pyrazolyl lower alkyl which may have lower alkyl; thiomorph-linylcarbonylalkyl lower; (3-azabicyclo- [3.2.2] on- 3-i 1) carboni lalqui lo lower; or thienylcarbonyl lalky lower, 1,2,3,6-te t rahidropyridi lower alkyl, 1,2,3,6-tet rahydropyridi lalquin lower, 1,2,3,4-tetrahydroisoquinolyl lower alkyl, 4,5,6 , 7-tetrahydrothieno [3, 2-c] pyridinium lower alkyl, saturated lower alkyl, saturated heterocyclic lower alkenyl, saturated heterocyclic lower alkynyl, saturated tertiary cycloalkyl, saturated heterocyclic lower alkenyl or lower alkynyl saturated saturated, each of which may have suitable substituents or substituents, and a pharmaceutically acceptable salt thereof.

It should be noted that the object compound (I) may include one or more stereoisomers due to the asymmetric carbon atoms and the double bond, and all of these isomers and a mixture thereof are included within the scope of the present invention. It should be further noted that the isomerization or rearrangement of the object compound (I) may occur due to the effect of light, acid, base or the like and the compound obtained as a result of isomerization or rearrangement is also included within the scope of the present invention. It should also be noted that the solvation form of the compound (I) (eg 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 through processes which are illustrated in the following schemes.

Proc so 1 iii) (I) or its reactive derivatives or a salt thereof of an imino group or its salts thereof Process 2 CU (la) or its reactive derivatives or a sa | of | same from an imino group or its salts from it Process 3 (III) (Ib, or its reactive derivatives or a salt thereof of a carboxy group or its salts thereof Process 4 (Id) or a salt thereof or a salt thereof Process 5 (Id) (le) or a salt thereof or a salt thereof Process 6 df) < tg) or a salt of it or a sa | rje | Same Process 7 (ig) (ih) or a salt thereof or a salt thereof wherein R, R1, R2, R3 and R4 are each as defined above, X is lower alkylene R is lower alkoxyphenyl-lower alkyl or lower phenyl alkanoyl, R6 is piperazinyl which has cyclopentyl or halophenyl; or t iornor fol ini lo, R7 is acyloxy, R? is pyridylalkylamino lower; N- (lower alkyl) -N- [pyridylalkyl the lower] amino; t iazol ilamino; mor fol inamino; lower alkoxy-lower alkylamino; lower bis-lower-alkyl-lower alkyl; N- (lower alkyl) -N- [(lower alkoxy-lower alkyl] -amino; imidazolyl; pyrazoyl; or 1,2,3,6-tetrahydro-pyridyl, t, 2, 3, -tetrahydroisoquinolyl, 4,5 6,7-te t rahidrot ieno [3, 2-c] pir idini lo or saturated heterocyclic, each of which may have substituent or suitable substituents, R9 is lower alkanoyl and Wi and W2 are each a leaving group. As for the initial compounds (II), (III), (IV), (V), (VI), (VII) and (VII), some of them are new and can be prepared by the processes described in the Preparations and Examples mentioned before similarly thereto Suitable salts and pharmaceutically acceptable salts of the subject and initial compounds are conventional non-toxic salts and include an acid addition salt such as an organic acid salt (for example acetate, trifluoroacetate, fumarate, maleate, tartrate, me tansul fonate, benzenesul fonate, formate, toluensul fonate, etc.) an inorganic acid salt (for example hydrochloride, bromohydrate, hydroiodide, sulfate, nitrate, phosphate, etc.), or a salt with an amino acid (for example arginine, aspartic acid, glutamic acid, etc.), or a metal salt such as an alkali metal salt (for example, sodium salt, potassium salt, etc.). ) and an alkaline earth metal salt (eg, calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (eg, tri et i metal salt, triethylamine salt, salt of pyridine, picoline salt, dicyclohexy 1 amine salt, N, N'-dibention salt and lendia ina salt, etc.), or the like. In the foregoing and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention proposes to include within the scope thereof are explained in detail as follows. The term "lower" is intended to mean 1 to 6, preferably 1 to 4, carbon atoms, unless otherwise indicated. The suitable "lower alkylene" may include a linear or branched one having from 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, propylene, tetramethyl, methyl-methylene, methyltrimethylene, hexamethylene, and the like, in which one of the preferred ones is methylene, ethylene, trimethylene or methylimethyl. The "halogen portion" and "halogen" suitable in the terms "dihalobenzoalkyl lower" and "halophenyl" may include fluorine, chlorine, bromine and iodine. ? ^ ¡- ^. The "lower alkyl" and "lower alkyl" portion suitable in the terms "pyridyl-lower alkylamino-lower alkyl", "lower pyridylalkylamino-lower alkenyl", "N- (lower alkyl) -N-" [pyridylalkyl lower] aminoalkyl lower "," triazolyl aminoalkyl lower "," lower alkoxy-lower alkylamino-lower alkyl "," bis [(lower alkoxy-lower alkyl) -aminoalkyl lower "," N- (lower alkyl ) -N- [lower alkoxy-lower alkyl] lower aminoalkyl ", lower hydroxyalkyl", lower alkylsulfo-nyloxy-lower alkyl "," lower phenylalkyl "," lower dialkylaminocarbonyl "," lower alkoxy-lower alkylcarbonyl lower alkyl " "," benzoi lower alkyl "," lower dialkylamino ", lower benzoylalkyl", lower dihalobenzoylalkyl "," lower dialkylbenzoyl-lower alkyl "," 3-fluorobenzoylalkyl lower, "pipera-zini lcarbonyl-lower alkyl," ( 2-pir idyl) alky lower "," imidazolylalkylamino Rior ", pyrazolyl-lower alkyl", "t iomor fo 1 ini lcarboni lalqui lo", "(3-azabicyclo [3.2.2] non-3-yl) carbonylalkyl-lower", "thienylcarboni lalqui lo lower", "1,2,3,6-tetrahydro-iridylalkyl lower", "1,2,3,4-tetrahydroisoquinolyl-lower alkyl", "4,5,6,7-tetrahydrothieno [3,2-c] pyridinyl-lower alkyl", "heterocyclic saturated lower alkyl", "saturated heterocyclic-lower aminoalkyl" and "alkoxyphenyl lower-lower alkyl "may include a linear or branched one having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and the like, preferably one having from 1 to 5 atoms of carbon. The "lower alkenyl" portion suitable in the term "lower chloroalkenyl", "lower pyridylalkylamino-lower alkene", "saturated heterocyclic lower alkenyl" and "saturated heterocyclic lower alkenyl" may include vinyl, 1- (or 2-) propenyl, l- (or 2- or 3-) butenyl, 1- (or 2- or 3- or 4-) pentenyl, l- (or 2- or 3- or 4- or 5-Jhexenyl, methylvinyl, ethylvinyl, l- (or 2- or 3-) methyl-l- (or 2-) -propenyl, l- (or 2- or 3-) ethyl- l- (or 2-) propenyl, l- (or 2- or 3- or 4-) et i 1- 1 - (or 2- or 3-) butenyl, and the like, in which - * the most preferred example may be C2-C4 alkenyl The "lower alkynyl portion" Suitable in the terms "lower chloroalkynyl", "lower (3-pyridyl) alkynyl", "1,2,3,6-tetrahydro-pyrilalkyl lower", "lower alkynyl" saturated heterocyclic "saturated lower alkynyl heterocyclic" may include ethynyl , 1-propynyl, propargyl, 1-methyl-1-propargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 O 2 6 3 O 4 or 5-hexynyl and the like, in which the most preferred example may be C2-C5 alkynyl. Suitable "aryl" may include phenyl, naphthyl, and the like, in which a preferred one is C 6 -C 0 aryl and one of the most preferred is phenyl. The "lower alkanoyl" and "lower alkanoyl" portion suitable under the terms "lower alkanoylamino," "lower alkanoylbenzoyl," "lower alkanoyl phenyl," may include formyl, acetyl, propanoyl, butanoyl, 2-me thiolpropanoyl, pentanoyl, 2,2. -dimet i lpropanoyl, hexanoyl, and the like. The "lower alkoxy portion" suitable in the terms "lower alkoxy phenyl lower alkylcarbonyl" and "lower alkoxyphenyl lower alkyl may include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t- pentyloxy, hexyloxy and the like.

The "saturated heterocyclic saturated" and "saturated heterocyclic" portion suitable in the terms "saturated heterocyclic lower alkyl", "saturated heterocyclic lower alkynyl", "saturated lower heterocyclic aminoalkyl", "saturated lower heterocyclic aminoalkene" and alkynylamino saturated heterocyclic "may include a saturated heterocyclic group of 3 to 8 members (most preferably 5 to 7-members) a heteromonocyclic group containing from 1 to 4 nitrogen atoms, for example, pi id rolyl, imide zo 1 idini lo, piperidilo, piperaz ini lo, hexameth and lenimino, etc .; a saturated heteromonocyclic group of 3 to 8 members (more preferably 5 or 6 members) containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, morpholinyl, sidinium, etc.; a saturated heteromonocyclic group of 3 to 8 members (more preferably 5 or 6 members) containing 1 or 2 .. sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazole, idinyl,. t iornor-fol ini lo, etc .; a saturated heterobicyclic group of the formula: (wherein f, m and n are each an integer from 1 to β); a saturated heterobicyclic group of the formula (where q, r, s and t are each an integer from 1 to 6); and similar.

The "substituent" suitable in the terms "aryl which may have suitable substituent or substituents", "aryl or indolyl each of which may have suitable substituent or substituents", "lower alkylcarbonate, 1, 2, 3 , 6-tetrahydropyridylalkyl, lower, 1, 2, 3, 6- 1, etrahydropyridine, lower, 1, 2, 3, 4- terahydrate and soquinol, and lower, 4, 5, 6, 7-tetrahydrothieno [3,2-c] pyridylalkyl, saturated heterocyclic lower alkyl, saturated heterocyclic lower alkenyl, saturated heterocyclic lower alkynyl, saturated heterocyclic lower alkylamino, saturated heterocyclic lower lamino alkyne or heterocyclic alkanoylamino saturated, each of which may have 'substituent or suitable substituents' and' 1,2,3,4-tetrahydroisoquinolyl, 4,5,6,7-te trahidrot ieno- [3, 2-c] pyridinium or heterocyclic saturated each of which may have suitable substituent or substituents "may include lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, etc.) , lower cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), lower alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, tert-butoxy, pentyloxy, neopent i loxi, ter-pent i loxi , hexyloxy, etc. ), lower alkoxy-lower alkyl (for example, toxi etyl, ethoxy ethyl, 1-methoxyethyl, 2-methoxyethyl, 1-ethoxyethyl, 2-ethoxyethyl, etc.), lower alkanoyl (for example, formyl, acetyl, propionyl, butyryl, isobutyryl, etc.), 'lower alkenyl (for example, vinyl, 1-propenyl, allyl, 1-methyl, 1, 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 O 2 O 3 or 4 or 5-hexenyl, etc.), lower alkynyl (for example ethynyl, 1-propynyl, propargyl, 1-methypropropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 6 2 6 3 or 4 6 5 -hexynyl, etc.), mono (or di otri) has loalqui the lower (eg, fluorine, di fluorometyl, trifluoromethyl, chloromethyl, dichloromethane, trichloromethyl, bromomethyl) , dibromomet i lo, tribro-mometil, 1 or 2-fluoroetheyl, 1 or 2-bromoetyl, 1 or 2-chloroeti lo, 1, 1-di fluoroethoyl, 2, 2-di fluoroeti lo, etc .), halogen (for example, chlorine, bromine, fluorine and iodine), carboxy, protected carboxy, hydroxy, protected hydroxy, aryl (for example or phenyl, naphthyl, etc.), lower aralkyl such as phenylalkyl lower (e.g., benzyl, phenethyl, phenylpropylo, etc.), carboxyalkyl lo where the lower alkyl moiety can be referred to as exemplified above, protected lower carboxyalkyl wherein the lower alkyl moiety can be referred to as exemplified herein, nitro, amino, protected amino, lower dialkylamino (eg, dimethylamino, diethylamino, diisopropylamino, ethyl-methylamino, isopropylmethyl, et i 1 isopropylamino, etc.), hydroxyalkyl lower - / * protected lower hydroxyalkyl, acyl, cyano, oxo, mercapto, lower alkylthio (for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, etc.), lower (for example met i lsul fini lo, et i lsul f ini lo, propi 1 sul fi ini lo, isopropylsul f ini lo, but i i sul f ini lo, etc.), imino, morpholinyl (for example, 2- mor fol ini lo, 3- morpholinyl, morpholino), a bivalent group of the formula: 0 and similar. Suitable "leaving group" can include lower alkoxy (for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, etc.), aryloxy (e.g., phenoxy, naphthoxy, etc.), 5 and acid residue or the like. The suitable "acid residue" can be halogen (for example chlorine, bromine, iodine, etc.), sulfonyloxy (for example methylsulphonyloxy, phenylsulfonyloxy, mesitylensulphonyloxy, toluensul fonil-p ox-i, etc.). ) or similar. ** Suitable "acyloxy" may include hydroxy sulphonic acid, lower alkyl lower alkoxy (for example methoxy sulphonyloxy, ethyl sulphonyloxy, etc.), phosphonoxy and the like.

Preferred embodiments of the object compound (I) are as follows: Y is lower alkylene (more preferably C 1 -C 4 alkylene, more preferably methylene); R1 is aryl (more preferably aryl of Ce-Cio, more preferably phenyl) which may have from 1 to 3 (most preferably 1 or 2, most preferably 2) substituent or suitable substituents [most preferably mono (or di otri) haloalkyl the lower (more preferably trihalonic lower, more preferred trifluoromethyl)]; R2 is aryl (more preferably aryl of Ce-C? O / most preferably phenyl or naphthyl) or indolyl each of which may have from 1 to 3 (most preferably 1 or 2, most preferred 2) suitable substituent or substituents [more preferably substituent or substituents selected from the group consisting of lower alkyl (more preferably C 1 -C 4 alkyl, more preferably methyl), lower alkoxy (more preferably C 1 -C 4 alkoxy) , more preferably methoxy), mono (or di or tri) lower haloalkyl (more preferably mono (or di ot ri) haloalkyl of C1-C4, more preferably trifluoromethyl) and halogen (more preferably chlorine or fluoro)]; R3 is hydrogen; and R < it is chloroalken and the lower (most preferably chloroalkaryone of C2-C4, most preferably 4-chloro-2-buteni); lower chloroalkynyl (more preferably C2-C4 chloroalkynyl, more preferably -chloro-2-butyl); lower pyridylalkylamino-lower alkyl [most preferably pyridylalkylamino of C 1 -C 4 -alkyl of Ca-C4 / most preferably 2 - [(3-pyridylmethyl) amino] ethyl, 2- [(4-pyridylmethyl) ami-no] ethyl or 3- [(3-pyridylmet i 1) amino] propyl]; pyrid-di 1-alkylamino lower-alkene lower (most preferably pyridylalkylamino of C? -C4-alkynyl of C2-C4, more preferably 4 - [(3-pyridy-methy1) amino] -2 -butenyl); N- (lower alkyl) -N- [pyridi lower alkyl] lower aminoalkyl [more preferably N- (d-C4 alkyl) -N- [pyridylalkyl] of C1-C4] aminoalkyl of C1-C4, more preferably 2 - [N-me.ti 1-N- (3-pyridylmethyl) 1 -amino] et i]; t r ia zoli laminoalqui lower (most preferred triazolylaminoalkyl of C 1 -C 4, more preferably 3- (1,2,2-triazol-3-ylamino) -propyl); lower alkoxy-lower alkylamino-lower alkyl (more preferably Ci-C4 alkoxy -alkylamino of Ci-C4-alkyloxy) of C-C, more preferably 2- (2-methoxy-t-one) aminoethoxy 1 ); bis [lower alkoxy-lower alkyl] aminoalkyl lower [more preferably bis [C 1 -C 4 alkyloxy C 1 -C 4 alky] aminoalkyl C 1 -C 4 alkoxy, more preferably 3- [bis (2-methoxy- ethyl) amino] -propyl]; N- (lower alkyl) -N- [lower alkoxy-lower alkyl] amino- (lower alkyl [most preferably N- (C1-C alkyl) -N- [d-C4 alkoxy-Ca-C4 alkyl] ] aminoalkyl of C1-C4, more preferably 2- [N-methyl-N- (2-methoxyethyl) amino] ethyl]; hydroxyalkyl lower (more preferably hydroxyalkyl Ci-C4, more preferably hydroxypropyl); lower foniloxy-lower alkyl (more preferably C 1 -C 4 alkylsulphonyloxy -alkyl of C?-C4, more preferably methylsulfo-ni loxypropyl); phenylalkyl lower (more preferably phenylalkyl of C 1 -C 4, more preferably benzyl) which can have lower alkanoyl (more preferably C 1 -C 4 alkanoyl, more preferably acetyl), amino, lower alkanoylamino (more preferably alkanoylamino of Ca-C4, more preferably acetylamino), dialkylaminocarboni lower (more preferred ... »-.-dialkylaminocarboni lo of Cj-C4, most preferably diethylaminocarbon i lo) or nitro; alkoxyphenyl in ferior-alkyicarboni lower (more preferably C1-C-alkoxycarbonyl C1-C4 alkyl, more preferably methoxy-phenyl-1-carbonyl); alkanoylbenzoi lower (more preferably lower C 1 -C 4 alkanoylbenzoyl, more preferably acetylbenzoyl lo); benzoylalkyl, the lower (most preferably benzoylalkyl of C, -C4, more preferably benzoymethyl) which has lower alkyl (more preferably C1-C4 alkyl, more preferably methyl), chloro or dialkylamino lower (higher lamino dicalk preference of C1-C4, more preferably dimethylamino); lower benzoylalkyl (more preferably benzoylalkyl of C 1 -C 4, more preferably benzoylmethyl) which has halogen (more preferably fluoro) and lower alkyl (more preferably C 1 -C 4 alkyl, more preferably methyl); dihalobenzoi lower alkyl- [(most preferred dihalobenzoyl C1-C4 alkyl, more preferred (difluoro-benzoyl) methyl]; dialkyl benzoi lower alkyl-lower alkyl [more preferred dialkyl benzoyl] C1-C4 alky1 C1 alkyl -C4, more preferably dimethylbenzoylmethyl] 3-f luorobenzoyl lal qai lower (more preferably 3- f luorobenzoyl lalkyl of C? -C4, most preferably 3- fluorobenzo-ylmethyl); (4-f luorobenzoi 1) propi lo; 4,4-ethylene-dioxy-4- (4-fluorophenyl) utilo; pipera zinylcarbonyl-lower alkyl (more preferably piperazine Icarboni C 1 -C 4 alkyl, more preferably piperazinylcarboni lmet ilo) which has cyclopentyl or halophenyl (more preferably fluorophenyl); (2-pyridyl) lower alkyl (more preferably (2-pyridyl) C 1 -C 4 alkyl, more preferably (2-pyridyl) methyl); (3-pyridyl) propyl (most preferably 3- (3-pyrid-di 1) propyl); (3-pyridi 1) alkyne lower (most preferably (3-pyridyl) alkyloxy) of C2-C4, more preferably 3- (3-pyridyl) -2-propynyl); imidazoli lalqui lower (more preferably imidazole and C1-C4 alkyl), more preferably (1H-imidazole-1-yl) meth i, (1H-imidazole-2-yl) meth i lo (lH-imidazole- i) methyl) which may have lower alkyl (more preferably alkyl) C? -C4 / most preferably methyl); pyrazolyl-lower alkyl (more preferred pyrazolyl-C1-C4-alkyl, more preferred (1H-pi-razol-4-yl) me ti lo or 3- (lH-pi ra zol-4-i1) propi 1) which may have lower alkyl (more preferably C 1 -C 4 alkyl, more preferably methyl); thiomorfolini Icarboni lower alkyl (most preferably thiomor fol ini Icarboni 1-alkylo C1-C4, most preferably thiomor fol ini 1-carbonylmethyl); (3-azabicyclo [3.2.2] -non-3-yl) -carbonylalkyl (more preferably (3-azabicyclo [3.2.2] non-3-yl) carbonyl C1-C4 alkyl, more preferably ( 3-a-zabicyclo- [3.2.2] non-3-yl) carboni lmet i lo); Other lower alkylcarbonyl (more preferred is the C1-C4 alkylcarbonate, most preferably carbonyl alcohol), 1, 2, 3, 6-tetrahydropyridi-1-lower alkyl (most preferably 1, 2, 3, 6-tet rahidropiridi lalqui lo of Ci-C4, more preferably 3- (1, 2, 3, 6- tet rahi-dropiridin-1-yl) -propyl), 1,2, 3, 6- tetrahydropyridin-dilalkolinyl (more preferably 1, 2, 3, 6-tetrahydropyridi-1-alkylo-C2-C4, most preferably 4- (1, 2, 3, 6-tetrahydropyridin-1-yl) -2-butinyl ), 1,2,3,4-tetrahydroisoquinolyl-lower alkyl (more preferably 1,2,3,4-tetrahydroisoquinolyl-C1-C4, more preferably 1,2,3-tetrahydro-isoquinolylpropyl), , 5, 6, 7-tetrahydrothieno [3,2-c] pyridinyl-lower alkyl (more preferably 4,5,6,7-tetrahydro-ieno [3, 2-c] -pyridinium lalqui lo of C1-C4, more preferably 4, 5, 6, 7- tet ra-hydrotin [3, 2-c] pyridiniumpropyl), heterocyclic lower alkyl (more preferably saturated C 1 -C 4 alkyl heterocyclic, more preferably saturated heterocyclic ethyl or saturated heterocyclic propyl, more preferably saturated heterocyclic saturated heterocyclic lower alkenyl propylene (more preferably saturated heterocyclic C 2 -C 4 alkenyl, most preferably butenyl saturated heterocyclic), saturated heterocyclic lower alkynyl (more preferably saturated heterocyclic C2-C5 alkynyl, more preferably saturated heterocyclic butynyl or saturated heterocyclic pentinyl), saturated lower heterocyclic aminoalkyl (more preferably saturated heterocyclic C1-C4 aminoalkyl, higher saturated heterocyclic aminopropyl preference), saturated heterocyclic lower aminoalkenyl (more preferably saturated heterocyclic C2-C4 aminoalkenyl), more preferably aminobut eni saturated heterocyclic) or saturated heterocyclic lower aminoalkynyl (more preferably aminoalkynin saturated heterocyclic C2-C5 most preferred saturated aminobutyne saturated heterocyclic) [wherein "the saturated heterocyclic portion" is saturated from 3 to 8 members (more preferably 5 to 7 members) the hetero-monocyclic group contains from 1 to 4 (most preferably 1 6 2) nitrogen atoms (most preferably n pi rrolidini, piperidyl, piperazinyl or hexamethyleneimino), higher piperidyl preference); from 3 to 8 saturated members (more preferably from 5 to 7 members) the heteromonocyclic group contains 1 6 2 (most preferably 1) oxygen atoms and from 1 to 3 (most preferably 1) nitrogen atom (greater preference morpholinyl or homomor folini lo, more preferably morpholinyl); from 3 to 8 saturated members (most preferably 5 or 6 members) the hetero-monocyclic group contains 1 or 2 (most preferably 1) sulfur atoms and 1 to 3 (most preferably 1) nitrogen atoms ( more preferably tiomorfolini lo); or the saturated heterocyclic group of the formula: (where q, r, s and t are each an integer from 1 to 6); and similar. (more preferably 3-azabic or [3.2.2] non-3-i 1)], each of which d have from 1 to 3 (most preferably 1 or 2, substituent or suitable substituents [more preferably substituent or substituents selected from the group consisting of lower cycloalkyl (more preferably cyclohexyl), lower alkanoyl (more preferably C 1 -C 4 alkanoyl, more preferably acetyl), lower alkyl (more preferably C 1 -C 4 alkyl, higher preferably methyl), mono (or di or tri) haloalkyl, lower (more preferably onohaloalkyl, C1-C4, more preferably fluorometho1), lower alkoxy (more preferably C1-C4 alkoxy, more preferably methoxy) , lower alkoxy-lower alkyl (more preferably C 1 -C 4 alkoxy C 1 -C 4 alkoxy, more preferably methoxymethyl), halogen (more preferably chlorine), aryl (most preferably phenyl), cyano, oxo and the bivalent group of the formula:) ' The most preferred embodiments of the object compound (I) are as follows: Y is lower alkylene (more preferably alkylene- of Ci-Ci, - "> > higher preference methylene); R1 is phenyl which may have 1 6 2 mono (or di otri) haloa lqui lo lower [greater Preference bis (trihaloalkyl lobe) phenyl, most preferably bis (tri fluoromethyl) phenyl, R 2 is phenyl which may have 1 or 2 substituents or suitable substituents selected from the group consisting of lower alkyl, lower alkoxy, mono (or di or tri) haloalkyl the lower and halogen [more preferably dialkyl, lower phenyl, lower alkoxy-phenyl, lower alkyl] phenyl, [lower alkyl] halo phenyl, halophenyl or dihalephenyl, Most preferred are dimethyl, 1-phenyl, methoxy-phenyl, phenyl (trifluoromethyl), methyl-1-fluorophenyl, fluorophenyl or difluoro-chlorophenyl], naphthyl or indolyl, R 3 is hydrogen, and R 4 is lower alkyl, which may be have * 1 or 2 lower alkyl (more preferably methyl) ), ho omorfolini the lower alkyl, t iomorfolini lalqui the lower, (hexamethylene-imino) lower alkyl, (3-azabicyclo [3.2.2] non-3-yl) lower alkyl, piperazine lalqui the lower which may have phenyl or cycloalkyl lower (more preferably piperazini lalqui the lower which has phenyl or cyclohexyl), mor folini lalqueni the lower which may have 1 or 2 lower alkyl (most preferably methyl), mor fol ini lalquini the lower which may have a selected substituent of the group consisting of lower alkyl (more preferably methyl), lower alkoxy-lower alkyl (more preferably me toxymethyl) and mono (or di or tri) haloalkyl lower (most preferably fluoromethoxy), thio orfo-1 ini lalqueni the lower, thiomorfolini lower alkynyl, pyrrole idini lower alkynyl which may have lower alkoxy-lower alkyl (more preferably methoxymethyl), lower piperazinyl-alkynyl which may have lower cycloalkyl (more preferably cyclohexyl), lower morpholine-1-inylaminoalkyl, lower-inorganic-laminoalquene-lower, lower-laminoalkyne-folin, or lower piperidylalkyl which may have 1 or 2 substituents or suitable substituents selected from the group consists of the bivalent group of the formula: IJ JI 't phenyl, cyano, lower alkanoyl, lower alkoxy, piperidinyl, and oxo [most preferably [spiro [indan-l, 4'-piperidine] -1'-yl]) alkyl lower, piperidylalkyl lower »which ... has phenyl, acetyl, methoxy, piperidino or oxo, or piperidylalkyl lower which has phenyl and cyano]. The processes 1 to 7 for preparing the subject compound (I) of the present invention are explained in detail in the following.

