MXPA99011778A

MXPA99011778A - Aroyl-piperazine derivatives, their preparation and their use as tachykinin antagonists

Info

Publication number: MXPA99011778A
Application number: MXPA/A/1999/011778A
Authority: MX
Inventors: Sasaki Hiroshi; Eikyu Yoshiteru; Miyake Hiroshi; Take Kazuhiko; Shigenaga Shinji; Azami Hidenori; Nakai Kazuo; Oshida Junya; Manabe Takashi
Original assignee: Astellas Pharma Inc
Priority date: 1997-06-17
Filing date: 1999-12-15
Publication date: 2000-06-01

Abstract

This invention relates to piperazine derivatives of formula (I), wherein Y is bond or lower alkylene, R1 is aryl which may have substituent(s), R2 is aryl or indolyl, each of which may have substituent(s), R3 is hydrogen or lower alkyl, and R4 is as defined in the description, and its pharmaceutically acceptable salt, to processes for preparation thereof, to pharmaceutical composition comprising the same, and to a use of the same for treating or preventing Tachykinin-mediated diseases in human beings or animals.

Description

. , - i PIPERAZINE DERIVATIVES TECHNICAL FIELD The present invention relates to novel piperazine derivatives and a salt thereof. More particularly, it relates to novel piperazine derivatives and a salt thereof which have pharmacological activities such as antagonism to tachykinin, especially antagonism to substance P, antagonism to neurotoin A, antagonism to neurotoxin B and the like, to a process for preparation thereof, to a pharmaceutical composition comprising the same, and to the use thereof as a medicament. Accordingly, an object of the present invention is to provide novel and useful piperazine derivatives, and salts thereof, which have pharmacological activities such as tachykinin antagonism, especially substance P antagonism, antagonism to neurokinin A , antagonism to neurocimna B and the like. Another object of the present invention is to provide a process for the preparation of such piperazine derivatives and salts thereof. It is a further object of the present invention to provide a pharmaceutical composition comprising, as an active ingredient, such piperazine derivatives and a pharmaceutically acceptable salt thereof. A further objective of the present invention is to provide a use of piperazine derivatives or a pharmaceutically acceptable salt thereof as tachykinin antagonists, especially substance P antagonists, neurokinin A antagonists or neurokinin B antagonists, useful for the treatment or prevention of tachykinin-mediated diseases, for example, respiratory diseases such as asthma, bronchitis, rhinitis, cough, expectoration and the like; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis and the like; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria and other eczematoid dermatitis, and the like; inflammatory diseases such as rheumatoid arthritis, osteoarthritis and the like; pain or discomfort (eg migraine.) headache, tooth pain, cancerous pain, pain in the back, etc.,); and similar in humans or animals. ~ Some piperazine derivatives having pharmaceutical activities such as tachykinin antagonism have been known and described in EP 0655442 Al and WO 97/22597 Al. 7 DESCRIPTION OF THE INVENTION The objective compound of the present invention can be represented by the following general formula (I): wherein Y is a bond or lower alkylene, R1 is aryl which may have substituent or substituents R2 is aryl or indolyl, each of which may have substituent or substituents, R3 is hydrogen or lower alkyl, R4 is pyridylalkyl (lower) lower aminoalkynyl; N- (lower alkyl) -N- [pyridylalkyl-lower] amino-lower alkyl; hydroxyalkoxy (lower) lower alkyl; lower alkoxy lower alkoxy lower alkyl, lower phenylalkyl which has lower hydroxyalkyl or lower morpholinylalkyl; lower aralkoxycarbonyl: (2-pyridyl) lower alkyl which may have 1 to 3 substituents or substituents which are selected from the group consisting of lower alkyl, lower alkoxy, lower alkoxycarbonyl, mono (or di or tri) lower haloalkyl, and halogen; (3-pyridyl) ropyl which may have lower alkoxy or amino; (3-pyridyl) butyl which may have lower alkoxy or amino; lower pyridylalkenyl which may have lower alkoxy or amino; (2-pyridyl) lower alkynyl which may have 1 to 3 substituent or substituents selected from the group consisting of lower alkyl, lower alkoxy, lower alkoxycarbonyl, mono (or di or tri) lower haloalkyl, and halogen; (3-pyridyl) lower alkynyl which may have lower alkoxy or amino; pyridyl, thiazolyl, imidazolyl or pyrazolyl, each of which may have substituents or substituents; imidazolylalkyl lower which may have 1 or 2 substituents or substituents which are selected from: group consisting of lower alkyl, lower alkynyl, lower aralkyl, lower pyridylalkyl, - mono (or di or tri) lower alkoalkyl and halogen; The pyrazolyl lower alkyl which may have lower hydroxyalkyl, lower carboxyalkyl, 7-lower alkoxycarbonylalkyl, morpholinyl-lower alkyl or morphonylcarbonylalkyl-lower; * - thiazolylalkyl lower which may have lower alkyl; piperidyl-lower alkyl which may have lower hydroxyalkyl or lower alkoxy; E-morpholinyl lower alkyl which may have 1 or 2 -P- substituents which are selected from the group of ethyl, t-hydroxyalkyl, lower haloalkyl and lower alkoxyalkyl, - morpholinyl lower alkyl which has lower alkyl and lower alkoxy lower alkyl, - Ia- ^ (3,5-dimethylmorpholinyl) lower alkyl; = Lower morpholinoalkenyl which may have alkyl "__. lower or lower alkoxy) lower alkyl; 7 (2- or 3-morpholinyl) lower alkenyl which may J = have lower alkoxycarbonyl; - * lower pyrrolidinyl alkynyl which may have lower alkoxy lower alkoxy; "lower morpholinylalkyl which may have 1 or 2 - substituents which are selected from the group consisting of ethyl, propyl, isopropyl, isobutyl, z-lower-pyrrocycloalkyl, lower alkoxy, lower alkyl, lower hydroxyalkyl, carboxyalkyl lower t di (lower alkyl) carbamoyl, alkoxycarbonyl - lower and lower haloalkyl; lower morpholinylquinoline which has methyl and lower alkoxy; "(dimethylmorpholino) lower alkynyl, lower homomorpholinylalkynyl which has halogen; (morpholinylamino) ropyl which may have lower alkanoyl; lower thiomorpholinylalkynyl which may have substituent or substituents; homomorpholinylamino lower alkyl; - lower thiomorpholinyl aminealkyl; or saturated lower heterocyclic iminoalkyl, saturated heterocyclic carbamoyl lower alkyl or heterocyclic alkoxy lower saturated lower alkyl, each of which may have substituent or substituents, condition that when it is 2- [N-methyl-N- (3-pyridylmethyl) amino] ] ethyl, 3- (3-pyridyl) ropyl, ~~ 3- (3-pyridyl) -2-propynyl, n 4- [(2-methoxymethyl) pyrrolidino] -2-butynyl, T 4-thiomorpholino-2-butynyl , "3- (morpholinoamino) propyl," - 4- (morpholino-2-butenyl, 4-morpholino-2-butinyl, or 4- (3,3-dimethylmorpholino) -2-butinyl, then R1 is not 3, 5-bis (trifluoromethyl) phenyl. It should be noted that the objective compound (I) may include one or more stereoisomers due to the asymmetric carbon_ atoms or double bonds, and that all such isomers and mixtures of they are included within the scope of the present invention. It should be noted that the isomerization or rearrangement of the objective compound (I) can be to produce due to the effect of light ^ acid, base or the like, and the compound obtained as the result of such isomerization or rearrangement is also included within. of the scope of the present invention It should also be noted that the solvated form of the compound (I) (for example hydrate, etc.) and any form of the crystal of the compound (I) are included within the scope of the present invention. In accordance with the present invention, the objective compound (I) or a salt thereof can be prepared by the process which is illustrated in the following schemes.

Process 1 (IV) (II) or a salt thereof (I) or its reactive derivative or a salt thereof in the imino group or a s ~ a, l thereof Process 2 - (la) (Ib) or a s to the same or a salt of the same Process 3 ~ (III) (le) or its reactive reagent or a salt thereof in the carboxy group or a salt thereof Process 4 : (vi) (Id) or a salt thereof or a salt thereof Process 5 - (VIII) (le) or a salt thereof or a salt thereof Process 6 or a salt of the same R (X) (If) or a salt thereof or a salt thereof wherein Y, R1, R2, R3 and R4 are each as defined above, X1 # X2 and X3 are each lower alkylene, Z1 and Z3 are each lower alkynylene, Z2 is lower alkenylene, Rs is 2 -pyridyl which may have 1 to 3 substituents which are selected from the group consisting of lower alkyl, lower alkoxy, lower alkoxycarbonyl, mono (or di or tri) lower haloalkyl, and halogen; or 3 -pyridyl which may have lower alkoxy or amino, R6 is saturated heterocyclic which may have substituent or substituents, R7 is lower pyridylalkylaryl; - N- (lower alkyl) -N- [pyridylalkyl] amino; 1-imidazolyl which may have 1 or 2 substituents or substituents which are selected from the alkyl group - lower, lower alkynyl, lower aralkyl, lower pyridylalkyl, mono (or di or tri) alkoalkyl * lower and halogen; The l-pyrazolyl which may have hydroxyalkyl ; lower t, lower carboxyalkyl, lower coxycarbonylalkyl, lower morpholinylalkyl or morpholinylcarbonylalkyl TB, inferior; piperidino which may have lower hydroxyalkyl or lower alkoxy; - morpholino which has 1 or 2 substituents or substituents which are selected from the group consisting of ethyl, hydroxyalkyl, lower haloalkyl and lower alkoxy lower alkyl; 7 ~ morpholino which has lower alkyl and lower alkoxy lower alkyl; 3, 5-dimethyl-morpholino; morpholinylamino which may have lower alkanoyl; homomorpholinylamino; or r ~ thiomorpholinyl amino, R8 is morpholino which may have lower alkyl or lower alkoxy lower alkyl, R9"is pyrrolidino which may have lower alkoxy lower alkyl; morpholino which may have one or two substituents 7 which are selected from the group consisting of ethyl, propyl, isopropyl, "isobutyl, spirocycloalkyl, lower, lower alkoxy, lower alkyl, lower hydroxyalkyl, lower carboxyalkyl, lower di (lower alkyl) carbamoyl, lower alkoxycarbonyl and lower haloalkyl. morpholino which has methyl and lower alkoxy; 5 dimethylmorpholino; or homomorpholino which has - halogen, Wx, W2, _3 and W4 are each a leaving group X With respect to the initial compounds (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) and (X), some of them are novel and can be prepared by the procedures described in the Preparations and Examples mentioned later or in similar ways thereto Suitable salts of the starting and target compounds are conventional, non-toxic and pharmaceutically acceptable salts and include an acid addition salt such as an organic acid salt (e.g. acetate, trifluoroacetate, f umarate, maleate, tartrate, methanesulfonate, benzenesulfonate, formate, toluenesulfonate, etc.,), an inorganic acid salt (for example, hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.), or a. salt with an amino acid (eg arginine, aspartic acid, glutamic acid, etc.,), or a metal salt such as an alkali metal salt (eg, sodium salt, potassium salt, etc.), and a alkaline earth metal salt (for example calcium salt, magnesium salt, etc.), an ammonium salt, an organic base salt (for example trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, salt of dicyclohexylamine, N, N'-dibenzylethylenediamine salt, etc.,) or the like. Z- In the above and below descriptions of the present specification, suitable examples and illustrations of the "various definitions which the present invention attempts to include within the scope thereof are explained in detail as follows.

The term "lower" is understood to mean 1 to 6, preferably from 1 to 4 carbon atoms, unless otherwise indicated.The term "lower alkylene" suitable may include linear or branched having 1 to 6 carbon atoms, such as methylene, ethylene, trimethylene, propylene, tetramethylene, methylmethylene, methyltrimethylene, hexamethylene and the like, in which the preferred are methylene, ethylene, trimethylene or methymethylene The appropriate term "lower alkenylene" can include linear or branched having 2 to 6 carbon atoms such as vinylene, propenylene, 1- (or 2-) butenylene, 1- (or 2- or 3-) pentenylene, 1- (or 2- or 3-) hexenylene, ilvinileno, etilvinileno, 1- (or 2- or 3-) methylpropenileno, 1- (or 2- or 3 -) - ethylpr penileno, 1- (or 2- or 3- or 4-) methyl-1- ( or 2-) butenylene and the like. The term "lower alkynylene" suitable may include one having 2 to 6 carbon atoms, such as ethynylene, propynylene, butynylene and the like, in which the preferred is propynylene or butynylene. The term "halogen" suitable and the portion "halogen" in the terms "mono (or di or tri) haloalkyl lower", "mono (or di or tri) haloalkyl of C1-C4", etc., may include fluorine , chlorine, bromine and iodine.

- The suitable "lower alkyl" and the "lower alkyl" portion in the terms "lower pyridylalkyl (lower) aminoalkynyl", "N- (lower alkyl) -N- (pyridylalkyl) lower aminoalkyl", etc., may include one linear or branched having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl and the like, preferably one having 1 to 5 carbon atoms. The "lower alkenyl" portion suitable in the terms "lower 3-pyridylalkenyl" "lower saturated heterocyclic alkenyl", etc., may include vinyl, 1- (or 2-) propenyl, 1- (or 2-io-3) butenyl , 1- (or 2- or 3- or 4-) -pentenyl, 1- (or 2- or 3-or 4- or 5-) -butyl, methylvinyl, ethylvinyl, 1- (or 2- or 3-methyl) l- (or 2-propenyl, 1- (or 2- or 3-) -ethyl-1- (or 2-) propenyl, 1- (or 2- or 3- or 4-) methyl-1- (or 2) or 3-) -butenyl, and the like, and in which the most preferable example may be C2-C4 alkenyl, the "lower alkynyl" portion suitable in the terms "pyridylalkyl (lower) aminoalkynyl lower", "(2) - pyridyl) - lower alkynyl, etc., may include ethinyl, 1-propynyl, propargyl, 1-methylpropargyl, 1- (or 2- or 3-) butynyl, 1- (or 3-) methyl-2-butynyl, 1- (or 3-) ethyl-2-butynyl, 1- (or 3 -) - propyl-2-butynyl, 1- (or 3-) isopropyl-2-butynyl, 1- (or 2- or 3- or 4-) pentinyl, 1- (or 2- or 3- or 4- or 5-) hexinyl and the like, in which the most preferable example may be C2-C3 alkynyl. * > Suitable "aryl" may include phenyl, naphthyl and the like, in which the preferred is C3-C10 aryl and the most preferred is phenyl or naphthyl. Suitable "lower alkanoyl" and the "lower alkanoyl" portion in the term "lower alkoxy- (lower) lower alkyl" may include formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl , hexanoyl and the like. Suitable "lower alkoxy" and the "lower alkoxy" portion in the terms -hydroxyalkoxy (lower) lower alkyl "," lower alkoxy (lower) alkoxy, lower alkyl ", etc., may include methoxy, ethoxy_, propoxy, isopropoxy , butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like The suitable "saturated heterocyclic" and the "saturated heterocyclic" in the terms "heterocyclicimino saturated lower alkyl" "saturated heterocyclic aminocarbonylalkyl", etc., may include a 3- to 8-membered saturated heteromonocyclic group (more preferably from 5 to 7 members) containing 1 to 4 atoms of nitrogen, for example, pyrrolidinyl, imidazolidimyl, piperidyl, piperazinyl, hexamethyleneimino, etc .; ? _ the 3- to 8-membered heteromonocyclic (more preferably 5 or 6 membered saturated) group containing 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms, eg, morpholinyl, homomorpholinyl, sidnonyl, etc., the heteromonocyclic group from 3 to 8 members (more preferably 5 or 6 members) saturated containing 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolidinyl, thiomorpholinyl, etc., a saturated heterobicyclic group of the formula: (where u, m and n are each an integer from 1 to 6) a saturated heterobicyclic group of the formula: (where q, r, s and t are each an integer from 1 to 6), - and the like. = _ The "suitable" substituent in the terms aryl which may have substituent or substituents "," aryl or indolyl, each of which may have substituent or substituents "," pyridyl, thiazolyl, imidazolyl or pyrazolyl, each of which may have substituent or substituents "and" saturated lower heterocycliciminoalkyl, saturated lower heterocycliccarbonylalkyl or heterocyclylalkoxy (lower) saturated lower alkyl, each of which may have substituent or substituents "may include lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, terbutyl, pentyl, neopentyl, terpentyl, hexyl, etc.,), lower cycloalkyl (by * example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.,), lower alkylenedioxy (for example methylenedioxy, ethylenedioxy, propylenedioxy, etc. .,), lower alkoxy (for example methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, terbutoxy, pentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, etc., lower alkoxy) lower alkoxy (for example methoxymethyl, ethoxymethyl, 1-methoxyethyl, 2-methoxyethyl) , 1-ethoxyethyl, 2-ethoxyethyl, etc.), lower alkanoyl (for example formyl, acetyl, propionyl, butyryl, isobutyryl, etc.), lower alkoxycarbonyl (for example methoxycarbonyl, ethoxycarbonyl, propylcarbonyl, isopropylcarbonyl, etc.) , lower alkenztl (for example vinyl, 1-propenyl, allyl, 1-methylane, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, etc.,), lower alkynyl (for example ethynyl "l-propynyl, propargyl, 1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, I or 2 or 3 or 4 or 5- hexinyl, * -a, etc.,), mono (or di or tri) lower alkoalkyl (for example fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, 1 or 2-fluoroethyl, 1 or 2-bromoethyl) , 1 or 2-chloroethyl, 1,1-difluoroethyl, 2, 2-difluoroethyl, etc.), halogen (for example chlorine, bromine, fluorine and iodine), carboxy, protected carboxy, hydroxy, protected hydroxy, aryl ( for example phenyl, naphthyl, etc.,), lower aralkyl such as phenylalkyl lower (for example benzyl, phenethyl, phenylpropyl, etc.,), lower carboxyalkyl wherein the lower alkyl portion may refer to those exemplified above, protected lower carboxyalkyl in where the lower alkyl portion can be referred to those exemplified above, nitro, amino, protected amino, lower alkylamino (for example methylamino, ethylamino, isopropylamino, etc.,), dialkylamino lower (for example dimethylamino, diethylamino, diisopropylammo, ethylmethyl amino, sodium propylmethylamino, etc.), hydroxy, lower hydroxyalkyl (eg hydroxymethyl, hydroxyethyl, etc.), protected lower hydroxyalkyl, acyl, cyano, oxo, mercapto, lower alkylthio (eg methylthio, ethylthiopropylthio, isopropylthio, butylthio) , etc.,), lower alkylsulfinyl (for example methylsulfinyl, ethylsulphyl, propylsulphyl, isopropylsulphyl, butylsulfinyl, etc.,) imino, morpholinyl (for example 2-morpholinyl, 3-morpholinyl, morpholino), a divalent group of the formula: lower carboxyalkyl (e.g. carboxymethyl, carboxyethyl, carboxypropyl, etc.,), lower alkoxycarbonyl (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pent i 1 oxycarbonyl or, neopentyl oxy oxycarbonyl, ter- pentyloxycarbonyl, hexyloxycarbonyl, etc.,), lower spirocycloalkyl (eg, spirocyclopropyl, spirocyclobutyl, spirocyclopentyl, etc.,), lower alkylaminocarbonylalkyl (eg, benzyl oxocarbonyl, benzoxycarbonylethyl, benzyloxycarbonylpropyl, etc., ), lower pyridylalkyl (for example pyridylmethyl, pyridylethyl, etc.), l = _ carbamoyl, lower alkylcarbamoyl (for example, methylcarbamoyl, ethylcarbamoyl, etc.), di (lower alkyl) carbamoyl (for example dimethylcarbamoyl, diethylcarbamoyl, etc.). ,) and similar. "The suitable" leaving group "may include lower alkoxy (for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, etc.,), aryloxy (for example phenoxy, naphthoxy, etc.), an acid residue or the like. The "suitable acid residue" can be halogen (for example ** "chlorine, bromine, iodine, etc.), sulfonyloxy (for example methanesulfonyloxy, phenylsulphonyloxy, mesitylenesulfonyloxy, toluensulphonyloxy, etc.). , or similar. The preferred embodiments of the subject compound (I) are the following: ~ Y is lower alkylene (more preferably "C 1 -C 6 alkylene, more preferably methylene); R 1 - is aryl (more preferably C 6 -C 10 aryl / more preferably phenyl) which may have 1 to 3 (more preferably 1 or 2, more preferably 2) substituent or substituents [more preferably a - substituent selected from the group consisting of mono (or di or tri) lower haloalkyl (more preferably lower trihaloalkyl, more preferably trifluoromethyl), halogen (more preferably chloro), lower alkylamino (more preferably alkyl) less than CL-OJ, more preferably methylamino), dialkylamino lower (plus 7 preferably dialkylamino of CL-, more preferably- dimethylamino) and nitro], -R2 is aryl (more preferably C3-C10 aryl, more preferably phenyl or naphthyl) or indolyl, each = __ of which may have 1 to 3 (more preferably 1 z_ or 2) substituent or substituents [more preferably, "= the substituent is selected from the group consisting of of lower alkyl (more preferably C 1 -C 6 alkyl, more preferably methyl), mono (or di or tri) haloalkyl (lower) (more preferably mono (or di or tri) haloalkyl of C, .- ^, more preferably trifluoromethyl), lower alkylenedioxy (more preferably C 1 alkylenedioxy, most preferably methylenedioxy or ethylenedioxy), hydroxy, lower hydroxyalkyl (more preferably hydroxyalkyl more preferably hydroxymethyl), lower alkoxy (more preferably C 1 -C 6 alkoxy), more preferably methoxy), lower alkylamino, (more preferably, CL-CT alkylamino, most preferably methylamino) and lower dialkylamino and lower dialkylamino (more preferably C 1 -C 4 dialkylamino, more preferably dimethylamino)]; R3 is hydrogen; and R 4 is pyridylalkyl (lower) aminoalkynyl lower (more preferably pyridylalkyl (C 1 -C 4) aminoalkynyl most preferably 4 - [(3-pyridylmethyl) amino] -2-bünynyl), - N- (lower alkyl) -N- lower pyridylalkyl] lower aminoalkyl [more preferably N- (LC-N- alkyl- [C 1 -C 4 aminoalkyl pyridylalkyl, more preferably 2- (N-methyl-N- (3-pyridylmethyl) -amino]] ethyl); hydroxyalkoxy (lower) lower alkyl (more preferably hydroxyalkoxy (Ci-C Ct-C4 alkyl, most preferably hydroxyethoxy) ethyl); lower alkoxy (lower) lower alkoxy lower alkyl (more preferably alkanoyl (C- ^ j) alkoxy (C ^ C alkyl of CL-QJ, more preferably for il methoxyethyl); phenylalkyl lower (more preferably phenylalkyl of Ci-, more preferably preferable benzyl) which has lower hydroxyalkyl (more preferably CLC hydroxyalkyl, most preferably hydroxymethyl) or lower morpholinylalkyl (more preferably morpholinylCLC alkyl and most preferably orpholinylmethyl) [more preferably a- (hydroxymethyl) -benzyl) or o- (morpholinomethyl) benzyl], lower aralkoxycarbonyl (more preferably (C3-C10 aryl) C ^ -C ^ alkoxycarbonyl, more preferably phenylmethoxycarbonyl); (2-pyridyl) lower alkyl (more preferably ( 2-pyridyl) -CLd alkyl, more preferably (2-pyridyl) propyl or (2-pyridyl) butyl) which may have 1 to 3 (most preferably 1 or 2) substituent or substituents which are selected from the group consisting of lower alkyl (more preferably Cx-C4 alkyl, more preferably methyl), lower alkoxy "(more preferably C ± -C4 alkoxy, much more preferably methoxy), lower alkoxycarbonyl (more preferably C 1 -C 4 alkoxycarbonyl, much more preferably methoxycarbonyl), mono (or di or tri) lower haloalkyl (more preferably trihaloalkyl of C-L-C ^ more preferably trifluoromethyl) and halogen (more preferably fluorine)); (3-pyridyl) propyl (more preferably 3- (3-pyridyl) propyl) which may have lower alkoxy) more preferably Cx-C4 alkoxy, more preferably methoxy); (3-pyridyl) butyl (more preferably 4- (3-pyridyl) util; lower pyridylalkenyl (more preferably pyridylalkenyl CL-, much more preferably 3- (3-pyridyl) -2- propenyl), - (2-pyridyl) lower alkynyl (more preferably (2-pyridyl) -alkynyl of C2-C4, and more preferably 3- (2-pyridyl) -2-propynyl or 4- (2-pyridyl) -3-butynyl) which may have 1 to 3 (from most preferable 1 or 2) substituent or substituents that are selected from the group consisting of lower alkyl (more preferably C 1 -C 4 alkyl, and most preferably methyl), lower alkoxy (more preferably CL-alkoxy, much more preferably methoxy), lower alkoxycarbonyl (most preferably alkoxycarbonyl), -C, much more preferably methoxycarbonyl), mono (or di or tri) lower haloalkyl (more preferably "_ trihaloalkyl of Cx-C4, more preferably trifluoromethyl) and halogen (more preferably fluorine); (3-pyridyl) lower alkynyl (more preferably (C2-C4) 3- (3-pyridyl) alkynyl, more preferably 3- "" "" (3-pyridyl) -2-propynyl or 4- (3-pyridyl) -3-butynyl) which may have lower alkoxy (more preferably Cx-C4 alkoxy, much more = preferably methoxy) or amino; pyridyl, thiazolyl, imidazolyl or pyrazolyl, each of which may have 1 to 3 (more preferably 1 j- or 2) substituent or substituents [more preferably the substituent is selected from the group consisting of lower alkyl (more preferably Cx-C4 alkyl, much more preferably methyl or isopropyl), lower aralkyl (more preferably phenylalkyl of Cx-C4, more preferably benzyl) and pyridylalkyl lower (from ~ 7 most preferably pyridylalkyl of C -.- C4, so More preferable is pyridylmethyl)], -imidazolylalkyl (more preferably imidazolylalkyl-C1-C4, most preferably 3- (lH-imidazol-4-yl) -propyl) which may have 1 or 2 substituents or substituents which are selected from the group consisting of lower alkyl (more preferably Cx-C4 alkyl, more preferably methyl or isopropyl), lower alkynyl (more preferably C2-C3 alkynyl, more preferably propargyl), lower aralkyl (more preferably phenyl C 1 -C 4 alkyl, more preferably benzyl), lower pyridylalkyl (more preferably C 1 -C 4 pyridylalkyl, more preferably pyridylmethyl), mono (or di or tri) lower haloalkyl (so more preferable trihaloalkyl of Cx-C4), more preferably trifluoromethyl) and halogen (more preferably fluorine); pyrazolyl-lower alkyl (more preferably pyrazolyl-C 1 -C 4 -alkyl most preferably (1H-pyrazol-4-yl) methyl or 3- (1H-pyrazol-1-yl) -propyl) which may have lower hydroxyalkyl (more preferably hydroxyalkyl) of Cx-C4), more preferably 2-hydroxyethyl), lower carboxyalkyl (more preferably carboxyalkyl of C ^ Cj, much more preferably carboxymethyl), lower alkoxycarbonylalkyl (more preferably alkoxy (CLC carbonylalkyl of C ^ -d , more preferably terbutoxycarbonylmethyl), morpholinylalkyl (more preferably morpholinylalkyl of d ^ d, more preferably 2-morpholinoethyl or morpholinylcarbonylalkyl (lower) (more preferably morpholinylcarbonylalkyl) C-C, much more preferably morpholinocarbonylmethyl) '; thiazolylalkyl lower (more preferably thiazolylalkyl of dd, much more preferably 4-thiazolylmethyl) which may have lower alkyl (more preferably d-C4 alkyl, much more preferably methyl, -piperidylalkyl lower (so more preferable piperidylalkyl of C ± -C, much more preferably piperidylethyl) which may have lower hydroxyalkyl (more preferably hydroxyalkyl of Cx-C4, much more preferably hydroxymethyl) or lower alkoxy (more preferably alkoxy of Cx-C4, much more preferably ethoxy); morpholinyl-lower alkyl (more preferably morpholinylalkyl-Cx-C4, much more preferably morpholinylethyl or morpholinylpropyl) which has 1 or 2 substituents that are selected from the group consisting of ethyl , lower hydroxyalkyl (more preferably Cx-C4 hydroxyalkyl, much more preferably hydroxymethyl), haloalkyl ^ lower (more preferably haloalkyl of Cx-C4, much more preferably fluoromethyl) and _, lower alkoxy lower alkyl (more preferably (C x C 4) alkoxy C 1 -C 4 alkyl, more preferably methoxymethyl); : morpholinyl lower alkyl (more preferably morpholinyl alkyl of Cx-C4, much more preferably morpholinoethyl or morpholinopropyl) which has lower alkyl (more preferably Cx-C4 alkyl, much more preferably methyl) and lower alkoxy lower alkyl (more preferably CX-C4 alkoxy) CX alkyl -C4, much more preferably methoxymethyl; (3,5-dimethylmorpholino) lower alkyl (more preferably "3, 5-dimethylmorpholino) Cx-C4 alkyl, much more preferably (3, 5- di-ethylmorpholino) ethyl); _- lower morpholinoalkenyl (most preferably morpholinoalkenyl of C2-C4, much more so "" preferable 4-morpholino-2-butenyl) which may have a lower alkyl (more preferably C 1 -C 4 alkyl, much more preferably isopropyl or lower alkoxy) lower alkyl (more preferably C 1 -C 4 alkoxy C 1 -C 4 alkyl, more preferably methoxymethyl) (2- or 3-morpholinyl) lower alkenyl (more preferably (2- or 3-morpholinyl) alkenyl of C2-C4, much more preferably 3- (2- or 3-morpholinyl) -2-propenyl) which may have lower alkoxycarbonyl (more preferably Cx-C4 alkoxycarbonyl, much more preferably terbutoxycarbonyl); lower pyrrolidinyl alkynyl (most preferably C2-C4 pyrrolidinylalkyl, more preferably 4-pyrrolidinyl-2-butynyl) which may have lower alkoxy lower alkyl (more preferably C2-4) alkoxy; C4, much more preferably methoxymethyl); lower morpholinylalkenyl (more preferably C2-C4 morpholinylkynyl, much more preferably 4-morpholino-2-butynyl or 3- (3-morpholinyl) -2-propynyl) which may have 1 or 2 substituents which are selected from the a group consisting of ethyl, propyl, isopropyl, isobutyl, lower spirocycloalkyl (more preferably spirocycloalkyl of C3-C6, more preferably spirocyclopropyl), lower alkoxy, lower alkyl (more preferably lower alkoxy (CX-C4) alkyl) lower, most preferably methoxymethyl or ethoxymethyl), lower hydroxyalkyl (more preferably Cx-C4 hydroxyalkyl, much more preferably hydroxymethyl), lower carboxyalkyl (more preferably carboxykyl of Cx-C4, much more preferably plus preferably carboxymethyl), dialkylcarbamoyl (lower) = -. (more preferably dialkylcarbamoyl of Cx-C4, much more preferably dimethylcarbamoyl), - lower alkoxycarbonyl (more preferably Cx-C4 alkoxycarbonyl, much more preferably ethoxycarbonyl) and lower haloalkyl (more preferably ^ = - preferably Cx-C4 haloalkyl, much more preferably fluoromethyl); morpholinyl-lower alkynyl (more preferably C2-C4 morpholinylkynylquinyl, more preferably ^ 4-morpholinyl-2-butynyl) which has methyl and lower alkoxy lower alkyl (more preferably C 1 -C 4) alkoxy C 1 -C 4 alkyl, more preferably methoxymethyl), lower alkyl (dimethylmorpholino) alkynyl (more preferably (dimethylmorpholino) alkynyl of C 2 -C4, de = __ more preferable 4- (3, 3-dimethylmorpholino) -2-butinyl, 4- (2,6-dimethylmorpholino) -2-butinyl); ^ homomorpholinylalkylquinyl (more preferably C2-C4 homomorpholthylalkynyl / most preferably 4-homomorpholinyl-2-butinyl) which may have halogen (more preferably fluorine), -morpholinyl aminepropyl (more preferably 3-morpholinoamino) propyl) which may have lower alkanoyl (more preferably Cx-C4 alkanoyl, more preferably formyl); lower thiomorpholinylalkynyl (more preferably C2-C4 thiomorpholinylalkynyl, much more preferably 4-thiomorpholino-2-butynyl); homomorpholinylamino-lower alkyl (more preferably homomorpholinylaminoalkyl of Cx-C4, more preferably homomorpholinyl-aminopropyl), -thiomorpholinylamino-lower alkyl (more preferably thiomorpholino-aminoalkyl of Cx-C4, most preferably thiomorpholino-aminopropyl); or saturated lower heterocycliciminoalkyl (more preferably saturated Cx-C4 iminoalkyl heterocyclic, more preferably saturated iminoethyl heterocyclic), saturated lower heterocycliccarbonylalkyl (more preferably saturated Cx-C4 heterocycliccarbonylalkyl, more preferably saturated aminocarbonylmethyl heterocyclic) or heterocyclic alkoxy (lower) saturated lower alkyl (more preferably heterocycloalkoxy (Cx-C4) saturated Cx-C4 alkyl, more preferably saturated heterocyclic ethoxyethyl); (wherein the "saturated heterocyclic" portion is saturated with 3 to 8 members (most preferably 5 to 7 members) of a heteromonocyclic group containing 1 to 4 (most preferably 1 or 2) nitrogen atoms (so more preferable pyrrolidinyl, piperidinyl or piperazinyl), a 3- to 8-membered saturated heteromonocyclic group (more preferably 5 to 7 members) containing 1 or 2 (most preferably 1) oxygen atom or atoms and 1 to 3 (more preferably 1) nitrogen atom (s) ~~ (most preferably morpholyl or homomorpholinyl); a 3- to 8-membered heteromonocyclic group (more preferably 5 or 6-membered saturated (containing 1 or 2 ( more preferably 1 sulfur atom or atoms and 1 to 3 (most preferably 1) nitrogen atom (s) (most preferably thiomorpholinyl), or a saturated heterocyclic group of the formula (where q, r, s and t are each as defined in the above) t (more preferably 3-azabicyclo [3.2.2] non-Sil)], each of which may have 1 to 3 (most preferably 1 or 2) substituent or suitable substituents [more preferably a substituent than it is selected from lower cycloalkyl (more preferably cyclohexyl), lower alkanoyl (more preferably Cx-C4 alkanoyl, much more preferably formyl), lower alkyl (more preferably CX-C4 alkyl, much more preferably more preferable methyl, ethyl, isopropyl or isobutyl), mono (or di or tri) lower haloalkyl (more preferably monohaloalkyl of Cx-C4 or trihaloalkyl of Cx-C4, most preferably fluoromethyl or trifluoromethyl), lower alkoxy (from more preferably C 1 -C 4 alkoxy, more preferably methoxy), lower alkoxy lower alkyl (more preferably C 1 -C 4) alkoxy C 1 -C 4 alkyl, more preferably methoxymethyl), halogen (so more preferable chlorine or fluorine), aryl (more preferably phenyl), cyano, oxo, a bivalent group of the formula: lower carboxyalkyl (more preferably Cx-C4 carboxyalkyl »more preferably carboxypropyl), lower alkoxycarbonyl (more preferably Cx-C4 alkoxycarbonyl, much more preferably terbutoxycarbonyl), lower spirocycloalkyl (more preferably spirocycloalkyl) dd more preferably spirocyclopropyl), aralkoxy (lower) carbonylalkyl lower (more preferably benzyloxycarbonyl-Cx-C4 alkyl, more preferably benzyloxycarbonylpropyl), hydroxyalkyl (lower) (more preferably Cx-C4 hydroxyalkyl, more preferably hydroxymethyl), carbamoyl, lower alkylcarbamoyl (more preferably Cx-C4 alkylcarbamoyl, more preferably methylcarbamoyl) and di (lower alkyl) carbamoyl (more preferably di (Cx-C4 alkyl) carbamoyl, more preferably dimethylcarbamoyl)].

The most preferred embodiments of the objective compound (I) are as follows: Y is lower alkylene (more preferably C 1 -C 4 alkylene, much more preferably methylene); R1 is phenyl which may have 1 or 2 substituents which are selected from the group consisting of mono (or di or ; tri) lower haloalkyl, halogen (more preferably ^ - chloro), lower alkylamino, lower dialkylamino and nitro [more preferably bis (trihalo lower alkyl) phenyl or dichlorophenyl, more preferably bis (trifluoromethyl) phenyl], - R2 is phenyl which may have 1 or 2 substituents what -l is selected from the group consisting of lower alkyl, mono (or di or tri) lower haloalkyl, lower alkylenedioxy, hydroxy, hydroxyalkyl = lower, lower alkoxy, lower alkylamino and - dialkylamino lower [more preferably - di (lower alkyl) phenyl or [trihalo lower alkyl] phenyl, more preferably dimethylphenyl ^ o (trifluoromethyl) phenyl], naphthyl or indolyl; R3 ~ is hydrogen; and "R4" is lower (lower) pyridylalkyl aminoalkynyl (more preferably pyridylalkyl (Cx-C4) aminoalkynyl of C2-C4 more preferably 4- [(3-pyridylmethyl) amino] -2-butynyl) or (2-pyridyl) lower alkyl (more preferably (2-pyridyl) Cx-C4 alkyl, more preferably (2-pyridyl) propyl or (2-pyridyl) butyl, more preferably 3- (2-pyridyl) propyl. __ Other additional preferred embodiments of the compound (I) are as follows: Y is lower alkylene, R1 is C6-C10 aryl which may have 1 or 2 of mono (o ^ di or tri) lower haloalkyl, R2 __ is C6-C10 aryl or indolyl , each of which may have 1 to 3 substituents which are selected from 17- group consisting of lower alkyl, mono (or di or "2-tri) lower haloalkyl, lower alkylenedioxy, fexyhydroxy, lower hydroxyalkyl, lower alkoxy," lower alkylamino and lower dialkylamino, R3 is hydrogen, and R4 is lower (pyridylalkyl) aminoalkynyl, - (2-pyridyl) propyl which may have 1 to 3 substituents that are selected from the group consisting of~~ of lower alkyl, lower alkoxy, mono (or di or - tri) lower haloalkyl and halogen; pyridyl, thiazolyl, imidazolyl or pyrazolyl, each of which may have 1 or 2 substituents which are selected from the group consisting of lower alkyl, lower aralkyl and pyridylalkyl; lower imidazolylalkyl which has 1 or 2 substituents which are selected from the group consisting of lower alkynyl, lower aralkyl, lower pyridylalkyl, mono (or di or tri) lower haloalkyl, and halogen; (2-methyl-lH-imidazol-4-yl) lower alkyl which has 1 or 2 substituents which are selected from the group consisting of isopropyl, lower alkynyl, lower aralkyl, lower pyridylalkyl, mono (or di or tri) lower haloalkyl and halogen; (5-methyl-lH-i? R? Idazol-4-yl) lower alkyl which has 1 or 2 substituents which are selected from the group consisting of isopropyl, lower alkynyl, lower aralkyl, pyridylalkyl, mono (or di or tri) lower haloalkyl and halogen, -piperidylalkyl lower which may have lower hydroxyalkyl or lower alkoxy; morpholinyl lower alkyl which has 1 or 2 substituents which are selected from the group consisting of ethyl, lower hydroxyalkyl, lower haloalkyl and lower alkoxy lower alkyl; morpholinyl lower alkyl which has lower alkyl and lower alkoxy lower alkyl; (3, 5-dimethylmorpholino) lower alkyl; lower morpholinoalkenyl which may have lower alkyl- or lower alkoxy- lower alkyl; - (2- or 3-morpholinyl) lower alkenyl which may have lower alkoxycarbonyl; lower pyrrolidinyl alkynyl which may have lower alkoxy lower alkyl; lower morpholinylalkynyl which may have 1 or 2"= substituents which are selected from the group consisting of ethyl, propyl, isopropyl, isobutyl, - lower spirocycloalkyl, lower alkoxy lower alkyl, lower hydroxyalkyl, lower carboxyalkyl, di (alkyl) lower) carbamoyl, lower alkoxycarbonyl and lower haloalkyl; __ lower morpholinyl alkynyl which has methyl and lower alkoxy) lower alkyl, - (dimethylmorpholino) lower alkynyl, or "lower homomorpholinylalkynyl which may have halogen." Processes 1 to 6 for preparing the objective compound (I) of the present invention are explained in detail in the following.

Process 1 The objective 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 compound (II) may include an imino-type Schiff base or its isomeric enamine of the isomeric type 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 (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide, bis (trimethylsilyl) urea or the like; a derivative formed by reaction of the compound (II) with phosphorus trichloride or phosgene and the like. = 7 ~ Usually the reaction is carried out in a conventional solvent such as water, alcohol [eg methanol, ethanol, etc.], acetone, dioxen, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, 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 an alkali metal carbonate, an alkali metal bicarbonate, lower trialkylamino, pyridine, N-lower alkyl morpholine, N, N-dialkyl (lower ) benzylamine or similar. The reaction temperature is not critical, and the reaction is usually carried out under "cooling or heating.

Process 2 _. The objective compound (Ib) or a salt thereof can be prepared by subjecting the compound ^ (la) or a salt thereof to a reduction reaction. Z. The reaction can be carried out in the manner described in Example 3 mentioned below or in a Tumilar manner thereto.