Process 1 The object compound (I) or a salt thereof can be prepared by reacting the compound "(II) or its reactive derivative in the imino group or a salt thereof with the compound (IV) or a salt thereof. The suitable reactive derivative in the imino group of the compound (II) may include a Schiff base type imino or its taumeric enamine type isomer formed by the reaction of the compound (II) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as bis (tri et i1sily1) acetamide, mono (trimethylsilyl) acetamide, bis (trimethylsilyl) urea or the like; a derivative formed by the reaction of the compound (II) with phosphorus trichloride or phosgene and the like. The reaction is usually carried out in a conventional solvent such as water, alcohol [for example methanol, ethanol, etc.], acetone, dioxen, acetonitrile, chloroform, methylene chloride, ethylene chloride, tatrahydrofuran, ethyl acetate, N , N-dimethylformamide, pyridine or any other organic solvent which does not adversely affect the reaction. These conventional solvents can also be used in a mixture with water. The reaction can also be carried out in the presence of an inorganic or organic base such as alkali metal carbonate, alkali metal bicarbonate, trialkylamine lower, pyridine, Lower N-alkylmorphine, N, N-dialkylbenzene lower plate, or the like. The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

Process 2 The object compound (s) or a salt thereof can be prepared by reacting the compound (V) or its reactive derivative in the carboxy group or a salt thereof with the compound (II) or its reactive derivative in the imino group or a salt of it. The suitable reactive derivative in the carboxy group of the compound (V) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like. The suitable example of the reactive derivative may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid [for example dialkyl phosphoric acid, phenyl phosphoric acid, di-phenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.], dialkyl phosphorous acid, lower alkene sonic acid [eg, methansulonic acid, ethansulonic acid, etc.], sulfurous acid, thiosulfuric acid, sulfuric acid, aliphatic carboxylic acid [eg acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylic acid I for example benzoic acid, etc.]; a symmetrical anhydride; an amide activated with imidazole, substituted 4-imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester [for example, cyanomethyl ether, methoxymethyl ether, dime ti 1imino-met i 1 [(CH3) 2N ~ = CH-] ester, vinylester, propargi lester, p-nor t rofeni les er , 2, -dini t rofeni les t er, trichlorophenylester, pentachlorophenol es ter, mesi 1 pheni ter, pheni lazofeni les ter, feni 1 t ioes ter, p-ni t rofeni 1-thioester, p-cresi 1 t ioester, carboxymethyl thioester, pyranylester, pyridyl lester, piper idiester, 8-quinolyl ioes ter, etc.], or an ester with an N-hydroxy compound [for example N, N-dimethexydroxylamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyftalimide, 1-hydroxy-1H-benzotriazole, etc.], and the like. These reactive derivatives can optionally be selected from those according to the type of compound (V) that will be used. The reaction is usually carried out in a conventional solvent such as water, alcohol [for example methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N , N-dimeti 1 formamide, pyridine or any other organic solvent which does not. Influences in the reaction adversely. These conventional solvents can also be used in a mixture with water.

In this reaction, when the compound (V) is used in the form of a free acid or a salt thereof, the reaction is preferably carried out in the presence of a conventional condensing agent such as N, N'-dichlorohexycarbodiimide; N-cyclohexyl-N '-morpholinoethylcarbodiimide; N-cyclohexyl-N '- (4-diethylaminocyclohexyl) carbodiimide; N, N '-diethylcarbodiimide; N, N '-di-isopropyl-1-carbodiimide; N-ethyl-Nr- (3-dimethylaminopropyl) carbodiimide; pentamet i lenceten-N-cyclohexy 1 imine; diphenyl-cetem-N-cyclohexylimine; Etoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; Isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; fos fori diphenyl lazide; thienyl chloride; oxalyl chloride; lower alkyl haloformate [for example ethyl chloroformate, isopropyl chloroformate, etc.]; triphenylphosphine; salt of 2-et i 1-7-hydroxybenzi soxazole io; intra-molecular salt of 2-ethyl-5- (m-sul-phenyl) -i-soxazole hydroxide; 1- (p-chlorobenzenesulfonyloxy) -6-chloro-lH-benzotriazole; 2-chloro-1-met ipyridinium iodide; 1- (3-dimethylaminopropyl) -3-ylcarbodiimide hydrochloride; the so-called vilsmeier reagent prepared by the reaction of N, N-dimethylformamide with thionyl chloride, phosgene, chloroformate of tlorchloromethane, phosphorus oxychloride, etc.; or similar. The reaction may also be carried out in the presence of an inorganic or organic base, such as alkali metal carbonate, alkali metal bicarbonate, trialkylamine lower, pyridine, lower N-alkylmorphine, N, N-dialkylbenzylamine lower, or similar. The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

Process 3 The object compound (Ib) or a salt thereof can be prepared by reacting the compound (III) or its reactive derivative in the carboxy group or a salt thereof, with the compound (VI) or a salt thereof. The reaction mode and the reaction conditions of this reaction are referred to as those explained in Proc.s * or 2.

Process 4 The object compound (Id) or a salt of > It can be prepared by subjecting the compound (LE) or a salt thereof to an acylation reaction. The reaction can be carried out in the manner described in Example 20 mentioned below or similar forms thereto.

Process 5 The compound (le) or a salt thereof can be prepared by reacting the compound (Id) or a salt thereof with the compound (VII) or a salt thereof. This reaction is usually carried out in a solvent such as water, alcohol (for example methanol, ethanol, etc.), benzene, N, N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, acetonitrile, diethyl ether or any other solvent which does not adversely affect the reaction, or a mixture thereof. The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.

The reaction can also be carried out in the presence of an inorganic or organic base such as alkali metal (for example sodium, potassium, etc.), alkali metal hydroxide (for example, sodium hydroxide, potassium hydroxide, etc.) , alkali metal acid carbonate (eg, sodium acid carbonate, potassium hydrogen carbonate, etc.), alkali metal carbonate (eg, sodium carbonate, potassium carbonate, etc.), trialkylamine lower (eg, tr ime ti lamina, triethylamine, di isopropy le ti lamina, etc.), alkali metal hydride (eg, sodium hydride, etc.), alkali metal lower alkoxide (eg, sodium methoxide, sodium ethoxide, etc. .), pyridine, lutidine, picoline, dimethyl-aminopyridine, N-lower alkylmorpholine, lower N, N-dialkylbenzylamine, N, -dialkylanyl-lower or the like. When the base * and / or the initial compound are in liquid, they can also be used 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. The reaction can be carried out in the manner described in Example 29 mentioned below or similar forms thereto.

Process 7 The object compound (Ih) or a salt thereof can be prepared by subjecting the compound (Ig) or a salt thereof to an acylation reaction. The reaction can be carried out in the manner described in Example 31 mentioned below or similar forms thereto. The subject compound (I) and a pharmaceutically acceptable salt thereof have pharmacological activities such as Tachykinin antagonism, especially Substance P antagonism, Neurocyanin A antagonism or Neurocyanin B antagonism, and, therefore, are useful for the treatment or prevention of diseases mediated by Tachykinin, particularly diseases mediated by Substance P, for example, respiratory diseases such as asthma, bronchitis (for example chronic bronchitis, acute bronchitis and panbronquiol it is diffuse, etc.), rhinitis, cough, expectoration and the like; ophthalmic diseases such as conjunctivitis, spring 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, osteoarthritis, and the like; pain or discomfort (for example, migraine, headache, pain in general, tooth pain, cancerous pain, back pain, neuralgia, etc.) and the like. In addition, it is expected that the subject compound (I) and a pharmaceutically acceptable salt thereof of the present invention are useful for the treatment or prevention of ophthalmic diseases such as glaucoma, uveitis and the like.; gastrointestinal diseases such as ulcer, ulcerative colitis, irritable bowel syndrome, food allergy, and the like; inflammatory diseases such as nephritis, and the like; circulatory diseases such as hypertension, angina pectoris, heart failure, Raynaud's disease-thrombosis, and the like; epilepsy, epical paralysis; polaquiurua; cystitis; hyperref bladder destructive lag; urinary incontinence; Parkinson's diseases; dementia, dementia related to AIDS; Alzheimer's diseases; Dawn syndrome; Huntington's disease; Calcinoid syndrome; diseases related to immune improvement or suppression; disorders caused by Helicobacter pylori or other gram negative bacteria positive to spiral urease; sunburns; angiogenesis or diseases caused by angiogenesis; and simi lares. In addition it is expected that the object compound (I) and a pharmaceutically acceptable salt thereof of the present invention are useful for treating or preventing chronic obstructive pulmonary diseases, particularly chronic pulmonary emphysema, iritis; vi t reor re inopathy of proliferation; psoriasis; intestinal inflammatory diseases; particularly CrcffPn diseases; hepatitis; superficial pain due to frostbite, burns, shingles or diabetic neuropathy; tenalgia due to hyperlipidemia; post-operative neuroma, particularly mastectomy; vulvar vestibulitis; associated itching by hemodialysis; lichen planus; laringofaringi t is; bronchoectasis; coniosis; whooping cough; pulmonary tuberculosis; cystic fibrosis; emesis; mental illnesses, particularly anxiety, depression, dysthymic disorders and schizophrenia; desmiel ination diseases such as multiple sclerosis or amyotrophic lateral sclerosis; morphine withdrawal attenuation; oedema, such as oedema caused by thermal damage; small cell carcinomas, particularly small cell lung cancer (SCLC); hypersensitivity disorders such as sumaque poisonous; fibrous and collagen diseases such as scleroderma and eosinophilic fascioliasis; sympathetic reflex dystrophy such as shoulder / hand syndrome; addiction disorders such as alcoholism; somatic disorders related to tension; rheumatic disorders such as fibrositis; and similar. In addition, the subject compound (I) and a pharmaceutically acceptable salt thereof of the present invention are penetrants in the Central Nervous System (CNS).

For therapeutic purposes, the compound (i) and a pharmaceutically acceptable salt thereof of the present invention can be used in the form of a pharmaceutical preparation containing one such compound, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as a solid or liquid, organic or inorganic excipient suitable for oral, parenteral, external, including topical, enteral, intravenous, intramuscular, inhalant, nasal, intraarticular, int raespinal, trans tracheal or transocular administration. The pharmaceutical preparations can be solid, semi-solid solutions or such as capsules, tablets, pills, dragees, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, poultices, gels, tapes, eye drops, solution, syrup , aerosols, suspension, emulsion, or the like. If desired, auxiliary substances, stabilizing agents, wetting agents or emulsifiers, pH regulators and other commonly used additives may be included in these preparations. Since the dose of compound (I) will vary depending on the age and condition of the patient, an average individual dose of approximately 0.1 mg 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound ( I) may be effective for treating tachykinin-mediated diseases, such as asthma and the like, in general, amounts between 0.1 mg / body and approximately 1000 mg / body may be administered per day. In order to show the usefulness of the object compound (I) and a pharmaceutically acceptable salt thereof, the pharmacological test data of some representative compounds of the present invention are shown in the following.

A. Evaluation of the transport efficiency of the NKi antagonist to the central nervous system using a h-NKi receptor binding assay [I] Test Method (1) Administration of the test compound and extraction of the brain compound.

Male SD rats are given an i.v. of a solution containing a test compound (1 mg / kg) after 5 minutes, the animals were anesthetized with ether, bled and perfused through the ascending aorta with 20 ml of saline. The brain is quickly removed, weighed and homogenized in 4 volumes of ice-cold distilled water using Polytoron (KINEMATICA). To extract the test compound, 500 μl of the ogenate, 100 μl of methanol, 500 μl of 0.1 N NaOH and 4 ml of ethyl acetate are mixed by stirring for 10 minutes at room temperature. The organic phase (2.5 ml) is recovered by centrifugation at 3000 rpm for 10 minutes, dried and dissolved in dimethyl sulfoxide. (2) H-NKx receptor binding assay (a) Preparation of crude CHO cell membrane CHO cells were harvested by permanently expressing h-NKi receptors and homogenized with a Dounce homogenizer at 4 ° C in a pH regulator ( 0.25 m sucrose, 25 mM. - Tris-HCl (pH 7.4) 10 mM MgCl 2, 1 mM EDTA, 5 μg / ml p-APMSF). The homogenate is centrifuged (500 x .. * -, 10 * min) and the pellet is resuspended in the same pH regulator, homogenized and centrifuged. The two supernatants are combined and centrifuged (100,000 x g, 1 hour). The crude cell membranes thus isolated are resuspended in a pH regulator (25 mM Tris-HCl (pH 7.4), 10 BM ^ MgCl2, 1 mM EDTA, 5 μg / ml p-APMSF) and stored at -80 ° C until used. (b) Binding of 125 I -BH-Susten P to the prepared membrane. Cell membranes (6 μg / ml) are incubated with 125 I-BH-Substance P (0.1 nM) with or without the extracted compounds in 0.25 ml) of a medium (50 mM Tris-HCl (pH 7.4), 5 mM of MnCl2, 20 μg / ml of chemostat ina, 40 μg / ml of bacitracin, 4 μg / ml of leupeptin, 5 μg / ml of p-APMSF, 200 μg / ml of BSA) at 22 ° C for 90 minutes. At the end of the incubation period, the contents were quickly filtered through a Blue Mat 11740 filter (pretreated with 0.1% polyethylenimine for 3 hours before use) using a SKATRON cell harvester. The filter was then washed with a washing pH regulator (50 mM Tris-HCl (pH 7.4), 5 mM MnCl2). Radioactivity is counted using an auto-qamma meter (Packard RIASTAR 5420A). All the presented data are of specific union defined as that displaceable by 3 μm of substance P not marked.

[II] Test Result • **. All -the following test compounds showed more than 80% inhibition rate of binding of 12: > I-BH-Substance P to h-NKa receptors at a dose of 1 mg / kg. The Test Compounds: The objective compounds of Examples 7, 11, 12, 22, 23, 24- (2), 26, 35, 36, 37- (2), (4), (5), (6) , (8), 44- (l), (2), (4), (5), (7), 46, 47, 51, 52- (l), 53- (l), 54, 55, 58, 59- (l), (3), 62- (l ), 67- (4), (5), (6), (7), (13), 71, 72, 73, 74, 75, 76, 77, 81, 82- (l), 82- (4), 82- (5), 82- (7), 82- (8), 82- (9), 82- (10), 82- (12), 84- (l) and 86 B. Emesis in the ferret [I] Test Method Adult male ferrets individually stored (Marshall Farms, 1.4 to 2.2 kg) are given an i.p. of a solution containing a test compound. 30 minutes later, emetic responses (naucea and vomit) were induced through the administration of intragastric copper sulfate (40 mg / kg / ml) and were observed during the following 30 minutes. The time and the number of nauceas and vomito observed were registered in each animal. An individual animal was tested with at least 10 days between experiments.

[II] Test Result All of the following test compounds showed 100% inhibition rate of emesis in the ferret at the dose of 3.2 and / or 10 mg / kg. Test Compounds: The Compounds Object of Examples 12, 22, 23, 24- (2) and 37- (5), (6) The following Preparations and Examples are presented for the purpose of illustrating this invention.

Example 1 A mixture of (2R) -1- [3, 5-bi s (t-ri-luoro-methyl) -benzoyl] -2- (lH-indol-3-ylmethyl) -piperazine (5 g) and 3-bromopropanol (1.68 g) in N, N-di-ethylformamide (40 ml) is heated at 60 ° C in the presence of potassium carbonate (4.55). After 9 hours, the reaction mixture is poured into water (400 ml) and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the obtained residue is purified by silica gel column chromatography using dichloromethane-methanol (30: 1) as a diluent to give (2R) -l- [3,5-bis (trifluoromethyl) benzoyl) ] -4- (3-hydroxypropyl) -2- (1H-indol-3-ylmethyl) piperazine (5.36 g) as a powder. IR (Pure): 3600-3100, 1625, 1275, 1170, 1128, 898 cm "1 NMR (DMSO-de, d): 1.6-5.0 (16H, m); 6.6-8.2 (8H, m); 10.84 ( 1H, s) MASS: 514 (M + l), 454 Example 2 The following compound is obtained according to a form similar to that of Example 1. (2R) -l- [3,5-Bis (trifluoromethyl) benzoyl-2- (3,4-dimethylbenzyl-4- (3- hydroxypropyl) piperazine IR (Nujol): 3400 (br), 3000-2700, 1625, 1430, 1270, 1120 cm "1 NMR (DMSO-de, d): 1.55-1.75 (2H, m); 2.05-4.9 (19H ,); 6.5-8.2 (6H, m) MASS: 503 (M + l) Example 3 A mixture of (2R) -1- [3,5-bis (t-fluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) piperazine (0.3 g), 2-bromo- ' chloroacetofenone (0.2 g) and potassium carbonate (0.16 g) in N, N-dimethylformamide (5 ml) is stirred at room temperature for 1 hour and 20 minutes. The reaction mixture is poured into water (20 ml) and extracted with ethyl acetate. The organic layer is washed with water and dried over magnesium sulfate. After evaporation of the solvent, the obtained residue is purified by silica gel column chromatography using toluene-ethyl acetate (4: 1) as a diluent. The fractions containing the objective compound are collected and concentrated under reduced pressure. The product obtained is dissolved in ethyl acetate, treated with 4N hydrochloric acid, ethyl acetate solution and after evaporation under reduced pressure. The residue is triturated with n-hexane to give (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -4- (4-chloro-phenylcarbonylmethyl) -2- (lH-indole-3-hydrochloride. i lmet il) piperaz ina (0.31 g) as a powder. mp: 140 ° C (dec.) [a] 20 D: -22.6 ° (C = 0.5, MeOH) IR (Nujol): 3500-3100, 2700-2150, 1690, 1635, 1275, 1100 cm "1 NMR (DMSO) -de / d): 2.9-5.3 (11H, m), 6.4 8.3 (12H), 10.7-11.05 (2H, "m) MASS: 608 (M + l) (free) EXAMPLE 4 The following compound is obtained according to a form similar to that of Example 3. (2R) -1- [3,5-Bis (t-fluoromethyl) -benzoyl] -4- [(5)] hydrochloride. -chloro-2-thienyl) carboni lmet il] -2- (lH-indol-3-ylmethyl) piperazine [a] 20D: -55.2 ° (C = 0.5, MeOH) IR (Pure): 3700-3100, 2700- 2150, 1635, 1415, 1275, 1130 cm "1 NMR (DMSO-d6, d): 3.0-5.2 (11H, m); 6.8-8.3 (10H, m); 10.97 (1H, s) MASS: 651 (M + l) (free), 614 Example 5 A mixture of (2R) -1- [3,5-bis (t-fluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) piperazine (0.3g), 2-bromo-3 '-chloroacetophenone (0.19 g) and potassium carbonate (0.16 g) in N, N-dimethylformamide (5 ml) is stirred at room temperature for 1 hour and 20 minutes. The reaction mixture is poured into water (20 ml) and extracted with ethyl acetate. The organic layer is washed with water and dried over magnesium sulfate. After evaporation of the solvent, the residue obtained is purified by column chromatography on silica gel using toluene-ethyl acetate (2: 1) as a diluent. The product obtained is dissolved in ethyl acetate (2 ml) and treated with 4N hydrochloric acid in ethyl acetate solution (164 μl). The resulting precipitate is collected by filtration and dried at 50 ° C for 5 hours to give (2R) -1- [3,5-bis (trifluoro-methyl) benzoi 1] -4- (3-fluorophene) hydrochloride Icarbonylmethyl) -2- (1H-indol-3-ylmethyl) piperazine (0.2 g) as a powder, mp: 195 ° C (dec.) [A] 20D: -34.2 ° (C = 0.5, MeOH) IR (Nujol): 3200-2650, 2200-1695, 1655, 1270, 1125 cm "1 NMR (DMSO-de / d): 3.3-5.3 (11H, m); 6.6-8.3 (12H, m) 10.8-11.4 (2H, m) MASS: 592 (M + l) (free) Analysis Calculated for C3oH24F7N302 • HCl: C 57.38, H 4.01, N 6.69 Found: C 57.23, H 3.79, N 6.49 Example 6 The following compound is obtained according to to a form similar to that of Example 5. (1) (2R) -1- [3,5-Bis (tri-f-rom-romethyl) -benzoyl] -4- (3, -difluorophenylcarbonylmethyl) -2- (lH) hydrochloride -indol-3-ylmethyl) piperazine mp: 171 ° C (dec.) [a] 2%: -31.6 ° (C = 0.5, MeOH) IR (Nujol): 3550-3100, 2650-2150, 1690, 1640, 1510, 1275, 1130 cm "1 NMR (DMSO-d6, d): 3.0-5.3 (11H, m); 7.6-8.3 (11H, m); 10.7-11.5 (2H, m) MASS: 610 (M + l) (free) Analysis Calculated for C30H23F8N302 • HCl: C 55.78; H 3.74; N 6.50 Found: C 55.54; H 3.72; N 6.41 (2) (2R) -1 - [3,5-Bis (trifluo-romethyl) benzoyl] -2- (lH-indol-3-ylmethyl) -4-methylphenylcarbonylmethyl) piperazine hydrochloride mp: 203 ° C (dec.) [a] 20D: -37.4 ° (C = 0.5, MeOH) - # f? * f IR (Nujol): 3550-3100, 2650-2150, 1690, 1640, 1280, 1175, 1125 cm "1 NMR (DMS0-d6, d): 2.43 (3H, s); 3.1-5.3 (11H, m ); 6.8-8.3 (12H, m); 10.8-11.2 (2H, m) MASS: 587 (M + l) (free) (3) (2R) -1- [3, 5-Bis (trif luo) hydrochloride -romethyl) benzoyl] -4- (3, -dimethylphenylcarbonylmethyl) -2- (lH-indol-3-ylmethyl) piperazine mp: 166 ° C (dec.) [a] 25D: -36.8 ° (C = 0.5, MeOH) IR (Nujol): 3600-3150, 2700-2300, 1685, 1635, 1275, 1130 cm "1 NMR (DMSO-de / d): 2.34 (6H, s); 3.2-5.3 (11H,); 6.6-8.3 (11H, m); 10.6-11.2 (2H, m) MASS: 601 (M + l) (free) Analysis Calculated for C32H29F6N302 -HC1 • 1.1H20: C 58.42; H 4.93; N 6.39 Found: C 58.46; H 4.90; N 6.27 (4) (2R) -1 - [3,5-Bis (tri-f-rom-romethyl) benzoyl] -4- (4-f luoro-3-methylphenylcarbonylmethyl) -2- (lH-indole) hydrochloride -3-ylmethyl) piperazine [a] 25D: -28.8 ° (C = 0.5, MeOH) IR (Nujol): 3600-3100, 2700-2200, 1685, 1635, 1275, 1130 c "1 NMR (DMSO-d6, d): 2.34 (3H, s); 3.1-5.3 (11H, m); 6.6-8.3 (11H, m); 10.7-11.2 (2H, m) MASS: 606 (M + l) (free) Example 7 A mixture of (2R) -1 - [3,5-b s (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) piperazine (228 mg), 1 - [4 - (bromomet i 1) phenyl] ethanone (107 mg) and potassium carbonate (42 mg) in acetonitrile (2 ml) is brought to reflux for 4.5 hours. The mixture is evaporated in vacuo, ethyl acetate and water are added to the residue and the organic layer is separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo, the residue is purified by means of gel column chromatography. of silica with a mixture of dichloromethane and methanol as a diluent to give (2R) -4- (-acet i lbenz i 1) -1- [3, 5-bis (trifluoromethyl) benzoyl] -2- (lH-) hydrochloride indol-3-ylmethyl) -piperazine (0.30 g) is added to a solution of piperazine (0.30 g) in ethyl acetate hydrochloric acid in a solution ethyl acetate (0.3 ml) and the whole is evaporated in vacuo. The residue is triturated with a mixture of ethyl acetate and ether to give (2R) -4 - (-acetyl-1-benzyl) -2- (3, 5-bis (tri-fluoromethyl) benzoyl] -2- hydrochloride. (lH-indol-3-ylmethyl 1) piperazine (283.5 mg) as a powder, mp: 172 ° C (dec.) [a] 28 -30.0 ° (C = 0.27, MeOH) IR (Nujol): 3350, 1675 , 1655, 1635, 1610, 1275 cm "1." NMR (CDC13, d): 2.36-5.60 (11H, m), 6.10-9.30 (13H, m), 12.90 (1H, broad s) MASS: 588 ( M) (free) Example 8 A mixture of (2R) -1- [3,5-bis (trifluoromethyl) benzoi 1] -2- (lH-indol-3-ylmethyl) piperazine (0.3g), 2-bromo-4 ' dimethyl-ilaminoacetophenone (0.2 g) and potassium carbonate (0.16 g) in N, N-dimethylformamide (5 ml) is stirred at room temperature for 2 hours. The reaction mixture is poured into water (20 ml) and extracted with ethyl acetate. The organic layer is washed with water and dried over magnesium sulfate. After evaporation of the solvent, the residue obtained is purified by column chromatography on silica gel using toluene-ethyl acetate (2: 1) as a diluent. The fractions containing the objective compound are collected and evaporated under reduced pressure to give (2R) -1- [3,5-bis (trifluoromet i 1) benzoi 1] -4- (4-dimethylaminophenylcarbonylmethyl) -2- (lH-indol-3-ylmethyl) piperazine (0.26 g). mp: 185 ° C (dec.) [a] 2: -44.6 ° (C = 0.5, MeOH) IR (N-i-jOl): 3300, 1650, 1590, 1290, 1150 cm "1 NMR (DMSO-d6 , d): 2.05-4.9 (11H, m), 3.03 (6H, s) 6.55-8.2 (12H, m), 10.80 (1H, s) MASS: 617 (M + l) Example 9 A mixture of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorobenzyl) piperazine hydrochloride (200 mg), 4-nor t robencyl chloride (158 mg) ) and triethylamine (268 μl) in tetrahydrofuran (5 ml) is refluxed overnight. After cooling, the precipitate is removed by filtration and the filtrate is evaporated in vacuo. The residue is purified by means of silica gel column chromatography with a mixture of toluene acetate and ethyl acetate as a diluent to give (2R) -1- [3,5-bis (trifluoromethyl) -benzoi 1] - 2- (3,4-dichloro-benz 1) -4- (4-n-trobenci-1) -piperazine (169.8 mg). IR (Pure): 3100-2750, 1770, 1730, 1635, 1520, 1440, 1340, 1275, 1130 'cm "1 NMR (DMSO-de, d): 2.10-5.40 (11H, m); 6.85-8.30 (10H, m) MASS: 621 (M + l) Example 10 The The following compound is obtained according to a form similar to that of Example 9. (2R) -l- [3,5-Bis (trifluoromethyl) enzoyl] -2- (3,4-dimethylbenzyl) -4- (4-nitrobenzyl) ) piperazine IR (Pure): 3100-2750, 1635, 1515, 1430, 1340, 1275, 1130 cm "1 NMR (DMSO-de, d): 2.00-4.85 (17H, m); 6.50-8.10 (10H, m) MASS: 580 (M + l) Example 11 To a mixture of (2R) -1- [3,5-bis (trifluoro-methyl) benzoyl] -2- (3,4-dimethylbenzyl) piperazine (0.25 g), 4-acetylbenzene acid (0.09 g) ) in dichloromethane (8 ml) is added diethylamine (0.2 ml) at room temperature. 2-Chloro-1-methylpyridinium iodide (0.17 g) is added, and the mixture is stirred at room temperature for 2.5 hours. The resulting mixture is concentrated under reduced pressure and the residue is partitioned between ethyl acetate and water. The organic layer is washed with aqueous sodium bicarbonate solution and dried over magnesium sulfate. After evaporation of the solvent, the residue is purified by column chromatography using ethyl acetate-1-n-hexane (1: 1) as a diluent to give (2R) -4- (-aceti-l-benzoi-1) -1- [3,5-bis (trifluoromethyl) benzoi 1] -2- (3, -dimeti-becyl) piperazine (0.31 g). NMR (DMS0-d6, d): 1.9-2.4 (8H, m); 2.5-5.2 (10H,); 6.4-8.2 (10H, m) MASS: 591 (M + l) Example 12 To a mixture of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorobenzyl) -piperazine hydrochloride (200 mg), and 4-acetic acid hydrochloride The lbenzoic acid (57 mg) in dichloromethane (5 ml) is added triethylamine (171 μl) at room temperature. 2-Chloro-1-methyl iodide idiodide (107 mg) is added, and the mixture is stirred at room temperature for 1.5 hours. The resulting mixture is washed successively with an aqueous solution of hydrochloric acid 0.1N, saturated aqueous sodium acid carbonate solution and brine, and dried over magnesium sulfate. After evaporation of the solvent, the residue is purified by column chromatography using toluene-ethyl acetate (5: 1) as a diluent to give (2R) -4 - (-acet-il-benzoyl-1) -1- [3, 5] bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorobenzyl) piperazine (158 mg). [a] 20D: 11.2 ° (C = 0.5, MeOH) IR (Pure): 3100-2850, 1685, 1630, 1440, 1275, 1130 cm "1 NMR (DMSO-d6, d): 2.15-5.15 (9H, m); 2.62 (3H, s; 6.8-8.3 (10H, m) MASS: 633 (M + 2), 631 Analysis Calculated for C29H22F6C12N203: C 55.17; H 3.51; N 4.44 Found: C 55.22; H 3.53; N 4.28 Example 13 (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -piperazine fumarate (785 mg) is added, added to a mixture of sodium hydroxide solution 2N sodium (5 ml) and ethyl acetate. The organic layer is 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, -dimethyl ilformamide (7 ml) is added to a mixture of. 2-acetylbenzoic acid (230 mg), 1- (3-dimethyl-laminopropyl-1) -3-ethylcarbodiimide hydrochloride (295 mg) and 1-hydroxybenzothiazol (208 mg) in N, N-dimethyl formamide- ( 3 ml) and the whole was stirred at room temperature overnight. The mixture was poured into a saturated sodium hydrogen carbonate solution (78 ml) and the resulting precipitates were filtered. Upon filtration, they were evaporated in vacuo to give (2R) -4- (2-acetylbenzoyl) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethyl-benzyl) piperazine (0.45 g) as a powder mp: 82-85 ° C [a] 29 D: -22.7 ° (C = 0.33, MeOH) IR (CH2C12): 1750, 1635, 1615, c "1 NMR (CDC13, d): 1.75-5.40 (18H, m ); 6.40-8.10 (10H, m) MASS: 591 (M) Example 14 The following compound is obtained according to a form similar to that of Example 13. • *? 2R) -4- (3-trcetylbenzoyl) -1- [3,5-bis (trifluoromethyl) benzoyl] -2 - (3, -dimethylbenzyl) piperazine mp: 155.5-157 ° C [a] 24D: 5.8 ° (C = 0.26, MeOH) IR (Nujol): 1688, 1630 cm "1 NMR (CDC13, d): 2.05-2.32 (6H, m); 2.63 (3H, s); 2.70-5.40 (9H, m); 6.40-8.15 (10H, m) MASS: 592 (M + l) Example 15 To a stirring mixture of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) -piperazine (250 mg), 2-methoxy-phenylacetic acid ico (92 mg) and 1-hydroxybenzothiazole (75 mg) in dichloromethane (8 ml) is added l- (3-dimethyl ila inopropyl 1) -3-ylcarbodiimide hydrochloride (106 mg) at room temperature. After 3 hours, the reaction mixture was poured into the aqueous sodium bicarbonate solution and extracted with dichloromethane. The extract is washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue is purified by silica gel column chromatography using ethyl acetate and ilo-n-hexane (1: 1.5) as a diluent to give (2R) -l- [3, 5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) -4- (2-methoxy-phenyl-lime-1-carbonyl) piperazine (290 mg) as a powder. NMR (DMSO-de, d): 2.6-5.0 (14H, m); 6.4-8.2 (12H, m); 10.8 (1H, m) MASS: 604 (M + l) Example 16 The following compounds are obtained according to a form similar to that of Example 15. (2R) -4- (3-acetylbenzoyl) -1- [3 , 5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) piperazine mp: 186-187.5 ° C [a] 29 D: 4.2 ° (C = 0.29, MeOH) IR ( Nujol): 3260, 1690, 1638, 1600, 1275 cm "1 NMR (CDC1, d): 1.55-5.46 (12H, m); 6.55-8.50 (13H, m) MASS: 602 (M) (2) (2R) -4- (2-Acetylbenzoyl) -l- [3,5-bis (tri-fluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) piperazine mp: 190-192 ° C [a] 28 D: -2.1 ° (C = 0.28, MeOH) IR (Nujol): 3300, 2700, 1750, 1720, 1635, 1630, 1275 m "1 S-NMR (CDC13 # d): 1.46-5.45 ( 12H, m); 6.54-8.25 (13H, m) MASS: 602 (M) Example 17 '- * "To a stirring mixture of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -4- (carboxymethyl) -2- ( 1H- indol-3-ylmethyl) piperazine (0.4 g), and thiomorpholine 5 (0.08 g) in N, -dimet i 1 dry formamide (4 ml) is added 1 - (3-dimet i laminopropi 1) hydrochloride -3- ethylcarbodiimide (0.16 g) and 1-hydroxybenzothiazole (0.12 g) at room temperature After 3 hours, the reaction mixture was poured into the aqueous sodium bicarbonate solution (40 ml) and the precipitate The resulting product is collected by filtration The obtained crude product is purified by silica gel column chromatography using toluene-ethyl acetate (1: 2) as a diluent to give (2R) -15- [3, 5-bis] (trifluoromethyl) benzyl] -2- (lH-indol-3-ylmethyl) -4- (thiomorpholinocarbonylmethyl) piperazine (0.42 g). [a] 19 D: -10.0 ° (C = 0.5, MeOH) IR (Pure): 3650 -3100, 1634, 1274, 1170, 20 1122, 898 c "1 NMR (DMSO-d6, d): 2.00-5.00 (19H, m); 6.60- 8.20 (8H, m); 10.86 (1H, s) MASS: 599 (M + l) Example 18 The following compound is obtained according to a similar form to that of Example 17. (2R) -1 - [3, 5-Bis (trif luoro) hydrochloride e-tyl) benzoyl] -4- [(4- (4-fluorophenyl) -1-piperazinyl) -carbonylmethyl] -2- (1H-indol-3-ylmethyl) piperazine mp: 183 ° C (dec.) [ a] 5D: -24.0 ° (C = 0.5, MeOH) IR (Nujol): 3600-3100, 2650-2150, 1680-1580, 1510, 1275, 1130 cm "1 NMR (DMSO-d6, d): 3.05- 5.15 (19H,), 6.6-8.3 (12H, m), 10.40 (2H, broad), 11.02 (1H, s) MASS: 676 (M + l) (free) Example 19 To a stirring mixture of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -4- (carboxymethyl) -2- (1H-indol-3-ylmet i 1) piperazine (200 mg ), and 4-cyclopentylpiperazine (60 mg) in dry N, N-dimethylformamide (5 ml) is added 1- (3-dimet i inopropyl) -3-et lcarbodiimide hydrochloride (82 mg) and 1 - hydroxybenzoate and azole (58 mg) at room temperature. After 7 hours, the reaction mixture was poured into water (30 ml) and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate. After evaporation of the solvent ", the residue is purified by chromatography * * on a silica gel column using dichloromethanemethanol (10: 1) as a diluent and then treated with 4N hydrochloric acid in an ethyl acetate solution (80 μl). ) to give (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -4- [(4-cyclopentyl-1-piperazinyl) carbonylmethyl] -2- (1H-indol-3-ylmet i 1 ) -piperazine (140 mg) .pf: 270 ° C (dec.) [a] 25D: -24.2 ° (0 = 0.5, MeOH) IR (Nujol): 3270, 2430-2150, 1630, 1275, 1180 , 1125 cm "1 NMR (DMSO-de, d): 1.45-5.0 (28H, m); 6.55-8.25 (8H, m); 10.90 (1H, s); 11.21 (2H, broad s) MASS: 650 (M + l) (free) Analysis Calculated for C33H37F6N502 • HCl: C 57.77; H 5.58; N 10.21 Found: C 57.91; H 5.64; N 10.18 Example 20 A solution of methanol-sulphonyl chloride (1.1 g) in dichloromethane (4 ml) is added to a stirred solution of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -4- (3-hydroxypropyl) ) -2- (lH-indol-3-ylmethyl) piperazine (4.99 g) and triethylamine (1.1 g) in dichloromethane (50 ml) at bath temperature with ice for a period of 20 minutes. After stirring at the same temperature for 1 hour, the reaction mixture is diluted with dichloromethane (50 ml) and washed with water and aqueous sodium bicarbonate solution. The dichloromethane layer is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography using dichloromethane-me tanol (30: 1 as a diluent to give (2R) -1- [3, 5-bis (trifluoroethyl) benzoyl] -2- ( lH-indol-3-ylmethyl) -4- (3-methylsul-fonyloxypropyl) piperazine (4.31 g) as a powder MASS: 592 (M + l) Example 21 The following compound is obtained according to a similar form to that of Example 20. (2R) -l- [3,5-Bis (trifluoromethyl) enzoyl] -2- (3,4-dimethylbenzyl) -4- ( 3-methylsulfonyloxypropyl) -piperazine IR (Nujol): 2950-2700, 1635, 1430, 1350, 1275, 1165, 1125 cm "1 NMR (DMSO-de, d): 1.8-4.95 (19H, m); 3.19 (3H , s), 4.31 (2H, t, J = 6.2Hz), 6.95-8.2 (6H, m) MASS: 581 (M + l) Example 22 A mixture of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) - - (3-met i lsul foni loxipropi 1) piperazine (0.2 g ), 3-a-zabicyclo [3.2.2] nonane (0.05 g) and triethylamine (0.09 ml) in N, N-dimethyl-1-formamide (1 ml) is heated to 80 ° C. After 8 hours, the reaction mixture is poured into water (10 ml) and the resulting precipitate is collected by filtration. The crude product is dissolved in ethanol (2 ml) and then treated with 17.6% hydrochloric acid in ethanol solution (0.3 ml) to give (2R) -4 - [3- (3-azabicyclo [3.2. 2] non-3-yl) propyl] -l- (3, 5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) -piperazine (0.12 g) as a powder - mp: 194 -202 ° C [a] 19D: "- 6.0 ° (C = 0.5, MeOH), + IR (Nujol): 3600-3100, 2750-2000, 1680-1550, 1275, 1172, 1126, 900 cm" 1 NMR (DMSO-dfc, d): 1.50-5.20 (29H, m), 6.60 8.25 (8H,), 9.80 (1H, broad), 10.96 (1H, s), 11.60 (1H, broad) Example 23 A mixture of (2R) -1- [3, 5-bi s (trifluoro-methyl) benzoyl] -2- (lH-indol-3-ylmethyl) -4- (3-methylsul-foni loxypropyl) piperazine (0.2 g), thiomorpholine (0.42 g) and triethylamine (0.09 ml) in dry acetonitrile (2 ml) is stirred at 90 ° C for 15 hours. The reaction mixture is concentrated under reduced pressure and the resulting residue is separated between ethyl acetate and water. The organic layer is washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue is purified by silica gel column chromatography using ethyl acetate-me tanol (10: 1) as a diluent to give (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) -4- (3- t iomor fol inopropyl) piperaz ina. The product obtained is dissolved in ethanol and treated with 17.6% hydrochloric acid in an ethanol solution to give (2R) -1- [3, 5-bi s (trifluoromethyl) benzoyl] -2- hydrochloride ( lH-indol-3-ylmethyl) -4- (3-thiomorpholinopropyl) piperazine (0.19) as a powder. [a]? 0D: -4.6 ° C (C = 0.5, MeOH) IR (Nujol): 3650-3050, 2750-1980, 1635, 1274, 1170, 1123, 900 cm "1 NMR (DMSO-d €, d ): 2.20-5.20 (23H,), 6.50-8.25 (8H, m), 10.96 (1H, s), 11.00-11.90 (2H, m) MASS: 599 (M + l) (free) Dimaleate of (2R) -4- (3-1 iomor fol inpropi 1) - 1 - [3,5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) piperazine mp: 110-115 ° C [a ] 21D: -14.2 ° (C = 0.25, MeOH) IR (Nujol): 3350, 2720, 1690, 1620, 1605, 1280, 1130 cm "1 NMR (DMSO-de, d): 1.70-5.12 (23H, m ), 6.14 (4H, s), 6.55-8.32 (8H, m), 10.90 (1H, s).

Example 24 The following compounds are obtained according to a form similar to that of Example 23. (1) (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3) dihydrochloride -ylmethyl) -4- (3-morpholinopropyl) piperazine mp: 265 ° C (dec.) [a] 31 D: -6.0 ° (C = 0.5, MeOH) IR (Nujol): 3650-3100, 2750-2200, 1655 , 1275, 1120 cm "1 NMR (DMSO-de, d): 2.2-2.45 (2H, m), 3.0-5.25 (21H, m), 6.55-8.25 (8H, m), 10.96 (1H, s), 11.1-12.85 (2H, m) MASS: 583 (M + l) (free) Analysis Calculated for C29H32F6N4? 2- 2HC1 • 0.4H20: C 52.56; H 5.29; N 8.45 Found: C 52.54; H 5.33; N 8.25 (2) (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2 (3,4-dimethylbenzyl) -4- (3-thiomorpholinopropyl) piperazine dihydrochloride mp: 272 ° C (dec. ) [a] 31D: -11.6 ° (C = 0.5, MeOH) IR (Nujol) 3650-3100, 2750-2650, 1635, 1270, 1120 cm "1 NMR (DMSO-de, d): 2.1-2.5 (8H , m), 2.7-5.2 (21H, m), 6.6-8.25 (6H, m), 11.15-11.75 (2H, m) MASS: 588 (M + l) (free) Example 25 A mixture of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) -4- (3-methylsulfoni loxipropi 1) piperazine (200 mg) and 1, 2, 3, 4- tet rahydroisoquinol ina (90 mg) in methanol (3 ml) is stirred for 1.5 hours at reflux temperature. The reaction mixture is evaporated under reduced pressure and the residue is purified by silica gel column chromatography using ethyl acetate-methanol (10: 1) as a diluent to give (2R) -1- [3, 5] -bis (tri f luoromet i 1) -benzoi 1] -2- (lH-indol-3-ylmethyl) -4- [3- [l, 2,3,4-tetrahydroisoquinolin-2-yl] propi 1] piperazine (167 mg) as a powder. [a] 20 D: -9.6 ° (C = 0.5, MeOH) IR (Pure): 3260, 1630, 1430, 1380, 1350, 1270 cm "1 NMR (DMSO-de, d): 1.60-4.93 (21H, m ); 6.60-8.37 (12H, m); 10.85 (1H, s) MASS: 629 (M + l) EXAMPLE 26 The following compound is obtained according to a similar form to that of Example 25. (2R) -l- [3,5-bis (trifluoromethyl) benzoyl) -2- (lH-indol-3-ylme fl) - 4- [3- (4,5,6,7-tetrahydro-ieno- [3,2-c] pyridin-5-yl) propyl] piperazine [a] 18D: -9.0 ° (C = 0.5, MeOH) IR ( Pure): 3260, 1630, 1430, 1350, 1275 cm "1 NMR (DMSO-d ,, d): 1.55-4.97 (21H, m); 6.30-8.24 (10H, m); 10.85 (1H, s) MASS : 635 (M + l) Example 27 A mixture of (2R) -1 - [3,5-bis (t-ri-luoro-methyl) -benzoyl] -2- (lH-indol-3-ylmethyl) -4- (3-methylsul-foniloxipropi 1) Piperazine (150 mg) and 4-cyano-4-phenylpiperidine hydrochloride (70 mg) in methanol (5 ml) is stirred at reflux temperature in the presence of sodium carbonate (100 mg). After 2 hours, the reaction mixture is evaporated under reduced pressure. The residue is extracted with ethyl acetate and the extract is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using ethyl acetate and methanol (10: 1) as a diluent to give (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -4- [ 3- (4-Cyano-4-phenylpiperidino) propyl] -2- (1 H -indol-3-ylmethyl) -piperazine (89 mg) as a powder. [a] 20 D: -19.2 ° (C = 0.5, MeOH) NMR (DMSO-de, d): 1.52-4.96 (23H, m); 6.60-8.26 (13H, m); 10.85 (1H, s) MASS: 682 (M + l) Example 28 A mixture of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (lH-indo-1-3-ylmethyl) - 4- (3-methylsulphoryloxypropyl) piperazine (200 mg) and spiro [indan-1,4'-piperidine] (70 mg) in acetonitrile (3 ml) is refluxed for 1.5 hours. The reaction mixture is evaporated under reduced pressure and then the residue is purified by silica gel column chromatography using dichloromethane-methanol (10: 1) as a diluent to give (2R) -l- [3, 5-bis ( trifluoromethyl) benzoyl] -4- [3- (spiro [indane-1,4'-piperidine] -1'-yl) propyl] -2- (1H-indol-3-ylmet i 1) piperazine (208 mg ) like a powder. [a] 22D: -21.4 ° (C = 1.0, MeOH) IR (Pure): 3260, 1630, 1435, 1380, 1350, 1275 cm "1 NMR (DMSO-de, d): 1.45-5.00 (27H, m); 6.62-8.28 (12H, m); 10.88 (1H, s) MASS: 683 (M + l) Example 29 A mixture of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorobenzyl) -4- (4-nor trobenzyl) piperazine (157 mg), ammonium chloride (15.7 mg) and iron powder (157 mg) in a mixture of ethanol (5 ml) and water (1.25 m "l) is refluxed for 1.5 hours. After cooling, the precipitates are removed by filtration and the filtrate is evacuated in vacuo. The residue is purified by column chromatography on silica gel with a mixture of toluene and ethyl acetate as a diluent to give (2R) -4- (4-aminobenzyl) - 1 - [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorobenzyl) piperazine (128.4 mg). IR (Pure): 3350, 2970-2700, 1630, 1515, 1460, 1430, 1275, 1130 cm "1 NMR (DMSO-de, d): 1.95-5.05 (13H, m); 6.50-8.25 (10H, m) MASS: 592 (M + 2), 590 (M) EXAMPLE 30 The following compound is obtained according to a form similar to that of Example 29. (2R) -4- (4-aminobenzyl) -1- [3,5-bis (trifluoromethyl) -benzoyl] -2- (3, -dimethylbenzyl) piperazine IR iPuro): 3450, 3300, 3100-2650, 1625, 1515, 1435, 1275, 1125 cm "1 NMR (DMSO-de / d): 1.90-4.80 (17H, m); 4.98 (2H, s); 6.40-8.20 (10H, m) MASS: 550 (M + l) E j us 31 * -. -f "Pyridyria is added successively (" 23 3f); vi? .and-acetyl chloride (16 μl) to a solution of (2R) -4- (4-aminobenzyl) -1- [3,5-bis (trifluoromethyl) enzoyl] -2- [3,4-dichlorobenzyl] -piper azine (113 mg) and the whole is stirred at room temperature for 1.5 hours. The mixture is poured into water and the separated oil is extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by column chromatography on silica gel with a mixture of toluene and ethyl acetate as a diluent to give (2R) -4- (-acetylaminobenzyl) -1- [3, 5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorobenzyl) piperazine (98.3 mg). The piperazine obtained is dissolved in ethyl acetate. 4N hydrochloric acid is added in ethyl acetate solution (43 μl) is added to the solution and the mixture is evaporated in vacuo. The residue is triturated with n-hexane to give (2R) -4- (4-acetylamino-benzyl) -1- [3, 5-bis (trifluoromethyl) -benzoyl] -2- (3., 4) hydrochloride. - Dichlorobenz 1) Piperazine (92 mg). [a] 20D: -11.8 ° (C = 0.5, MeOH) IR (Pure): 3600-3150, 2750-2100, 1635, 1600, 1525, 1415, 1270, 1130 cm "1 NMR (DMSO-d6, d) : 2.07 (3H, s); 2.85-5.15 (11H, m); 6.80-8.30 (10H, m); 10.13 (1H, s) MASS: 632 (M + l) (free) Example 32 The following compound is obtained according to a similar form to that of Example 31. (2R) -4 - (-acetyl laminobenzi 1) -1- [3,5-bis (trifluoromethyl) benzoyl] -2 hydrochloride - (3,4-dimethylbenzyl) piperazine [a] 25D: -23.2 ° (C = 0.5, MeOH) IR (Nujol): 3650-3100, 2750-2100, 1640, 1600, 1530, 1275, 1170, 1130 cm " 1 NMR (DMSO-de, d): 1.95-2.10 (9H, m), 2.80-5.05 (11H, m), 6.50-8.30 (10H, m), 10.17 (1H, s), 11.00-11.40 (1H, m) MASS: 592 (M + l) (free) Example 33 (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) -4- (thiomorpholinecarbonylmethyl) -piperazine is converted to the corresponding hydrochloride by treatment with 17.6% of hydrochloric acid in ethanol solution.

IR (Nujol): 3650-3100, 2750-1980, 1638, 1276, 1171, 1129, 900 cm "1 NMR (DMSO-de, d): 2.55-5.15 (19H, m); 6.60-8.25 (8H, m ); 10.99 (1H, s) MASS: 599 (M + l) (free) Preparation 1 A mixture of formaldehyde (37% in water, 20.7 ml) and morpholine (17.1 ml) is adjusted to a pH of 3.5 with dilute sulfuric acid. Propargyl alcohol (10 g), potassium iodide (0.3 g), and copper (II) sulfate (0.14 g) are added to the solution and the whole is stirred at 95 ° C for 6 hours. After cooling, the insoluble material is removed by filtration and the pH of the filtrate is adjusted to 9 with 24% sodium hydroxide solution. Brine (100 ml) is added to the solution and the solution is extracted eight times with a mixture of ethyl acetate and ethanol (10: 1) and then six times with n-butanol. The combined extract is dried over magnesium sulfate and evaporated in vacuo. The residue is distilled under reduced pressure to give 4 -mor fol ino-2-but-in-ol (14.03 g). eg: 124-131 ° C IR (Pure): 3350, 2850, 1105, 1000 cm "1 NMR (CDCI3, d): 2.18 (1H, broad s), 2.57 (4H, t, J = 4.7Hz), 3.31 (2H, t, J = 1.9Hz), 3.75 (4H, t, J = 4.7Hz), 4.30 (2H, t, J = 1.9Hz) MASS: 156 (M + l) Preparation 2 The following compound is obtained according to a form similar to that of Preparation 1 with the exception of purification by silica gel column chromatography using a mixture of ethyl acetate and methanol (30: 1) as a diluent. instead of distillation under reduced pressure. 4-Tiomorfolino-2-butin-l-ol IR (Pure): 3350, 2900, 2800, 1420, 1330, 1115, 1100 cm "1 NMR (CDCI3, d): 1.93 (1H, broad s), 2.65-2.90 (8H, m), 3.32 (2H, t, J = 1.9Hz), 4.30 (2H, t, J = l .9Hz) MASS: 172 (M + l) Preparation 3 Thionyl chloride (2.1 ml) is added to a solution of -mor folino-2-but-1-ol (1.47 g) in dichloromethane (10 ml) with a cold ice bath.