Process ~ 3 ~ The objective compound (le) or a salt thereof can be prepared by rationing the compound (III) or its reactive derivative in the carboxy group or a salt thereof with the compound (V) or its reactive derivative in the amino group or a salt thereof. The suitable reactive derivative in the carboxy group of the compound (III) can 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, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.], dialkylphosphorous acid, lower alkanesulfonic acid [for example methanesulfonic acid, ethanesulfonic acid, etc.], sulphurous 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 [e.g. benzoic acid, etc.], - a symmetric and anhydride; an amide activated with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester [for example cyanomethylester, methoxymethyl ester, dimethyl iminomethyl [(CH3) 2N + = CH-] ester, vinylester, proparglyester, p-nitrophenylester, 2,4-dinitrophenylester, trichlorophenylester, pentachlorophenylester, mesylphenylester, phenylazophenylester, phenylthioster, p-nitrophenylthioses , p-cresylthioester, carboxymethyl thioester, pyranylester, pyridylester, piperidylester, 8-quinolyl thioester, etc.] or an ester with an N-hydroxy compound [for example N, N-dimethylhydroxylamine, l-hydroxy-2- (1H) pyridino, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc.], and the like. These reactive derivatives can optionally be selected therefrom, according to the class "of the compound (III) to 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-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. In this reaction, when the compound (III) is used in free acid form or a salt thereof, the reaction is preferably carried out in the presence of a conventional condensing agent such as Trsr, N'-dichlorohexylcarbodiimide, -N-cyclohexyl- N 1 -morpholinoethylcarbodiimide; N-cyclohexyl-N 1 - (4-diethylaminocyclohexyl) carbodiimide; N, N '-diethylcarbodiimide; N, N'-diisopropylcarbodiimide; N-ethyl-N '- (3-dimethylaminopropyl) -carbodiimide; pe t amet Ilethylenetene-N-cyclohexylimine; diphenyl ketene-N-cyclohexylimine; Etoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate, isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride), - phosphorus trichloride; diphenylphosphorylazide; thienyl chloride; oxalyl chloride; lower alkyl haloformate (for example ethyl chloroformate, isopropyl chloroformate, etc.], - triphenylphosphine, 2-ethyl-7-hydroxybenzisoxazole salt; intramolecular salt of 2-ethyl-5- (m-sulfophenyl) -isoxazolyl hydroxide; 1- (p-chlorobenzenesulfonyloxy) -6-chloro-lH-benzotriazole; 2-chloro-1-methylpyridinium iodide; 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; the so-called vilsmeier reagent prepared by the reaction of N, N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc.; or similar. - The reaction can also be carried out in the presence of an inorganic or organic base such as an alkali metal carbonate, alkali metal bicarbonate, lower trialkylamine, pyridine, N-a 1 qu i 1 (lower) mo rfo 1 i na , N, N-dialkyl (lower) benzylamine or the like. 5_ The reaction temperature is not critical, and the reaction is usually carried out under cooling or heating.

Process 4 - The objective compound (Id) or a salt thereof can be prepared by reacting the compound (VI) or a salt thereof with the compound (VII) or a salt thereof. The reaction can be carried out in the manner described in Example 30 mentioned below or in similar manners thereto.

Process 5 The objective compound or a salt thereof can be prepared by reacting the compound (VIII) or a salt thereof with the compound (IX) or a salt thereof. The reaction can be carried out in the manner described in example 35 mentioned below or in similar ways thereto.

Process 6 The objective compound (If) or a salt thereof can be prepared by reacting the compound (X) or a salt thereof with the compound (XI) or a salt thereof. The reaction can be carried out in the manner described in example 8 mentioned below or similarly thereto. The objective compound (I) and a pharmaceutically acceptable salt thereof have pharmacological activities such as tachykinin antagonism, especially antagonism to substance P, antagonism to neurokinin A or antagonism to neurokinin B, and are therefore useful for the treatment or prevention of tachykinin-mediated diseases, particularly diseases mediated by substance P, for example respiratory diseases such as asthma, bronchitis (eg chronic bronchitis, acute bronchitis and diffuse panbronchiolitis, etc.), rhinitis, cough, expectoration and the like; ? ophthalmic diseases such as conjunctivitis, vernal conjunctivitis and the like; t_ cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria and other ezcematous dermatitis and the like; inflammatory diseases such as rheumatoid arthritis, osteoarthritis and the like; pain or discomfort (for example migraine, headache, group headache, tooth aches, cancerous pain, back pain, neuralgia, etc.); and similar. In addition, it is expected that the objective compound (I) and a pharmaceutically acceptable salt thereof of the present invention be useful for treating or preventing ophthalmic diseases such as glaucoma, uveitis and the like, - intestinal diseases such ulcer, ulcerative colitis, bowel syndrome irritable, allergy to food and the like; ~ inflammatory diseases such as nephritis and the like; i- circulatory diseases such as hypertension, angina pectoris, heart failure, thrombosis, Raynaud's disease and the like; epilepsy, spastic paralysis; pola iuria; cystitis; hyperreflexia detrusor of the bladder; urinary incontinence; Parkinson's disease; dementia, dementia related to AIDS; Alzheimer disease; Down's Syndrome; Korea of Hungtiriton; carcinoid syndrome; disorders related to immune improvement or suppression; disorders caused by Helicobacter pilory or other Gram-negative urease-positive spiral bacteria; Sun burns; angiogenesis or diseases caused by angiogenesis; and similar. It is further expected that the objective compound (I) and a pharmaceutically acceptable salt thereof of the present invention will be useful for treating or preventing chronic obstructive pulmonary diseases, particularly chronic pulmonary emphysema; iritis; proliferative vitreoretinopathy; psoriasis; inflammatory bowel diseases, particularly Chron diseases; hepatitis; superficial pain due to frostbite, burns, Zoster herpes or diabetic neuropathy; tenalgia attended to hyperlipidemia; postoperative neuroma, particularly mastectomy; vulgar vestibulitis; itching associated with hemodialysis; lichen planus; laryngopharyngitis, -bromquiectasis; coniosis; cough with rales; pulmonary tuberculosis; cystic fibrosis; hemesis (eg, nausea, bowel movements, vomiting, acute emesis, delayed emesis, anticipatory emesis, postoperative nausea and vomiting (PONV), acute and / or delayed emesis induced by medications such as chemotherapeutic agents for cancer, etc.); mental illness, particularly anxiety, depression, dysthymic disorders and schizophrenia; demyelinating diseases such as multiple sclerosis and amyotrophic lateral sclerosis; attenuation of the morphine suspension; edema, such as edema caused by thermal damage; small cell carcinomas, particularly small cell lung cancer (SCLC); hypersensitivity disorders such as ivy poisoning; fibrosing and collagen diseases such as scleroderma and eosinophilic fasciolasis; Reflex sympathetic dystrophy such as shoulder / hand syndrome; addiction disorders such as alcoholism; somatic disorders related to stress; rheumatic diseases such as fibrositis; and similar. In addition, the objective compound (I) and a pharmaceutically acceptable salt thereof of the present invention are central nervous system (CNS) penetrants. For therapeutic purposes, the compound (I) and a pharmaceutically acceptable salt thereof of the present invention can be used in a pharmaceutical preparation form containing one such compound, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as a solid or liquid excipient, organic or inorganic, suitable for oral, parenteral, external administration including topical, enteral, intravenous, intramuscular, inhalant, nasal, intraarticular, intraspina, transtracheal or transocular.The pharmaceutical preparations can be solid, semi-solid or solutions such as capsules, tablets, tablets, dragees, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, cataplasms, gels, tapes, eye drops, solutions, syrups, aerosols, suspensions, emulsions or the like. If desired, auxiliary substances, stabilizing agents can be included in these preparations s, wetting or emulsifying agents, buffers and other commonly used additives. "Although the dosage of compound (I) will vary based on the age and condition of the patient, a single average 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 compound (I) objective and a pharmaceutically acceptable salt thereof, are shown in the following pharmacological test data of some representative compounds of the present invention.

A. Evaluation of the efficiency of NKX antagonistic transport to the central nervous system using the h-NKx 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). 5 min later, the animals are anesthetized by ether, bleeds hyperfused through the ascending aorta with 20 ml of saline. The brain is rapidly removed, weighed and homogenized in 4 volumes of ice-cold distilled water using Polytoron (KINEMATICA). To extract the test compound, 500 μl of the homogenate, 100 μl of methanol, 500 μl of 0.1N NaOH and 4 ml of ethyl acetate are mixed by stirring for 10 min at room temperature. The organic phase (2.5 ml) is recovered by centrifugation at 3000 rpm for 10 min, dried and dissolved in dimethyl sulfoxide. (2) H-NKx receptor binding assay (a) Membrane preparation of crude CHO cells t CHO cells that permanently express h-NKx receptors are harvested and homogenized with a Dounce homogenizer at 4 ° C "in a buffer (0.25 mM 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 g, 10 min), and the pellet is resuspended in the same buffer, homogenized and centrifuged. The two supernatants are combined and centrifuged (100,000 x g, 1 hour). The crude cell membranes isolated from this maine are resuspended in a buffer (25 mM Tris-HCl (pH 7.4), 10 mM MgCl 2, 1 mM EDTA, 5 μg / ml p-APMSF) and stored at -80 °. C until its use. (b) Binding of 125 I-BH-substance 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 m of a medium (50 mM Tris-HCl) (pH 7.4), 5 mM MnCl2, 20 μg / ml chymostatin, 40 μg / ml bacitracin, 4 μg / ml leupeptone, 5 μg / ml p-APMSF, 200 μg / ml BSA) at 22 ° C during 90 min. At the end of the incubation period, the contents are quickly filtered through a Blue Mat 11740 filter (pretreated with 0% polyethylenimine for 3 hours before use) by using a SKATRON cell harvester.

Then the filter is washed with a wash buffer (TRis-HCl 50 mM JpH 7.4), 5 mM MnCl 2). A radioactivity account is made using an automatic gamma counter (Packard RIASTAR 5420A). All data presented are specific binding defined as the displaceable substance per substance P 3 μM unlabelled.

[II] Result of the test.

All of the following test compounds showed more than 80% in the binding inhibition rate of 125I-BH- "substance P to the receptors h-NKx at 1-a dose of 1 mg / kg.

Test compounds: The objective compounds of the compounds 1- (1), 5- (2), 6- (1), 15, 16- (2), 17, 18, 22, 29, 30, 38, 40, 45, 0 56- (2), 68, 70- (l), 70- (2), 71- (1), 71- (3), 71 ^ (5), 71- (6), 73- ( 2), 73- (3), 76- (l), 76- (3), 77, 78- (3), 78- (4), 79- (1), 79- (2), 80- ( l) 7 80- (2), 80- (3), 80- (4), "80- (6), 80- (7). 81- (1), 81- (2), 5 81- ( 3), _81- (4), 81- (5), 81- (7), 81- (10), 82", 83- (2), 84, 85- (3), 89- (l), 89- (2), 90- (2), 90- (3), 90- (4), 90- (5) and 90- (6). 0 B. Emesis in the ferret [I] Test method t Adult male ferrets housed individually 5 (Marshall Farms, 1.4-2.2 kg) are given an i.v. of a solution containing a test compound. Induction responses (arches and vomiting) are induced by intragastric administration of copper sulfate (40 mg / kg / ml) and observed for the next 30 min. The time and number of the animals are recorded for each animal. Observed arches and vomiting An individual animal is tested with at least 10 days between experiments.

[II] Test results All of the following test compounds showed a 100% inhibition rate to emesis in the ferret at a dose of 1.0 mg / kg.

Test compounds: The objective compounds of examples 4- (2), 26, 29, 40 and 41. _- (Continued on next page) The following preparations and examples are provided for the purpose of illustrating this invention.

Preparation 1 A mixture of 6.25 ml of 3-bromopyridine, 4.9 ml of propargyl alcohol, 0.45 g of bis (triphenylphosphine) palladium (II) chloride and 125 mg of copper iodide in 100 ml of triethylamine is stirred under reflux for 1.5 hours.

After cooling to room temperature, the reaction mixture is filtered and the insoluble material in the filter is washed with about 200 ml of ethyl acetate. The filtrate and the washing are combined and evaporated under reduced pressure. The resulting residue is purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate as eluent. The fractions containing the objective compound are collected and evaporated under reduced pressure to provide 7.9 g of 3- (3-pyridyl) -2-propyn-1-ol as brown crystals. ~~ IR (Nujol): 3160, 1480, 1460, 1400 cm "1 NMR (CDC13, d): 3.87" (1H, t, J = 5.9 Hz), 4.51 (2H, d, J = 5.9 Hz), 7.24 -7.30 (1H, m), 7.73 (1H, dd, _ J = 1.9 and 7.4 Hz), "8.52 (1H, d, J = 5.1 Hz), 8.78 (1H, d, J = 1.9 Hz"). MASS: 134 (M + H) + Preparation 2 t The following compounds are obtained according to a manner similar to that of preparation 1. (1) 4- (3-pyridyl) -3-butyn-1-ol NMR (CDC13, d): 2.61 (1H, s) , 2.71 (2H, t, J = 6.3 Hz), 3.85 (2H, t, J = 6.3 Hz), 7.19-7.25 (1H, m), - 7.70 (1H, dd, J = 2.0, 8.0 Hz), 8.48 (1H, dd, J = 1.4, 5.0 Hz), 8.63 (1H, d, J = 1.4 Hz) MASS: 279, 148 (M + H) + (2) 3- (6-Methoxypyridin-3-yl) -2-propin-l-ol IR (Nujol) 3300, 1610, 1560, 1490, 1460, 1370, 1350, 1310, 1300 cm "1 NMR (CDC13, d): 3.94 (3H, s), 4.52 (2H, s), 6.70 (1H, dd, J = 0.7, 8.6 Hz), 7.60 (1H, dd, J = 2.2, 8.6 Hz), 8.30 (1H, d , J = 2.2 Hz) MASS: 164 (M + H) +, 134 (3; 3- (4-Methoxypyridin-3-yl) -2-propin-l-ol IR (KBr): 3172, 2854, 1585, 1498 cm "1 NMR (CDC13, d): 3.90 (3H, s) , 4.33 (2H, d, J = 4.0 Hz), 5.38 (1H, t, = 4.0 Hz), 7.12 (1H, d, J = 5.8 Hz), 8.24 (2H, broad s) MASS: 164 (M + H ) +, 134 (4) 3- [6- (tert-butoxycarbonylamino) pyridin-3-yl] -2-propin-l-ol _ IR (Nujol): 3500, 3210, 1725, 1625, 1600, 1580, 1430, 1380 cm "1 NMR (CDC13, d): 1.54 (9H, s), 4.99 (2H, s), 7.70 (! H, 7 dd, J = 2.2, 8.7 Hz), 7.97 (1H, d, J = 8.7 Hz), 8.40: (1H, d, J = 2.2 Hz), 8.51 (1H, broad s) - MASS. • 217 (M + H *) +, 175 Preparation 3 11.9 g of thionyl chloride is added dropwise to a solution of 13.3 g of 3- (3-pyridyl) -2-propyn-1-ol in 266 ml of dichloromethane at room temperature. After the addition is complete, the mixture is stirred for 2 hours at room temperature. The resulting precipitates are collected by filtration and washed with diethylether to provide 14.5 g of l-chloro-3- (3-pyridyl) -2-propyne hydrochloride as brown crystals.

Preparation 4 The following compounds are obtained according to a manner similar to that of preparation 3. (1) L-Chloro-3- (6-methoxypyridin-3-yl) -2-propyne hydrochloride (2) L-Chloro-3- (4-methoxypyridin-3-yl) -2- ~ propyne hydrochloride Preparation 5 4.4 ml of isobutyl chloroformate are added dropwise to a suspension of 5.0 g of (E) -3- (3-pyridyl) acrylic acid and 4. 05 ml of N-methylmorpholine in 50 ml of 1,2-dimethoxyethane under -18 ° C. After stirring at the same temperature for 0.5 hours, "a solution to the mixture is added all at once. 1. 86 g of sodium borohydride in 10 ml of water. The resulting mixture is poured into water and extracted with ethyl acetate. The extract is washed with brine and dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate as eluent. The fractions containing the objective compound are collected and evaporated under reduced pressure to provide 1.0 g of (E) -3- (3-pyridyl-2-propen-1-ol as an oil. 1 NMR (CDC13, d): 4.40 (2H1, d, J = 4.0 Hz), 6.52 (1H, dt, J = 4.0, 16.1 Hz, trans), 6.65 (1H, d, J = 16.1 Hz, trans), 7.45 (1H, dd, J = 5.6, 8.0 Hz), 7.89 (1H, d, J = 8.0 Hz), 8.44 (1H, d, J = 5.6 Hz), 8.58 (1H, s) MASS: 136 (M + H) + Preparation 6 0.22 ml of methanesulfonyl chloride are added to a mixture of 0.36 g of (E) -3- (3-pyridyl) -2-propen-1-ol and 0.74 ml of triethylamine in 5 ml of low dichloromethane. { 10 ° C. After stirring at the same temperature for 0.5 hours, the reaction mixture is washed with saturated sodium bicarbonate, dried over magnesium sulfate and evaporated under reduced pressure to give (E) -3- (3-pyridyl) methanesulfonate. -2-propen-l-ilo. Crude mesylate is used in the next step without further purification.

Preparation 7 4- (3-Pyridyl) -3-butin-1-yl methanesulfonate is obtained according to a manner similar to that of Preparation 6.

Preparation 8 A solution of 300 mg of 3- (3-pyridyl) -2-propyl-1-ol in methanol is hydrogenated using a Lindlar catalyst for 4 hours at atmospheric pressure. After removal of the catalyst by filtration, the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel using ethyl acetate as eluent. The fractions containing the objective compound are collected and evaporated under reduced pressure to provide 50 mg of (Z) -3- (3-pyridyl) -2-propen-1-ol as an oil. IR (Nujol): 3600-2700, "1590, 1575, 1480 cm" 1 NMR (CDC13, d): 4.42 (2H, dd, J = 1.6, 6.4 Hz), 6.04 (1H, dd, J = 6.4, 12.0 Hz, cis), 6.52 (1H, d, J = 12.0 Hz, cis), 7.25-7.31 (1H, m), 7.55 (1H, d, J = 8.0 Hz), 8.30-8.70 (2H, broad s) - "" "MASS: 136 (M + H) + Preparation 9 A mixture of 3.0 g of 4-formyl-1-methylimidazole and 6.3 g of triethylphosphonoacetate in 30 ml of N, N-dimethylformamide is stirred under ice-cooling. After several minutes, sodium hydride (1.63 g, 60% in mineral oil) is added to the mixture, which is stirred for 30 minutes at the same temperature. The resulting mixture is poured into ice-water, neutralized with an aqueous solution of ammonium acetate and 1- »a. extract "with ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to provide 4.63 g of ethyl (E) -3- (1-methyl-lH-imidazol-4-yl) acrylate. IR (Nujol): 2900, 1700", 1625 cm-i NMR (CDC13, d): 1.31 (3H, t, J = 7.1 Hz), 3.70 (3H, s), 4.23 (2H, c, J = 7.1 Hz ), 6.53 (1H, d, J = 15.6 Hz), 7.07 (1H, s), 7.45 (1H, s), 7.54 (1H, d, J = 15.6 Hz) _ MASS: 181 (M + H) + Preparation 10 A solution of 2.5 g of ethyl (E) -3- (1-methyl-1H-imidazol-4-yl) acrylate in 100 ml of tetrahydrofuran is hydrogenated over 0.2 g of 10% palladium on activated carbon at room temperature under a pressure of 2 atmospheres. After removal of the catalyst by filtration through a pad of Celite, the filtrate is concentrated under reduced pressure to provide 2.63 g of ethyl 3- (l-methyl-lH-imidazol-4-yl) propionate.