After stirring for 0.5 hour, the solution is evaporated in vacuo. The residue is triturated with ethyl acetate to give 4-mohlorochloride hydrochloride ino-2-butyl in (1.91 g). mp: 162-165 ° C IR (Nujol): 2640, 2510, 2450, 2350, cm "1 NMR (DMSO-de, d): 3.31 (4H, broad s), 3.92 (4H, broad s), 4.21 ( 2H, t, J = 1.9Hz), 4.57 (2H, t, J = 1.9Hz), 12.23 (1H, broad s) MASS: 174 (M) (free) Preparation 4 The following compound is obtained according to a form similar to that of Preparation 3. Chloride hydrochloride of 4 - 1 iomor fol ino-2-but ini lo mp: 185-187 ° C IR (Nujol): 2600, 2450 , 2380, 1280, 1260, 1160, 915 cm "1 NMR (DMSO-dÉ, 6): 2.58-4.00 (8H, m), 4.21 (2H, t, J = 2.0Hz), 4.58 (2H, t, J = 2.0 Hz), 12.08 (1H, broad s) MASS: 190 (M) (free) Preparation 5 A mixture of -chloro-1 - ( 4-phlorophenyl-1-butanone (500 mg), ethylene glycol (247 mg) and a catalytic amount of p-toluenesulphonic acid monohydrate in benzene (5 ml) is refluxed for 20 hours with continuous water removal using a Dean-Stark apparatus After cooling, the solution is washed successively with 1N NaOH solution and brine, dried over magnesium sulfate, and evaporated in vacuo to give 1-chloro- (4-fluorofeni 1) ethylenacetal. - 1 - cyclic butanone (613.2 mg) as an oil IR (Pure): 2950, 2870, 1600, 1500, 1220, 1030 cm "1 NMR (DMSO-d6, d): 1.60-1.80 (2H, m), 1.90- 2.00 (2H, m), 3.61 (2H, t, J = 6.5Hz), 3.70-4.10 (4H, m), 7.10-7.50 (4H, m) MASS: 245 (M + l), 209 Example 34 A mixture of (2R) -1 - [3,5-bis (t-fluoromethyl) benzoyl] -2- (2-naphthylmethyl) piperazine (1.0 g) and 3-bromopropanol (330 mg) in N, N-di-ethylformamide (2.5 ml) is stirred at room temperature in the presence of powdered potassium carbonate (444 mg). After 17 hours, the reaction mixture is diluted with ethyl acetate (30 ml) and then washed successively with water and brine, and dried over magnesium sulfate. Evaporation of the solvent in vacuo gives (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -4- (3-hydroxypropyl) -2- (2-naphthylmethyl) piperazine (1.19 g). IR (Pure): 3425, 1635, 1430, 1340, 1275, 1170, 1130 c "1 NMR (CDC13, d): 1.50-5.28 (16H, m), 7.40-7.93 (10H, m) MASS: 525 (M + l) Example 35 A mixture of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (2-naphthylmethyl) -piperazine (200 mg) and 1 - (-chloro-2-butynyl) morchloride folin (95 mg) in N, N-dimet and 1 formamide (0.5 ml) is stirred at room temperature in the presence of powdered potassium carbonate (177 mg). After 17 hours, the reaction mixture is diluted with ethyl acetate (30 ml) and then washed successively with water and brine, and dried over magnesium sulfate. After evaporation of the solvent in vacuo, the resulting residue is purified by silica gel column chromatography using ethyl acetate as a diluent. The product obtained is dissolved in ethyl acetate and treated with 4N hydrochloric acid in ethyl acetate solution to give (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -4- (4-morpholinohydrochloride. -2-butynyl) -2- (2-naphthylmethyl) piperazine (257 mg). [a] 21D: -21.5 ° (C = 0.5, MeOH) IR (Nujol): 3350, 2550, 1630, 1275 cm "1 NMR (DMSO-de, d): 2.80-5.31 (21H, m), 7.0- 8.28 (10H, m) MASS: 604 (M + l) (free) Example 36 A mixture of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3, -dichlorobenzyl) -piperazine hydrochloride (150 mg) and 1- (4-chloro-2-hydrochloride -but ini 1) mor folin (63 mg) in N, N-dimethylformamide (0.5 ml) is stirred at room temperature in the presence of powdered potassium carbonate (160 mg). After 17 hours, the reaction mixture is diluted with ethyl acetate (30 ml) and then washed successively with water and brine, and dried over magnesium sulfate. After evaporation of the solvent in vacuo, the resulting residue is purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol (10: 1) as a diluent to give (2R) -l- [3, 5-bis (trifluoromethyl) benzoyl] -2- (3, -dichlorobenzyl) -4- (-morphon-2-butyl) piperazine. The product obtained is dissolved in ethyl acetate and treated with 4N hydrochloric acid in ethyl acetate solution to give (2R) -l- (3,5-bis (trifluoromethyl) benzoi 1] -2- (3, -dichlorobenzyl) -4- (-mor fol ino-2-butyl) piperazine (155 mg). [a] 20D: -3.9 ° (C = 0.5, MeOH) IR (Pure): 3400, 2350, 1640.1425 , 1275 cm "1 NMR (DMSO-de, d): 2.91-5.20 (21H, m), 7.0-8.26 (6H, m) MASS: 622 (M + l) (free) EXAMPLE 37 The following compounds are obtained according to a similar form to that of Example 7. (1) (2R) -4- (-mor fol ino-2-butynyl) -1- [3, 5-bis ( trifluoromethyl) benzoyl] -2- (1H-indol-3-ylmethyl) -piperazine mp: 165-169 ° C [a] 21 D: -0.4 ° (C = 0.26, MeOH) IR (Nujol): 3350, 2550, 2320 , 1635, 1550, 1270, 1120 cm "1 NMR (DMSO-de, d): 2.80-5.25 (21H, m), 6.56-8.30 (8H, m), 10.96 (1H, s) MASS: 593 (M) (free) (2) (2R) -4 - (-mor-fol-ino-2-butynyl) -1- [3, 5-bis (trifluoromethyl) benzoyl] -2- (3,4 -dimethylbenzyl) piperazine dfl. : 155-162 ° C [a] 21D: -11.5 ° (C = 0.26, MeOH) IR (Nujol): 3350, 2650, 2300, 1655, 1640, 1275, 1120 cm "1 NMR (DMSO-de, d) : 2.02-2.30 (7H, m), 2.64-5.30 (20H,), 6.60-8.30 (6H, m) MASS: 582 (M) (free) (3) (2R) -4- (4-1) dihydrochloride iomor fol ino-2-butynyl) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimet i Ibene i 1) -piperazine mp: 162-170 ° C [a] 22 D: -9.4 ° (C = 0.27, MeOH) I R (Nujol): 3350, 2650, 2320, 1655, 1640, 1275, 1125 cm "1 NMR (DMSO-de, d): 2.04-2.35 (7H, m). 2.65-5.25 (20H,), 6.57-8.28 (6H, m) MASS: 598 (M) (free) (4) (2R) - 4 - (- 1 yomor ino-2-butynyl) -l- hydrochloride [3, 5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) piperazine mp: 166-170 ° C [a] 22 D: -1.5 ° (C = 0.26, MeOH) IR (Nujol) : 3350, 2650, 2300, 1635, 1275, 1125 cm "1 NMR (DMSO-de, d): 2.58-5.30 (21H, m), 6.54-8.30 (8H, m), 10.98 (1H, broad s), 12.10 (2H, broad s) MASS: 609 (M) (free) (5) (2R) -4- (2-morpholinoethyl) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- ( 3, 4-dimethylbenzyl) piperazine mp: 223-228 ° C [a] 27-2D: -13.0 ° (C = 0.28, MeOH) IR (Nujol): 3350, 2550, 1630, 1450, 1275, 1120 cm "1 NMR (DMS0-d6, d): 1.95-5.25 (27H, m), 6.50-8.32 (6H, m), 10.80-11.90 (2H, broad m) MASS: 558. < (M) (free) (6) "'(2R) -4- (2-yl-rhemethyl) -l- [3, 5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) -hydrochloride ) iperazine mp: 170-182 ° C [a] 2B-5D: -4.5 ° (C = 0.39, MeOH) IR (Nujol): 3350, 2600, 1640, 1275, 1125 cm "1 NMR (DMSO-de, d) ): 2.60-5.30 (21H, m), 6.50-8.30 (8H, m), 10.96 (1H, s), 11.10-12.10 (2H, broad m) MASS: 585 (M) (free) (7) Dihydrochloride (2R) -4- (2-morpholinoethyl) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) piperazine mp: 170-176 ° C [a] 28- 5D: -3.0 ° (C = 0.30, MeOH) IR (Nujol): 3350, 2570, 1640, 1275, 1125 c "1 NMR (DMSO-de, d): 2.60-5.30 (21H, m), 6.55-8.40 (8H, m), 10.95 (1H, s), 11.10-12.04 (2H, broad m) MASS: 569 (M) (free) (8) (2R) -4 - (2-1 iomor fo-linoethyl) ) -1- [3,5-bis (trifluoromethyl) -benzoyl] -2- (3, -dimethylbenzyl) -piperazine mp: 261.5 ° C [a] 28-5D: -1.9 ° (C = 0.29, DMF) IR (Nujol): 3350, 2350, 1640, 1275, 1130 c "1 NMR (DMSO-de, d): 2.00-5.30 (27H, m), 6.60-8.30 (6H, m), 10.60-12.00 (2H, broad m) MASS: 574 (M) (free) Example 38 * A mixture of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) piperazine (300 mg), ethylenacetal 4- chloro-l- (-f luorofeni 1) -1-cyclic butanone (161 mg), potassium carbonate (182 mg), or potassium iodide (109 mg) in acetonitrile (10 ml) is refluxed for 20 hours. After cooling, the insoluble material is removed by filtration and the filtrate is evaporated in vacuo.The residue is purified by column chromatography on silica gel with a mixture of toluene and ethyl acetate as a diluent to give (2R) -4 - [4, -et i lendioxi- - (4-fluorophenyl) butyl] -1- [3,5-bis (trifluoromethyl) -benzoi 1] -2- (lH-indol-3-lmeth i 1) piperaz ina As a powder, this compound is further purified by washing with diisopropyl ether Pf: 145-146 ° C IR (Nujol): 3200, 1620, 1600, 1275, 1120 cm "1 NMR (DMSO-de, d): 1.35-1.55 (2H, m), 1.80- 4.90 (17H, m), 6.55-8.20 (12H, m), 10.87 (1? , broad) MASS: 664 (M + l) Example 39 To a stirring mixture of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -4- (carboxymethyl) -2- (1H-indole -3-ylmethyl) piperazine (0.2 g) and 3-azabicyclo [3.2.2] nonane (0.05 g) in N, N-dimet and 1-formamide (2 ml) are added l- (3-dimethyl hydrochloride ilaminopropyl) -3-ethyldicarbodiimide (0.082 g) and 1-hydroxybenzothiazole (0.058 g) at room temperature. After 6 hours, the reaction mixture is emptied into aqueous sodium bicarbonate solution (20 ml) and the resulting precipitate is collected by filtration. The obtained crude product is purified by silica gel column chromatography using toluene-ethyl acetate (1: 2) as a diluent and treated with 17.6% hydrochloric acid in ethanol solution to give (2R) hydrochloride - 4 - [(3-azabicyclo [3.2.2] nonane-3-yl) carbonylmethyl] -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) piperazine (0.2 g) as a white powder. [a] 0D: -32.0 ° (C = 0.5, MeOH) - »- #» IR (Nujol): 3650-3100, '2750-2000, 1637, 1276, 1172, 1130, 900 cm "1 NMR (DMSO -de, d): 1.50-1.75 (8H, m), 2.07 (2H, broad s), 3.15-5.10 (15H, m), 6.60-8.25 (8H, m), 10.15 (1H, broad s), 11.00 (1H, s) MASS: 621 (M + l) (free) Example 40 To a stirring mixture of (2R) -l- [3,5-bis (tri fluoromethyl) benzoyl] -4- (4-carboxybenzyl) -2- (lH-indol-3-ylmethyl) piperazine (150 mg ) and diethylamine hydrochloride (28 mg) in dry dichloromethane (5 ml) is added a solution of l- (3-dimethylaminopropy 1) -3-et i -carbodiimide (40 mg) in dichloromethane (1 ml) and 1-hydroxybenzot Riazole (34 mg) at room temperature. After 5 hours, the reaction mixture is poured into aqueous sodium bicarbonate solution (20 ml). The organic layer is separated and washed with brine and dried over magnesium sulfate. The obtained crude product is purified by silica gel column chromatography using ethyl acetate-n-hexane (4: 1) to give (2R) -1- [3, 5-bi s (tri fluoromethyl) -benzoyl] - [4- (N, N-diethylaminocarbonyl) -benzyl] -2- (1H-indol-3-ylmethyl) piperazine (107 mg) as a powder. [a] 21D: -40.3 ° (C = 0.5, MeOH) IR (Pure): 3250, 1620, 1430, 1275, 1130 c "1 NMR (CDCI3, d): 1.10-5.00 (25H, m), 6.40- 8.00 (8H,), 9.14. (1H, s) MASS: 645 (M + l) Example 41 To a stirring mixture of (2R) -l- [3,5-bis (trifluoromethyl) benzo-yl] -4- (3-hydroxypropyl) -2- (2-naphthylmethyl) piperazine (1.1 g) and triethylamine (425 mg) in dichloromethane (10 ml) is added in drops of methylene chloride (252 mg) at bath temperature with ice. After 2 hours, the reaction mixture is washed with water and then dried over magnesium sulfate. After evaporation of the solvent, the resulting residue is chromatographed on silica gel using ethyl acetate as a diluent to give (2R) -1- [3, 5-bi s (tri fluoromethyl) benzoyl] -2- ( 2-naphthylmethyl) -4- (3-methylsulfonyl-oxypropyl) piperazine (988 mg). IR (Pure): 1635, 1430, 1350, 1280, 1170, 1130 cm "1 NMR (CDC13, d): 1.59 (3H, s), 1.90-5.28 (15H, m), 7.40-7.90 (10H, m) MASS: 603 (M + l) Example 42 The following compounds are obtained according to a similar form to that of Example 41. (1) (2R) -1 - [3,5-bis (tri fluoromet i 1) benzoyl] 2- (3,4-dichlorobenzyl) -4- (3-methylsulfonyloxypropyl) -piperazine IR (Pure): 1630, 1470, 1430, 1340, 1270 cm "1 NMR (CDC13, d): 1.55-5.14 (15H, ), 3.04 (3H, s), 7.00-7.95 (6H, m) (2) (2R) -l- [3,5-bis (trifluoromethyl) enzoyl] -2- (2-naphthylmethyl) -4- (2 -methylsulfonyloxyethyl) -piperazine IR (Pure): 1635, 1430, 1350, 1275, 1170, 1125 cm "1 Example 43 A mixture of (2R) -1 - [3,5-bis (trifluoromethyl) enzoyl] -2- (naphthylmethyl) -4- (3-methylsul-fonyloxypropyl) piperazine (250 mg), thiomorpholine (43 mg) and triethylamine (46 mg) in dry methanol (5 ml) is refluxed for 2 hours. The reaction mixture is concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography using ethyl acetate as a diluent. The product obtained is dissolved in ethyl acetate and treated with 4N hydrochloric acid in ethyl acetate solution to give (2R) -1- [3,5-bis (tri-fluoro-methyl) enzoyl] -2- dihydrochloride ( 2-naphthylmethyl) -4- (3-thiomorpholino-propyl) piperazine (195 mg). [a] 23D: -23.0 ° (C = 0.5, MeOH) IR (Nujol): 3400, 2500, 1640, 1275, 1170, 1130 cm "1 NMR (CDC13, d): 1.50-5.69 (23H, m), 7.34-7.93 (10H, m) MASS: 610 (M + l) (free) Example 44 The following compounds are obtained according to a form similar to that of Example 43. (1) (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (2-naphthylmethyl) -dihydrochloride - 4- (2-mor fol inoethyl) piperazine [a] 23 D: -25.2 ° (C = 0.5, MeOH) IR (Nujol): 3400, 2510, 2425, 1635, 1425, 1275, 1170, 1130 cm "1 NMR ( DMSO-de, d): 2.88-5.31 (21H, m), 7.07-8.24 (10H,) MASS: 580 (M + l) (free) (2) (2R) -l- [3,5-] dihydrochloride bis (tri fluoromethyl) benzoyl] -2- (2-naphthylmethyl) -4- (2-thiomorpholinoethyl) piperazine [a] 22D: -23.7 ° (C = 0.5, MeOH) IR (Nujol): 2350, 1640, 1270, 1180 cm'1 NMR (DMSO-de, d): 2.80-5.31 (21H, m), 7.03-8.20 (10H, m) MASS: 596 (M + l) (free) (3) (2R) -1- [3, 5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) -4- [3- (4-oxopiperidino) -propyl] piperazine [a] 4D: -19.0 ° (C = 0.5, MeOH) IR (Nujol): 3270, 1720, 1625, 1430, 1340, 1275, 1125 cm "1 NMR (CDC13, d); 1.66-5.20 (23H, m), 6.69-8.28 (8H, m) MASS: 595 (M + l) (4) (2R) -1- (3,5-bis (trifluoromethyl (benzoyl) -2-) dihydrochloride (3, -dichlorobenzyl) -4- (3-thiomor folinopropyl) piperazine [a] 18D: + 2.2 ° (C = 0.5 MeOH) IR (Nujol): 3400, 2400, 1650, 1280 cm "1 NMR (DMSO-d6 , d): 2.10-5.20 (23H, m), 6.92-8.32 (6H, m), 11.12 - 11.72"(2H, m) MASS: 628 (M + l) (free) (5) (2R) Dichlorohydrate - 1 - [3,5-bis (tri-fluoroorneti Dbenzoyl] -2- (3,4-dichlorobenzyl) -4- (3-morpholinopropyl) piperazine [a] 19 D: + 2.3 ° (0 = 0.5, MeOH) IR (Nujol): 3400, 2550, 2450, 1650, 1280 cm "1 NMR (DMSO-de, d): 2.10-5.20 (23H, m), 6.94-8.34 (6H, m), 11.08-11.76 (2H, m) MASS: 612 (M + l) (free) (6) Dihydrochloride of (2R) -4- [3- (4-acetylpiperidino) propyl] -1- [3,5-bis (tri fluoromethyl) -benzoyl] -2- (1H-indol-3-ylmethyl) piperazine [a ] 20D: -7.2 ° (C = 0.5, MeOH) IR (Nujol): 3300, 2600, 1700, 1630, 1275 cm "1 NMR (DMSO-de, d): 1.67-5.24 (24H, m), 2.16 ( 3H, s), 6.62-8.28 (8H, m), 10.95 (1H, s) MASS: 623 (M + l) (free) (7) (2R) -4 - [3- (thiazole idino- 3-yl) propyl] -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) piperazine [a] 25 D: -5.4 ° (C = 0.5, MeOH) IR ( Nujol): 36D0-3100, 2700-2250, 1660-1580, 1270, 1120 c "1 NMR (DMSO-de, d): 2.20-2.40 (2H, m), 3.00-5.20 (19H, m), 6.40- 8.25 (8H, m), 10.97 (1H, m), 11.20-11.90 (2H,) MASS: 585 (M + l) (free) (8) (2R) -4- [3- (4-phenyl) trichlorohydrate 1- 1 -piperazinyl) propyl] -1- [3,5-bis (trifluoromethyl) -benzoyl] -2- (lH-indol-3-ylmethyl) piperazine [a] 25D: -8.0 ° (C = 0.5 , MeOH) IR (Nujol): 3600-3100, 2750-2300, 1630, 1275, 1120 cm "1 NMR (DMSO-de, d): 2.05-2.45 (2H, m), 3.05-5.20 (21H, m) , 6.60-8.05 (13H, m), 10.97 (1H, s), 11.00-11.85 (3H, m) MASS: 658 (M + l) (free) (9) Trichlorohydrate of (2R) -4- [3- (4-cyclohexyl-l-piperazinyl) propyl] -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) -piperazine mp: 250 ° C (dec.) [Dec ] 5D: -7.8 ° (C = 0.5, MeOH) IR (Nujol): 3600-3100, 2650-2200, 1640-1600, 1370, 1270, 1120 cm "1 NMR (DMSO-de, d): 1.00-2.40 (11H, m), 3.00-5.30 (23H, m), 6.60-8.30 (8H, m), 10.97 (1H, s), 11.30-12.30 (3H, m) MASS: 664 (M + l) (free) Example 45 A mixture of (2R) -1- [3, 5-bi s (tri fluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) -4- (2-methylsul-foniloxiet il) piperazine (200 mg), -aminomor folin (36 mg) and triethylamine (52 mg) in dry methanol (5 ml) is refluxed for 2 hours. The reaction mixture is concentrated under reduced pressure and the resulting residue is partitioned between ethyl acetate aqueous sodium hydrogen carbonate solution. The organic layer is washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue is purified by silica gel column chromatography using a mixture of ethyl acetate and methanol (10: 1) as a diluent to produce (2R) -1- [3, 4-bis] (tr if luorome ti 1) -benzoyl] -2- (lH-indol-3-ylmethyl) -4- [2- (morpholino-amino) ethyl] piperazine (55 mg). [a] 22D: -16.2 ° (C = 0.5, MeOH) IR (Nujol): 3300, 1615, 1275 c "1 NMR (DMSO-de, d): 2.14-5.10 (21H, m), 6.0- 8.26 (8H, m), 10.91 (1H, s) MASS: 584 (M + l) Example 46 A mixture of (2R) -1 - [3,5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) -4- (3-methylsulphonylxopropyl) piperazine (100 mg) and phenylpiperidine (60 mg) in acetonitrile (3 ml) is refluxed for 2 hours.The reaction mixture is concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography using ethyl acetate-methanol (5: 1) as a diluent to give (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) -4- [3- (4-phenylpiperidino) propyl] piperazine (90 mg). [a] 20D: -24.6 ° (C = 1.0, MeOH) IR (Pure): 3250, 1630, 1430, 1275, 1130 cm "1 NMR (DMSO-de, d): 1.52-4.93 (24H, m), 6.60-8.28 (13H, m), 10.87 (1H, s) MASS: 657 (M + l) Example 47 A solution of (2R) -2- (3,4-dichlorbenzyl) -1- [3,5-bis (trifluoromethyl) enzoyl] -4- (2-hydroxyethyl) -piperazine (50 mg) in ethyl acetate Ethyl (3 ml) is treated with 4N-hydrochloric acid in ethyl acetate solution (0.2 ml) and the resulting mixture is concentrated in vacuo to give (2R) -2- (3, -dichlorobenzyl) -1- hydrochloride. [3,5-bis (tri-fluororneti-1) -benzoyl] -4- (2-hydroxyethyl-1) -piperazine (45 mg) as a powder. IR (Pure): 3260, 2550, 1640, 1425, 1275 cm'1 NMR (DMSO-de, 6): 2.80-5.53 (13H, m), 6.91-8.32 (6H, m), 10.96 (1H, broad s ) MASS: 530 (M + l) (free) EXAMPLE 48 The following compounds are obtained according to a similar form to that of Example 47. (1) (2R) -4- (4-aminobenzyl) -1- [3,5-bis (trifluoromethyl) benzoyl] -hydrochloride] - 2- (3,4-dimethylbenzyl) piperazine mp: 179 ° C (dec.) [A] 25 D: -16.6 ° (C = 0.5, MeOH) IR (Nujol): 3400-3050, 2650-2300, 1660-1580 , 1275, 1125 cm "1 NMR (DMSO-de, d): 2.00-2.20 (6H, m), 2.80-5.05 (11H, m), 6.45-8.25 (10H, m), 11.40-11.90 (2H, m ) MASS: 550 (M + l) (free) (2) (2R) - 4 - (-n-t-robenz 1) -1- [3, -bis (trifluoromethyl) -benzoyl] -2- (3) dihydrochloride (3) , 4.,.,. ^, Dimethylbenzyl) piperazine mp: 140 ° C (dec.) [A] 25D: -18.4 ° (C = 0.5, MeOH) IR (Nujol): 3600-3200, 2650-2200, 1640, 1520- 1350, 1275, 1130 cm "1 NMR (DMSO-de, d): 2.00-2.20 (6H, m), 2.80-5.00 (11H,), 6.50-8.40 (10H, m) MASS: 580 (M + l) (free) Example 49 To a solution of (2R) -4- [, 4-et i lendioxy-4- (4-fluorophenyl) butyl] -l- [3,5-bis (trifluoromethyl) -benzoyl] -2- (1H- indol-3-ylmethyl) piperazine (210 mg) in ethyl acetate add 4N hydrochloric acid in ethyl acetate solution (0.5 ml) and the whole is stirred at room temperature for 23 hours. The solution is evaporated in vacuo. The residue is triturated with a mixture of ethyl acetate and diisopropyl ether to give hydrochloride of (2R) -4- [- (-f-chlorophenyl) -4-oxobutyl] -1- [3,5-bis (trifluoromethyl) ) benz'oyl] -2- (lH-indol-3-ylme ti 1) piperazine (183.7 mg). mp: 161 ° C (dec.) [a] 2 D: -14.2 ° (C = 0.5, MeOH) IR (Nujol): 3400-3150, 2650-2300, 1675, 1635, 1595, 1280, 1250, 1275, 1125 cm "1 NMR (DMS0-d6, d): 2.00-2.25 (2H, m), 3.05-5.20 (13H, m), 6.55-8.25 (12H, m), 10.95 (1H, s), 11.10-11.50 (1H, m) MASS: 620 (M + l) (free) Preparation 6 Tetrahydrofuran (15 ml) is added to 70% of a solution of sodium bis (2-methoxy-toxy) aluminum hydride in toluene (49.7 g) under a nitrogen atmosphere and then cooled. A solution of 4-mor fol ino-2-but-in- 1-yl (3.0 g) in tetrahydrofuran (15 ml) is added dropwise maintaining the reaction temperature 4-5 ° C.