IR (pure): 2900, 1720 cm "1 7_ NMR (CDC13, d): 1.24 (3H, t ', J = 7.1 Hz), 2.62 (2H, ~ t, J = 7.4 Hz), 2.89 (2H, t , J = 7.4 Hz), 3.62 (3H, s), 4.16 (2H, c, J = 7.1 Hz), 6.64 (1H, s), 7.33 (1H, s) MASS: 183 (M + H) + Preparation 11 To an ice-cooled solution of 2.63 g of ethyl 3- (l-methyl-1H-imidazol-4-yl) propionate in 26 ml of tetrahydrofuran is added 0.55 g of lithium aluminum hydride in small portions under an atmosphere of nitrogen. The mixture is then stirred for 0.5 hour, and water and an aqueous solution of 15% sodium hydroxide are added successively to the mixture. The resulting precipitates are separated by filtration through a pad of Celite and the filtrate is extracted with ethyl acetate. ~ The organic layer is washed with water and brine successively, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by column chromatography on silica gel using dichloromethane-methanol (100: 1) as eluent to provide 940 mg of 3- (1-methyl-1H-imidazol-4-yl) -1-propanol. IR (pure) 3250, 2900 cm-i NMR (CDC13, d): 1.86 2H, m), 2.69 (2H, t, J = 6.7 Hz), 3.63 (3H, s), ~ 3.73 (2H, t, J = 6.0 Hz), 6.62 (1H, s), 7.34 (lH, _sj MASS: 141 (M + H) + Preparation 12 - To a solution of 0.361 ml of oxalyl chloride in 10 ml of dichloromethane cooled below -65 ° C with a dry ice-acetone bath, a solution of 0.381 ml of dimethyl sulfoxide in 1 ml of dichloromethane is added. with efficient stirring for 10 minutes. After 20 minutes below -65 ° C, a solution of 3- (1-methyl-1H-imidazol-4-yl) -1-propanol in 2 ml of dichloromethane is added to the mixture for 10 minutes below. -65 ° C and the mixture is stirred at the same temperature for 20 minutes and then at -45 ° C ~ -40 ° C for 30 minutes. After the portionwise addition of 1.0 ml of triethylamine to the mixture for 1 minute followed by stirring for 30 minutes, the reaction mixture is concentrated in vacuo. The resulting residue is purified by column chromatography on silica gel using dichloromethane-methanol (20: 1) as eluent to provide 103 mg of 3- (1-methyl-1H-imidazol-4-yl) propanol. IR (neat): 1715 cm'1 ~ "NMR (CDC13, d): 2.85 (4H, m), 3.63 (3H, s), 6.63 (1H," S), 7.34 (1H, s), 9.83 (1H , s) ^ MASS: 139 (M + H) + Preparation 13 The following compound is obtained according to a manner similar to that of preparation 12. 4-formyl-1- (triphenylmethyl) pyrazole NMR (DMS0-ds, d): 7.05-7.10 (6H, m), -7.36-7.41 (9H, M), 8.15 (2H, s), 9.81 (1H, s) Preparation 14 To a solution of 13.67 g of (3R) -4-benzyl-3- (hydroxymethyl) -morpholine in 140 ml of methanol and 10 ml of water are added 10.4 g of ammonium formate and palladium on activated carbon (50%, 1.4 g). The resulting mixture is stirred at 60 ° C for s hours. After removal of the insoluble material by filtration, the filtrate is concentrated under reduced pressure to provide 16.43 g of the crude or untreated amine. To a solution of the amine obtained in 160 ml of tetrahydrofuran are added 32.2 ml of triethylamine and 50.4 g of diterbutyl carbonate at 0 ° C. After stirring at room temperature for 12 hours, the mixture is suspended with water and extracted with ethyl acetate three times. The organic layer is washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to provide the crude oil which is purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (6: 4). ) as eluent to provide 8.64 g of (3R) -4- (tert-butoxycarbonyl) -3- (hydroxymethyl) morpholine as a colorless solid. NMR (CDC13, d): 1.47 * (9H, s), 3.16-3.24 (1H, m), 3.40-3.61 (2H, m), 3.71-4.00 (6H, m) Preparation 15 The following compound is obtained according to a manner similar to that of preparation 14. (2R, 2S) -4- (tert-butoxycarbonyl) -2- (hydroxymethyl; morpholine IR (neat) 1695 cm "1 NMR (CDCl-j, d): 1.47 (9H, m), 2.03 (1H, t, J = 6.7 - Hz), 2.70-3.00 (2H, m), 3.45-3.74 (4H, m), 3.84- - 3.95 (3H, m) Preparation 16 The following compounds are obtained according to a manner similar to that of preparation 12. (1) (3S) -4- (tert-butoxycarbonyl) -3-formylmorpholine IR (KBr): 1734, 1695 cm "1 NMR (CDC13, d): 1.47 (9H, s), 3.00-3.30 (1H, m ), 3.48 (1H, dt, J = 2.8, 11.7 Hz), 3.67 (1H, dt, J = 4.2, 12.1 Hz), 3.60-3.90 (2H, m), 4.25-4.50 (2H, m), 9.66 ( 1H, s) (2) (2R, 2S) -4- (-ter-butoxycarbonyl) -2-formylmorpholino IR (neat): 1737, 1681 cm * 1 NMR (CDC13, d): 1.47 (9H, m), 2.80-5.00 ( 7H, m), 9.65 (1H, m) Preparation 17 __ The following compounds are obtained in a manner similar to that of preparation 9: D (2E) -3- [(3R-) -4- (tert-butoxycarbonyl) morpholin-3-yl] ethyl acrylate IR (pure): 2978, 1716, 1697 cm "1 NMR (CDC13, d): 1.26 (3H, t, J = 7.4 Hz), 1.46 (9H, s), 3.16 (1H, dt, J = 3.7, 13.2 Hz), 3.49 (1H, dt, J = 2.9, 11.9 Hz), 3.69 (1H, dd, J = 3.6, 11.7 Hz), 3.80-3.99 (3H, m), 4.21 (2H, c, J = 7.1 Hz ), 4.50-4.60 (1H, m), "5.93 (1H, dd, J = 1.8, 15.9 Hz), 6.99 ^ (1H, dd, J = 5.3, 15.9 Hz) (2) (2E) -3 - [(2R, 2S) - (4-tert-butoxycarbonyl) morpholin-2-yl] acrylate IR (pure): 1737, 1681 cm "1 NMR (CDCI3, d) _1.27 (3H, t, J = 3.3 Hz), 1.47 (9H, s), 2.30-3.10 (3H, m), 3.57 (1H , dt, J = 2.7, 11.3 Hz), 3.80-4.20 (3H, m), 4.21 (2H, c, J = 7.1Hz), 6.12 (1H, dd, J =? ".7, 1-5.8 Hz) , 6.83 (1H, dd, J = 4.2, 15.8 Hz) Preparation 18 To a solution of 1 T? g of (2E) -3- [(3R) -4- (tert-butoxycarbonyl) morpholin-3-yl] ethyl acrylate in 10 ml of toluene is added isobutylaluminum hydride (1.02 M in toluene, 7.6 ml) to - 78 ° C ~ -40 ° C. After stirring for 2 hours at 0 ° C, the mixture is suspended with 1.2 ml of methanol and stirred for 1 hour at room temperature. After the resulting precipitate is filtered off, the filtrate is evaporated and purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (3: 7 - 4: 6) as eluent to give 0.71 g of (3R ) -4- (tert-butoxycarbonyl) -3- [(E) -3-hydroxy-1-propenyl] morpholino as a colorless oil. _ IR (pure): 1691 cm "1 NMR (CDC13, d): 1.47 ^ (9H, s), 3.17 (1H, dt, J = 3.7 12.2 Hz), 3.48 (1H, dt, J = 2.7, 11.3 Hz ), 3.65 (1H, dd, J = 3.4, 11.6 Hz), 3.70-3.91 (3H, m), 4.17-4.19 (2H, m) 74.40-4.50 (1H, m), 5.82-5.93 (2H, m) Preparation 19 ~ The following compound is obtained according to a manner "similar to that of preparation 18.

Z (2R, 2S) -4- (tert-butoxycarbonyl) -2- [(E) -3-hydroxy-1-propenyl] morpholino NMR (CDC13, d): 1.47 (9H, s), 2.62-3.00 (2H , m), 3.56 (1H, dT, J = 2.7, 11.4 Hz), 3.81-3.94 (4H, m), 4.18 (2H, d, J = 5.0 Hz), 5.64-6.04 (2H, m) Preparation 20 ~ The following compounds are obtained according to a manner similar to that of Preparation 6 (1) (3R) -4- (tert-butoxycarbonyl) -3- [(E) -3-methanesulfonyloxy-1-propenyl] morpholino NMR (CDC13, d): 1.47 (9H, s), 3.02 (3H, s ), 3.10-3.25 (1H, m), 3.48 (1H, dt, J = 2.8, 11.5 Hz), 3.63-3.93 (4H, m), 4.45-4.55 (1H, m), 4.74 (2H, d, J = 6.2 Hz), 5.75-5.86 (1H, m), 6.05 (1H, dd, J = 5.5, 15.6Hz) (2) (2R, 2S) -4- (tert-butoxycarbonyl) -2- [(E) -3- metansul foniloxi -1-propenyl] morf olino NMR (CDC13, d): 1.47 (9H, m), 2.60-2.72 (1H, m), 2. 89-3.02 (1H, m), 3.02 (3H, s) ~, 3.55 (1H, dt, J = 2.7, 11.4 Hz), 3.82-4.00 (4H, m), 4.73 (2H, d, J = 5.1 Hz ), 5.79-6.01 (2H, m) Preparation 21 To a mixture of ll g of l-amino-1-cyclopropanmethanol hydrochloride, 945 mg of benzaldehyde and 1.24 ml of triethylamine in 10 ml of 1,2-dichloroethane, 5.66 g of sodium triacetoxyborohydride is added under ice-cooling, 5 minutes . After stirring at room temperature for 13 hours, the mixture is poured into an aqueous solution of sodium bicarbonate and stirred for several hours.The organic layer is separated, dried over magnesium sulfate and evaporated under reduced pressure to provide 641 mg of 1- (N-benzylamino) -1-cyclopropanmethanol IR (Nujol) 3300-2700 cm "1 i. NMR (CDC13, d) _: 0.50 ^ 0.77 (4H, ra), 3.51 (2H, s), 3.84 (2H, s), 7.19-7.36 (5H, s) MASS 178 (M + H) + _ Preparation 22 The following compound is obtained according to a manner similar to that of preparation 19. (2S) -2- (N-benzylamino) -4-methyl-1-pentanol NMR (CDC13, d): 0.84-0.94 (6H, m), 1.17-1.70 (3H, m), 2.72-2.81 (1H, m), 3.28 (1H, dd, J = 6.0, 10.6 Hz), 3.66 (1H, dd, J = 3.9, 10.6 Hz), 3.78 (2H, s), 7.20-7.38 (5H, m) MASS 208 (M + H) + Preparation 23 421 mg of chloroacetyl chloride are added dropwise to a mixture of 600 mg of 1- (N-benzylamino) -1-cyclopropane-methanol and 702 mg of potassium carbonate sprayed in 6 ml of dichloromethane under cooling with ice and then the mixture is mixed with water. Stir at room temperature for 2 hours. The resulting mixture is washed with dilute hydrochloric acid and brine successively, and concentrated under reduced pressure. A mixture of the oil obtained by the above procedure and 380 mg of potassium terbutoxide in 6 ml of tert.-butanol is stirred for 2 hours under reflux. After cooling to room temperature, the mixture is diluted with 10 ml of ethyl acetate. The resulting mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is dissolved with ethyl acetate and the ethyl acetate solution is washed with dilute hydrochloric acid and successively brine., dried over magnesium sulfate and concentrated under reduced pressure to give 695.3 mg of a solid of 4-benzyl-5-oxo-7-oxa-4-azaspiro [2.5] octane. IR (KBr): 3100-2800, 1643 cm * 1-NMR (DMS0-d6, 6): 0.64-1.02 (4H, m), 3.69 (2H, s), 4.43 (2H, s), 4.45 (2H, s), 7.17-7.37 (2H, m) MASS: 218 (M + H) + Preparation 24 The following compound is obtained according to a manner similar to that of preparation 21. - (5S) -4-benzyl-5- (2-methylpropyl) -3-morpholino IR (neat): 1655 cm "1 NMR (CDC13 , d): 0.83 (3H, d, J = 6.3 Hz), 0.95 (3H, d, J = 6.4 Hz), 1.33-1.60 (2H, m), 1.79-1.92 (1H, m), 3.08-3.17 ( 1H, m), 3.56-3.79 (1H, m), 3.82 (2H, d, J = 15.0 Hz), 4.23 and 4.27 (2H, ABc, J = 16.7 Hz), 5.47 (1H, d, J = 14.9 Hz ), 7.24-7.39 (5H, m) MASS: 248 (M + H) + Preparation 25 A solution of 695.3 mg of 4-benzyl-5-oxo-7-oxa-4-azaspiro [2.5] octane in 8 ml of tetrahydrofuran is added dropwise to an ice-cooled suspension of 112 mg of lithium aluminum hydride in 5 ml of tetrahydrofuran, for 20 minutes and then the mixture is stirred at 50 ° C for 2 hours under a nitrogen atmosphere. After cooling to room temperature, 495 mg of sodium fluoride is added to the mixture. The mixture is stirred vigorously and cooled with an ice bath. 0.16 ml of water is added thereto and the mixture is filtered. The filtrate is concentrated under reduced pressure to provide an oil. The oil is purified by column chromatography on silica gel using a mixture of hexane and ethyl acetate as eluent "to provide 334.8 mg of 4-benzyl-7-oxa-4-azaspiro [2.5] octane. -7-oxa-4-azaspiro [2.5] octane in 8 ml of ethanol on palladium hydroxide on carbon for 2 hours at atmospheric pressure After the catalyst is removed by filtration, the filtrate is treated with 4N hydrogen chloride in acetate of ethyl (2 ml) and concentrated under reduced pressure to provide 81 mg of 7-oxa-4-azaspiro [2.5] octane hydrochloride. __ IR (KBr): 3350, 3000-2400 cm "1 NMR (CDC13, d ): 0.8.4-1.10 (4H, m), 3.75 (2H, s), 3.90-4.10 (4H, m), 10.11 (1H, broad s) ~ MASS: 114 (M + H) + (free) Preparation 26 - The following compound is obtained according to a similar manner to that of preparation 23. (3S) -4-benzyl-3- (2-methylpropyl) morpholino NMR (CDCl3, d): 0.89 (3H, d, J = 6.2 Hz), 0.93 (3H, d, J = 6.3 Hz), 1.20-1.40 (1H, m), 1.40-1.61 (2H, m), 2.17-2.27 (1H, m), 2.40-2.50 (1H, m), 2.59- 2.68 (1H, m), 3.16 (1H, d, J = 13.3 Hz), 3.40 (1H, dd, J = 11.2, 7.8 Hz), 3.59-3.83 (3H, m), 4.04 (1H, d, J = 13.3 Hz), 7.21-7.36 (5H, m) MASS: 234 (M + H) + Preparation 27 The following compound is obtained according to a manner similar to that of preparation 23. (3S) -3- (2-methylpropyl) morpholino-NMR hydrochloride (DMS0-ds, d: 0.87 (3H, s), 0.90 (3H, s), 1.26- 1.52 (2H, m), 1.65"-1.78 ( 1H, m), 3.12-3.48 (4H, m), 3.69 (1H, dt, J = 3.4, 12.3 Hz), 3.87-3.95 (2H, m) MASS: 144 (M + H) + (free) Preparation 28 A solution of 5.0 g of 2-amino-5-bromopyridine and 6.39 g of diterbutyl dicarbonate in 100 ml of terbutanol is stirred at room temperature for 15 hours. The resulting suspension is concentrated under reduced pressure and the residue is chromatographed on silica gel using an eluent of dichloromethane. The fractions containing the objective compound are collected and concentrated under reduced pressure to provide 3.25 g of 2- (tert-butoxycarbonylamino) -5-bromopyridine IR (Nujol): 3210 172 1580, 1525, 1460, 1370 cm "1 NMR ( CDC13, d): 1.56 (9H, s), 7.76 (1H, dd, J = 2.5, 8.9 Hz), 7.95 (lH, d, J = 8.9 Hz), 8.38 (1H, d, J = 2.5 Hz), 8.93 (1H, broad s) Preparation 29 _ = - To a solution of 5.03 g of (2R) -4-benzyl-1- (3,5-dichlorobenzoyl) -2- (3,4-dimethylbenzyl) piperazine in 50 ml of dichloromethane are slowly added at 0 ° C 1.51 ml of 1-chloroethyl chloroformate and then the mixture is heated to reflux with stirring. After 5.5 hours, the solvent is removed in vacuo and subsequently the resulting residue is dissolved in 20 ml of methanol and refluxed for 0.5 hour. After removal of the solvent, the resulting residue is triturated with isopropyl ether to provide 4.84 g of (2R) -1- (3,5-dichlorobenzoyl) -2- (3,4-dimethylbenzyl) piperazine hydrochloride.

IR (Nujol) 3350, 1625 cm "1 NMR (DMS0-ds) d: 2.10-4.60 (15 H, m), 6.50-9.70 (6H, m) MASS: 377 (M + H) + (free) Preparation 30"The following compounds are obtained according to a manner similar to that of the preparation. (1) (2R) -1- (3,5-dichlorobenzoyl) -2- [(1H-indol-3-yl) methyl] piperazine hydrochloride IR (KBr): 1637 cm "1 NMR (DMS0-d6) d : 2.80 ^ 4.80 (9H, m), 6.80-10.20 (8H, m) ^ MASS 388 (M + H) + (free) (2) (2R) -1- (3, 5-dichlorobenzoyl) -2- (2-naphthylmethyl) iperazine-NMR (DMSO-d6, d) hydrochloride: 2.80-4.70 (9H, m), 6.50-8.00 (10H , - m) MASS: 399 (M + H) + (free) (3) T (2R) -1- (3,5-dichlorobenzoyl) -2- [4- (trifluoromethyl) -benzyl] piperazine hydrochloride (KBr): 3430, 2930, 2790, 1648, 1164 cm "1 NMR (DMSO-d6, d: 2.70-5.30 (9H, m), 6.50-7.90 (7H, m), 9.62 (1H, broad s): MASS 417 (I + H) + (free) (4) "(2 R) -1 - [3,5-bis (tri-fluoromethyl) benzoyl] -2- (2-naphthylmethyl) piperazine dihydrochloride IR (KBr): 3700-3200, 1639, 1281, 1136 cm "1 NMR (DMS0-d6, d): 2.90-3.80 (7H, m), 4.40-5.30 (2H, m), 6.90-8. 0 (1 H, m). __ MASS 317 (M + H) + (free) Preparation 31 2 g of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (2-naphthylmethyl) piperazmaconl 4 ml of an aqueous 10% sodium hydroxide solution and 14 ml of dichloromethane are treated. . The organic layer is separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. A mixture of the free piperazine derivative obtained by the above procedure, 0.76 g of potassium carbonate and 0.43 ml of 1,4-dichloro-2-butyne in 15 ml of N, N-dimethylformamide is stirred for 4.5 hours at room temperature. ambient. The reaction mixture is poured into 75 ml of 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 gel column chromatography. of silica using a mixed solvent of toluene and ethyl acetate (10: 1) as eluent for T provide 1.18 g of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -4- (4-chloro-2) -butinyl) -2- (2-naphthylmethyl) iperazine ^ IR (pure): 3600-3100, 1638, 1275, 1127, 900 cm "1 NMR (CDC13, d): 2.31-5.30 (13H, m), 6.90- 7.95 (10H, m). - MASS: 553 (M + H) + Example 1 = (1) A mixture of 0.67 g of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- [(lH-indol-3-yl) methyl] piperazine, 0.3 g of hydrochloride of l -chloro-3- (3-pyridyl) -2-propyne and 0.52 g of potassium carbonate in 5 ml of N, N-dimethylformamide is stirred for 5 hours at 50 ° 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 column chromatography on silica gel using ethyl acetate as eluant to provide 0.25 g of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1H-indol-3) il) methyl] -4- [3- (3-pyridyl) -2-propynyl] -piperazine as a syrup. (2) The following compound is prepared by treatment of I2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1H-indol-3-yl) methyl] -4- [3- (3 -pyridyl) -2-propynyl] -piperazine with 4N hydrochloric acid in ethyl acetate. - (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- [(lH-indol-3-yl) methyl] -4- [3- (3-pyridyl) -2-propynyl hydrochloride ] -piperazine pf; 180-190 ° C - [a] D24 6: -10.50 '(C = 0.1, MeOH) IR (Nujol): 3600-3200, 2700-2500, 1643, 1530, 1428, - "1361, 1280 cm" 1 NMR (DMSO-ds, d): 3.20-5.20 (11H, m), 6.40-8.30 (10H, m), 8.74-8.80 (1H, m), 8.85-8.90 (2H, m), 10.90, 11.10 (1H, m) MASS: 571 (M + H) + (free) - Calculated Elemental Analysis for C30H24FsN40.2HC1.1.8H20: C 53.31, H 4.41, N 8.29 Found C 53.28, H 4.53, N 7.87 Example 2 The following compounds are obtained in a manner similar to that of Example 1. (1) (2_R) -1- [3,5-bis (trifluoromethyl) -benzoyl] -2- (3,4-dimethylbenzyl) -4- [3- (6-methoxypyridin-3-yl) -2-dihydrochloride -propinyl] piperazine pf : 160-170 ° C [C] D242: -14.72 ° (C = 0.55, MeOH) IR (KBr): 3600-3300, 2700-2500, 1648, 1617, 1494, 1430, 1280 cm "1 NMR (DMSO- d6, d): 2.05-2.20 (6H, m), 2.80-5.20 (11H, m), 3.90 (3H, s), 6.50-8.40 (9H, m) MASS: 590 (M + H) + (free) Elemental Analysis Calculated for C31H29FeN302. 2HC1. 0 5H20 C 55.45, H 4.80, N 6.26"Found C 55.28, H 4.86, N 6.12 (2) (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] 2- [(lH-indol-3-yl) methyl] -4- [3- (6-methoxypyridin-3-yl) hydrochloride ) -2-propinyl] piperazine ± pf : 183-189 ° C [] D23'9: -21.0 ° (C = 0.55 MeOH) IR (KBr): 3600-3300, 2700-2500, 1644, 1602, 1494, 1428, 1280 cm "1 NMR (DMSO- d6, d): 3.20-5.20 (11H, m), 3.90 (3H, s), 6.60-8.40 (11H, m), 10.95 (1H, broad), 12.00- 12.40 (2H, m) MASS: 600 ( M + H) + (free) Elemental Analysis Calculated for: C3XH2SF6N402.2HC1.H20 C 53.85, H 4.37, N 8.10 Found C 53.90, H 4.36, N 8.02 (3) (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- [(lH-indol-3-ylmethyl] -4- [3- (2-pyridyl) -2 -propinyl] piperazine Example 3 ... 0.2 g of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [3 - (2-pyridyl) -2 dihydrochloride are released. -propinyl] piperazine with a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract is dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue is dissolved in 10 ml of methanol and the solution is hydrogenated over 50 mg of 10% palladium on activated carbon at room temperature under 2-3 atmospheres.

After removal of the catalyst by filtration, the filtrate is concentrated under reduced pressure. The residue is treated with 4N hydrogen chloride in an ethyl acetate solution to give the (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4 dihydrochloride. - [3- (2-pyridyl) propyl] piperazine. p.f. : 120-130 ° C [a] D24'5: -12.81 ° (C = 0.32, MEOH) IR (Nujol): 3600-3300, 2700-2500, 1635, 1450, 1380, 1280 cm * 1 NMR (DMSO- ds, d): 2.00-5.20 (21H, m), 6.60-7.80 (5H,, m), 7.80 (1H, d, J = 8.0 Hz), 7.88 (1H, t, J = ~ _ 7.0 Hz), 8.18 (lH, "s), 8.49 (1H, t, J = 7.1 Hz), 8.81 (1H, d, J = 5.2 Hz), 11.20-12.20 (2H, m)" "MASS: 564 (M + H) + (free) Z Calculated Elemental Analysis for C30H3xF6N302.HCl .2.7H20: XC 52.59, H 5.65, N 6.13 * '- Found C 52.66, H 5.78, N 5.77 Example "4 (1) Dihydrochloride of (2 R) -l- [3, 5-r-bis (trifluoromethyl) benzoyl] -2- [(lH-indol-3-yl) methyl] -4- "7 [3- ( 3-pyridyl) propyl] piperazine-mp: 150-160 ° C [a] D22'9: -2.86 ° (C = 0.42, MeOH) IR (KBr) 3600-3000, 2700-2010, 1641, 1554, 1461, 1428, 1280 cm * 1 NMR (DMSO-ds, d): 2.10-5.20 (15H, m), 6.60-8.30 (9H, m), 8.45-8.55 (1H, ~ m), 8.80-9.00 (2H, m ), 10.95- 11.05 (1H, m), 11.90-12.00 (2H, broad s) MASS: 575 (M + H) + (free) Elemental Analysis Calculated for C30H28FsN40.2HC1.1.2H20: C 50.71, H 5.25, N 7.89 Found C 50.65, H 5.35, N 7.20 (2) Dichlorhydrate (2 R) -l- [3, 5-bis (trifluoromethyl) benzoyl] -2- [(lH-indol-3-yl) methyl] -4- [3- (2-pyridyl) propyl] piperazine pf : 80-100 ° C [C-ID23'1 • 529 '(C = "0.86, MeOH) IR (KBr): 3600-3000, 2700-2500, 1637, 1617, 1460, 1282 cm" 1 NMR (DMSO- d6, d): 2.20-2.40 (2H, m), 3.10-5.20 (13H, m), 6.60-8.30 (10H, m), 8.49 (1H, d, J = 7.8Hz), 8.80 (1H, d, J = 5.0Hz), 10.90-11.05 (1H, broad s) MASS: 575 (M + H) + (free) Elemental Analysis Calculated for C30H2aFsN40.2HC1.1.2H20: C 53.85, H 4.88, N 8.37 Found C 53.92, H 5.30, N 7.66 (3) D iclo rh i dra to (2 R) -l- [3, 5-bis (trifluoromethyl) benzoyl] -2- [(lH-indol-3-yl) methyl] -4- [3- ( 3-pyridyl) propyl] piperazine pf : 140-145 ° C [] D22'3: -8.33 ° (C = 0.30, MeOH) IR (KBr): 3600-3000, 2700-2300, 1641, 1465, 1430, 1280 cm "1 NMR (DMSO-d6 , d): 1.60-5.20 (17H, m), 6.60-9.00 (12H, m), 11.00 (1H, broad s), 11.59 (2H, broad s) MASS: 589 (M + H) + (free) Analysis Elementary Calculated for C3XH30FSN40.2HC1.2H20: C 53.38, H 5.20, N 8.03 Found C 53.47, H 5.28, N 7.51 Example 5 7 (1) 0.04 ml of methanesulfonyl chloride is added to a mixture of 0.15 g of (Z) -3- (3-pyridyl) -2-propen-l-ol and 0.2 ml of triethylamine in 2 ml of dichloromethane under - 10 ° C. After stirring at the same temperature for 0.5 hoursThe reaction mixture is washed with saturated sodium bicarbonate, dried over magnesium sulfate and evaporated under reduced pressure. The mesylate obtained is added to a mixture of 0.5 g of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1H-indol-3-yl) methyl] piperazine, 0.61 g of powdered potassium carbonate and a catalytic amount of potassium iodide in a mixed solvent of 10 ml of acetonitrile and 2 ml of N, N-dimethylformamide. The resulting mixture is stirred at 50 ° C for 1.5 hours and then filtered. The filtrate is evaporated under reduced pressure and the resulting residue is purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol as eluent. Fractions containing the objective compound are collected and evaporated under reduced pressure to provide 0.49 g of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1H-indol-3-yl) methyl] ] -4- [(Z) -3- (3-pyridyl) -2-propenyl] piperazine as an Arabian j. - NMR (CDC13, d): 1.80-5.20 (11H, m), 5.97 (1H, dt, J - 6.6, 11.7 Hz, cis), 6.60 (1H, d, J = 11.7 Hz, cis), 6.80 -8.00 (10H, m), 8.23 (1H, s), 8.45-8.60 (2H, m) MASS: 562 (M + h) + (2) _ The following compound is prepared by treatment of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1H-indol-3-yl) methyl] -4- [(Z ) -3- (3-pyridyl) -3-propenyl] piperazine with 3N hydrogen chloride in ethyl acetate.

D iclo rhi drat or of (2 R) -l - [3,5-bis (trifluoromethyl) benzoyl] -2- [(lH-indol-3-yl) methyl] -4- [(Z) -3- ( 3-pyridyl) -2 -propenyl] piperazine pf : 165-177 ° C [Cí] D229: + 14.9 ° (C = 0.50, MeOH) IR (KBr): 3600-300JD, 2700-2500, 1641, 1457, 1427, 1359, 1280, 1184 cm "1 NMR ( DMSO-de, d): 3.00-5.20 (11H, m), 6.40-8.40 (12H, m), 8.70-8.85 (2H, "m), 11.05 (1H, broad), 12.00 (2H, m) MASS : 573 (M + H) + (free) Elemental Analysis Calculated for C30H26FsN40.2HC1.2.5H20: C 52.18, H 4.82, N 8.11 Found C 52.34, H 4.73, N 8.01 In emplo 6 The following compounds are obtained according to a manner similar to that of example 5. (1) ^ D hydrochloride (2 R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [(E) -3- (3-pyridyl) - 2-propenyl] -piperazine pf 170-174 ° C [Cí] D24 1: -8.50 ° (C = 0.20, MeOH) IR (KBr): 3600-3000, 2700-2500, 1644, 1554, 1432, 1367, 1280 cm "1 NMR (DMSO- d6, d): 2.00-2.30 (6H, m), 2.80-5.20 (6H, m), 6.60-9.05 (12H, m) MASS: 562 (M + H) + (free) Elemental Analysis Calculated for C30H29FsN30. 2HC1 .2 .0H20: C 53.74, H 5.26, N 6.27 Found C 53.71, H 5.33, N 5.83 (2) (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1 H -indol-3-yl) methyl] -4- [4- (3-pyridyl) -3 -butyl ] piperazine NMR (CDC13, d): 2.20-5.20 (13H, m), 6.80-8.00 (10H, m), 8.15 (1H, s), .49 (1H, d, J = 3.8 Hz), 8.64 (1H , s broad). MASS: 585 (M + H) + (3) (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [3- (1H-pyrazol-1-yl) propyl] piperazine hydrochloride pf 73-75 ° C [] D247: -17.30 ° (C = 0.50, MeOH) IR (KBr): 1640 cm "1 NMR (DMSO-ds, d): 1.85-5.20 (21H, m), 6.20-8.30 ( 9H, m) MASS: 553 (M + H) + (free) Elemental Analysis Calculated for C28H31CIFsN40.2H20: C 53.80, H 5.64, N 8.96 Found C 53.67, H 5.56, N 7.83 Example 7 The following compounds are obtained according to a manner similar to that of Example 5- (2). (1) Dichlorhydrate (2 R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- [(lH-indol-3-yl) methyl] -4- [3- (2-pyridyl) - 2-propyl] -piperazine pf 160-166 ° C [] D24 7: -16.80 ° (C = 0.50, MeOH) IR (KBr): 3600-3200, 2700-2500, 1643, 1540, 1380, 1280 cm "1 NMR (DMS0-ds, d ): 3.20-5.20 (11H, m), 6.60-8.30 (11H, m), 8.65 (1H, d, J = 2.7 Hz), 10.90-11.05 (1H, m) MASS: 571 (M + H) + ( free), 607 Calculated Elemental Analysis for C30H24F6N40.2HC1.1.5H20: C 53.74, H 4.36, N 8.36 Found C 53.73, H 4.66, N 7.71 (2) (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1 H -indol-3-yl) methyl] -4- [4- (3-pyridyl) -3-butynyl ] piperazine pf 175-185 ° C ~ [a] D21-7: -10.30 ° (C = 0.50, MeOH) IR (KBr): 3600-3300, 2700-2500, 1641, 1459, 1428, 1368, 1282 cm * 1 NMR ( DMS0-d6, d): 3.20-5.20 (13H, m), 6.60-8.30 (9H, m), 8.65-8.85 (2H / m), 10.99 (1H, s), 11.90-12.10 (2H, m). MASS: 585 (M + H) + (free) *** Calculated Elemental Analysis for C3XH2SF6N40.2HC1.1.2H20: C 54.83, H 4.51, N 8.25; = Found C 54.79, H 4.87, N 7.67 Example 8"A mixture of 0.25 g of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1H-indol-3-yl) methyl] -4- [4-chloro-2-butyl] ) Piperazine, 0.10 g of (R) -2- (methoxymethyl) pyrrolidine, 0.25 g of potassium carbonate and 10 mg of potassium iodide in 5 ml of dry N, N-dimethylformamide is stirred for 5 hours at room temperature. It is poured into water and extracted with ethyl acetate.The extract is washed with brine, dried over magnesium sulphate and evaporated under reduced pressure.The residue is purified by column chromatography on silica gel using ethyl acetate as eluant and treated with 4N hydrogen chloride in a solution of ethyl acetate to provide 0.19 g of (2R) -l- [3 dihydrochloride]., 5-bis (trifluoromethyl) benzoyl] -2- [(1H-indol-3-yl) methyl] -4- [4- [(2R) -2- (methoxymethyl) -pyrrolidino] -2-butynyl] piperazine. p.f. 190-195 ° C [a] D24'8: + 9.3 ° (C = 0.50, MeOH) i__ IR (KBr): 3600-3300, 2700-2500, 1641, 1552, 1428, 1280 cm "1 NMR (DMSO- d6, d): 1.6-2.40 (4H, m), 3.10-5.20 (18H, 'm), 6.60-8.30 (8H, m), 11.50-11.70 (3H, m) MASS: 621 (M + H) + (free) Calculated Elemental Analysis for C32H34F6N402.2HC1.1.5H20: C 53.34, H 5.46, N 7.78 Found C 53.35, H 5.54, N 7.60 Example 9 _ = To a mixture of 2.6 g of 3,5-dichlorobenzoic acid, 5.0 g of (3R) -1-benzyl-3- (3,4-dimethylbenzyl) piperazine dihydrochloride and 8.54 ml of triethylamine in 80 ml of dichloromethane are added. 3.83 g of 2-chloro-1-methylpyridinium iodide are added under cooling with ice, and then, the mixture is stirred at room temperature for 1 hour. The mixture is evaporated under reduced pressure and the resulting residue is dissolved in ethyl acetate. The ethyl acetate solution is filtered and evaporated under reduced pressure. The resulting residue is purified by column chromatography on silica gel using hexane-ethyl acetate (10: 1) as eluent to provide 5.58 g of (2R) -4-behcyl-l- (3,5-dichlorobenzoyl) -2 - (3,4-dimethylbenzyl) piperazine. IR (Nujol): 2500, iSS ^ cm "1 • ß NMR (DMSO-d6, d): 1.90-2.30 (8H, m), 2.55-4.80) 9H, ^ m), 6.50-7.15 (5H, m) , 7.20-7.40 (5H, m), 7.59 (1H, broad) '"MASS: 467 (M + H) + Example 10 The following compound is obtained according to a manner similar to that of Example 9. (2R) -4-Benzyl-1- (3,5-dichlorobenzoyl) -2- [4 - (trifluoromethyl) benzyl] piperazine IR (neat): 2942, 2809, 1641, 1070 c "1 - ~ NMR (DMS0 -d6, d): 2.00-4.90 (11H, m), 6.59 (1H, s),, 7.10-7.70 (11H, m) MASS: 507 (M + H) + Example 11 To a solution of 3.23 g of (3R) -l-benzyl-3- (2-naphthylmethyl) piperazine and 4.3 ml of triethylamine in 60 ml of dichloromethane is added a solution of 6.0 g of 3,5-dichlorobenzoyl chloride in 10 ml. ml of dichloromethane at 0 ° C. After stirring at room temperature for 3 hours, the mixture is suspended with water and extracted three times with ethyl acetate. The combined extracts are dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained is triturated with a mixture of dichloromethane and hexane to provide (2R) -4-benzyl-1- (3,5-dichlorobenzoyl) -2- (2-naphthylmethyl) -piperazine NMR (DMS0-ds, d ): 3.00-4.70 (9H, m), 6.66-7.86 (17H, -m). MASS: 689 (M + H) + (free) Example 12 The following compound is obtained according to a "" manner similar to that of example il. (2R) -4-Benzyl-1- (3,5-dichlorobenzoyl) -2- [lH-indol-3-yl) methyl] piperazine NMR (DMSO-ds, d): 2.10-4.60 (9H, m), 5.76 (2H, s), 6.70-7.68 (13H, m) MASS: 388 (M + H) + (free) In emplo 13 The following compound is obtained according to a manner "similar to that of Example 1- (1).

D iclo rh i dra to (2 R) - l - [3,5-bis (trifluoromethyl) benzoyl] -2- (2-naphthylmethyl) -4- [3- (3-pyridyl) -2-propyl ] piperazine pf : 140-150 ° C [a] D25 9: -9.2 ° (C = 0.50, MeOH) _ IR (KBr): 3700-320J), 3000-2300, 1644, 1550, 1428, 1367, 1280 cm "1 NMR (DMSO-d6, d): 2.20 ^ -5.20 (11H, m), 7.00-8.65 (14H,), MASS: 582 (M + H) + (free) Elemental Analysis Calculated for C3XH25F6N40.2HC1.2.57H20: C 54.85, H 4.62, N 6.00 Found C 54.85, H 4.56, N 5.86 Example 14 (1) 86 mg Lindlar catalyst is added Pd-CaCO3-PbO) a solution of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (2-naphthylmethyl) -4- (3- (3-pyridyl) -2-propynyl] piperazine The mixture is stirred for 2 hours under hydrogen at 25 ° C and filtered, the filtrate is concentrated under reduced pressure and the resulting residue is chromatographed on silica gel using a mixed eluent of hexane and ethyl acetate. The fractions that elute more rapidly are collected, concentrated under reduced pressure and treated with 4N hydrogen chloride in ethyl acetate to give (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] dichloride. 2- (2-naphthylmethyl) -4- [(2Z) -3- (3-pyridyl) -2-propenyl] piperazine mp 130-150 ° C [a] D27 S: -25.20 ° (C = 0.25, MeOH ) IR (KBr): 3700-3200, 1646, 1280 cm "1 NMR (DMS0-ds, d): 2.00-5.20 (11H, m), 6.30-8.90 (16H, m), MASS: 584 (M + H ) + (free) Elemental Analysis Calculated for C32H27F6N30.2HC1.3.7H20: C 53.19, H 5.07, N 5.82 Found C 5 3.19, H 5.21, N 5.61 (2) Fractions that elute more slowly are collected, concentrated under reduced pressure and treated with 4N hydrogen chloride in ethyl acetate to give (2RT-1- [3,5-bis (trifluoromethyl) benzoyl] -2- (2-naphthylmethyl) -4- [ 3- (3-pyridyl) -2-propyl] piperazine mp 138-148 ° C [a] D248: -28.60 ° (C = 0.25, MeOH) IR (KBr): 3700-2200, 1646, 1280, 1135 cm " 1 NMR (DMSO-d6 / d): 2.00 ^ -5.20 (15H, m), 6.30-8.90 (14H, m) MASS: 586 (M + H) + (free) Elemental Analysis Calculated for C32H29FsN30.2HC1.2.9H20 : C 54.10, H 5.22, N 5.92 Found C 54.11, H 5.37, N 5.70 - Example 15 _ A mixture of 400 mg of (2R) -l- (3,5-dichlorobenzoyl) -2- (3,4-dimethylbenzyl) piperazine hydrochloride and 223 mg of 4- (4-chloro-2-butynyl) morpholino hydrochloride in 4 ml of dry acetonitrile is stirred at 50 ° C in the presence of 534 mg of powdered potassium carbonate and 32 mg of potassium iodide. After 3 hours, the reaction mixture is filtered and the insoluble material on the filter is washed with acetonitrile. The filtrate and washing are combined and then concentrated in vacuo. The resulting residue is purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol (10: 1) as eluent. The product which is obtained is dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to provide 221 mg of (2R) -1- 3,5-dichlorobenzoyl) -2- (3, 4-) dihydrochloride. dimethylbenzyl) -4- (4-morpholino-2-butinyl) piperazine pf 175 ° C (decomposition) [a]: + 6.80 ° (C = 0.50, MeOH) IR (Nujol) 2400, 1640, 1120 cm "1 NMR (DMSO-ds, d): 2.10-4.40 (21H, m), 6.69 (3H, broad), 7.06 (2H, broad), 7.61 (1H, broad) * ~ MASS: 514 (M + H) + (free) Elemental Analysis Calculated for C28H33C12N302.2HC1.2H20: C 53.94, H 6.30, N 6.74 Found C 53.86, H 6.15, N 6.41 Example 16 The following compounds are obtained according to a manner similar to that of Example 15 (1) (2R) -1- (3,5-Dichlorobenzoyl) -2- (3, 4-dimethylbenzyl) -4- (4-thiomorpholino-2-butynyl] piperazine "" mf 128 ° C (decomposition) ) '- s - [] D28' °: + 6.40 ° (X = 0.50, MeOH) IR (Nujol) 2400, 1635 crn * 1 NMR (DMSO-d6, d): 2.05-4.70 (21H, m), 6.71 (3H, broad), 7.04 (2H, * broad), 7.61 (1H, broad) 7 MASS: 530 (M + H) + (free) Elemental Analysis Calculated for C28H33Cl2N3OS .2HC1.2H20: C 52.59, H 1530, N 6.57 Found C 52.72, H 6.19, N 6.35 (2) (2R) -? - (3,5-dichlorobenzoyl) -2- (3,4-dimethylbenzyl) -4- [(E) -4-morpholino-2-butenyl] piperazine dihydrochloride m.p. > 230 aC [a] D25-3: + 5.80 ° (C = 0.50, MeOH) - IR (Nujol) 3426, 2927, 1120, 970 cm "1 r" NMR (DMSO-d6, d): 2.10-4.70 (23H, m), 6.17 (2H, broad), 6.69 (3H, broad), 7.07 (2H, broad), r "7.63 (1H, broad) MASS: 516 (M + H) + (free) Elemental Analysis Calculated for- C38H37C14N302 .0.5H20: 'C 56.20, H 6.40 N 7.02 Found C 56.20, H 6.29, N 6.89 (3) (2R) -1- (3,5-dichlorobenzoyl) -2- [(1H-indol-3-yl) methyl] -4- (4-thiomorpholino-2-butynyl) piperazine dihydrochloride m.p. 175 ° (decomposition) * ~ [] D2S '°: + 26.0 ° C (C = 0.50, MeOH) - IR (Kbr) 3407, 2543, 1639 c "1 - NMR (DMSO-ds, 6): 2.60-5.10 (21H, m), 6.70-7.80 (8H, "m), 11.02 (1H, broad s) ^ MASS: 541 (M + H) + (free) Elemental Analysis Calculated for C28H32C14N40S .1.5H20: C 52.43, H 5.50 , N 8.73 Found C 52.34, H 5.60, N 8.42 (4) _ (2R) -1- (3,5-dichlorobenzoyl) -2 - [(1H-indol-3-yl) methyl] -4-morpholino-2-butynyl) piperazine dihydrochloride p.f. 165 ° C (decomposition) [] D2S 0: + 27.50 ° (C = 0.50, MeOH) IR (Kbr) 3407, 1639, 1126 cm * 1 NMR (DMSO-d6, d): 2.80-5.20 (21H, m) , 6.70-7.85 (8H, m), 11.00 (1H, broad s) MASS: 525 (M + H) + (free) Elemental Analysis Calculated for C28H32C14N402.3H20: C 51.55, H 5.87, N 8.59 Found C 51.59, H 5.52, N 8.33 (5) (2R) -1- (3,5-dichlorobenzoyl) -2- (2-naphethylmethyl) -4- (4-thiomorpholino-2-butynyl) piperazine dihydrochloride m.p. 154 ° C (decomposition) [a] D23 8: -14.10 ° (C = 0.50, MeOH) IR (Kbr) 3417, 2933, 2537, 1641 cm * 1 NMR (DMSO-d6, d): 2.70-5.20 (21H , m), 6.56 (1H, broad), 7.08 (1H, broad), 7.53 (4H, broad), 7.89 (4H, broad) MASS: 552 (M + H) + (free) Elemental Analysis Calculated for C30H33C14N3OS .1.5 H20:. C 55.22, H 5.56, N 6.44 Found C 55.09, H 5.64, N 6.31 (6) _ (2R) -1- (3,5-dichlorobenzoyl) -2- (2-naphthylmethyl) -4- (4-morpholino-2-butynyl) piperazine dihydrochloride m.p. 171 ° (decomposition) [] D233: -15.10 ° C (C "= 0.50, MeOH) ~~ IR (Kbr) 3407, 2931, 2561, 1641, 971 cm * 1 NMR (DMSO-d6, d): 3.00- 5.20 (21H, m), 6.56 (1H, broad), 7.08 (1H, broad), 7.53 (4H, broad), 7.89 (4H, broad) MASS.: 536 (M + H) + (free) Calculated Elementary Analysis for C30H33Cl4N3O2 .H20: C 57.43, H 5.62, N 6.70 Found C 57.67, H 5.68, N 6.31 (7) (2R) -1- (3, 5-dichlorobenzoyl) -2- [4-trifluoromethyl-1-benzyl] -4- (4-t-butyl-2-butynyl] piperazine dfl. ° C (decomposition) [] D2S'4: + 15.80 ° (C = 0.50, MeOH) - IR (Kbr) 3430, 2917, 2524, 1641, 1068 cm "1 NMR (DMSO-d6, d): 2.70-5.20 (21H, m), 6.69 (1H, s), 7.10-7.30 (2H, m), 7.62 (4H, broad) - MASS: 570 (M + H) + (free) Elemental Analysis Calculated for C27H30C14F3N3OS .0.5H20: C 49.71, H 4.79, N 6.44 Found _ C 49.37, H 5.09, N 6.30 (8) (2R) -1- (3,5-dichlorobenzoyl) -2- [4- (trifluoromethyl) -benzyl] -4- (4-morphino-2-butynyl) piperazine dihydrochloride m.p. 186 ° C (decomposition) [a] D25-4: + 17.50 ° (C = 0.50, MeOH) IR (Kbr) 3421, 2935, 2553, 1644, 1068 cm "1 NMR (DMSO-ds, d): 2.80- 5.20 (21H, m), 6.72 (1H, s), 7.10-7.40 (2H, m), 7.64 (4H, broad) - MASS: 554 (M + H) + (free) Elemental Analysis Calculated for C27H30Cl4F3N302.0.5H20 : - C 50.96, H 4.91, N 6.60 Found C 50.57, H 5.05, N 6.52 Example 17 A mixture of 100 mg of (2R) -l- (3,5-dichlorobenzoyl) -2- (3,4-dimethylbenzyl) piperazine hydrochloride 121 mg of 3-bromo-1-propanol, 251 mg of potassium carbonate and 24 mg of potassium iodide in 3 ml of dry acetonitrile is stirred at 50 ° C for 10 hours. After cooling to room temperature, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography on silica gel using ethyl acetate as eluent to give (2R) -1- (3,5-dichlorobenzoyl) -2- (3,4-dimethylbenzyl) -4- (3-hydroxypropyl) piperazine like a syrup. 58 mg of matansulfonyl chloride are added to an ice-cooled solution of the alcohol obtained in the above pellet (210 mg) and 97.6 mg of triethylamine in 4 ml of dichloromethane for 1.5 hours. After stirring for 1 hour, the reaction mixture is washed with a saturated solution of sodium bicarbonate, dried over magnesium sulfate and evaporated under reduced pressure to give the corresponding mesylate A mesylate mixture obtained by In the above procedure, 59.1 mg of 4-aminomorpholine and 73.2 mg of triethylamine in 4 ml of methanol are stirred under reflux for 4 hours.The reaction mixture is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel. using ethyl acetate as eluent and treated with 4N hydrogen chloride in an ethyl acetate solution to give (2R) -1- (3,5-dichlorobenzoyl) -2- (3,4-dimethylbenzyl) -4 dihydrochloride. - (N-morpholino-3-aminopropyl) iperazine. p.f. 71 ° C (decomposition) [] D22 S: + 1.00 ° (C = 0.50, MeOH) 'IR (Nujol) 3400, 2950, 1640, 1100 cm * 1 NMR (DMS0-ds, d): 2.10-4.70 (23H , m), 6.68 (3H, broad), 7. 06 (2H, broad), 7. 63 (1H, broad) MASS: 519 (M + H) + (free) Elemental Analysis Calculated for C27H38C14N402. 2 . 5H20: _ C 50.87, H 6.80, N 8.79 Found "C 51.03, H 7.15, N 8.84 Example 18 ~~ Under a nitrogen atmosphere, to a mixture of 315 mg of (2R) -1- [3,5-bis (trifluoromethyl] benzoyl] -2- (3,4-dimethylbenzyl) piperazine and 98 mg of 3- (l) -methyl-lH-imidazol-4-yl) propanal in 6 ml of dichloromethane is added 225 mg of sodium triacetoxyborohydride and stirred at room temperature.After 4 hours, an aqueous solution of sodium bicarbonate is added to the mixture. the mixture is stirred for several minutes The organic layer is separated, dried over sodium sulfate and evaporated under reduced pressure The resulting residue is purified by column chromatography on silica gel using dichloromethane-methanol (10: 1) as eluant and treated with 4N hydrogen chloride in an ethyl acetate solution to give 187.1 mg of (2R) -l- (3,5-bis (trifluoromethyl) benzoyl] -2- (3, 4 ~ - dihydrochloride. dimethylbenzyl) -4- [3- (1-methyl-1H-imidazol-4-yl) propyl) piperazine - ^ mp 91 ° C (decomposition) [«] D24'2: -11.20 ° (C = 0.50, MeOH) IR (Nuj ol) 1640 cm * 1 NMR (DMSO-d6, d): 2.00-5.20 (21H, m), 6.67 (1H, broad s), 6.90-7.20 (2H, m), 7.44 (1H, broad s), 7.56 (1H, broad s), 7.67 (1H, broad s), 8.18 (1H, broad s), 9.03 (1H, broad s) MASS: 567 (M + H) + (free) Elemental Analysis Calculated for C29H34C12F6N40.3.5H20 : C 49.58, H 5.88, N 7.97 - Found C 49.71, H 5.90, N 7.79 Example 19 A mixture of 500 mg of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3, 4-dimethylbenzyl) piperazine, 168 mg of 2- (2-chloroethoxy) -ethanol, 233 mg of potassium carbonate and 56 mg of potassium iodide in 10 ml of N, N-dimethylformamide is heated with stirring at 50 ° C for 17 hours, at 60 ° C for 13 hours and at 70 ° C for 1 hour. The reaction layer is partitioned between ethyl acetate and water, 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 dichloromethane-methanol. (10: 1) as eluent to provide 359 mg "of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl) -2- (3,4-dimethylbenzyl) -4- [2-hydroxyethoxy) ethyl] piperazine.