After stirring for 10 minutes, the reaction mixture is allowed to warm to room temperature.

After 1 hour, water is cautiously added (6 ml) and 10% aqueous sodium hydroxide solution (4.5 ml) and then filtered. The filtrate is dried over potassium carbonate and concentrated under reduced pressure to give an oily product, which is purified by column chromatography on silica gel using ethyl acetate (5%). : 1) to produce (E) - -mor fol ino-2-buten-l-ol (1.08 g).

IR (Pure): 3550, 1450, 1110, 990, 855 was "1 NMR (CDC13, d): 2.48 (4H, t, J = 4.7Hz), 2.77 (1H, s), 3.02 (2H, d, J = 5.4Hz), 3.73 (4H, t, J = 4.7Hz), 4.15 (2H, d, J = 4.0Hz), 5.64-5.96 (2H, m) MASS: 158 (M + l) Preparation 7 Thionyl chloride (0.96 ml) is added in drops to a solution of (E) -4 -mor folino-2-but en-l-ol (1.03 g) in dichloromethane (10 ml) at bath temperature with ice . After 3 hours, the reaction mixture is evaporated under reduced pressure and the resulting residue is triturated with ethyl acetate to give (E) -mormor ino-2-butenyl hydrochloride chloride (0.98 g). mp: 155-160 ° C IR (Nujol): 2750-2700, 1275, 1255, 1120, 1078, 1065, 975 c "1 NMR (DMSO-de, d): 2.80-3.55 (4H, m), 3.64-4.10 (6H, rfí), 4.26 (2H, d, J = 5.7Hz), 5.90-6.25 (2H, m), 11.82 (1H, broad s) MASS: 176 (M) (free) Example 50 A mixture of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) -piperazine (0.20 g), hydrochloride of 5-mor fol ino 3-pentinyl (0.175 g), potassium carbonate (0.303 g) and potassium iodide (10 mg) in dry acetonitrile (4 ml) are stirred under reflux for 60 hours. After removal of the solvent, the resulting residue is dissolved with ethyl acetate. The solution is washed with brine and dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified - by silica gel column chromatography using toluene-ethyl acetate (1: 2) as a diluent and treated with 4N hydrochloric acid in ethyl acetate solution to give (2R) -1- [-] dihydrochloride. 3, 5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) -4- (5-mor fol ino-3-pentyl ini 1) piperazine (0.174 g). [a] 21D: -19.5 ° (C = 0.5, MeOH) IR (Nujol): 3600-3150, 2700-2300, 1640, 1280, 1170, 1185 cm "1 RMN d): 2.90-5.20 (23H, m), 6.80- 8.30 (8H, m), 10.95 (1H, s), 11.79 (2H, broad s) MASS (APCI): 608 (M + 2), 607 (M + l) (free) Analysis Calculated for C3iH32F6N4? 2-2HCl '1.5H20: C 52.70, H 5.28, N 7.93 Econted: C 52.72, H 5.54, N 7.60 Example 51 To a mixture of (2R) -1- [3, 5-bi s (t-fluoromethyl) benzoyl] -2- (3, -dimethylbenzyl) -piperazine (0.2 g), 1-met il-4- form 1-lH-pi ra zolo (50 mg), and sodium triacetoxyborohydride (151 mg) in dichloromethane (2 ml) is added one drop of acetic acid. After stirring at room temperature overnight, the solution is evaporated under reduced pressure. The resulting residue is partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic layer is separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by silica gel column chromatography using ethyl acetate-methanol as a diluent and treated with 4-chloroic acid in solution of fciLjp acetate to give (2R) -1- [3] hydrochloride. , 5-bis (tri fluoromethyl) -benzoyl] -2- (3,4-dimethylbenzyl) -4 - [(1-methyl-1H-pyrazol-4-yl) methyl] -piperazine (97 mg). mp: 243-244 ° C [a] 16 2D: -16.8 ° (C = 0.3, MeOH) IR (Nujol): 3350, 2750-2000, 1655, 1635, 1275, 1165, 1130 cm "1 NMR (DMSO- from, d): 1.97-2.28 (7H, m), 2.78-5.10 (13H,), 6.50-8.30 (8H, m), 11.24-11.74 (1H, broad m) MASS (APCI): 539 (M + l ) (free) Analysis Calculated for C2 H28F6 4 • HCl • 2.7H20 C 52.00, H 5.56, N 8.98 Found: C 51.82, H 5.15, N 8.99 EXAMPLE 52 The following compounds are obtained according to a similar form to that of Example 51. (1) (2R) -1 [3,5-bis (trifluoromethyl) benzoyl] -2- (3, 4) dihydrochloride -dimethylbenzyl) -4- [(l-methyl-lH-imidazol-4-yl) methyl] -piperazine [a] 26 D: -11.80 ° (C = 0.5, MeOH) IR (Pure): 3350, 2550, 1640, 1430, 1275, 1170, 1130 cm "1 NMR (DMSO-de, d): 2.07 (3H, s), 2.17 (3H, s), 2.72-5.10 (11H, m), 3.88 (3H, s), 6.60-9.08 (8H , m) MASS: 539 (M + l) (free) (2) (2R) -l- [3,5-bi-s- (tri fluoromethyl) benzoyl] -2- (3, 4-dimethylbe? zil) -4 - [(L-methyl-lH-imidazol-2-yl) methyl] piperazine [a] 25 D: -12.10 ° (C = 0.5, MeOH) IR (Pure): 3350, 2500, 1640, 1430, 1280, 1175, 1130 cm "1 NMR (DMS0-d6, d): 2.07 (3H, s), 2.16 (3H, s), 2.53-5.14 (11H, m), 3.94 (3H, s), 6.47-8.26 (8H, m) MASS: 539 (M + l) (free) Example 53 The following compounds are obtained according to a form similar to that of Example 43. (1) (2R) -1- [3,5-b s (trifluoromethyl) benzoyl] -2- (3, -dimethylbenzyl) dihydrochloride ) -4- (3-morpholinopropyl) piperazine mp: 220-230 ° C [a] 21"s D: -17.3 ° (C = 0.3, MeOH) IR (Nujol): 3350, 2650, 1655, 1635, 1620, 1445, 1370, 1270 cm "1 NMR (DMSO-d6, d): 1.92-5.22 (29H, m), 6.56-8.28 (6H, m), 11.43 (2H, broad s) MASS (APCI): 572 (M + l) (free) Analysis Calculated for C29H35F6N302 • 2HC1: C 54.04, H 5.79, N 6.52 Found: C 53.72, H 5.80, N 6.29 (2) (2R) -4- [2- [N, N-bis (2-ethoxyethyl) amino] ethyl] -1- [3,5-bis (trifluoromethyl) -benzoyl] -2- (3,4-dimethylbenzyl) -piperazine [a] 22 D: -9.6 ° (C = 0.5, MeOH) IR (Nujol): 3350, 2650, 1655, 1635, 1620, 1445, 1370, 1270 cm "1 NMR (DMSO-de, d): 1.92-5.22 (27H, m), 3.32 (6H, s), 6.56-8.28 (6H, m) MASS (APCI): 604 (M + l) (free) Analysis Calculated for C3oH39F6N3? 3- 2HCl • 1.6H20: C 51.08, H 6.32, N 5.96 Found: C 51.06, H 6.40, N 6.14 (3) (2R) -1 - (3,5-bis (trifluoromethyl) benzoyl] - dihydrochloride 2- (1H-indol-3-ylmethyl) -4- [3- (1, 2, 3, 6-tetrahydropyridin-1-yl) propyl] piperazine mp:> 200 ° C [a] 23 D: -2.30 ( C = 0.5, MeOH) IR (Nujol): 3500-3100, 2700-2400, 1630 cm "1 NMR (DMSO-de, d): 2.20-4.20 (21H, m), 5.72 (1H, d, J = 10.2 Hz), 5.93 (1H, d, J = 10.2Hz), 6.55-8.23 (8H,), 10.95 (1H, broad s) MASS (APCI): 579 (M + l) (free) Analysis Calculated for C3oH3 FeN40 • 2HC1 • 2H20: C 52.41, H 5.57, N 8.15 Found: C 52.03, H 5.77, N 7.72 (4) (2R) -4- [3 (3-azabicyclo [3.3.23non-3-yl] propyl) dihydrochloride] -l- [3,5-bis (trifluoromethyl) benzoyl] -2-2 (3,4-dichlorobenzyl) piperazine mp: 150 ° C (dec.) [a] 22 D: -2.90 ° (C = 0.5, MeOH) IR (Nujol): 3500, 3100, 2700, 2400, 1630, cm "1 NMR (DMSO-de, d): 1.60-3.90 (29H, m), 6.90-8.30 (6H, m) MASS (APCI): 652 (M + 2), 650 (M + l) (free) Calculated Analysis or for C3? H35Cl2F6N30-2HCl • 1.6H20: C 50.22, H 5.30, N 5.67 Found: C 50.25, H 5.60, N 5.32 (5) (2R) -1- [3,5-bis (tr i-fluoromethyl) trichlorohydrate benzoyl] -2- (3,4-dichlorobenzyl) -4- [3- (4,1 '-piperidin-1-yl) propyl] piperazine mp:> 200 ° C [a] 23 D: -3.40 (C = 0.5, MeOH) IR (Nujol): 3300-2700-2400, 1630, 1450 c "1 NMR (DMSO-de, d): 1.60-3.90 (34H, m), 6.90-8.30 (6H, m) MASS (FAB ): 693 (M + l) 695 (free) Analysis Calculated for C33H40Cl2FeN? • 3HC1: C 49.36, H 5.40, N 6.98 Found: C 49.81, H 5.75, N 6.75 Example 54 A solution of (2R) -1 - [3,5-bis (t-fluoro-methyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- (4-morpholino-2-but ini 1) Piperazine (141 mg) in methanol (10 ml) is hydrogenated over 10% Pd-C (50 mg) at room temperature under 2-3 atoms. After removal of the catalyst by filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography using dichloromethane-methanol as a diluent and treated with 4N hydrochloric acid in ethyl acetate solution to give (2R) -1- [3,5-bis (trifluoromethyl) dihydrochloride. ) benzoyl] -2- (3,4-dimethylbenzyl) -4- (4-morpholinobutyl) piperazine (106 mg). mp: 279 ° C [a] 23 D: -13.5 ° (C = 0.5, MeOH) IR (Nujol): 3300, 2700-2400, 1645, 1500, 1445, 1370, 1270, 1170 cm "1 NMR (DMSO-de , d): 1.70-5.22 (31H, m), 6.56-8.28 (6H,), 11.00-11.40 (2H,) MASS (APCI): 586 (M + l) (free) Example 55 The following compound is obtained according to a form similar to that of Example 54. (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) dihydrochloride -4- (5-morpholinopentyl) piperazine [a] 21D: -6.10 ° (C = 0.5, MeOH) IR (Pure): 3400-3200, 2700-2400, 1640, 1430, cm "1 NMR (DMSO-de, d): 1.50-5.20 (27H, m), 6.60-8.30 (8H,), 10.80-11.50 (3H, m) MASS: 611 (M + l) (free) Analysis Calculated for C3iH36F6N402 '2HC1 • 1.3H20 C 52.67 , H 5.79, N 7.92 Found: C 52.66, H 6.13, N 7.76 'Example 56 A solution of (2R) -1 - [3, 5-bi s (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- (5-morpholino-3-pentynyl) piperazine (200 mg) is treated with 4N hydrochloric acid in ethyl acetate solution to give (2R) -l- [3,5-bis (trifluoromethyl) -benzoyl dihydrochloride. ] -2- (3,4-dimethylbenzyl) -4- (5-morpholino-3-pentynyl) piperazine [a] 21D: -25.2 ° (C = 0.5, MeOH) IR (Pure): 3700-3100, 2920, 2750, 2250, 1635, 1500, 1430, 1275, 1170, 1120 cm "1 NMR (DMSO-de, d): 2.05-2.20 (6H, m), 2.75-5.15 (23H, m), 6.65-8.28 (6H, m), 11.60-12.20 (2H, m) MASS: 596 (M + l) (free) Analysis Calculated for C3iH35F6N3? 2-2HCl- 1.5H20: C 53.53, H 5.80, N 6.04 Found: C 53.47, H 6.14, N 5.91 Example 57 (2R) -1- [3,5-bis (trifluoro-methyl) benzoyl-3- (3,4-dimethylbenzyl) piperazine fumarate (9.13 g) is treated with 10% aqueous sodium hydroxide solution. % (65 ml) and dichloromethane (65 ml). The organic layer is separated, washed with brine, dried over magnesium sulphate and evaporated under reduced pressure. A mixture of (2R) -l- [3,5-bis (tri fluoromethyl) bezoyl] -2- (3,4-dimethylbenzyl) -piperazine obtained by the above procedure, potassium carbonate (3.60 g) and 1.4 Dichloro-2-but ino (1.9 ml) in N, N-dimet and formamide (72 ml) is stirred for 4.5 hours at room temperature. The mixture is poured into water (360 ml) and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by silica gel column chromatography using toluene-ethyl acetate as a diluent to give (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzene). 1) -4- (4-chloro-2-butynyl) piperazine (4.86 g). IR (Pure): 1706, 1635, 1503, 1275, 1125 cm "1 NMR (CDC13, d): 2.05-5.20 (19H, m), 6.60-7.84 (6H, m) MASS (APCI): 531 (M + l) Example 58 A mixture of (2R) -1 - [3,5-bis (tri fluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- (4-chloro-2-butynyl) piperazine (0.49 g)3-methylammonium hydrochloride (0.15 g), potassium carbonate (0.39 g) and potassium iodide (10 mg) in dry N, N-dimethylformamide (5 ml) is stirred for 5 hours at room temperature. The mixture is poured into water and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by silica gel column chromatography using ethyl acetate as a diluent and treated with 4N hydrochloric acid in ethyl acetate solution to give (2R) -l- [3, 5-bis (trifluoromethyl) dihydrochloride. benzoyl] -2- (3,4-dimethylbenzyl) -4- [4- (3-methylmorpholino) -2-butyl] -piperazine (0.28 g). mp: 150-160 ° C [ct] 28: -5.71 ° (C = 1.0, MeOH) IR (Nujol): 3300, 2700-2400, 1650, 1430 cm "1 NMR (DMSO-de, d): 1.20- 5.22 (29H,), 6.60-8.20 (6H, m), 12.20-12.40 (2H, m) MASS (APCI): 596 (M + l) (free) Analysis Calculated for C 53.25, H 5.82, N 6.01 Found: C 53.28, H 5.97, N 5.80 Example 59 The following compounds are obtained "according to a form similar to that of Example 58. (1) (2R) -l- ( 3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [4- (2-methoxymethylmorpholino) -2-butynyl] piperazine mp: 150-165 ° C [a] 28 ?: -8.86 ° (C = 0.7, MeOH) IR (Nujol): 3300, 2700-2400, 1640, 1430 cm "1 NMR (DMSO-de, d): 2.00-5.22 (28H, m), 3.25 (3H, s), 6.50-8.20 (6H, m), 12.20-12.40 (2H, m) MASS (APCI): 626 (M + l) (free) Analysis Calculated for Cs? Ha FeNsOs • 2HC1 • H20: C 53.64, H 5.77, N 5.86 Found: C 53.60, H 5.94, N 5.67 (2) Dichlorohydrate of (2R) -l- [3, 5-bis (tri fluoromethyl) benzoyl] -2- (3, -di ethylbenzyl) -4- [4- (2-fluoromethylmorpholino) -2-butynyl] piperazine mp: 175-180 ° C [a] 28: -8.75 ° (C = 0.7, MeOH) IR (Nujol): 3300, 2700-2400, 1635, 1500 cm "1 NMR (DMSO-de, d): 2.00-5.22 (28H, m), 6.50-8.20 (6H, m) MASS (APCI): 614 (M + l) (free) 1) 5 Analysis Calculated for C3? H34 F N302 • 2HC1 • H20:. - C 52.85, H 5.44, N -5r96 Found: C 52.82, H 5.45, N 5.74 (3) (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3, 4-) dihydrochloride dimethylbenzyl) -4- [4- (3, 3-dimethylmorpholino) -2-butinyl] piperazine mp: 180-190 ° C [a] 28 > 3D: -7.24 ° (C = 1.05, MeOH) IR (Nujol): 3300, 2700-2400, 1635 cm "1 NMR (DMSO-de, d): 1.30-1.40 (6H, m), 2.00- 5.22 (25H , m), 6.60-8.20 (6H, m), 12.05-12.20 (2H, m) MASS (APCI): 610 (M + 1H) (free) Analysis Calculated for C32H31FeN302- 2HC1-2.5H20: C 52.82, H 6.09 , N 5.68 Found: C 52.84, H 5.89, N 5.78 (4) (2R) -1- [3,5-bis- (trifluoromethyl) enzoyl] -2- (3,4-dimethylbenzyl) -4- [] 4- ((2S) -2-methoxymethylpyrrolidino) -2-butyl] piperazine mp 195-197 ° C [aJ28-D: -19.79 ° (C = 0.7, MeOH) IR (Nujol): 3450, 2700-2400, 1640, 1450 cm "1 NMR (DMSO-de, d): 2.00-5.22 (28H,), 3.32 (3H, s), 6.50-8.20 (6H, m), 11.50-11.70 (2H, m) MASS (APCI ): 610 (M + l) (free) Analysis Calculated for CszHaTFeNaOz- 2HC1 • 2H20: C 53.49, H 6.03, N 5.85 Found: C 53.66, H 5.73, N 5.82 (5) (2R) -l- [-] Dihydrochloride 3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [4- (3-methoxymethylmorpholino) -2-butynyl] piperazine mp: 140-155 ° C [a] 28-4D : -7 .22 ° (C = 0.63, MeOH) IR (Nujol): 3300, 2700-2400, 1635, 1440 cm "1 NMR (DMSO-de, d): 2.00-5.22 (28H, m), 3.32 (3H, s ), 6.50-8.20 (6H, m) MASS (APCI): 626 (M + l) (free) Analysis Calculated for C32H37F6N303 • 2HC1: C 52.32, H 5.90, N 5.72 Found: C 52.35, H 6.11, N 5.43 Example 60 A mixture of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) piperazine (0.38 g), potassium carbonate (0.42 g), hydrochloride 3- (3-pyridyl) -2-propionylchloride (1.9 ml) and a small amount of potassium iodide in N, N-dimethylformamide (10 ml) is stirred for 2 hours at 40 ° C. The mixture is poured into water and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by silica gel column chromatography using ethyl acetate as a diluent and treated with 4N hydrogen chloride and ethyl acetate solution to give (2R) -l- [3,5-bis (tri fluoromethyl) benzoyl] -2- (3, -dimethylbenzyl) -4- [3- (3-pyridyl) -2-propynyl] piperazine (0.26 g). mp: 140-150 ° C [a] 28.4 D: -10.13 ° (C = 0.8, MeOH) IR (Nujol): 3300, 2700-2400, 1630, 1450 cm "1 NMR (DMSO-de, d): 2.00-5.22 (17H, m), 6.50-8.20 (8H, m), 8.70-8.85 (2H, m) MASS (APCI): 560 (M + l) (free) Analysis Calculated for C3oH27F6N30- 2HC1 -2.8H20: C 52.76, H 5.11, N 6.15 Found: C 52.74, H 4.96, N 6.05 Example 61 A mixture of (2R) -1 - [3,5-bis- (trifluoromethyl) benzoyl] -4- [(E) -4-chloro-2-butenyl] -2- (2-naphthylmethyl) piperazine (300 g), thiomorpholine (0.054 ml) and potassium carbonate powder (100 mg) in dry acetonitrile (3 ml) was heated at 50 ° C for 10 hours. Additional potassium carbonate (100 mg) and thiomorpholine (0.054 ml) are added and then the resulting mixture is further heated to the same temperature. After 2 hours, the reaction mixture is cooled and then filtered. The filtrate is concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography using a mixture of dichloromethane and methanol (40: 1). The product obtained is dissolved in ethyl acetate and treated with 4N hydrochloric acid in ethyl acetate (0.6 ml) to give (2R) -1- [3,5-bis (tri-fluoro-methyl) benzoyl] -2-dihydrochloride. - (2-naphthylmethyl) -4- ((E) -4-thiomorphol-2-buteni 1) piperazine (190 mg). pf: >; 230 ° C [a] 28-9 D: -14.50 ° (C = 0.5, MeOH) IR (Nu ol): 3650-3100, 2410, 1640, 1274, 1130 cm "1 NMR (DMSO-d6, d): 2.55-5.30 (21H, m), 6.00-6.30 (2H, m), 7.00-8.20 (10H) MASS: 622 (M + l) (free) Example 62 The following compounds are obtained according to a form similar to that of Example 61. (1) (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (2-naphthylmethyl) -4 - [(E) -4-morpholino-2-butenyl] dihydrochloride] piperazine mp:> 230 ° C [a] 28-7 D: -16.60 ° (C = 0.5, MeOH) IR (Nujol): 3600-3100, 2450, 1639, 1273, 1130 cm "1 NMR (DMSO-de, d): 280-5.30 (21H, m), 6.10-6.30 (2H, m), 7.00-8.25 (10H, m) MASS: 606 (M + l) (free) (2) (2R) -1 [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [(E) -4-thiomor-fol-ino-2-butenyl) piperazine dihydrochloride pf: > 230 ° C [a] 26-8D: 5.20 ° (C = 0.25, DMSO) IR (Nujol): 3600-3100, 2450, 1642, 1274, 1130 cm "1 NMR (DMSO-de, d): 2.10-5.10 (27H,), 5.90-6.30 (2H, m), 6.65-7.05 (3H, m), 7.57 (2H, s), 8.05 (1H, s) MASS: 600 (M + l) (free) Example 63 A mixture of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -4- [(E) -4-chloro-2-buteni 1] -2- (3, 4-dimet i lbenci 1) piperazine (450 mg), 3, 3-dimethylol folin hydrochloride (130 mg) and powdered potassium carbonate (350 mg) in dry acetonitrile (5 mg). ml) is heated at reflux temperature for 3 hours Additional potassium carbonate (350 mg) and 3,3-dimethyl-chlorohydrochloride (130 mg) are added and then the resulting mixture is further heated to reflux temperature. After 6 hours, the reaction mixture is cooled and then filtered, the filtrate is concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography using a mixture of dichloromethane and methanol (50: 1). The product obtained is dissolved in ethyl acetate and treated with 4N hydrochloric acid in sol acetate-6-ethyl acetate to give (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4 - [(E) dihydrochloride] -4- (3, 3-dimet ilmor folino) - 2 -but eni. piperazine (370 mg). pf: > 230 ° C [a] 2 6.8 -11.70 ° (C = 0.5, MeOH) IR (Nujol): 3400-2450, 1639, 1274, 1130 cm ": NMR (DMSO-de, d): 1.34-1.40 (6H, ) 2.10-2.18 (6H, m), 2.70-5.20 (19H, m), 6.10-6.30 (2H, m), 6.65-6.30 (6H, m), 11.20-12.00 (2H, m) MASS: 612 (M + l) (free) Example 64 A mixture of (2R) -l- [3,5-bis (trifluoromethyl (benzoyl) -2- (3,4-dimethylbenzyl) -piperazine (1.0 g), (E) -l, 4-dichloro-2 -butene (0.31 ml) and mg) and potassium carbonate powder (0.4 g) in dry acetonitrile (10 ml), heat to 50 ° C. After 4 hours, the reaction mixture is cooled and then filtered. The filtrate is concentrated under reduced pressure and the resulting residue is purified and by column chromatography on silica gel using a mixture of toluene and ethyl acetate. (4: 1) to give (2R) -1- [3, 5-bis (t-ri-luoro-methyl) -benzoyl] -2- (3,4-dimethylbenzyl) -4- [(E) -4- ( chloro-2-butenyl] piperazine (0.53 g) as an oil.

IR (Pure): 3460, 1638, 1272, 1125, 900 c "1 NMR (CDC13, 6): 2.00-5.20 (19H, m), 5.75-6.00 (2H, m), 6.60-8.00 (6H, m) MASS: 533 (M + l) Example 65 The following compound is obtained according to a missile form from that of Example 64. (2R) -1- [3,5-bis (tri fluoromethyl) benzoyl] -2- (2 -naphthylmethyl) -4- [(E) -4-chloro-2-butenyl] piperazine IR (Pure): 1637, 1273, 1128, 900 cm "1 NMR (CDC13, d): 2.05-5.20 (13H, m) , 5.80-6.00 (2H, m), 7.10-8.10 (10H, m) MASS: 555 (M + l) Example 66 A mixture of (2R) -1- [3,5-bis (tri fluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) -4- (3-methylsulfoni loxipropi 1) piperazine (150 mg) , 4-aminomor folin (36 mg) and triethylamine (52 mg) in dry methanol (5 ml) is refluxed for 2 hours. The reaction mixture is concentrated under reduced pressure and the resulting residue is partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic layer is washed with brine and dried over magnesium sulfate.After evaporation of the solvent, the residue is purified by silica gel column chromatography using a mixture of ethyl acetate and methanol (10: 1) produce an oily product, which is treated with 4N hydrochloric acid in ethyl acetate solution (0.5 ml) to give (2R) -1- [3, 5-bi s (trifluoromet i 1) -benzoyl dihydrochloride ] -2- (lH-indol-3-ylmethyl) -4- [3- (morpholino-amino) propi 1] piperazine (58 mg). [A] 23D: -3.60 ° (C = 0.5 MeOH) IR ( Nujol): 3300, 2500, 1630, 1420, 1275cm_1 NMR (DMSO-d6, d): 2.00-5.24 (23H, m), 6.60-8.28 (8H, m), 10.94 (1H, s), 11.50 (1H, broad s) MASS: 598 (M + l) ( free) EXAMPLE 67 The following compounds are obtained according to a form similar to that of Example 66. (1) (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (lH-indole-3-dihydrochloride. -ylmethyl) -4- [2- (cis-2,6-dimethylmorpholino) ethyl] piperazine [a] 20D: -2.60 ° (C = 0.5, MeOH) IR (Nujol): 3350, 2600, 1640, 1280, 1175 , 1130 crn "1- NMR (DMSO-d6, d): 1.55 (6H, m), 2.52-5.20 (19H, m), 6.60-8.24 (8H, m), 10.95 (1H, s) MASS: 597 (M + l) (free) (2) (2R) -l- [3,5- is (tri fluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) -4- [3- (cis- 2, 6-dimet i lmorfol ino) propi 1] piperazine [a] 20 D: -5.30 ° (C = 0.5, MeOH) IR (Nujol): 3350, 2600, 1640, 1280 cm "1 NMR (DMSO-d6, d ): 1.20 (6H, m), 2.08-5.20 (21H, m), 6.63-8.33 (8H, m), 10.94 (1H, s) MASS: 611 (M + l) (free) (3) Dihydrochloride ( 2R) -l- [3,5- is (tri fluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [2- (1-imidazolyl) ethyl] piperazine [a] 21D: -16.20 ° ( C = 0.5, MeOH) IR (Nujol): 3350, 2700, 2575, 1640, 1430, 1280, 1170, 1130 cm "1 NMR (DMSO-de, d): 2.04-5.20 (13H, m), 2.09 (3H, s), 2.18 (3H, s), 6.55-8.22 (8H, m), 9.29 (1H, s) MASS: 539 (M + l) (free) (4) Dichlorohydrate (2R) -l- [3,5- is (trifluoromethyl) benzoyl 3 -2- (3,4-dimethylbenzyl) -4- [3-ftnor folinoamino) propyl] piperazine [a] 0D: -14.10 ° (C = 0.5, MeOH) IR (Nujol ): 3350, 2550, 1640, 1430, 1280 cm "1 NMR DMSO-de, d): 1.97-5.14 (23H,), 2.10 (3H, s), 2.18 (3H, s), 6.64-8.24 (6H, m), 10.92 (1H, broad s) MASS: 587 (M + l) (free) (5) (2R) -l- [3,5-bis (trifluoromethyl (benzoyl) -2- (3) trichlorohydrate dimethylbenzyl) -4- [2- (3-pyridylmethylamino) ethyl] -piperazine [a] 21D: 3.50 ° (C = 0.5, MeOH) IR (Nujol): 3400, 2600, 1640, 1430, 1280, 1170, 1130 cm "1 NMR (DMSO-de, d): 2.07-5.20 (13H, m), 2.10 (3H, s), 2.18 (3H, s), 4.50 (2H, s), 6.60-9.09 (10H, m ), 10.32 (1H, broad s) MASS: 579 (M + l) (free) (6) (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3, -dimethylbenzyl) dihydrochloride ) -4- (2-homomorpholinoethyl) piperazine [a] 17D: -9.90 ° (C = 0.5, MeOH) IR (Nujol): 3400, 2600, 2450, 1640, 1430, 1280 cm "1 NMR (DMSO-de, d): 2.04-5.17 (23H, m), 2.10 (3H, s), 2.18 (3H, s), 6.62-8.26 (6H, m) MASS: 572 ( M + l) (free) - (7) (2R) -l- [3,5- is (trifluoromethyl) enzoyl] -2- (3,4-dimethylbenzyl) -4- (3-homomor folinopropy 1) dihydrochloride piperazine [a] 19D: -10.0 ° (C = 0.5 MeOH) IR (Nujol): 3400, 2600, 1635, 1430, 1280 cm "1 NMR (DMSO-de, d): 1.73-5.20 (25H, m), 2.10 (3H, s), 2.18 (3H, s), 6.62-8.24 (6H,) MASS: 586 (M + l) (free) (8) (2R) -l- [3,5- is (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) -4- (3-homomorpholinopropyl) piperazine-dlhydrochloride [a] 17D: -5.50 ° (C = 0.5, MeOH) IR (Nujol): 3300, 2650, 1640, 1275 cm "1 NMR (DMSO-de, d): 1.90-5.23 (25H, m), 6.62-8.34 (8H, m), 10.95 (1H, s) MASS: 597 (free) (9) (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dichlorobenzyl) -4- [3- (3-) dihydrochloride] (4-acetylpiperidino) propyl] piperazine [a] 20D: 2.20 ° (C = 0.5, MeOH) IR (Nujol): 3350, 1700, .4 30, 1275 cm "1 NMR (DMSO-de, d): 1.69- 5.21 (24H, m), 2.16 (3H, s), 6.97-8.36 (6H, m) MASS: 652 (M) (free) (10) (2R) -l- [3,5- is (tri) -hydrochloride fluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [3- (4-acetylpiperidino) propi 1] -piperazine [a] 20D: -11.30 ° (C = 0.5, MeOH) IR (Nujol): 3425, 3375, 2500, 1705, 1640, 1275 cm "1 NMR (DMSO-de, d): 1.67-5.20 (24H, m), 2.16 (6H, s), 2.18 (3H, s), 6.62-8.25 (6H, m), 10.60 (1H, s) broad), 11.49 (1H, broad s) MASS: 612 (M + l) (free) (11) (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3, 4) dihydrochloride -dichlorobenzyl) -4- (2-morpholinoethyl) piperazine [a] 20D: 6.10 ° (C = 0.5, MeOH) IR (Nujol): 3350, 2600, 1630, 1270 cm "1 NMR (DMSO-de, d): 2.14-5.16 (21H, m), 6.93-8.27 (6H, m) MASS: 598 (M) (free) (12) (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2-dihydrochloride - (lH-indol-3-ylmethyl) -4- [3- (4-methoxypiperidino) propi 1] piperazine [a] 19 D: -6.70 ° (C = 0.5, MeOH) IR (Nujol): 3300, 2550, 1625 , 1270 cm "1 NMR (DMSO-de, d): 1.57-5.20 (24H, m), 3.27 (3H, s), 6.60-8.28 (8H, m), 10.95 (1H, s) MASS: 611 (M + l) (free) (13) Dihydrochloride of (2R) -l- [3,5- is (tri f luoromet i Dbenzoyl] -2- (3,4-dimethylbenzyl) -4- [2- [N- (2-methoxyethyl) -N-methylamino] ethyl ] piperazine mp: 222 ° C (dec.) [a] 3D: -12.50 ° (C = 0.5, MeOH) IR (Nujol): 3380, 2400, 1644, 1275, 1130 cm_1 NMR (DMSO-de, d): 2.0-2.3 (7H, m), 2.88 (3H s), 3.33 (3H, s), 2.3-5.3 (18H, m), 6.6-8.3 (6H, m) MASS: 560 (M + l) (free) (14) (2R) -l- [3,5-Bis (trifluoromethyl) benzoyl-3- (3,4-dimethylbenzyl) -4- [3- (hexamethyleneimino) propi 1] piperazine [a] 26 D -hydrochloride: - 11.70 ° (C = 0.5, MeOH) IR (Pure): 3400, 2600, 1640, 1430, 1280 cm "1 NMR (DMSO-de, d): 1.49-5.20 (27H, m), 2.10 (3H, s), 2.19 (3H, s), 6.67-8.23 (6H,) MASS: 584 (M + l) (free) (15) (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [2 ~ '(4-pyridinimethylamino) ethyl 3-trichlorohydrate pipera ina [a] 25D: -0.20 ° (C = 0.5, MeOH) IR (Pure): 3400, 2600, 1640, 1430, 1280, 1175, 1130 c "1 NMR (DMSO-de, d) 2.10 (3H, s), 2.18 (3H, s), 2.64-5.20 (13H,), 4.16 (2H, s), 6.40-8.97 (10H, m) MASS: 579 (M + l) (free) (16) Dihydrochloride ( 2R) -l- [3,5- 5-bis (trifluoromethyl) benzoyl-3- (3, -dimethylbenzyl) -4- [3- (1, 2,4-triazol-3-ylamino) propyl] piperazine [a] 4D: -10.50 ° (C = 0.5, MeOH) IR (Pure): 3075, 2700, 1675, 1640, 1430, 1280, 1170, 1130 cm "1 10 NMR (DMSO-de, d): 2.05-5.20 (15H , m), 2.09 (3H, s), 2.18 (3H, s), 6.60-8.34 (9H, m) MASS: 569 (M + l) (free) EXAMPLE 68 A mixture of (2R) -1- [3,5-bis- (trifluoromethyl) benzoyl] -2- (2-naphthylmethyl) piperazine (300 mg), hydrochloride of 4-1 iomor folino-2-but i 1 chloride (170 mg) and potassium carbonate powder (210 mg) in dry acetonitrile (3 ml) is brought to Reflux for 7.5 hours in the presence of iodide of t * "- ^,» p t-á ^ f? O - "(20, -? Ig). The reaction mixture is cooled and then filtered, the filtrate is concentrated under reduced pressure and the resulting residue is purified by silica gel column chromatography. using a mixture of ethyl acetate and methanol (50: 1). The product obtained is dissolved in ethyl acetate and treated with 4N hydrochloric acid in ethyl acetate solution (0.6 ml) to give (2R) -1 - [3,5-bis (tri fluoromethyl) -benzoyl] -hydrochloride] - 2- (2-naphthylmethyl) -4- (4-1 iomor folino-2-butyl) -piperazine (300 mg). mp: 152-156 ° C [a] 7D: -47.30 ° (C = 0.5, MeOH) IR (Nujol): 3350, 2500, 1637, 1275, 1125 cm "1 NMR (DMSO-de, d): 2.70-5.30 (21H, m), 7.00-8.20 (10H, m) MASS: 620 (M + l) (free) Example 69 A mixture of (2R) - [3,5-bis (trifluoromethyl) benzoyl] -2- (3, -dimethylbenzyl) -4- (4-chloro-2-butyl) piperazine (200 mg), 1- Cyclohexylpiperazine (63 mg) and potassium carbonate powder (210 mg) in N, N-dimet and 1 dry formamide (2 ml) is stirred for 12 hours at room temperature. Additional 1-cyclohexylpiperazine (25 mg) is added and after 2 hours the reaction mixture is poured into water (20 ml) and extracted with ethyl acetate. The organic layer is washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the resulting residue is purified by column chromatography on silica gel using a mixture of dichloromethane and methanol (30: 1). The product obtained is dissolved in ethyl acetate and treated with 4N hydrochloric acid in ethyl acetate solution (0.6 ml) to give (2R) -1- [3, 5-bi s (tri fluoromethyl) -benzoyl trichlorohydrate] -2- (3,4-Dimethylbenzyl) -4- [4- (4-cyclohexyl-piperazin-1-yl) -2-butynyl] piperazine (220 mg). Mp: 175-190 ° C [a] 25.2 D: -7.20 ° (C = 0.5, MeOH) IR (Nujol): 3370, 2750-1920, 1635, 1276, 1126 cm "1 NMR (DMSO-de, d) ): 1.02-5.20 (38H, m), 6.60-8.30 (6H, m) MASS: 664 (M + l) (free) Example 70 Potassium carbonate (187 mg) and 2- (chloromet i 1) pyridine hydrochloride (81 mg) are added to a solution of (2R) -1- [3,5-bi (trifluoromethyl) benzoyl] - • -. * 2- (3,4-Dimethylbenzyl) piperazine (200 mg) in N, N-dimethyl formamide (4 ml) at room temperature with stirring. After 2 hours, the reaction mixture is poured into water (50 ml) and extracted with ethyl acetate. The organic layer is washed with water and then dried over magnesium sulfate, and evaporated under reduced pressure. The residue obtained is purified by silica gel column chromatography using a mixture of ethyl acetate and toluene (1: 3) and treated with 4N hydrochloric acid in ethyl acetate solution to produce (2R) -1- [3,5-bis (tri fluoromethyl) -benzoyl] -2- (3,4-dimethylbenzyl) dihydrochloride. ) -4- (2-pyridylmethyl) -piperazine (123 mg). [a] 23D: -28.30 ° (C = 0.5, MeOH) IR (Nujol): 3360, 2560, 1640, 1278, 1130 cm "1 NMR (DMSO-de, d): 2.0-2.3 (10H, m), 2.6-5.8 (9H, m), 6.6-8.7 (10H, m) MASS: 536 (M + l) (free) Example 71 A Lindlar catalyst (Pd-CaCO3-Pb (OAc) 2) (40 mg) is added to a solution of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (lH-indole 3-ylmethyl) -4- (4-morpholino-2-butyl) piperazine in methanol (8 ml). The mixture is stirred for 2 hours under hydrogen at 25 ° C and then filtered. The filtrate is concentrated under reduced pressure and the resulting residue is chromatographed on silica gel with dichloromethane-methanol (20: 1) as a diluent to give the material which is treated with 4N hydrochloric acid in ethyl acetate solution to produce dihydrochloride of (2R) -1- [3, 5-bis (trifluoro-methyl) -benzoyl] -2- (lH-indol-3-ylmet i 1) -4- [(Z) -4-mor fol -2-buteni 1] piperazine (104 mg). [a] 21D: + 0.40 ° (C = 0.5, MeOH) IR (Nujol): 3700-3150, 2750-2300, 1635, 1275, 1170, 1120 cm "1 NMR (DMSO-de, d): 3.00-4.10 (21H,), 6.05-6.35 (2H, m), 6.80-8.10 (8H, m), 10.72 (1H, s) MASS: 595 (M + l) (free) Example 72 The following compound is obtained according to a form similar to that of Example 71. (2R) -1- [3,5-bis (trifluoro-methyl) benzoyl] -2- (3,4-dimethylbenzyl) dihydrochloride ) -4- [(Z) -4-morpholino-2-butenyl] piperazine mp: 243-246 ° C [a] 21 D: -5.30 ° (C = 0.5, MeOH) IR (Nujol): 3600-3150, 2600 -2300, 1645, 1275, 1170, 1130 cm "1 NMR (DMSO-d, d): 2.10-2.20 (6H, m), 3.0-4.2 (21H, m), 6.05-6.35 (2H, m), 6.80 -7.10 (3H,), 7.60 (2H, s), 8.09 (1H, s) The NMR spectrum of this compound is measured at 90 ° C MASS: 584 (M + l) (free) Example 73 A solution of (2R) -l- [3,5-bis (tri fluoromethyl) benzoi 1] -2- (1H, indol-3-ylmethyl) -4- (-mor fol ino-2) is hydrogenated. but butyl) piperazine in methanol (10 ml) in the presence of 10% Pd-carbon (50 mg) at room temperature. After the reaction mixture is complete (1 hour, and 20 minutes), the reaction mixture is filtered and then subjected to silica gel column chromatography with dichloromethane-methanol (20: 1) to give the material which is treat with 4N hydrochloric acid in an ethyl acetate solution to produce (2R) -l- [3,5-bis (trifluoromethyl) -benzoyl] -2- (lH-indol-3-ylmethyl) -4 - ( -mor fol inobut i 1) piperazine (165.1 mg). [a] 21D r -7.10 ° (C = 0.5, MeOH) IR (Nujol): 3700-3150, 2720-2450, 1635, 1275, -H80-1080 cm "1 NMR (DMSO-de, d): 1.70- 2.00 (4H, m), 2.95-5.20 (21H, m), 6.60-8.25 (8H, m), 10.95 (1H, s), 11.10-11.80 (2H, m) MASS: 597 (M + l) (free ) Example 74 The following compound was obtained according to a form similar to that of Example 73. (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4-hydrochloride - (5-morpholinopentyl) piperazine mp: 235-238 ° C [a] 22 D: -13.90 ° (C = 0.5, MeOH) IR (Nujol): 3500-3100, 2600, 1630, 1270, 1180-1060 c "1 NMR (DMSO-d6, d): 1.2-2.0 (6H, m), 2.0-2.5 (8H, m), 2.6-5.2 (19H, m), 6.6-8.3 (6H, m), 11.26 (2H, m) ) MASS: 600 (M + l) (free) Example 75 (2R) -1- [3,5-bis (tri fluoromethyl (benzoyl) -2- (3,4-dimethylbenzyl) piperazine (200 mg) and potassium carbonate (187 mg) is added to a mixture of chloride of hydrochloride (E) -4-mor folino-2-butenyl (105 mg) and acetonitrile (3 ml) The resulting mixture is heated to reflux temperature with stirring.After 16 hours, the reaction mixture is evaporated under pressure The organic phase is separated and washed with brine, and dried over magnesium sulfate, the solvent is removed in vacuo to leave an oil which is brought to gel chromatography. of silica with dichloromethane methanol (50: 1) as a diluent to give a methanol which, in treatment with 4N hydrochloric acid in ethyl acetate solution (0.2 ml), produces (2R (-1- [3,5-bis ( tri fluoromethyl) -benzoyl] -2- (3, -dimethylbenzyl) -4- (E) -4-morpholino-2-butenyl] piperazine (194 mg) mp: 236-242 ° C [a] 19-6D: -1 0.8 (C = 0.3, MeOH) IR- (Nujol): 3350, 2900, 1645, 1275, 1185, 1170, 1135 cm "1 NMR (DMSO-de, d): 2.16 (3H, s), 2.20 (3H, s), 2. 60-4.80 (19H, m), 3.91 (4H, t, J = 4.8Hz), 6.04-6.40 (2H, m), 6.74-7.15 (3H, m), 7.61 (2H, s), 8.08 (1H, s) The NMR spectrum of this compound is measured at 90 ° C MASS: 584 (M + l) (free) Example 76 The following compound is obtained according to a similar form to that of Example 75. (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) dihydrochloride) -4- [(E) -4-morpholino-2-butenyl] piperazine mp: 123-126 ° C [a] 0 D: -0.2 ° (C = 0.3, MeOH) IR (Nujol): 3350, 2750-2000, 1655, 1635, 1275, 1175, 1125 cm "1 NMR (DMSO-de, d): 2.60-5.00 (17H, m), 3.89 (4H, t, J = 4.8Hz), 6.00-6.40 (2H, m) , 6.70-7.50 (5H, m), 7.80 (2H, s), 8.03 (1H, s), 10.74 (1H, s) The NMR spectrum of this compound is measured at 90 ° C. MASS: 595 (M + l ) (free) Example 77 To a stirring mixture of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-i-methyl-1) -piperazine (0.2 g) 1-methyl 4-formyl 1-lH-pyrazole (0.05 g) in dichloromethane (2 ml) under nitrogen atmosphere was added sodium t-riacetoxyborohydride (151 mg) at room temperature. After 4 hours, the reaction mixture is evaporated under reduced pressure, and ethyl acetate (20 ml) and aqueous sodium hydrogen carbonate solution (10 ml) are added to the residue. The organic layer is separated and washed with brine, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue is purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol (50: 1). The product obtained is dissolved in ethyl acetate and treated with 4N hydrochloric acid in ethyl acetate solution to give (2R) -1- [3,5-bis (tri fluoromethyl) -benzoyl] -2- (lH-hydrochloride. -indol-3-ylmet i 1) -4- [(1-met yl-lH-pyrazol-4-yl) met yl] piperazine (154 mg). mp: 122-136 ° C [a] 18.8 D: -8.50 ° (C = 0.3, MeOH) IR (Nujol): 3350, 2750-2000, 1655, 1640, 1275, 1175, 1125 cm "1 NMR (DMS0 -d6, d): 2.80-5.20 (14H, m), 6.50- 8.30 (10H,?), 10.90 (1H, s), 11.40-11.90 (1H, broad s) MASS: 550 (M + l) (free Example 78 A mixture of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [2- (met i lsul foni loxi) et i 1] Piperazine (200 mg), 2-ethoxyethylamine (0.044 ml) and triethylamine (0.098 ml) in acetonitrile (5 ml) is refluxed for 1.5 hours.The reaction mixture is concentrated under reduced pressure and the resulting residue divided between ethyl acetate and aqueous sodium hydrogen carbonate solution.The organic layer is washed with brine and dried over magnesium sulfate.After evaporation of the solvent, the residue is purified by silica gel column chromatography using a mixture of dichloromethane and methanol (20: 1) to produce an oily product, which is dissolved in ethyl acetate It is treated with 4N hydrochloric acid in ethyl acetate solution to give (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [2-dihydrochloride]. - (2-ethoxyethylamino) et i 1] piperazine (64.5 mg) [a] 2o: -6.70 ° (C = 0.5, MeOH) IR (Pure): 3400, 265T, - * 1640, 1430, 1280, 1170 , 1150, 900 cm "1 NMR (DMSO-de, d): 1.63 (3H, m), 2.0-2.30 (6H,), 2.6-5.3 (20H, m), 6.6-8.3 (6H, m), 9.2 -9.6 (1H, broad s), 11.2-11.8 (1H, broad s) MASS: 560 (M + l) (free) Preparation 8 To a mixture of N- (tert-butylcarbonyl) -4-f luoro-D-phenylalanine (5.25 g), N-benzylglycine hydrochloride benzyl ester (5.41 g) and triethylamine (9.04 ml) in dichloromethane ( 50 ml) is added 2-chloro-1-methylpyridinium iodide (5.21 g) at room temperature, and the mixture is stirred for 2.5 hours. The mixture is evaporated under reduced pressure, and the resulting residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with dilute hydrochloric acid, saturated aqueous sodium carbonate aqueous solution and successively brine, and dried over magnesium sulfate. After evaporation of the solvent, the resulting residue is chromatographed on silica gel using a mixture of toluene and ethyl acetate as a diluent to give (2R) -N-benzyl-N-benzyloxycarbonylmethyl-2- (tert-butoxycarbonyl) amino) -3- (4-f luoropheni 1) propanamide (9.62 g). [a] 23-6 D: + 9.10 ° (C = 0.5, MeOH) IR (Nujol): 3350, 1735, 1680, 1650 cm "1 NMR (DMSO-de, d): 1.24, 1.30 (9H, 2s), 2.70-2.90 (2H,), 3.85-4.80 (5H, m), 5.12 (2H, d, J = 3.2Hz), 6.95-7.45 (14H, m) MASS: 521 (M + l) Preparation 9 To an ice-cooled solution of (2R) -N-benzyl-1-N-benzyloxycarbonylmethyl 1 - 2 / - (tert-butoxycarbonylamine) -3- (4-fluorophenyl) propanamide (9.48 g) in dichloromethane (55 ml) is added 4N hydrochloric acid in dioxane solution (54.6 ml). The mixture is stirred at the same temperature for 15 minutes and at room temperature for one hour. After removal of the solvent by evaporation, the excess of the aqueous sodium hydrogen carbonate solution is added to the resulting residue. The mixture is heated to about 50 ° C for several minutes and the resulting precipitate is collected by filtration and washed with water and dried in vacuo * to give (3R) -l-benzyl-3- (4-fluorobenzyl) piperazine -2, 5-dione (5.00 g). [a] 27-3D: -20.30 ° (C = 0.5, MeOH) IR (Nujol): 3200, 3050, 1665, 1220 cm -i NMR (DMSO-de, d): 2.80 (1H, d, J = 17.3 Hz), 2. 88 (1H, dd, J = 13.7Hz, 4.7Hz), 3.15 (1H, dd, J = 13.7Hz, 4.1Hz), 3.53 (1H, d, J = 17.3Hz), 4.15 (1H, d), J = 14.4Hz), 4.26 (1H, m), 4.63 (1H, d, J = 14.4 Hz), 6.80-7.40 (9H, m), 8.33 (1H, broad s) MASS: 313 (M + l) Preparation 10 To a suspension cooled with ice of lithium aluminum hydride (1.2 g) in tetrahydrofuran (91 ml) is added (3R) -1-benzyl 1-3- (4-f luorobenz 1) piperazine-2,5-dione (4.95 g) by small portions . The mixture is stirred at the same temperature for 15 minutes and at room temperature. atmosphere for one hour. After removing the solvent by evaporation, aqueous sodium hydrogen carbonate solution is added to the resulting residue. The mixture is heated to about 50 ° C for several minutes and the presipitados results are collected by filtration, washed with water and dried in vacuo to give (3R) -1-benzyl-3; - (4-f luorobenzyl) piperazine (4.60 g) as an oil. IR (Pure): 3300, 1215 cm'1 NMR (DMSO-de, d): 1.90 (2H, m), 2.45-2.90 (5H, m), 3.30-3.45 (4H, m), 6.95-7.35 (9H , m) MASS: 285 (M + l) Preparation 11 A mixture of (2R) -4-benzyl 1 -1- [3,5-bis (tri fluoromethyl (benzoyl) -2- (4-fluorobenzyl) -piperazine (7.92 g), ammonium formate (2.38 g) and 10% palladium on carbon (0.79 g) in a mixed solvent of ethanol (80 ml) and water (8 ml) is stirred for 1.5 hours at 60 ° C under nitrogen atmosphere.The reaction mixture is cooled to room temperature and filtered through a pad of Celite.RTM .. The filtrate is concentrated under reduced pressure and the residue is dissolved in ethyl acetate.The solution is washed with water and brine successively, dried over magnesium sulfate, and evaporated under reduced pressure. reduced reaction to give (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (4-fluorobenzyl) -piperazine (6.04 g) as an oil. [a] 27-8D: -11.70 ° (C = 0.5, MeOH) IR (Pure): 3300, 1630, 1150 cm "1 NMR (DMSO-de, d): 2.55-3.80 (8H, m), 4.25 (1H, m), 6.90-7.50 ( 5H, m), 7.64 (1H, broad s), 8.13 (1H, broad s) MASS: 435 (M + l) Preparation 12 The following compounds were prepared by a form similar to that of Preparation 8. (1) (2R) -N-benzyl-N-benzyloxycarbonylmethyl-2- (tert-butoxycarbonyl-lamino) -3- (4-methoxy phenyl) -propanamide [a] 24- ° D: + 6.60 ° (C = 0.5, MeOH) IR (Pure): 3300, 1740, 1700, 1650, 1240 cm "1 NMR (DMSO-de, d): 1.27, 1.31 (9H, s), 2.76 (2H, m), 3.96, 3.70 (3H, 2s), 3.95-4.90 (5H, m), 5.13 (2H, d, J = 4.9Hz), 6.70-7.36 (14H, m) MASS: 533 (M + l) (2) (2R) -N-benzyl-N-benzyloxycarbonylmethyl- 2- (tert-butoxycarboni lamino) -3- (4- trifluoromethyl-phenyl) propanamide [a] 6-4D: + 9.00 ° (C = 0.5, MeOH) IR (Nujol): 3350, 1735, 1720, 1670, 1650 cm "1 NMR (DMSO-de, d): 1.19, 1.27 (9H, 2s), 2.90 (2H, m (, 4.00-4.75 (5H, m), 5.12 (2H, s), 7.10-7.60 (15H, m) MASS: 571 (M + l) (3) (2R) -N-benzyl-N -benzyloxycarbonylmethyl-2- (terbutoxy carboni lamino) -3- (1-naphthyl) propanamide [a] 2> 7D: -0.60 ° (C = 0.5, MeOH) IR (Pure): 3300, 2970, 1740, 1700, 1645 cm "1 NMR (DMSO-de, d): 1.18, 1.26 (9H, 2s), 3.20-3.50 (2H, m), 3.90-5.20 (7H, m), 7.10-8.10 (17H, m) MASS: 553 (M + l) Preparation 13 The following compounds are prepared by a form similar to that of Preparation 9. (1) (3R) -l-benzyl-3- (4-methoxybenzyl) -piperazine-2, 5-dione [a] 27-9D: -38.60 ° (C = 0.5, MeOH) IR (Nujol): 3250, 1680, 1640, 1245 cm "1 NMR (DMSO-de, d): 2.60 (1H, d , J = 17.2Hz), 2.80 (1H, dd, J = 13.6Hz, 4.7Hz), 3.09 (1H, dd, J = 13.6Hz, 3.8Hz), 3.46 (1H, d, J = 17.2Hz), 3.67 (3H, s), 4.11 (1H, d, J = 14.4Hz), 4.22 (1H, broad s), 4.65 (1H, d, J = 14.4Hz), 6.63 (2H, d, J = 8.7Hz), 6.93 (2H, d, J = 8.7Hz), 7.10-7.40 (5H, m), 8.30 (1H, broad s) MASS: 325 (M + l) (2) - ~ (3R) -l-benzyl-3 - (4-trifluoromethylbenzyl) piperazin-2, 5-dione [a] 26'8D: -12.00 ° (C = 0.5, MeOH) IR (Nujol): 3250, 1680, 1650 cm "1 NMR (DMSO-de, d ): 2.85 (1H, d, J = 17.4Hz), 3.00 (1H, dd, J = 13.4Hz, 4.8Hz), 3.25 (1H, dd, J = 13.4Hz, 4.4Hz), 3.59 (1H, d, J = 17.4Hz), 4.08 (1H, d, J = 14.4Hz), 4.35 (1H, broad s), 4.74 (1H, d, J = 14.4Hz), 7.00-7.15 (2H, m), 7.25-7.35 (5H, m), 7.48 (2H, d), J = 8.1Hz), 8.41 (1H, s) MASS: 363 (M + l) (3) (3R) -l-benzyl-3- (1-naphthylmethyl) ) pipera zin-2, 5-dione IR (Nujol): 3250, 1685, 1655 cm "1 NMR (DMSO-de, d): 2.92 (1H, d, J = 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 (1H, dd, J = 6.5Hz, 3. 0Hz), 7.94 (1H, m), 8.14 (1H, m), 8.31 (1H, d, J = 3.0Hz) MASS: 345 (M + l) Preparation 14 The following compounds are prepared in a manner similar to that of Preparation 10. (1) (3R) -l-benzyl-3- (4-methoxybenzyl) piperazine IR (Pure): 3250, 1240 cm "1 NMR ( DMSO-de, d): 1.60-2.00 (4H, m), 2.40-2.90 (5H,), 3.30-3.50 (2H, m), 3.70 (3H, s), 6.81 (2H, d, J = 8.6Hz ), 7.07 (2H, d, J = 8.6Hz), 7.15-7.40 (6H, m) MASS: 297 (M + l) (2) (3R) -l-benzyl-3- (4-tri fluoromethylbenzyl) piperazine [a] 27 2D: -5.80 ° (C = 0.5, MeOH) IR (Pure): 3250, 2925, 2800, 1320 cm "1 NMR (DMSO-de, d): 1.72 (1H, t, J = 10.0Hz ), 1. 91 (1H, m), 2.55-2.95 (6H, m), 3.30-3.50 (3H, m), 7.15-7.35 (6H, m), 7.40 (2H, d, J = 8.0Hz), 7.60 (2H, d, J = 8.0Hz) MASS: 335 (M + l) (3) (3R) -l-benzyl-3- (1-naphthylmethyl) piperazine [a] 7-6D: -21.80 ° (C = 0.5, MeOH ) IR (Pure): 3300, 3050, 2925, 2800 cm "1 NMR (DMSO-de, d): 1.75-2.05 (2H, m), 2.50-3.60 (9H, m), 7.10-7.65 (9H, m ), 7.77 (1H, d, J = 7.9Hz), 7.90 (1H, m), 8.12 (1H, dd, J = 7.1Hz, 2.3Hz) MASS: 297 (M + l) (2) (3R) - l-benzyl-3- (4-tri fluoromethylbenzyl) piperazine [a] 27-D: -5.80 ° (C = 0.5, MeOH) IR (Pure): 3250, 2925, 2800, 1320 cm "1 NMR (DMSO-de , d): 1.72 (1H, t, J = 10.0Hz), 1.91 (1H, m), 2.55-2.95 (6H, m), 3.30-3..50 (3H, m), 7.15-7.35 (6H, ), 7.40 (2H, d, J = 8.0Hz), 7.60 (2H, d, J = 8.0Hz) MASS: 335 (M + l) (3) (3R) -l-benzyl-3- (1-naphthylmethyl) ) piperazine [a] 2 -6D: -21.80 ° (C = 0.5, MeOH) IR (Pure): 3300, 3050, 2925, 2800 cm "1 NMR (DMSO-de, d): 1.75-2.05 (2H,) , 2.50- 3.60 (9H, m), 7.10-7.65 (9H, m), 7.77 (1H, d, J = 7.9Hz), 7.90 (1H, m), 8.12 (1H, dd, J = 7.1Hz, 2.3Hz) MASS: 317 (M + l) Preparation 15 The following compounds are prepared by a similar manner to that of Preparation 11. (1) (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (4-methoxybenzyl) piperazine [a] 28- ^: -32.60 ° (C = 0.5, MeOH) IR (Pure): 3300, 1630, 1280 cm "1 NMR (DMSO-de, d): 2.40-3.55 (9H, m), 3.72 (3H, s ), 6.70-8.45 (7H, m) MASS: 447 (M + 1) (2) (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (4-tri fluoromethylbenzyl) piperazine NMR ( DMSO-de, d): 2.60-3.70 (9H, m), 7.15-7.40 (2H,), 7.50-7.75 (4H, m), 8.12 (1H, s) MASS: 485 (M + l) (3) (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (1-naphthylmethyl) piperazine [a] 8?: + 24.70 ° (C = 0.5, MeOH) IR (Pure): 3340, 3050 , 2950, 2825, 1630 cm'1 NMR (DMSO-de, d): 2.50-4.30 (9H, m), 7.10- 8.55 (10H, m) MASS: 467 (M + l) Preparation 16 A mixture of 1-met yl-lH-pyrazole-4-carboxaldehyde (2.0 g) and triethyl phosonoacetate (4.52 g) in N, N-dime ti 1 formamide (20 ml) is stirred under ice-cooling. After several minutes, sodium hydride (1.09 g, 60% in mineral oil) is added to the mixture, which is stirred for 1 hour at the same temperature. The resulting mixture is poured into ice water, neutralized with aqueous aminium acetate solution and extracted with ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is chromatographed on silica gel using a mixture of hexane and ethyl acetate as a diluent to give (E) -3- (1-methyl-1-1H-pyrazole-4-yl) ethyl acrylate . IR (Nujol): 2975, 1700, 1635 cm'1 NMR (DMSO-de, d): 1.32 (3H, t, J = 7.1Hz), 4.23 (2H, g, J = 7.1Hz), 6.16 (1H, d, J = 16.0Hz), 7.54 (1H, s), 7.55 (1H, d, J = 16.0Hz), 7.69 (1H, s) MASS: 181 (M + l) Preparation 17 A solution of 2- (E) -3- (1-meth i 1- lH-pyrazol-4-yl) acrylate (1.04 g) in tetrahydrofuran (50 ml) is hydrogenated over 10% palace on carbon (0.2 g) at room temperature at 2 atm of hydrogen. After removal of the catalyst by filtration through the Celite® bed, the filtrate is concentrated under reduced pressure to give ethyl 3- (l-methyl-lH-pyrazol-4-yl) -propionate. IR (Pure): 2950, 1725 cm "1 NMR (DMSO-de, d): 1.24 (3H, t, J = 7.1Hz), 2." 50 (2H, t, J = 7.5Hz), 2.78 (2H , t, J = 7.5Hz), 3.84 (3H, s), 4.13 (2H, c, J = 7.1Hz), 7.18 (1H, s), 7.31 (1H, S) MASS: 183 (M + l) Preparation 18 To an ice-cooled solution of ethyl 3- (1-methyl-1-yl-pyrazol-4-yl) propionate in tetrahydrofuran (10 ml) is added lithium-aluminum hydroxide (0.22 g) under nitrogen atmosphere.