IR (pure): 3450, 1640, 1440, 1280, 1130 cm "1 NMR (DMSO-d6, d): 2.03-4.93 (23H, m), 6.60-8.20 (6H, m) MASS: 533 (M + H) + Example 20 To a stirred solution of 151 mg of oxalyl chloride in 3 ml of dichloromethane are added dropwise a solution of 123 mg of dimethyl sulfoxide in 0.25 ml of dichloromethane at -78 ° C under a nitrogen atmosphere. After 15 minutes, "317 mg of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl) -2- (3,4-dimethylbenzyl) -4- [2- (2-hydroxyethoxy) are added. ethyl] piperazine at the same temperature. After 15 minutes, the resulting mixture is stirred at -45 ° C for 1 hour. 446 mg of triethylamine is added at -45 ° C, and the whole is stirred at 0 ° C for 20 minutes and then treated with 10 ml of an aqueous solution of ammonium chloride. The organic layer is separated and dried over magnesium sulfate. After evaporation of the solvent, the resulting residue is purified by column chromatography on silica gel using ethyl acetate as eluent to give 171 mg of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl) -2 - (3,4-dimethylbenzyl) -4- [2-formylmethoxy) ethyl] piperazine.

IR (pure): 3450, 1740, 1640, 1440, 1280, 1130 cm "1 NMR (DMSO-ds, d): 1.91-4.91 (22H, m), 6.53-8.20 (6H, m) MASS: 351 ( M + H) + Example 21 To a stirred mixture of 63 mg of 3,3-dimethylmorpholine hydrochloride and 42 mg of triethylamine in 5 ml of dichloromethane is added 200 mg of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl) -2- (3, 4-dimethylbenzyl) -4- [2-formylmethoxy) ethyl] piperazine and 120 mg of sodium triacetoxy borohydride at room temperature. The resulting mixture is stirred for 1 hour and then treated with an aqueous solution of sodium bicarbonate. The organic layer is separated and dried over magnesium sulfate. After evaporation of the solvent, the residue is purified by column chromatography on silica gel using dichloromethane-methanol (10: 1) as eluent and treated with 4N hydrogen chloride in ethyl acetate to provide 193 mg of dihydrochloride ( 2R) -1- [3,5-bis (trifluoromethyl) benzoyl) -2- (3,4-dimet iBenei1) -4- [2- [2- (3,3-dimethylmorpholino) ethoxy) ethyl] -piperazine as a powder _ _ [] D23: -18.20 ° (C = 0.50, MeOH) IR (pure) 3450, 2600, 1640, 1430, 1280, 1140 cm "1 I NMR (DMS0-d6, d): 1.33 (6H, s), 2.04-5.23 (29H, m), "6.60-8.26 (6H, m) 7 MASS: 630 (M + H) + (free) Elemental Analysis Calculated for" C32H41F6N303.2HC1.3.32H20: C 50.41, H 6.56, N 5.51 Found C 50.41, H 6.29, N 5.31 - "Example" _22 The following compound is obtained according to an imilar way to that of example 21. _ D iclo rh a ra to (2 R) -l - [3,5-bis (trifluoromethyl) benzoyl] -2 - (3, 4-dimethylbenzyl) -4 - [2 - (2-morpholinoethoxy) ethyl] piperazine [] D23: -21.4 ° (C = 0.50, MeOH) IR (pure) 3450, 2600, 1640, 1430, 1280, 1180, 1135 cm "1 NMR (DMS0-d6, d): 2.08-5.20 (31H, m), 6.60-8.24 (6H, m) MASS: 602 (M + H) + (free) Elemental Analysis Calculated for C30H37FsN3? 3.2HC1. 2.66H20: C 49.87, H 6.18, N 5.82 Found C 49.87, H 6.25, N 5.65 Example-23 A mixture of 250 mg of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl) -2- [(lH-indol-3-yl) methyl] -4- (3-methyl-sulphonyloxypropyl) piperazine90 mg of 4-aminothiomorpholine and 180 mg of sodium carbonate in 5 ml of methanol are stirred at reflux temperature for 3 hours. The reaction mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel using ethyl acetate-methanol (10: 1) as eluent and treated with 4N hydrogen chloride in ethyl acetate (3 ml) to provide 62 mg of (2R) dihydrochloride. ) -l- [3,5-bis (trifluoromethyl) benzoyl) -2- [(1H-indol-3-yl) methyl] -4 - [3 - (thiomorpholinoamino) ropil] piperazine as a powder. [a] D27: -5.80 ° (C = 0.50, MeOH) 1 IR (pure) 3300, 2500, 1630, 1420, 1275, 1130 c "1 NMR (DMS0-d6, d): 2.03-5.20 (23H, m ), 6.60-8.24 (8H, _ m), 10.95 (1H, s) MASS: 614 (M + H) + (free) Elemental Analysis Calculated for C29H35C12F6NS0S, 3H20: ~ 47. 10, ~ H, 5. 37, N 8, 88 Found, C 47.03, H5.58, N9.46 Example 24 A mixture of 200 mg of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl) -2 - (3,4-dimethylbenzyl) -4 - (2-met ylsulphonyloxyethyl) piperazine, 44 mg of 3-hydroxymethylpiperidine and 73 mg of triethylamine in 5 ml of methanol is stirred at reflux temperature for 2.5 hours. The reaction mixture is evaporated under reduced pressure and the residue is partitioned between 30 ml of ethyl acetate and 10 ml of water. The organic layer is dried over magnesium sulfate and then evaporated under reduced pressure. The resulting residue is purified by column chromatography on silica gel using dichloromethane-methanol (10: 1) as eluent and treated with 4N hydrogen chloride in ethyl acetate (0.2 ml) to give 85 mg of dihydrochloride ( 2R) -1- [3,5-bis (trifluoromethyl) benzoyl) -2- (3,4-dimethylbenzyl) -4- [2- (3-hydroxymethylpiperidino) ethyl] piperazine. [a] D25: -5.3080 ° (C = 0.50, MeOH) IR (pure) 3350, 2500, 1640, 14620, 1280, 1180, 1130 cm "1 NMR (DMSO-ds, 6): 1.0-5.20 (30H, m), 6.66-8.31 (6H, m) MASS: 586 (M + H) + (free) Elemental Analysis Calculated for C30H39Cl2FgN3O2.3H20: C 50.58, H 6.36, N 5.90 Found C 50.58, H 6.24, N 5.87 Example 25"" Nail mixture of 600 mg of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl) -4- (4-chloro-2-butynyl) -2- (2-naphthylmethyl) piperazine, 197 mg of 3,3-Dimethylmorpholine hydrochloride and 420 mg of potassium carbonate in 10 ml of N, N-dimethylformamide is stirred at room temperature in the presence of 10 mg of potassium iodide for 2 days. The reaction mixture is partitioned between 50 ml of ethyl acetate and 100 ml of water, and the organic layer is separated, washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue is purified by column chromatography on silica gel using a mixture of ethyl acetate-hexane (10: 1). The product that is obtained is. Dissolve in ethyl acetate and treat with 4N hydrogen chloride in ethyl acetate to provide 360 mg of (2R) -1- [3,5-bis (trifluoromethyl) berizoyl) -4- (3, 3-dihydrochloride. dimethylmorpholino) -2-butyl] -2- (2-naphthylmethyl) piperazine.

IR (Kbr) 3401, 2929, 2578, 2512, 1644, 1284, 1135 cm "1 NMR (DMSO-ds, d): 1.32 (3H, s), 1.39 (3H, s), 3.05- 5.4 (19H, m ), 7.0-8.2 (10H, m) MASS: 632 (M + H) + (free) Calculated Elemental Analysis for C34H37C12FSN302.2.5H20: C 54.48, H 5.65, N 5.61 _ Found C 54.25, H 5.53, N 5.39 Example 26 209 mg of acetic anhydride are added to 94 mg of formic acid. Allow the resulting mixture to warm to 50 ° C for 30 minutes and then add to 200 mg of (2R) -l- [3,5-bis (trifluoromethyl (benzoyl) -2- (3,4-dimethylbenzyl) -4- [3 - (morpholinoamino) propyl] piperazine at room temperature The whole is stirred overnight and then evaporated under reduced pressure.The resulting residue is dissolved in ethyl acetate and treated with 4N hydrogen chloride. in ethyl acetate (0.2 ml) to provide 112 mg of hydrochloride, (2R) -1- [3,5-bis (trifluoromethyl) benzoyl) -2 - (3,4-dimethylbenzyl) -4- [(3- (N-formylmorpholinoamino) propyl] piperazine. [A] D23: -16.3 ° (C = 0.50, MeOH) IR (pure) 3450, 2800, 2620, 1660, 1430, 1280, 1185, 1140 cm "1; L NMR ( DMSO-d6, d): 1.94-5.16 (29H,), 6.62-8.35 (7H, m) MASS: 615 (M + H) + (free) Elemental Analysis Calculated for C30H37ClFsN4O3.1.36H20: C 53.34, H 5.93, N 8.29 Found C 53.33, H 5.79, N 8.06 Example 27 To a mixture of 3.71 g of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl) -2- (3,4-dimethylbenzyl) piperazine, and 3.66 g of 4-formyl-1- (triphenylmet) pyrazole in 80 ml of 1,2-dichloroethane, 2.86 g of sodium triacetoxyborohydride are added. After stirring at room temperature for 3 hours, an aqueous solution of sodium bicarbonate is added to the mixture and the mixture is extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue is dissolved in 40 ml of dichloromethane and added to a mixture of 30 ml of trifluoroacetic acid and 15 ml of anisole. After stirring for 7.5 hours at room temperature, the mixture is suspended with 150 ml of 10% sodium hydroxide and aqueous sodium bicarbonate, and extracted with dichloromethane. The extract is washed with an aqueous solution of sodium bicarbonate and brine, successively, and dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (3: 7) to provide 2.84 g of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2 - (3,4-dimethylbenzyl) -4 - (4-pyrazolylmethyl) piperazine. NMR (DMSO-ds, d): 2.04-2.14 (6H, m), 2.60-4.76 (11H, m), 6.49-6.54 (1H, m), 6.86-6.96 (2H, m), 7.45 (2H, s) broad), 7.64-7.68 (2H, m), 8.14 (1H, m) MASS: 525 (M + H) + Example 28 158 mg of potassium carbonate and 0.045 ml of 2-bromoethanol are added to a solution of 300 mg of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -27- (3,4-dimethylbenzyl) - 4- (4-pyrazolylmethyl) piperazine in 3 ml of N, N-dimethylformamide at room temperature with stirring. After stirring at 100 ° C for 5 hours, the reaction mixture is poured into water and extracted with ethyl acetate.The organic layer is washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained is purified by column chromatography (30 ml) on silica gel using a mixture of ethyl acetate and hexane (3: 7) to provide 255.2 mg of (2R) -1- [3,5-bis] (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [[1- (2-hydroxyethyl) -lH-pyrazol-4-yl] methyl] piperazine IR (KBr) 1640 cm * 1" "" NMR (DMSO-ds, d): 2.04-2.15 (6H, m), 2.60-4.80 (11H, m), 3.67-3.75 (2H, m), 4.10 (2H, t, J = 5.7 Hz), 4.86 (1H, t, J = 5.3 Hz), 6.50-6.56 (1H, m), 6.90-6.98 (2H, m), 7.36 (1H, broad s), 7.43 (1H, broad s), 7.61 (1H, s broad), 7.67 (1H, broad s), 8.13 (1H, broad s). MASS: 569 (M + H) + Example 29 To a solution of 152 mg of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4 - [[1- (2-hydroxyethyl) -lH-pyrazole 4-yl] methyl] piperazine in 2 ml of ethyl acetate were added 0.48 ml of triethylamine and 0.027 ml of methanesulfonyl chloride at room temperature. After stirring for 10 minutes, the mixture is suspended with water and extracted with ethyl acetate. The combined extracts are washed with water and brine successively, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue is dissolved with 2 ml of N, N-dimethylformamide and 0.028 ml of morpholine, 74 mg of potassium carbonate and 13 mg of potassium iodide are added. After stirring at 70 ° C for 6 hours, the mixture is suspended with water and extracted with ethyl acetate. The combined extracts are washed with water and brine successively, dried over magnesium sulfate and evaporated under reduced pressure. The resulting residue is dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate (0.2 ml) at room temperature, hexane is added, filtered, dried under reduced pressure to provide 188.7 mg of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethyl-ylbenzyl) -4- [[1- (2-morpholinoethyl) -lH-pyrazole dihydrochloride] -4-yl] methyl] piperazine as a solid. "*" * Mp: 115-116 ° C [C] D25: -9.70 ° (C = 0.50, MeOH) IR (KBr) 1640 cm "1 7 NMR (DMSO -dg, d): 2.06-2.16 (6H, m), 2.85-5.00 (23H, m), 6.60-6.64 (1H, m), 6.91-7.08 (2H, m), 7.57 (1H, s), 7.74 (1H, broad s), 7.78 (1H, broad s), = _ 8.10 (1H, broad s), 8.18 (1H, broad s) - MASS: 638 (M + H) + (free) Example 30 A solution of 200 mg of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -4- (4-chloro-2-butynyl) -2 - (2-naphthylmethyl) piperazine, 47 mg of 3- (aminomethyl) pyridine and 0.08 ml of triethylamine in 2 ml of acetonitrile is stirred under reflux for 3 hours and evaporated under reduced pressure. The residue obtained is purified by column chromatography on silica gel (10 ml) using dichloromethane-methanol (30: 1) as eluent. The oil obtained is dissolved in ethyl acetate and treated with a solution of 4N hydrogen chloride in ethyl acetate. The mixture is evaporated under reduced pressure to provide 60 mg of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -4- [4- (3-pyridylmethylamino) -2 -butynyl-2- trichlorohydrate ( 2-naphthylmethyl) piperazine as a powder. [a] D29 -20.80 ° (C = OT25, MeOH) IR (pure) 3650-3100, 2750-1950, 1630, 1273, 1122 cm "1 NMR (DMSO-dg, d): 2.60-5.30 (16H, m ), 7.00-9.10 (14H, m) MASS: 625 (M + H) + (free) Calculated Elemental Analysis for C34H33C13FSN40.3.3H20: C 51.43, H 5.03, N 7.06 Found C 51.42, H 4.91, N 6.78 Example 31 2 A mixture of 300 mg of (2R) -l- [3, 5-bis (tr fluoromethyl) benzoyl] -4- (4-chloro-2-butinyl) -2- (2-naphthylmethyl) piperazine, 94 mg of cis-2,6-dimethylmorpholine and 210 mg of powdered potassium carbonate in 5 ml of dry N, N-dimethylformamide is stirred at room temperature overnight. The reaction mixture is poured into 50 ml of water and extracted with ethyl acetate. The extract 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 ethyl acetate and hexane (4: 1) as eluent. The product which is obtained is dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give 170 mg of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -4- dihydrochloride. [4-cis-2,6-dimethylmorpholino) -2-butinyl] -2- (2-naphthylmethyl) piperazine IR (Kbr) 3428, 2931, 2559, 1644, 1432, 1282, 1184 cm "1 NMR (DMSO-dg , d): 1.13 (3H, s), 1.16 (3H, s), 2.60- 5.40 (21H, m), 7.00-8.15 (10H, m) - MASS: 632 (M + H) + (free) Elemental Analysis Calculated for C34H37C12FSN302.2H20: - C 55.14, H 5.58, N 5.67 T Found C 54.89, H 5.59, N 5.31 Example 32 The following compound is obtained according to a manner "similar to that of Example 31. 1,3, [Bis (trifluoromethyl) benzoyl] -4- [4- (2-methyl-ethyl-azol-4-yl) methyl] -2- [(lH-indol-3-yl) methyl] piperazine] RMN hydrochloride (DMSO) -dg, d): 2.65 (3H, s), 3.00-5.20 (11H, m), 6.80-8.24 (9H, m), 'l0.93 (1H, broad d) MASS: 567 (M + H) + (free) Example 33 _. To a stirred solution of 943 mg of (2R) -l- [3,5-bis (trifluoromethyl) enzoyl] -2- (3,4-dimethylbenzyl) piperazine and 880 mg of potassium carbonate in 10 ml of dimethylformamide are added 0.2 ml of propargyl bromide at room temperature. After 1 hour, the reaction mixture was poured into 100 ml of water and extracted with ethyl acetate. The extract is washed with brine and concentrated under reduced pressure. The resulting residue is purified by column chromatography on silica gel using a mixture of hexane and ethyl acetate (5: 1) as an eluent to provide 1.09 g of (2R) -l- [3,5-bis ( trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4-propargylpiperazine as an oil. NMR (DMS0-d6, d): 2.00-2.20 (6H, m), 2.20-5.00 (12H, 'm), 6.60-8.20 (6H, m) MASS: 483 (M + H) + Example 34 A mixture of 286 mg of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4-propargylpiperazine, 118 mg of (3S) -3-isopropylmorpholine hydrochloride and 92 mg of N, N-diisopropylamine in 3 ml of dioxane is stirred at room temperature. 22 mg of paraformaldehyde and 10 mg of copper chloride (I) are added and the whole is stirred for 30 minutes and then heated at 80 ° C for 4 hours. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel using a mixture of hexane and ethyl acetate (1: 1) as eluent. The product which is obtained is dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give 190 mg of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] dihydrochloride] -4- [4- ((3S) -3-isopropylmorpholino) -2-butinyl] -2- (3,4-dimethylbenzyl) piperazine. IR (KBr) 3438, 2971, 2551, 1644, 1438, 1282, 1216, 1135 cm "1 NMR (DMSO-dg, d): 1.01 (6H, d, J = 6.8 Hz), 2.09-2.17 (6H, m ), 2.36 (1H, m), 2.60-5.30 (22H, m), 6.60- 8.30 (6H, m) MASS: 624 (M + H) + (free) Example 35 A mixture of 150 mg of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -4- (4-chloro-2-butenyl) -2- (3,4-dimethylbenzyl) piperazine, 47 mg of (3S) -3-isopropylmorpholine hydrochloride and 117 mg of potassium carbonate sprayed in 1 ml of dry N, -dimethylformamide is stirred at 50 ° C for 1. 5 hours. The reaction mixture is poured into 10 ml of water and extracted with ethyl acetate. The extract 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 ethyl acetate as eluent. The product obtained is dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to provide 110 mg of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] dihydrochloride] [4- ((3S) -3-isopropylmorpholino) -2-butenyl] -2- (3,4-dimethylbenzyl) piperazine. IR (KBr) 3430, 2971, 2661, 1644, 1434, 1280, 1135, 985, 680 cm "1 NMR (DMSO-ds, d): 1.01 (6H, m), 2.00-2.20 (6H, m), 2.40 (1H, m), 2.60-5.20 (24H, m), 6.60-8.20 (6H, m) MASS: 626 (M + H) + (free) Elemental Analysis Calculated for C33H43C12FSN302.3H20: C 52.66, H 6.56, N 5.58 Found C 52.45, H 6.55, N 5.49 Example 36 To a stirred solution of 133 mg of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [2- ((3R, 3S) -3 -hydroxymethylpiperidino) ethyl] piperazine in 1 ml of N, N-dimethylformamide are added 109 mg of 60% sodium hydride at the temperature of an ice-salt bath. A solution of 53 mg of ethyl iodide in 0.5 ml of N, N-dimethylformamide and the whole is stirred for 15 minutes and then at room temperature for 1 hour. The reaction mixture is poured into 20 ml of water and extracted with ethyl acetate. The extract is washed with brine and concentrated under reduced pressure. The residue that The residue is purified by column chromatography on silica gel using a mixture of dichloromethane and methanol (10: 1) as eluent. The product obtained is dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to provide 101 mg of (2R) -l- [3,5- 20 bis (trifluoromethyl) benzoyl] -2 dihydrochloride. - (3,4-dimethylbenzyl) -4- [2- ((3R, 3S) -3-ethoxymethylpiperidino) ethyl] piperazine. [a] D23: -8.0 ° (C = 0.50, MeOH) - IR (KBr) 3400, 2630, 2540, 1645, "435, 1280, 1180, 1135 cm" 1 NMR (DMSO-dg, d): 0.72- 5.24 (32H, m), 1.12 (3H, t), 6.62-8.26 (6H, m) MASS: 614 (M + H) + (free) Example 37 The requisite mesylate is prepared by the treatment of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- (2-hydroxyethyl) iperazine chloride with chloride. methanesulfonyl. A mixture of 200 mg of the mesylate and 66 mg of 4-hydroxymethylpiperidine hydrochloride in 1 ml of methanol is heated to reflux in the presence of 150 mg of potassium carbonate. After 3 hours, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The residue obtained is purified by column chromatography on silica gel using a mixture of dichloromethane and methanol (5: 1) as eluent. The product which is obtained is dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give 32 mg of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -4-dihydrochloride. - [2- (4-hydroxymethylpiperidino) ethyl] -2- (3, 4-dimethylbenzyl) piperazine. [A] D26: -5.8 ° (C = 0.50, MeOH) ~ "~ IR (KBr) 3370, 2600, 1645 , 1430, 1280, 1180, 1140 cm "1" NMR (DMSO-dg, d): 1.40-5.24 (30H, m), 6.60-8.24 (6H,, m), 8.45 (1H, s) MASS: 586 ( M + H) + (free) Elemental Analysis Calculated for C30H37FSN302.2HC1.4.85H20: C 48.36, H 6.57, N 5.64 Found ~ C 48.31, H 5.95, N 4.96 Example 38 'A mixture of 150 mg of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -4- (4-chloro-2-butynyl) -2 - (3,4-dimethylbenzyl) piperazine, hydrochloride of (3S) -3-ethylmorpholine and 117 mg of potassium carbonate sprayed in 1 ml of dry N, N-dimethylformamide is stirred at 50 ° C for 1.5 hours. The reaction mixture is poured into 10 ml of water and extracted with ethyl acetate. The extract is washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue obtained is purified by column chromatography on silica gel using ethyl acetate as eluent. The resulting product is dissolved in ethyl acetate and treated with 4N hydrogen chloride in the solvent. ethyl acetate to provide 177 mg of (2R) -l- [3,5-bis (trifluoromethyl) enzoyl] -4- [4 - ((3S) -3-ethylmorpholino) -2-butynyl] hydrochloride] -2- (3, 4-dimethylbenzyl) piperazine. [a] D26: 4.8 ° (C = 0.50, MeOH) IR (neat) 3430, 2580, 1645, 1435, 1280, 1180, 1135 cm * 1 NMR (DMSO-dg, d): 1.27 (3H, t), 1.45-5.20 (28H, m), 6.64-8.28 (6H, m) MASS: 610 (M + H) + (free) Elemental Analysis Calculated for C32H37FgN302.2HC1.3.5H20: C 51.55, H 6.22, N 5.64 Found C 51.61, H 6.02, N 5.60 Example 39 The requisite mesylate is prepared by the treatment of 150 mg of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- (2-hydroxyethyl) piperazine with 37 mg of methanesulfonyl chloride. A mixture of the mesylate and 51 mg of (3S) -3-ethylmorpholine hydrochloride in 1 ml of N, N-dimethylformamide is heated at 50 ° C in the presence of 85 mg of potassium carbonate. After ~~ 2 hours, the reaction mixture was poured into 10 ml of water and extracted with ethyl acetate. The extract 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 ethyl acetate as eluent. The product obtained is dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to provide 45 mg of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -4- dihydrochloride. [2 - ((3S) -3-ethylmorpholino) ethyl] -2- (3,4-dimethylbenzyl) piperazine.

[] D24: 1.60 ° (C = 0.50, MeOH) IR (KBr) 3430, 2610, 1645, 1435, 1280, 1180, 1135 cm "1 NMR (DMSO-ds, d): 0.95 (3H, s), 1.16 -5.20 (28H, m), 6.64-8.24 (6H, m) MASS: 586 (M + H) + (free) Elemental Analysis Calculated for C30H37F6N3O2.2HC1.1.8H20: C 52.15, H 6.21, N 6.08 Found C 52.15 , H 6.42, N 6.00 Example 40 A mixture of 200 mg of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -4- (2-methyl-sulfonyloxyethyl) -2- (2-naphthylmethyl) piperazine, 73 mg of 3- (N-dihydrochloride -methylaminomethyl) pyridine and 120 mg of triethylamine in 5 ml of dry methanol is refluxed for 4 hours. The reaction mixture is concentrated under reduced pressure and the resulting residue is partitioned between ethyl acetate and an aqueous solution of sodium bicarbonate. The organic layer is washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue is purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol (10: 1) as eluent to give an oily product, which is treated with hydrogen chloride. 4N in ethyl acetate (0.5 ml) to provide 78 mg of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -4- [2- [(N-methyl-N- (3-) dihydrochloride] pyridylmethyl) amino] ethyl] -2- (2-naphthylmethyl) piperazine. [] D2S: -12.9 ° (C = 0.50, MeOH) IR (KBr) 3410, 2600, 1640, 1430, 1280, 1180, 1135 cm "1 NMR (DMSO-d6, d): 2.40-5.28 (15H, m), 2.74 (3H, s), 7.00-9.10 (14H, m) MASS: 615 (M + H) + (free) Elemental Analysis Calculated for C33H32F6N40 .2HC1.4.6H20: C 51.45, H 5.65, N 7.27 Found C 51.40, H 5.35, N 7.07 Example 41 The following compound is obtained according to a manner similar to that of Example 40. i- D iclo rhidrat o de (2 R) - l - [3, 5-bis (trifluoromethyl) benzoyl] -2- [(lH-indol-3-yl) methyl] -4- [N-methyl-N- (3-pyridylmethyl) amino] ethyl] -piperazine [] D24: -0.8 ° (C = 0.50, MeOH) IR (KBr) 3400, 2600, 1640, 1280, 1180, 1135 cm "1 NMR (DMSO-ds, 6 ): 1.12-5.20 (15H, m), 2.84 (3H, s), I 6.63-9.00 (12H, m), 10.95 (1H, s) ^ MASS: 604 (M + H) + (free) Calculated Elemental Analysis for C3xH3XFgNsO .2HC1.4.5H20: -r C 49.15, H 5.59, N 9.24 Found C 49.19, H 5.41, N 9.08 Example 42 7 To a stirred mixture of 500 mg of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1H-indol-3-yl) methyl] -4- [N- ( 1-piperazinyl) carbamoylmethyl] piperazine and 302 mg of triethylamine in 10 ml of tetrahydrofuran is added a solution of 192 mg of benzyl 4-bromobutanoate in 2 ml of tetrahydrofuran at room temperature for 24 hours. As a part of the initial material that remains, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. To the resulting residue are added 192 mg of benzyl 4-bromobutanoate, 310 mg of potassium carbonate and 2 ml of N, N-dimethylformamide. The whole is stirred at room temperature for 7 hours and then diluted with ethyl acetate and filtered. The filtrate is washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the residue is purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol (5: 1) as an eluent to provide 296 mg of (2R) -l- [3.5 -bi s (tri fluoromethyl) benzoyl] -4 - [N- [4 - (3-benzyloxycarbonylpropyl) piperazin-1-yl] carbamoylmethyl] -2- [(1H-indol-3-yl) methyl] piperazine.

IR (pure): 3250, 1720, 1670, 1630, 1430, 1350, 1270, 1120 cm "1 NMR (DMSO-dg, d): 1.60-3.66 (25H, m), 5.10 (2H, s), 6.80- 7.86 (8H, m), 7.32 (5H, s), 8.21 (1H, s) MASS: 773 (M + H) + Example 43 A mixture of 1.3 g of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -4 - [N - [4 - (3-benzyloxycarbonylpropyl) piperazin-1-yl] -carbamoylmethyl] -2 - [(1H-indol-3"^ il) methyl] piperazine, 265 mg of ammonium formate and 130 mg of palladium 10% on activated carbon in 2.5 ml of water and ml of ethanol is heated to 70 ° C with stirring under a nitrogen atmosphere. After 1 hour, the reaction mixture is filtered and the filtrate is concentrated under reduced pressure. The product is triturated with ethyl ether to provide 1.19 g of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -4- [N- [4- (3-carboxypropyl) piperazin-1-yl] carbamoylmethyl] -2- [(lH-indol-3- il) methyl] piperazine as a powder. [a] D28: -18.60 ° (C = ^ 0.50, MeOH) IR (pure) 3200, 1680, 1620, 1425, 1275, 1120 cm "1 NMR (CDC13, d): 1.72-4.60 (25H, m), 6.71-7.93 (8H, m) MASS: 683 (M + H) + Z Example 44 The following compounds are obtained according to a manner similar to that of Example 5- (1). (1) (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -4 - [(2E) -3- [(3R) -4- (tert-butoxycarbonyl) morpholin-3-yl] -2 -propenyl] - 2- (3,4-dimethylbenzyl) piperazine IR (pure) 2973, 1697, 1645 cm "1 NMR (CDC13, d): 1.39 (9H, s), 2.00-2.16 (6H, m), 2.48-5.00 (18H, m), 5.40-5.80 (2H, m), 6.60-6.80 (1H, m), 6.90-7.20 * (2H, m), 7.30-7.70 (3H, m), 8.13 (1H, broad s) MASS: 670 (M + H) + _ (2: (2R) -1- [3, 5-bis (trifluoromethyl) benzoyl] -4- [(2E) -3- [(2R, 2S) -4- (tert-butoxycarbonyl) morph olin-2- il] -2- propenyl] -2- (3,4-dimethylbenzyl) piperazine NMR (DMSO-dg, d): 1.41 (9H, s), 2.08-2.16 (6H, m), 2.50-4.80 (18H, m), 5.55-5.85 (2H, m), 6.60-6.80 (1H, m) ), 6.90-7.20 (2H, m), 7.30-7.70 (2H, m), 8.13 (1H, broad s) MASS: 670 (M + H) + Example 45 A solution of 1.36 g of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -4- [(2E) -3- [(3R) -4- (ter-b utox ic arbonyl) morpholino- 3-yl] -2-propenyl] -2- (3,4-dimethylbenzyl) piperazine in 13 ml of ethyl acetate is treated with 4N hydrogen chloride in ethyl acetate (3.12 ml) at room temperature for 18 hours and then at 40 ° C during hours . The solution is diluted with hexane and stirred for 1 hour. The resulting precipitate is collected by filtration and dried under reduced pressure to provide 1.11 g of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4 dihydrochloride. - [(2E) -3 - [(3R) -3-morpholinyl] -2-propeny] piperazine as a white powder. p.f. : 125-232 ° C [] D2S: -12.00 ° (C = 0.50, MeOH) IR (KBr) 1645 cm * 1 = NMR (DMSO-dg, d): 2.10-2.18 (6H, m), 2.70-5.10 (18H,), 5.80-6.25 (2H, m), 6.60-6.70 (1H, m), 6.90-7.20 (2H, m), 7.39-7.69 (2H, m), 8.15-8.20 (1H, m), 9.60-10.0 (2H, m) MASS: 570 (M + H) + (free) Elemental Analysis Calculated for "C29H33F6N302.2HC1.1.0H20: C 52.73, H 5.65, N 6.36 ~ Found C 52.65, H 5.76, N 6.26 Example 46 To a solution of 500 mg of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- (4-pyrazolylmethyl) piperazine and 225 mg of bromoacetate of ter -butyl in 7.5 ml of N, N-dimethylformamide is added 390 mg of potassium carbonate, and the mixture is stirred at 60 ° C for 7 hours. Water is added to the mixture and the resulting mixture is extracted with ethyl acetate.The organic layer is washed with brine, dried over magnesium sulfate, evaporated under reduced pressure and purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (1: 1) as eluent to give (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -4- [[1- (tert-butoxycarbonylmethyl) -1H-pyrazole 4-yl] methyl] -2- (3,4-dimethylbenzyl) piperazine as an oil NMR (DMSO-ds, d): 1.01 (9H, s), 2.05-2.15 (6H, s), 2.52-4.90 ( 11H, m), 4.90 (2H, s), 6.53-6.58 (1H, m), 6.90-7.00 (2H, a), 7.41 (2H, s), 7.65 (2H, s), ~ 8.13 (1H, s broad) MASS: 639 (M + H) + Example 47 A solution of 425 mg of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -4- [[1- (tert-butoxycarbonylmethyl) -1H-pyrazol-4-yl] methyl] -2- ( 3,4-dimethylbenzyl) piperazine in 2.5 ml of dichloromethane is treated with 2.5 ml of trifluoroacetic acid at room temperature for 1 hour. The mixture is adjusted to pH 7.4 with an aqueous solution of sodium bicarbonate and evaporated under reduced pressure. The residue is washed with a mixture of dichloromethane and methanol (9: 1), and the solution is evaporated under reduced pressure and purified by column chromatography on silica gel using a mixture of methanol and chloroform (1: 9) as eluent and the subsequent crystallization from ethyl acetate, isopropyl ether and hexane to provide 395 mg of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -4- [[1- (carboxymethyl) -1H-pyrazolyl-4-yl] methyl] - 2- (3, 4-dimethylbenzyl) piperazine as a white powder mp: 223-230 ° C [«] • 15.10 ° (C = 0.50, MeOH) IR (KBr) 1683, 1604 cm * 1 NMR (DMSO-dg) , d): 2.06-2.15 (6H, m), 2.52-4.90 (11H, m), 4.54 (2H, s), 6.50-6.60 (1H, m), 6.90-7.00 (2H, m), 7.31 (1H , s), 7.40 (1H, s), 7.57-7.64 (2H, m), 8.14 (1H, s) Example 48 To a solution of "120 mg of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -4- [[1- (carboxymethyl) -lH-pyrazol-4-yl] methyl] -2- ( 3,4-dimethylbenzyl) piperazine in 1 ml of tetrahydrofuran is added 176 mg of 1-hydroxybenzotriazole hydrate, 240 mg of "l-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 0.11 ml of morpholine at room temperature, and the mixture is stirred at room temperature overnight. The mixture is suspended with water, and extracted with ethyl acetate. The organic layer is washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel using a mixture of methanol and ethyl acetate (1: 9) as eluent to give 76.7 mg of a crude oil. The oil is dissolved in 0.7 ml of ethyl acetate and 4N hydrogen chloride in ethyl acetate (0.15 ml) is added at room temperature. After the addition of isopropyl ether, the resulting precipitate is filtered off and dried under reduced pressure to provide 40 mg of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3-hydrochloride. , 4-dimethylbenzyl) -4- [[1- (morpholinocarboxymethyl) -lH-pyrazol-4-yl] methyl] piperazine as a powder. p.f. : 120-130 ° C - [] D2S: - 19. 40 ° (C = 0.25, MeOH) IR (KBr) 1649 cm "1 * _ NMR (DMSO-dg, d): 2.06-2.16 (6H, m), 2.52-5.00 (19H, m), 5.19 ( 2H, s), 6.55-6.62 (1H, m), 6.92-7.03 (2H, m), 7.44 (lUT S), 7.66-7.68 (2H, m), 7.92 (1H, broad s), 8.19 (1H, s broad) MASS: 652 (M + H) + (free) Elemental Analysis Calculated for C22H3SFsN503.HCl .2.6H20: TC 52.30, H 5.65, N 9.53 Found C 52.58, H 5.63, N 9.22 Example 49 The following compound is obtained according to a manner similar to that of Example 34.

D iclo rh i drat o of (2 R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [4- [(3S) -3- (2 -methypropyl) morpholino] -2-butinyl] piperazine p.f. : 125-138 ° C [] D2S: + 13.90 ° (C = 0.50, MeOH) IR (KBr) 1645 cm * 1 NMR (DMSO-ds, d): 0.80-1.80 (9H, m), 2.02-2.18 ( 6H, m), 2.83-5.13 (20H, m), 6.60-6.70 (1H, m), 6.96- 7.14 (2H, m), 7.46 (1H, broad), 7.67 (1H, broad), 8.16 ( 1H, broad s) - MASS: 638 (M + H) + (free) Elemental Analysis Calculated for C34H43Cl2FgN302.1.1H20: C 55.91, H 6.24, N 5.75 Found "C 56.24, H 6.75, N 5.74 Example 50 The following compound is obtained according to a manner "similar to that of Example 31.