After the mixture is stirred for 30 minutes, water and 15% aqueous sodium hydroxide solution are successively added to the mixture. The resulting precipitates are removed by filtration through the Celite® bed and the filtrate is extracted with ethyl acetate. The organic layer is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 3- (1-meth i-lH-pyrazol-4-yl) -1-propanol. IR (Pure): 3300, 2930 cm "1 NMR (DMSO-de, d): 1.87 (2H, m), 2.55 (2H, t, J = 7.6Hz), 3.68 (2H, t, J = 6.1Hz) , 3.85 (3H, s), 7.16 (1H, s), 7.31 (1H, s) MASS: 141 (M + l) Preparation 19 To a solution of oxalyl chloride (0.361 ml) in dichloromethane (10 ml) cooled to -65 ° C with a dry ice-acetone bath, a solution of dimethyl sulfoxide (0.381 ml) in dichloromethane (1 ml) is added. ml) with efficient agitation for 10 minutes. After 20 minutes under -65 ° C, a solution of 3- (1-meth i 1- 1 H -pyrazol-4-yl) -1-propanol in dichloromethane (2 ml) is added to the mixture for 10 minutes under - 65 ° C and the mixture is stirred at the same temperature for 20 minutes and then at -45 - -40 ° C for 30 minutes. After the trickle addition of triethylamine to the mixture for 10 minutes followed by stirring for 15 minutes, 1N hydrochloric acid solution is added to the mixture. The resulting mixture is extracted with a mixture of dichloromethane and methanol several times. The extract is concentrated under reduced pressure and the resulting residue is chromatographed on silica gel using a mixture of dichloromethane and methanol as a diluent to give 3- (1-methyl-1H-pyrazol-4-yl) -1- propanal IR (Pure): 2925, 1720 cm "1 NMR (DMSO-de, d): 2.65-2.90 (4H, m), 3.86 (3H, s), 7.17 (1H, s), 7.32 (1H, s), 9.80 (1H, s) MASS: 139 (M + l) Example 79 To a mixture of 3,5-bis (tri fluoromethyl) benzoic acid (4.13 g) and pyridine (0.041 ml) in tetrahydrofuran (12.5 ml) is added oxalyl chloride (3.25 g) for 15 minutes at 22-38 ° C and the mixture is stirred at 55 ° C for 4 hours. The acid chloride solution obtained from the above procedure is added to an ice-cooled solution of (3R) -l-benzyl-3- (-fluorobenzyl) -piperazine (4.51 g) and triethylamine (4.83 g) in dichloromethane (45 ml). under 5 ° C for 30 minutes. After stirring for 2 hours at room temperature, the mixture is washed with water and brine successively, and dried over magnesium sulfate. After evaporation of the solvent, the resulting residue is chromatographed on silica gel using a mixture of toluene and ethyl acetate as a diluent to give (2R) -4-benzyl-l- [3, 5-bis (trifluoromethyl) benzoyl] -2- (4-fluorobenzyl) -piperazine (0.87 g) with a syrup. [a] 27-5D: -11.50 ° (C = 0.5, MeOH) IR (Pure): -1740, 1150 cm-1 NMR (DMSO-de, d): 2.00-4.40 (11H,), 6.80-7.50 ( 10H, m), 7.74 (1H, broad s), 8.13 (1H, broad) MASS: 525 (M + l) Example 80 The following compounds are prepared by a form similar to that of Example 79. (1) (2R) -4-benzyl-l- [3,5-bis (trifluoromethyl) -benzoyl] -2- (4-methoxybenzyl) piperazine [a] 28- ° D: -21.40 ° (C = 0.5, MeOH) IR (Pure): 1740, 1640 1270 cm "1 NMR (DMSO-de, d): 1.70-2.40 (3H,), 2.60- 3.80 (11H, m), 6.60-7.60 (10H, m), 7.65-8.55 (2H, m) MASS: 537 (M + l) (2) (2R) -4-benzyl-1- [3, 5 bis (trifluoromethyl) benzoyl] -2- (4-trif luoromet i lbenzyl) piperazine IR (Pure): 2950, 2800, 1765, 1740, 1640 cm "1 NMR (DMSO-de, d): 1.70-4.30 (1H,), 7.13 (1H, d, J = 7.8Hz), 7.20-7.70 (10H, m), 8.13 (1H, d, J = 7.8Hz) MASS : 575 (M + l) (3) (2R) -4-benzyl-l- [3,5-bis (trifluoromet i 1 benzoyl] -2- (1-naphthylmethyl) piperazine [a] 27-5D : + 9.70 ° (C = 0.5, MeOH) IR (Nujol): 1640 cm "1 NMR (DMSO-de, d): 2.00-4.40 (11H, m), 7.00-8.55 (15H, m) MASS: 557 ( M + l) Example 81 The following compound is prepared by a form similar to that of Example 66. (2R) -1- [3,5-bis (tri-fluoromethyl) benzoyl] -2- (3,4-di-ethylbenzyl) dihydrochloride -4- [3- (cis-2, 6-dimethylmorpholino) propi 1] -piperazine [a] 21- ° D: -11.10 ° (C = 0.5, MeOH) IR (Pure): 3400, 2550, 2450, 1640 , 1430, 1280, 1175, 1130 cm "1 NMR (DMSO-de, d): 1.14 (6H, m), 2.05-5.24 (19H, m), 2.10 (3H, s), 2.18 (3H, s), 6.64-8.24 (6H, m) MASS: 600 (M + l) (free) Analysis Calculated For C3iH39F6N302- 2 HCl • 2.35H20 C 52.08, H 6.29, N 5.77 Found: C52.08, H 6.44, N 5.88 Example 82., - *. The following compounds are obtained according to a form similar to that of Example 23 (1) (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4 trichlorohydrate. - [N- (3-pyridylmethyl) -3-aminopropyl] -piperazine [a] 28-4D: -13.60 ° (0 = 0.25, MeOH) IR (Pure): 3600-3100, 2800-1950, 1270, 1125 cm "1 NMR (DMSO-de, d): 2.09-5.20 (24H, m), 6.60-9.00 (10H, m) MASS: 593 (M + l) (free) Analysis Calculated for C2? H34F6N4? • 3HC1 • 4H20 C 48.10, H 5.86, N 7.24 Found: C 47.89, H 5.75, N 7.02 (2) (2R) -1- [3,5-bis- (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) hydrochloride ) -4- (N-morpholino-2-aminohexyl) piperazine [a] 28-5D: -26.80 ° (0 = 0.25, MeOH) IR (Pure): 3600-3000, 2800-2000, 1630, 1274, 1120 cm "1 NMR (DMSO-de, d): 2.02-5.20 (28H, m), 6.50- 8.30 (6H,) MASS: 573 (M + l) (free) Analysis Calculated For C2? H34F6N4? 2-2HCl- 9 / 2H20- 1 / 4CH3C02 C2H5: C 46.53, H 6.33, N 7.48 Found: C 46.64, H 6.26, N 6.67 (3) (2R) -l- [3,5- bis (tri fluoromethyl) benzoyl] dihydrochloride] -2- (3,4-dimethylbenzyl) -4- (N-morpholino-4-amino-2-butynyl) piperazine [a] 8- ° D: -9.80 ° (0 = 0.25, MeOH) IR (Pure): 3600-3000, 2600-1950, 1630, 1273, 1120 cm "1 NMR (DMSO-de, d): 2.10-5.20 (28H, m), 6.20- 8.30 (6H, m) MASS: 597 (M + l) (free) (4) Trichlorohydrate (2R) -l- [3,5-bis (tri fluoromethyl (benzoyl) -2- (3,4-dimethylbenzyl) -4- [N-methyl-N- (3-pyridylmethyl ) -2-aminoethyl] piperazine [a] 28-4D: -11.80 ° (0 = 0.25, MeOH) IR (Nujol): 3600-3100, 2700-1950, 1630, 1275, 1122 c "1 NMR (DMSO-de, d): 2.10-5.20 (24H, m), 6.60-7.80 (6H, m), 8.10-8.35 (2H, m), 8.70-8.95 (2H, m) MASS: 593 (M + l) (free) Analysis Falls for C3? H34F6N4? • 3HC1 • 7 / 2H20: "- ~ m 'C 48.67, H 5.80, N 7.32 Found: C 48.88, H 5.88, N 6.79 (5) Trichlorohydrate of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3) , 4-dimethylbenzyl) -4- [(E) -N- (3-pyridylmethyl) -4-amino-2-butenyl] piperazine [a] ze-5D: -10.40 ° (C = 0.25 MeOH) IR (Pure ): 3600-3100, 2800-1950, 1630, 1274, 1124 cm "1 NMR (DMSO-de, d): 2.09-5.20 (22H, m), 6.05-6.25 (2H, m), 6.60-9.00 (10H , m) MASS: 605 (M + l) (free) Analysis Calculated for c32H34FeN4? • 3HC1 • 5H20 C 47.80, H 5.89, N 6.97 Found: C 47.81, H 5.53, N 6.48 (6) (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) dihydrochloride -4- [(E) -N-morphino-n-amino-2-butenyl] -piperazine [a] 28-5D: -6.40 ° (0 = 0.25, MeOH) IR (Nujol): 3600-3000, 2750- 1950, 1620, 1273, 1120 cm "1 NMR (DMSO-de, d): 2.09-5.20 (28H, m), 5.80-8.30 (8H, m) MASS: 599 (M + l) (free) Analysis Calculated for C3oH36F6 402- 2HC1 • 7 / 2H20: C 49.05, H 6.17, N 7.63 Found: C 49.15, H 6.16, N 7.41 (7) (2R) -l- [3,5- is (trifluoromethyl) benzoyl] trichlorohydrate] - 2- (2-naphthylmethyl-4- [N- (3-pyridylmethyl) -2-aminoethyl] piperazine [a] 28-5D: -11.00 ° (0 = 0.25, MeOH) IR (Pure): 3600-3100, 2800 -1950, 1630, 1273, 1120 cm "1 NMR (DMSO-de, d): 2.50-5.20 (16H, m), 7.00-9.00 (14H, m) MASS: 601 (M + l) (free) Analysis Calculated for C32H3oF6 40 • 3HC1 • 4H20 C 49.15, H 5.28, N 7.16 Found: C 49.26, H 5.24, N 6.80 (8) (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (2-naphthylmethyl) -4-dichlorohydrate - (N-mor fol ino-2-aminoe t il) piperazine [a] 28-6D: -34.80 ° (0 = 0.25, MeOH) IR (Pure): 3600-3100, 2800-1950, 1630, 1273, 1120 cm "1 NMR (DMSO-de, d): 2.50-5.30 (22H, m), 7.00- 8.20 (10H,) MASS: 595 (M + l) (free) Analysis Calculated for C3? H32F6N4? 2-2HCl • 11 / 3H20: C 49.12, H 5.68, N 7.64 Found: C 49.04, H 5.57, N 7.39 (9) (2R) -l- [3,5-bis (trifluoromethyl) dihydrochloride] benzoyl] -2- (2-naphthylmethyl) -4- (N-morpholino-3-aminopropyl) piperazine [a] 28-6D: -40.10 ° (0 = 0.25, MeOH) IR (Nujol): 3650-3100, 2800 -1970, 1636, 1275, 1123 c "1 NMR (DMSO-de, d): 2.20-5.30 (24H, m), 7.00-8.20 (10H, m), 10.60-11.80 (3H, m) MASS: 610 ( M + l) (free) Analysis Calculated for C3iH3 F6N4? 2 • 2HC1 • 3H20 C 50.62, H 5.75, N 7.62 Found: C 50.72, H 5.58, N 6.99 (10) (2R) -l- [3,5-bis (trifluoromethyl) enzoyl] -2- (2-naphthylmethyl) -4-trichlorohydrate - ((E) -N- (3-pyridylmethyl) -4-amino-2-butenyl] piperazine [a] 28-4D: -20.40 ° (C = 0.25, MeOH) IR (Nujol): 3650-3100, 2750 -1930, 1620, 1272, 1122 cm "1 NMR (DMSO-de, d): - ^ 3.00-5.30 (16H, m), 6.00-6.30. (2H, - ~ * m), 7.00-9.10 (14H, m) ": ** MASS: 627 (M + l) (free) Analysis Calculated for C34H32F6 O • 3HC1 • 2H20: C 52.89, H 5.09, N 7.26 Found: C 52.73, H 5.09, N 7.16 (11) (2R) -l- [3,5- is (trifluoromethyl) benzoyl] -2- (2-naphthylmethyl) -4-dichloride. - [(E) -N-morpholino-4-amino-2-butenyl] piperazine [a] 28-6D: -13.00 ° (0 = 0.25, MeOH) IR (Pure): 3650-3000, 2750-1970, 1630 , 1274 cm "1 NMR (DMSO-de, d): 2.80-5.30 (22H, m), 6.15-9.50 (2H, m), 7.00-8.25 (10H, m) MASS: 621 (M + l) (free ) (12) (2R) -l- [3,5-bis (tri fluoromethyl) benzoyl] -2- (2-naphthylmethyl) -4- [N- (3-pyridylmethyl) -3-aminopropyl] piperazine trichlorohydrate] a] 28-6 D: -24.60 ° (C = 0.25, MeOH) IR (Nujol): 3600-3100, 2750-1950, 1630, 1273, 1121 cm "1 NMR (DMSO-de, d): 2.20-5.30 ( 18H, m), 7.00-9.10 (14H, m) MASS: 615 (M + l) (free) Analysis Calculated for C33H32F6N4? -3-HC1 • 10 / 3H? O: C 50.56, H 5.36, N 7.15 Found: C 50.53, H 5.38, N 6.94 Example 83 The following compounds are obtained according to a similar form to that of Example 35. (1) (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (2-naphthylmethyl) -4- (4-homomorpholino-2-butynyl) piperazine hydrochloride [a] 28- ° D : -19.80 ° (0 = 0.5, MeOH) IR (Pure): 3400, 2500, 1640, 1430, 1280, 1175, 1130 cm "1 NMR (DMSO-de, d): 1.95-5.34 (23H, m), 7.05-8.20 (10H, m) MASS: 618 (M + l) (free) Analysis Calculated for C33H33F6N302 • 2HC1 • 2.9H20: C 53.37, H 5.53, N 5.66 Found: C 53.38, H 5.47, N 5.67 (2) (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3-fluoro-4-methylbenzyl) -4 - [(E) -4 -morph ino-2-butenyl] piperazine dihydrochloride [a] 28- ° D: -4.50 ° (0 = 0.5, MeOH) IR (Nujol): 2400, 1645, 1275, ^ 1135 cm "1 NMR (DMSO-de, d): 2.20 (3H, s), 2.80-5.20 (21H, m) 6.00-8.26 (8H, m) MASS: 588 (M + l) (free) Analysis Calculated for C29H32F7 3? 2 • 2HC1: C 52.74, H 5.19, N 6.36 Found: C 52.39, H 5.20, N 6.29 (3) (2R) -l- [3,5-bis (trifluoromethyl (benzoyl) -2- (3-fluoro-4-methylbenzyl) -4- [(E) -4-chloro-2-butenyl] piperazine IR (Pure): 1640, 1430, 1275, 1130 cm'1 NMR (DMSO-de, d): 1.91-4.93 (13H, m), 5.71-8.20 (8H, m) MASS: 537 (M + l) (4) (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4-dichlorohydrate - (4 -mor fol ino-2-butinyl) piperazine mp: 98-101 ° C NMR (DMSO-de, d): 2.0-5.2 (25H, m), 5.74 (1H, broad d), 5.89 (1H, d broad), 6.6-8.2 (6H, m) MASS: 578 (M + l) (free) Analisys Calculated for C31H33F6N3O • 2HC1 • 2H20 C 54.23, H 5.73, N 6.12 Found: C 53.99, H 5.88, N 5.93 Example 84 The following compounds are obtained according to a form similar to that of Example 50. (1) (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (4-fluorobenzyl) -4- (4-t-butomer fol-ino-2-butyl) piperazine hydrochloride mp: 180 ° C (dec.) [A] 28- ° D: + 5.00 ° (C = 0.5, MeOH) IR (Nujol): 3350, 1630, 1125 cm "1 NMR (DMSO-de, d): 2.60-4.30 ( 21H, m), 6.85-7.25 (3H, m), 7.46 (2H, broad s), 7.75 (1H, broad s), 8.16 (1H, d, J = 9.4Hz) MASS: 588 (M + l) ( free) Calculated Analysis for C28H28F7N3? S • 2HC1 • H20 C 49.56, H 4.75, N 6.19 Found: C 49.47, H 5.13, N 5.93 (2) (2) -l- [3,5-Bis (trifluoromethyl) benzoyl] -2- (4-methoxybenzyl) -4-hydrochloride - (4-thiomorpholino-2-butynyl) piperazine mp: 197 ° C (dec.) [A] 28-1!): -8.60 ° (0 = 0.5, MeOH) IR (Nujol): 2500, 1640, 1275 cm "1 NMR (DMSO-de, d): 2.60-4.70 (24H, m), 6.70-8.30 (7H,) MASS: 600 (M + l) (free) Analysis Calculated for C29H3iF6N3? 2S • 2HC1 • 1.3H20: C 50.05, H 5.16, N 6.04 Found: C 50.06, H 5.36, N 5.77 (3) (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (4-trifluoromethylbenzyl) dihydrochloride -4- (4-thiomorpholino-2-butynyl) piperazine mp: 173 ° C (dec.) [A] 28- ° D: + 9.60 ° (0 = 0.5, MeOH) IR (Nujol): 2400, 1640 cm " 1 NMR (DMSO-de, d): 2.70-5.30 (21H, m), 7.22 (1H, d, J = 7.7Hz), 7.41 (1H, s), 7.50-7.80 (4H, m), 8.18 (1H , d, J = 7.0Hz) MASS: 638 (M + l) (free) Analysis Calculated for C29H28F9N3OS • 2HC1 • 1.3H20: C 47.46, H 4.48, N 5.73 Found: C 47.43, H 4.51, N 5.51 (4) (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (1-naphthylmethyl) -4- (4-thiomorpholino-2-butynyl) piperazine mp: 191 ° C (dec.) [A] 28 '° D: + 15.60 ° (C = 0.5, MeOH) IR (Nujol): 2500, 1635 cm "1 NMR (DMSO-de, d): 2.65-4.80 (21H, m), 7.10 * 8.60 (10H, m) MASS: 620 (M + l) (free) Analysis Calculated for C32H3? F6N3? S- 2HC1- 0.4H20: C 54.92, H 4.87, N 6.00 Found: C 54.88, H 5.04, N 5.65 Example 85 The following compound is obtained according to a form similar to that of Example 51. (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3, -dimethylbenzyl) -4- hydrochloride [3- (1-met i l-lH-pyrazol-4-yl) propyl] piperazine mp: 163-165 ° C [a] 25-3 D: -19.80 ° (0 = 0.5, MeOH) IR (Nujol): 2550, 1635 cm "1 NMR (DMSO-de, d): 1.90-2.25 (6H,), 3.00- 4.00 (15H, broad), 6.65-8.25 (8H,) MASS: 567 (M + l) (free) Analysis Calculated for C29H32F6N40 • HCl • H20: C 56.08, H 5.68, N 9.02 Found: C 56.44, H 5.76, N 8.98 Example 86 The following compound is obtained according to a similar form to that of Example 61. (2R) -1- [3,5-bis (tri fluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) -4- [4- (3,3-dimethylmorpholino) -2-butenyl] dihydrochloride] piperazine mp: 210 ° C (dec.) [a] 2? - D: + 0.63 ° (0 = 0.11, MeOH) IR (Nujol): 3660-3300, 2700-2300, 1640, 1445, 1430, 1370, 1270 cm "1 NMR (DMSO-de, d): 1.30-1.50 (6H,), 2.85-5.25 (19H, m), 6.05-6.30 (2H, m), 6.65-8.25 (8H, m), 10.97 (1H , s broad), 11.40-12.20 (2H, m) MASS: 623 (M + l) (free) Example 87 The following compound is obtained according to a similar form to that of example 54. (2R) -1- [3,5-bis (tri fluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -hydrochloride 4- [3- (3-pyridyl) propi 1] piperazine mp: 163-168 ° C [a] 24-7 D: + 5.77 ° (0 = 1.3, MeOH) IR (Nujol): 3600-3300, 2700-2300 , 1635, 1445, 1430, 1370, 1280 cm "1 NMR (DMSO-de, d): 1.92-5.22 (29H, m), 6.56-8.28 (6H, m), 11.43 (2H, broad s) MASS: 564 (M + l) (free) Analysis Calculated for 0-2HCl-2.4H20: C 53.01, H 5.60, N 6.18 Found: C 53.04, H 5.98, N 5.77

Claims (14)

1. A compound of the formula wherein Y is a bond or lower alkylene, RJ is aryl, which may have suitable substituent or substituents, R2 is aryl or indolyl each of which may have suitable substituent or substituents, R3 is hydrogen or lower alkyl; R 4 is lower chloroalkenyl; lower chloroalkynyl; lower pyridylalkylamino-lower alkyl; lower pyridylalkylamino-lower alkenyl; N- (lower alkyl) -N- [pyridylalkyl] -amino-lower alkyl; lower triazolylaminoalkyl; lower alkoxy-lower alkylamino-lower alkyl; bis [lower alkoxy-lower alkyl] aminoalkyl lower; N- (lower alkyl) -N- [lower alkoxy-lower alkyl] aminoalkyl lower; lower hydroxyalkyl; alkylsulphonyloxy-lower alkyl; lower phenylalkyl which may have lower alkanoyl, amino, lower alkanoylamino, lower dialkylaminocarbonyl or nitro; lower alkoxyphenyl-lower alkylcarbonyl; lower alkanoylbenzoyl; lower benzoylalkyl which has lower alkyl, chloro or dialkylamino lower; lower benzoylalkyl which has halogen and lower alkyl; dihalobenzoylalkyl lower; dialkylbenzoyl lower alkyl lower alkyl; 3- fluorobenzoi lalqui lower; 3- (- fluorobenzoyl) propyl; 4,4-ethylenedioxy-4- (4-fluorophenyl) butyl; piperazinylcarbonylalkyl lower alkyl which has cyclopentyl or halophenyl; (2-pyridi 1) lower alkyl; (3-pyridi 1) propyl; (3-pyridine D alkyne lower, imidazole lower alkyl which may have lower alkyl, pyrazolylalkyl lower which may have lower alkyl, thiomorpholinyl-carbonylalkyl lower, (3-azabicyclo [3.2.2] non-Sil) carbonylalkyl lower; or thienylcarbonylalkyl lower, 1, 2, 3, 6-tetrahydropyridylalkyl, lower, 1, 2, 3, 6-tetrahydropyridylalkyl, 1,2,3,4-tetrahydroisoquinolyalkyl, 4, 5, 6, 7-tetrahydrothien [3 , 2-c] pyridini lalqui lower, saturated lower heterocyclic alkyl, saturated heterocyclic lower alkenyl, saturated heterocyclic lower alkynyl, saturated heterocyclic lower alkyl, saturated heterocyclic lower alkenyl, or saturated heterocyclic saturated alkynyl, each of which may have substituent or suitable substituents, and a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein Y is lower alkylene, R1 is aryl of Ce-C? Or which may have 1 to 3 mono (or di or tri) haloalkyl, R 2 is aryl or indolyl of C 6 -C 0, each of which may have 1 to 3 substituents or suitable substituents selected from the group consisting of lower alkyl, lower alkoxy, momo (or di or tri) lower haloalkyl and halogen, R3 is hydrogen; and R 4 is lower chloroalkenyl; lower chloroalkynyl; lower pyridylalkylamino-lower alkyl; lower pyridylalkylamino-lower alkenyl; N- (lower alkyl) -N- [pyridylalkyl] aminoalkyl lower; t iazol lower ilaminoalkyl; lower alkoxy-lower alkylamino-lower alkyl; bis [lower alkoxy-lower alkyl] aminoalkyl lower; N- (lower alkyl) -N- [lower alkoxy-lower alkyl] lower aminoalkyl; lower hydroxyalkyl; lower alkylsulfonyloxy-lower alkyl; lower phenylalkyl which may have lower alkanoyl, amino, lower alkanoylamino, lower dialkylaminocarbonyl or nitro; lower alkoxyphenyl-lower alkylcarbonyl; alkanoi lbenzoi lower; lower benzoylalkyl which has lower alkyl, chloro or dialkylamino lower; lower benzoylalkyl which has halogen and lower alkyl; dihalobenzoylalkyl lower; lower dialkylbenzoyl-lower alkyl; 3- fluorobenzoylalkyl lower; 3- (4-fluorobenzoyl) propyl; 4,4-ethylenedioxy-4- (4-fluorophenyl) butyl; piperazinylcarbonylalkyl lower which has cyclopentyl or halophenyl; (2-pyridyl) lower alkyl; (3-pyridyl) propyl; (3-pyridyl) lower alkynyl; imidazolylalkyl lower which may have lower alkyl; pyrazolyl lower alkyl which may have lower alkyl; thiomofoli-nylcarbonylalkyl lower; (3-azabicyclo- [3.2.2] non-3-yl) carbonylalkyl lower; or thienyl-carbonylalkyl lower, 1, 2, 3, 6-tet rahidropyridi 1 alkyl inferred, 1, 2, 3, 6-tet rahidropi r i-di the inferior Iquini, 1, 2, 3, 4 -t et rahidroiso-quinol i lalqui lower, 4,5,6,7-tetrahydro-thieno [3,2-c] pyridinyl-lower alkyl, saturated lower heterocyclic alkyl, saturated heterocyclic lower alkenyl, saturated heterocyclic lower alkynyl, heterocyclic lower alkyl saturated, heterocyclic saturated lower alkenyl or saturated heterocyclic lower alkynyl [wherein "the saturated heterocyclic portion" is saturated from 3 to 8 members of the heteromonocyclic group containing from 1 to 4 nitrogen atoms; a saturated 3 to 8 membered heterocyclic group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms; a saturated 3 to 8 membered heterocyclic group containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms; or the saturated heterocyclic group of the formula: ) t (wherein q, r, s and t are each an integer from 1 to 6) each of which may have from 1 to 3 substituents or suitable substituents selected from the group consisting of lower cycloalkyl, lower alkanoyl, lower alkyl , mono (or di or tri) lower haloalkyl, lower alkoxy, lower alkoxy-lower alkyl halogen, C 6 -C 0 aryl, cyano, oxo and a bivalent group of the formula:

3. The compound of claim 2, wherein Y is lower alkylene, R1 is phenyl which may have 1 or 2 mono (or di or tri) lower haloalkyl, R2 is phenyl, naphthyl or indolyl, each of which may have 1 or 2 substituent or substituents or suitable substituents selected from the group consisting of lower alkyl, lower alkoxy, mono (or di or tri) haloalkyl lower and halogen, R3 is hydrogen, and R4 is lower chloroalkenyl; lower chloroalkynyl; lower pyridylalkylamino-lower alkyl; lower pyridylalkylamino-lower alkenyl; N- (lower alkyl) -N- [pyridylalkyl lower] aminoalkyl lower; t iazolylaminoalkyl lower; lower alkoxy-lower alkylamino-lower alkyl; bis [lower alkoxy-lower alkyl} aminoalkyl the lower; N- (lower alkyl) -N- [lower alkoxy-lower alkyl] amino- (lower alkyl); hidroxialqui the inferior; alkylsulphonyloxy-lower alkyl; lower phenylalkyl which may have lower alkanoyl, amino, lower alkanoylamino, lower dialkylaminocarbonyl or nitro; lower alkoxyphenyl-lower alkylcarbonyl; alkanoylbenzoyl lower; lower benzoylalkyl which has lower alkyl, chloro or dialkylamino lower; lower benzoylalkyl which has halogen and lower alkyl; dihalobenzoi lalqui lower; dialqui lbenzoi lower alkyl lower alkyl; 3- f luorobenzoylalkyl lower; 3- (4- fluorobenzoyl) propyl; 4,4-ethylenedioxy-4- (4-fluorophenyl) butyl; piperazinylcarbonylalkyl lower alkyl which has cyclopentyl or halophenyl; (2-pyridyl) lower alkyl; (3-pyridyl) propyl; (3-pyridyl) lower alkynyl; imidazolylalkyl lower which may have lower alkyl; pyrazolyl lower alkyl which may have lower alkyl; thiomor folinylcarbonylalkyl lower; (3-azabicyclo [3.2.2] non-3-yl) carbonylalkyl lower; Other lower alkylcarbonyl, 1, 2, 3, 6-tetrahydropylaryl lower alkyl, 1, 2, 3, 6-tetrahydropyridyl lalkyne lower 1, 2, 3, 4-tet rahidroisoqui-nolyalkyl-lower alkyl, 4, 5, 6 , 7- Tetrahydro-thieno [3,2-c] pyridinyl-lower alkyl, saturated heterocyclic lower alkyl, saturated heterocyclic lower alkenyl, alkynyl. saturated heterocyclic lower, saturated heterocyclic lower aminoalkyl, heterocyclic saturated lower aminoalkynyl saturated heterocyclic lower aminoalkenyl [wherein "the saturated heterocyclic portion" is pyrrolidinyl, piperidyl, piperazinyl, hexamethyliminimino, morpholinyl, homomorum folinyl, thiomorvinyl or 3-azabyl- Cyclo [3.2.2] non-3yl], each of which may have 1 6 2 substituent or substituent or suitable substituents selected from the group consisting of lower cycloalkyl, lower alkanoyl, lower alkyl, mono (or di or tri) alkoalkyl lower, lower alkoxy, lower alkoxy-lower alkyl, halogen, phenyl, cyano, oxo and a bivalent group of the formula: O:

4. The compound of claim 3, wherein Y is lower alkylene, R1 is phenyl which may have 1 or 2 mono (or di or tri) lower haloalkyl, R 'is phenyl which may have 1 substituent or substituent or suitable substituents selected of the group consisting of lower alkyl, lower alkoxy, mono (or di or tri) lower haloalkyl and halogen, naphthyl or indolyl, R3 is hydrogen, and R4 is (2-pyridyl) lower alkyl; (3-pyridi 1) propyl; (3-pyridyl) lower alkynyl imidazolylalkyl lower alkyl which may have lower alkyl; pyrazolyl lower alkyl, which may have lower alkyl; lower pyridylalkylamino-lower alkyl; lower pyridylalkylamino-lower alkenyl; N- (lower alkyl) -N- [pyridylalkyl lower)] aminoalkyl lower; lower triazolylaminoalkyl; lower alkoxy-lower alkylamino-lower alkyl; bis [(lower alkoxy-lower alkyl) lower aminoalkyl; N- (lower alkyl) -N- [lower alkoxy-lower alkyl] -amino-lower alkyl; 1,2,3,6-tetrahydropyridylalkyl-lower; 1, 2, 3 6-tetrahydropyridylalkolinyl, 1,2,4,4-tetrahydroisoquinolyl-lower alkyl, or 4, 5, 6, 7-tet rahydro-thieno [3,2-c] pyridylalkyl

5. The compound of claim 3, wherein Y is lower alkylene R1 is phenyl which may have mono (or di or tri) haloalkyl or lower alkyl, R2 is phenyl which may have 1 or 2 substituents or substituents or substituents suitable selected from the group consisting of lower alkyl, lower alkoxy, mono (or di or triethyl) haloalkyl and halogen, naphthyl or indole, R3 is hydrogen, and R "is morpholino lower alkyl which may have 1 or 2 alkyl lower; homomorpholinyl lower alkyl; tiomorfol ini lalkyl *** lower; (hexamethyl-amino-amino) lower alkyl; (3- azabicyclo [3.2.2] non-3-yl) lower alkyl; piperazinylalkyl lower which may have phenyl or lower cycloalkyl; mor folinilalqueni the lower which may have 1 6 2 lower alkyl; lower morpholinylalkyl which may have 1 6 2 lower alkyl, lower alkoxy-lower alkyl or mono (or di or tri) lower haloalkyl; lower thiomor folinyl alkenyl; thiomor fol ini 1-lower alkynyl; lower pyrrolidinyl alkynyl which may have lower alkoxy-lower alkyl; lower piperazinylalkyl which may have lower cycloalkyl; mor fol inilaminoalqui the inferior; lower laminóalkenyl mor folini; mor fol inilaminoalquini the inferior; [spiro [indan-1, 4 '-piperidine] -l'-yl] lower alkyl; piperidylalkyl lower which has phenyl, lower alkoxy, lower alkanoyl, piperidyl or oxo; or piperidylalkyl lower which has phenyl and cyano.

6. The compound of claim 5, wherein Y is lower alkylene, R1 is phenyl which may have 1 or 2 mono (or di or tri) lower haloalkyl, is phenyl which may have substituent suitably substituents selected from the group it consists of lower alkyl, lower alkoxy, mono (or di or tri) lower haloalkyl and halogen, naphthyl or indolyl, R3 is hydrogen, and R4 is morpholinyl lower alkyl which may have 1 6 2 methyl; homomorpholinyl lower alkyl; tiomor folinilalqui the inferior; (hexamethyl-enimino) lower alkyl; (3-azabicyclo [3.2.2] non-3-yl) to the lower chyl; piperazinyl lower alkyl which has phenyl or cyclohexyl; mor folinyl-lower alkeyl, which may have 1 6 2 methyl; lower morpholinylalkyl which may have 1 or 2 methyl, methoxymethyl or fluoro etiol; tiomor folinilalqueni the inferior; thiomor folinyl-lower alkynyl; lower pyrrolidinyl alkynyl which may have methoxymethyl; piperazinyl-lower alkynyl which may have cycloexil; mor fol ini laminoalkyl lower; mor-folinylamino-lower alkenyl; lower vinyllaminoalkynyl; [spiro [indan-l, 4'-piperidine] -l'-yl] lower alkyl; piperidylalkyl lower which has phenyl, methoxy, acetyl, piperidyl or oxo; or piperidylalkyl lower which has phenyl and cyano.

7. The compound of claim 6, wherein Y is methylene, R1 is bis (trifluoromethyl) phenyl R2 is phenyl or naphthyl, each of which may have suitably substituent or substituent or substituents selected from the group consisting of methyl , methoxy, tri-fluoromethyl i and fluoro, or indolyl, R3 is hydrogen, and R4 is thiomorpholiniyl (C1-C4) alkyl; mor folin lalkenyl of (C2-C4) which may have 1 or 2 methyl; morpholinylalkyl (C2-C5) which may have 1 or 2 methyl, methoxymethyl or fluoromethyl; or mor folini laminoalkyl (C1-C4).

8. The compound of claim 7, which is selected from the group consisting of (1) (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (lH-indol-3-ylmethyl) - 4- (3-thiomorpholinopropyl) -piperazine, (2) (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -4- (4 -mor fol ino-2-butyl) -2- (2 naphthylmethyl) -piperazine (3) (2R) -4- (4-morpholino-2-butynyl) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) piperazine , (4) (2R) -l- [3,5-bis (tri-fluor-meth i-1) -benzoyl] -2- (3,4-dimethylbenzyl) -4- [3- (morpholine-aminoamino) propi-1] -piperazine and (5) (2R) -l- [3,5-bis (trifluoromethyl) benzoiiy -2- (3,4-dimethylbenzyl) -4- [(E) -4-morpholino-2-butenyl] -piperazine, or a pharmaceutically acceptable salt thereof.

9. A process for the preparation of a compound of the following general formula: wherein Y is a bond or lower alkylene, R1 is aryl, which may have a suitable substituent or substituents or substituents, R2 is aryl or indolyl each of which may have a suitable substituent or substituent or substituents, R3 is hydrogen or lower alkyl; R 4 is lower chloroalkenyl; lower chloroalkynyl; lower pyridylalkylamino-lower alkyl; pyridylalkylamino lower-alkene lower; N- (lower alkyl) -N- [pyridylalkyl] -amino-lower alkyl; triazolylaminoalkyl the lower; lower alkoxy-lower alkyloxy lower alkyl; lower bisfalcoxy-lower alkyl] lower aminoalkyl; N- (lower alkyl) -N- [lower alkoxy-lower alkyl] lower aminoalkyl; hydroxyalkyl lowerv; lower alkylsulphonyloxy-lower alkyl; lower phenylalkyl which may have lower alkanoyl, amino, lower alkanoylamino, lower dialkylaminocarbonyl or nitro; lower alkoxyphenyl-lower alkylcarbonyl; lower alkanoyl benzoyl; lower benzoylalkyl which has lower alkyl, chloro or dialkylamino lower; lower benzoylalkyl which has halogen and lower alkyl; dihalobenzoylalkyl lower; lower dialkylbenzoyl-lower alkyl; 3-fluorobenzoylalkyl lower; 3- (4-f luorobenzoyl) propyl; 4,4-ethylenedioxy-4- (4-fluorophenyl) butyl; piperazinylcarbonyl lower alkyl which has cyclopentyl or halophenyl; (2-pyridyl) lower alkyl; (3-pyridyl) propyl; (3-pyridyl) alkyne lower; imidazolylalkyl lower which may have lower alkyl; pyrazolyl lower alkyl which may have lower alkyl; thiomorpholine-nylcarbonylalkyl lower; (3-azabicyclo [3.2.2] non-3-i 1) carbonylalkyl lo lower; or thienyl-carbonylalkyl lower, 1, 2, 3, 6-tetrahydropyridine-lower alkyl, * 1, 2, 3, 6-tet rahydropyridy 1-lower alkynyl, 1, 2, 3, - tet rahidroisoqui-nolyalkyl-lower alkyl, 4, 5, 6, 7- tet rahidrot ieno [3, 2-c] pyridinyl-lower alkyl, saturated heterocyclic lower alkyl, saturated heterocyclic lower alkenyl, saturated heterocyclic lower alkynyl, lower alkyl "heterocyclic saturated, lower alkenyl heterocyclic saturated or lower alkynyl heter-β-cyclic saturated, each of which may have substituent or substituent or suitable substituents, or a salt thereof, which comprise (1) reacting a compound of the formula: or its reactive derivative in the imino group or a salt thereof with a compound of the formula: Wi-R4 or a salt thereof to provide a compound of the formula: or a salt thereof, in the above formulas, Y, R1, R2, R3 and R4 are each as defined in the above, and Wa is a leaving group, or (2) reacting a compound of the formula or its reactive derivative in the imino group or a salt thereof with a compound of the formula: or its reactive derivative in the carboxy group or a salt thereof to provide a compound of the formula: or a salt thereof, in the above formulas, - * - 5"* Y, R1, R2 and R3 are each as defined above, and R5 is lower alkoxyphenyl-lower alkyl or lower alkanoylphenol, or (3) ) reacting a compound of the formula: or its reactive derivative in the carboxy group or a salt thereof with a compound of the formula H-R6 or a salt thereof to provide a compound of the formula: or a salt thereof, in the above formulas, Y, R1, -. are each as defined above, X is lower alkylene, and R 'is piperazinyl which has cyclopentyl or halopentyl; or thiomorpholini lo, or (4) subjecting a compound of the formula: or a salt thereof to an acylation reaction to provide a compound of the formula: or a salt thereof, in the above formulas, X, Y, R1, R2 and R3 are each as defined above, and R7 is acyloxy, or (5) reacting a compound of the formula: a salt thereof with a compound of the formula H-R ' or a salt thereof to provide a compound of the formula: or a salt thereof, in the above formulas, X, Y, * R1, R2 and R3 are each as defined above, and R8 is lower pyridylalkylamino; N- (lower alkyl) -N- [pyridylalkyl] amino; triazolyl, morpholinoamino; lower alkoxy-lower alkylamino; bis [lower alkoxy-lower alkyl] amino; N- (lower alkyl) -N-lower alkoxy-lower alkyl] amino; imidazolyl; pyrazolyl; or 1, 2, 3, 6-tetrahydropyridyl, 1,2,3,4-tetrahydroisoquinolyl, 4, 5, 6, 7-tetrahydrothieno [3,2-c] pyridinyl or saturated heterocyclic, each of which may have a substituent or substituent or suitable substituents, or (6) subjecting a compound of the formula: or a salt thereof to a reduction reaction to provide a compound of the formula: or a salt thereof, in the above formulas, X, Y, R1, R2 and R3 are each as defined in the foregoing, or (7) reacting a compound of the formula: or a salt thereof with a compound of the formula: W2-R9 or a salt thereof to provide a compound of the formula: or a salt thereof, in the above formulas, X, Y, R1, R2 and R3 are each as defined in the above, W2 is a leaving group, and R9 is lower alkanoyl.

10. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acetable carriers.

11. A use of a compound of claim 1 as a medicament.

12. A method for treating or preventing diseases mediated by Tachykinin which comprises administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof to humans or animals.

13. A compound of claim 1 for use as a medicament.

14. . The use of a compound of claim 1 for the manufacture of a medicament for treating or preventing diseases mediated by Tachykinin.