D-hydrochloride (2 R) -l- "3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [4- (7-oxa-4-azaspiro [2.5] octane-4 -yl] -2-but inyl] piperazine [< X] D27 9: -9.70 ° (C = 0.50, MeOH) IR (KBr) 3700-3000, 2700-2200, 1645, 1534, 1463, 1280, 1184 cm * 1 NMR (DMSO-dg, d): 0.90-1.00 (4H, m), 3.00-4.70 (19H, m), 6.60-8.20 (6H, m) MASS: 608 (M + H) + (free) Analysis Elementary Calculated for C32H35F6N302.2HC1.2H20: C 53.64, H 5.77, N 5.86 Found C 53.92, H 6.05, N 5.61 Example 51 The following compounds are obtained according to a manner similar to that of Example 1- (1) (1) (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1 H -indol-3-yl) methyl] -4- [3- (4-methoxypyridin-3-yl) -2-propynyl] -piperazine NMR (CDC13, d): 2.00 ^ 5.20 (11H, m), 3.92 (3H, s), 6.80-8.00 (11H, m), 8.30 (1H, broad s) MASS: 601 ( M + H) + (free) (2) (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [3- (4-methoxypyridin-3-yl) -2-propynyl] - piperazine NMR (CDC13, d): 2.00-5.20 (17H, m), 3.93 (3H, s), 6.60-8.80 (9H, m), 8.02 (1H, s), 8".30-8.50 (1H, m) MASS: 590 (M + H) + 52 The following compounds are obtained according to a manner similar to that of example 5- (2) (1) D hydrochloride (2 R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1H-) indol-3-yl) methyl] -4- [3- (4-methoxypyridin-3-yl) -2-propynyl] -piperazine _ ^ pf : 162-167 ° C ~ [a] D26'6: + 4.90 ° (C = 0.50, MeOH) - IR (KBr) 3700-3300, 2700-2300, 1641, 1502, 1430, 1363, 1280 cm * 1 NMR (DMSO-dg, d): 3.00-5.20 (14H, m), 6.60-8.30 (9H, m), 8.80-9.90 (2H, m), 10.96 (1H, broad s) MASS: 601 (M + H) + (free) Calculated Elemental Analysis for C31H2SFsN402.2HC1.2.2H20: C 52.16, H 4.91, N 8.32 Found C 52.21, H 4.58, N 7.86 (2) Dichlorhydrate (2 R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [3- (4-methoxypyridin-3-yl) -2 -propinyl] -piperazine pf : 150-153 ° C [C] D24'9: -7.45 ° (C = 0 55, MeOH) IR (KBr) 3600-3300, 2700-2200, 1639, 1500, 1430, 1317, 1280 cm "1 NMR ( DMSO-d6, d): 2.00-2.20 (6H, m), 2.80-5.20 (11H, m), 6.60-7.80 (6H, m), 8.20 (1H, broad), 8.81- 8.97 (2H, m) MASS: 590 (M + H) + (free) Elemental Analysis Calculated for C31H29F6N302.2HC1.2.2H20: C 52.97, H 5.27, N 5.93 Found C 53.03, H 5.08, N 5.98 53 The following compounds are obtained according to a manner similar to that of Example 3. (1) ID hydrochloride _ of (2 R) -l- [3, 5 - = * bis (trifluoromethyl) benzoyl] -2- [(lH-indol-3-yl) methyl] -4- _T [3- ( 4-methoxypyridin-3-yl) propyl] -piperazine 77 pf : 165-170 ° C [a] D24'9: -1.91 ° (C = 0755, MeOH) IR (KBr) 3700-2300, 1643, 1502, 1432, 1363, 1280, 1222 cm "1 - NMR (DMS0- d6, d): 2.00-2.30 (2H, m) _, 2.60-5.20 (16H, - m), 6.60-8.30 (9H, m), 8.70-8.90 (2H, m), 10.95 (1H, s broad) , 11-60-1180 (2H, ra) MASS: 605 (M + H) + (free) Elemental Analysis Calculated for C3XH30FgN402.2HC1.2.8H20: C 51.15, H 5.21, N 7.70 Found C 51.11, H 5.40, N 7.61 (2) Dichlorhydrate (2 R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [3-7 (4-methoxypyridin-3-yl) -propyl] piperazine-mp: 159-168 ° C - ta ^ D26 9: -10.91 ° (C = 0.55, MeOH) "IR (KBr) 3600-3300, 2700-2300, 1643, 1502, 1430, 1361, 1280 cm "1 NMR (DMSO-dg, d): 2.00-5.20 (21H, m), 4.13 (3H, s), 6.60-7.80 (6H, m) 8.20-8.30 (1H, m), 8.70-8.90 (2H , m), 11.60-11.90 (2H, m) MASS: 594 (M + H) + (free) Elemental Analysis Calculated for C31H33FgN302.2HC1.2.4H20: C 52.50, H 5.97, N 5.60 Found C 52.46, H 5.65, N 5.92 Ejeraplo 54 A solution of 127 mg of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1H-indol-3-yl) methyl] -4- [3- [6- (ter- butoxycarbonylamino) pyridin-3-yl] -2-propynyl] piperazine prepared in a manner similar to that of example 5- (1) and 5 ml of trifluoroacetic acid in 5 ml of dichloromethane is stirred at room temperature for 2 hours. The reaction mixture is concentrated under reduced pressure and the residue is partitioned between a saturated aqueous solution of sodium bicarbonate. The organic layer is separated, dried over magnesium sulfate and concentrated under reduced pressure. The resulting syrup is dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to provide 80 mg of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- dihydrochloride. [(1H-indol-3-yl) -methyl] -4- [3- (6-aminopyridin-3-yl) -2-propynyl] piperazine. p.f. : 190-195 ° C [a] D24 '°: -13.47 ° (C = 0.23, MeOH) IR (KBr) 3600-3000, 2700-2500, 1668, 1619, 1428, 1359, 1280 cm "1 NMR (DMSO) -dg, d): 3.00-5.20 (11H, m), 6.60-7.50 (6H, m), 7.70-8.30 (5H, m), 8.20-8.50 (2H, m), 11.95- 11.10 (1H, broad) ) MASS: 586 (M + H) + (free) Elemental Analysis Calculated for C30H2SFgN5O .2HC1.2.5H20: - C 51.22, H 4.58, N 9.95 Found C 51.17, H 4.40, N 9.27 Example 55 The following compound is obtained according to a manner similar to that of Example 54.

Dichlorhydrate (2 R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [3- (6-aminopyridin-3-yl) -2-propynyl] -piperazine _ pf : 183-189 ° C IR (KBr): 3600-2500, 1É > 44, 1596, 1525, 1375, 1280 cm "1 NMR (DMSO-d6, d): 2.00-2.25 (6H, m), 2.80-5.25 (13H, m), 6.60-8.40 (9H, m), 8.00-8.80 (2H, m) MASS: 575 (M + H) + (free) Elemental analysis calculated for C30H28FsN4O • 2HC1 • 1.5H20 : C 53.42, H 4.93, N 8.31 Found: C 53.08, H ~ 5.01, N 8.12 Example 56 _ The following compounds are obtained according to a manner similar to that of Example 5. (1) (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (2-naphethylmethyl) -4- [3- (2-pyridyl) -2-propynyl] piperazine IR (KBr): 3700-3200, 1641, 1278, 1136 cm "1 NMR (DMSO-dg, d): 2.2?" - 4.00 (9H, m), 4.30-5.20 (2H, m), 7.00-8.65 (14H , m) MASS: 582 (M + H) +, 467 - (2) D hydrochloride (2 R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1H-indol-3-yl) ) methyl] -4- [(2E) -3- (3-pyridyl) -2-propenyl] piperazine pf : 195-203 ° C [?] D24 9: -11.20 ° (C = 0.50, MeOH) IR (KBr): 3600-330, 2700-2500, 1644, 1430, 1363, 1280, 1184 cm "1 NMR (DMSO-dg, d): 3.00-5.20 (11H, m), 6.60-7.60 (6H, m), 7.70-9.00 (8H, m), 11.00 (1H, broad), 12.00- 12.40 (2H, m) MASS: 573 (M + H) + (free) Elemental analysis calculated for C30H2SFgN4O • 2HC1 -2.5H20 : C 52.18, H 4.82, N 8.11 Found: C 51.94, H 4.77, N 7.77 (3) Dichlorhydrate (2 R) -l- [3,5-bis (trifluoromethyl) benz "oyl] -2- (3,4-dimethylbenzyl) -4- [(2Z) -3- (3-pyridyl) -2-propenyl] -piperazine mp: 170-174 ° C [a] D23-0: -7.30 ° (C = 0.50, MeOH) IR (KBr): 3600-3300, 2700-2500, 1644, 1550, 1430, 1363, 1280 cm * 1 NMR (DMS0-ds, d): 2.00r2.30 (6H, m), 2.80-5.20 (11H, m), 6.40-8.40 (10H, m), 8.70-8.85 (2H, m ), 12.00-12.20 (2H, m) MASS: 562 (M + H) + (free) Elemental analysis calculated for C30H29FsN3O • 2HC1 • 2.5H20: C 53.03, H 5.34, N 6.18 Found: C 52.99, H 5.41, N 5.91 (4) (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1 H -indol-3-yl) methyl] -4- [4- (2-pyridyl) -3-butynyl ] piperazine ^ NMR (CDC13, d) 1.80-5.20 (13H, m), 6.80-8.00 (12H, m), 8.19 (1H, s), 8.55 (1H, d, J = 4.0Hz) MASS: 585 (M + H) + Eieraplo 57 The following compounds are obtained according to a manner similar to that of Example 5. (l) (2R) -1- [3,5-bis- (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [3- (6-methoxypyridin-3-yl) dihydrochloride ) ropil] -piperazine pf : 127-137 ° C [] D22 5: -15.93 ° (C = 0.16, MeOH) IR (KBr): 3600-3300, 2700-2500, 1646, 1556, 1434, 1280, 1184 cm "1 NMR (DMSO-dg, d): 1.90-5.20 (21H, m), 3.84 (3H, s), 6. 60-7.30 (4H, m), 7.40-7.80 (3H, m), 8.00-8.30 (2H, m) MASS: 594 (M + H) + (free) Elemental isis calculated for C3XH33F6N302-2HC1-1.2H20: C 54.11, H 548, N 6.11 Found: C. 54.09, H 5.75, N 5.83 (2) Dichlorhydrate (2 R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1H-indol-3-yl) methyl] -4- [3- (6-methoxypyridin-3 -yl) propyl] piperazine pf : 195-200 ° C [] D22's: -2.03 ° (C = 0.32, MeOH) IR (KBr): 3600-3300, 2700-2300, 1644, 1556, 1494, 1432, 1363, 1280, 1180 cm * 1 NMR (DMSO-dg, d): 2.20 ^ -5.20 (15H, m), 3.79 (3H, s), 6. 60-8.30 (11H, m), 10.95 (1H, broad s), 11.60-11.80 (2H, m) MASS: 605 (M + H) + (free) Elemental analysis calculated for C3XH30F6N4O2 • 2HC1 • 1.5H20 : C 52.58, H 5.01, N 7.95 Found: C 52.89, H 5.40, N 7.63 (3) D iclo rhi dra to of (2 R) -l- [3, 5-bis (trifluoromethyl) benzoyl] -2- (2-naphthylmethyl) -4- [3- (2-pyridyl) ropil] piperazine [ a] D26-8: -27.60 ° (C = 0.50, MeOH) IR (KBr): 3700-3000, 2700-2200, 1647, 1279, 1136 cm "1 NMR (DMSO-d6, d): 2.20-4.30 ( 13H, m), 4.40-5.40 (2H, m), 7.00-8.90 (14H, m) MASS: 586 (M + H) + (free) Elemental analysis calculated for C32H29FSN30-2HC1 -2.5H20: C 54.63, H 5.16 , N 5.97 Found: C 54.55, H 5.37, N 5.56 (4) Dichlorhydrate (2 R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1 H -indol-3-yl) methyl] -4- [4- (2-pyridyl) Piperazine pf : 155-160 ° C [a] D27 0: + 9.50 ° (C = 0.10, MeOH) IR (KBr): 3700-3000, 2700-2200, 1641, 1459, 1428, 1280, 1137 cm "1 NMR (DMSO-dg, d): 1.70-2.20 (4H, m), 2.60-5.20 (13H, m), 6.60-8.80 (12H, m), 11.00 (1H, broad s), 11.40- 11.80 (2H, m) MASS: 589 (M + H) + (free) Elemental analysis calculated for C31H30FSN40-2HC1 -2.0H2O : C 53.38, H 5.20, N 8.03 Found: C 53.34, H 5.38, N 7.78 Example 58 A mixture of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1H-indol-3-yl) methyl] piperazine (0.83 g), methyl bromopylacetate (0.42 g), Potassium carbonate (1.0 g) in N, N-dimethylformamide (5 ml) is stirred at 50 ° C for 3 hours. The reaction mixture is poured into water and the resulting precipitates are collected by filtration. The precipitates are purified by column chromatography on silica gel using a mixture of dichloromethane and ethyl acetate as eluent to provide a mixture of diastereomers, (2R, 2S) -2- [(2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1H-indol-3-yl) methyl] piperazin-4-yl] -2- methyl phenylacetate (1.00 g). NMR (CDC13, d): 2.00-5.20 (4H, m), 3.69 (3H, s), 6.70- 8.20 (14H, m) 7 MASS: 604 (M + H) + (free)Example 59 A solution of a mixture of the diastereoisomers, (2R, 2S) -2- [(2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1H-indol-3-yl) methyl] piperazin-4-yl] -2- Methyl phenylacetate (360 mg) in 1N sodium hydroxide (1.5 ml) in methanol (5 ml) is stirred at 50 ° C for 2 hours. The mixture is concentrated under reduced pressure to an aqueous solution. The solution is diluted with water and the solution becomes acidic (approximately pH 5) with dilute hydrochloric acid and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated under reduced pressure to provide a mixture of diastereoisomers, (2R, 2 S) -2 - [(2R) -1 - [3,5-bis (trifluoromethyl) enzoyl]] -2- [(1 H -indol-3-yl) methyl] -piperazin-4-yl] -2-phenylacetic acid (0.33 g). _- NMR (CDC13, d): 2.20-5.80 (10H, m), 6.60-8.20 (14H, m) MASS: 590 (M + H) + (free) Example 60 0.116 ml of isobutyl chloroformate are added dropwise to a suspension of the mixture of diastereomers, 0.5 g of (2R, 2S) -2- [(2R) -1- [3,5-bis (trifluoromethyl) benzoyl] - 2- [(1H-indol-3-yl) -methyl [piperazin-4-yl] -2-phenylacetic acid and 0.103 ml of N-methylmorpholine in 3 ml of 1,2-dimethoxyethane under -18 ° C.

After stirring at the same temperature for 30 minutes, a solution of 32 mg of sodium borohydride in 0.5 ml of water is added to the mixture, all at once. After stirring at room temperature for 30 minutes, a 1 N sodium hydroxide solution is added to the mixture and the whole is stirred at room temperature for 1 hour. The mixture is neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The extract is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel using a mixed eluent of dichloromethane and methanol. The fractions containing the objective compound are collected and evaporated under reduced pressure to provide a mixture of diastereomers, 0.42 g of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1H-indole. -3-yl) methyl] -4- [(IR, IS) -1-phenyl-2-hydroxyethyl] iperazine. - NMR (CDC13, d): 1.90-5. ^ 20 (13H, m), 6.60-8.20 (14H,? ¡N MASS: 576 (M + H) + Example 61 0.058 ml of methanesulfonyl chloride are added to a solution of the diastereomer mixture, and 0.36 g of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl + -2- [(1H-indole-3-yl)] methyl] -4- [(IR, ß-1-phenyl-2-hydroxyethyl] piperazine and 0.16 ml of triethylamine in 10 ml of dichloromethane at -18 [deg.] C. After stirring at the same temperature for 30 minutes, they are added to mix an additional 0.058 ml of methanesulfonyl chloride and 0.16 ml of triethylamine.After stirring at the same temperature for an additional 30 minutes, the reaction mixture is washed with water, dried over magnesium sulfate and evaporated under reduced pressure to provide The corresponding mesylate A mixture of the mesylate and 0.4 ml of morpholine in 1,4-dioxane is stirred at 50 ° for 3 hours.The reaction mixture is concentrated under reduced pressure to provide a syrup, which is divided between water and acetate The organic layer is separated, washed with brine, dried over sulfur The mixture is then concentrated under reduced pressure to provide the crude mixture of diastereoisomers, which is purified by silica gel column chromatography using a mixed eluent of dichloromethane and methanol. Fractions that elute more rapidly are collected, evaporated under reduced pressure and treated with 4 N hydrogen chloride in ethyl acetate to provide a diastereomer of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl dihydrochloride] ] -2- [(lH-indol-3-yl) methyl] -4- [(IR or ÍS) -1-phenyl-2-morpholinoethyl] -piperazine. "- pf : 203-207 ° C [] D21'7: -6.0 ° (C = 0.25, MeOH) - IR (KBr): 3700-3300, 3100-2200, 1641, 1450, 1432, 1363, 1280 cm "1-NMR (DMSO-dg, d): 2.40-5.20 (20H, m), 6.60-8.30 (8H, m), 10.95 (1H, s) r MASS: 644 (M + H) + (free) Elemental analysis calculated for C34H34F6N402 • 2HC1 - 2 / 3H20 : C 55.97, H 5.97, H 5.16, N 7.68 Found: C 55.98, H 5.48, N 7.26".- The fractions that elute more slowly are collected, evaporated under reduced pressure and treated with 4N hydrogen chloride in ethyl acetate to provide a diastereomer of (2R) -l- [3,5-bis (trifluoromethyl) dihydrochloride. ) benzoyl] -2- [(lH-indol-3-yl) methyl] -4- [(ÍS or IR) -l-phenyl-2-morpholinoethyl] piperazine, "pf : 207-212 ° C [0C] D21-7: -3.33 ° (C = 0.24, MeOH) IR (KBr): 3700-3200, 3000-2300, 1643, 1450, 1432, 1280, 1182, cm "1 NMR (DMSO-dg, d): 2.4? "- 5.20 (20H, m), 6.55-8.35 (8H, m), 10.95 (1H, s), 11.0D-12.10 (2H, m) MASS: 644 (M + H) + (free) - Elemental analysis calculated for C34H34F6N402 - 2HC1 - 0.5H20: C 56.20, H 5.13, N 7.71 Found: C 56.15, H 5.52, N 7.32 Example.62 The following compound is obtained according to a manner "similar to that of Example 45. Dichlorhydrate (2 R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) - 4- [3- [(2R, 2S) -2 -morpholinyl] -2-propenyl] -piperazine mp: 160-163 ° C [] D25: -12.50 ° (C = 0.50, MeOH) IR (KBr): 1645 cm "1 NMR (DMSO-dg, d): 2.08-2.18 (6H, m), 2.55-5.10 (18H, m), 5.80-6.20 (2H, m), 6.60-6.70 (1H,), 6.90- 7.20 (2H, m), 7.47-7.70 (2H, m), 8.15-8.20 (1H, xa) MASS: 570 (M + H) + (free) Elemental analysis calculated for C29H35FsN302 • 2HC1 • 1.0H2O : C 52.59, H 5.65, N 6.34 Found: C 52.85, H 5.97, N 6.16 Example 63 A mixture of 500 mg of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) iperazine and 15 μl of 1,8-diazabicyclo [5.4.0] undec-7 The ether in 2.5 ml of tetrahydran is cooled to -30 ° C with stirring under a nitrogen atmosphere. Acrolein (90%, 0.225 ml) is added to the mixture while maintaining the temperature at -20 ~ -40 ° C for a period of 10 minutes and then the resulting mixture is stirred at 0 ° C. After 6 hours, the reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with brine and dried over magnesium sulfate. After evaporation of the solvent under reduced pressure, the resulting residue is chromatographed on silica gel using a mixture of hexane and ethyl acetate as eluent to give 332 mg of (2R) -1- [3,5-bis ( trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- (2-formylethyl) piperazine as an oil. 7 NMR (DMSO-dg, d): 1.60 ^ 4.90 (19H, m), 6.55-6.75 (1H,), 6.90-7.15 (2H, m), 7.30-7.75 (2H, m), 8.13 (1H, s) broad), 9.70 (1H, s) MASS: 501 (M + H) + 5 Example 64 To a stirred mixture of 122 mg of 4-amino-3, 3-dimethylmorpholine hydrochloride in 5 ml of dichloromethane are added. mg of triethylamine at an ice bath temperature. A solution of 150 mg of (2R) -l- [3,5-bis (trifluoromethyl (benzoyl) -2- (3,4-dimethylbenzyl) -4- (2-formylethyl) piperazine in 2 ml is added. of dichloromethane and the resulting mixture is stirred at room temperature.

After 15 minutes, the reaction mixture is concentrated under reduced pressure. The resulting residue is chromatographed on silica gel using a mixture of hexane and ethyl acetate as eluent and the desired product is treated with 4N hydrogen chloride in ethyl acetate to provide 122 mg of dihydrochloride (2R) -1- [3,5-bis (trifluoromethyl) -benzoyl] -2- (3, 4-dimethylbenzyl) -4- [3- (3, 3-dimethylmorpholinimino) propyl] piperazine. IR (KBr): 3425, 2700, 2625, 1645, 1430, 1280, 1180, 1135 cm "1 NMR (DMSO-dg, d): 1-06-1.40 (6H, m), 2.00--2.40 (6H, m ), 2.60-5.80 (19H, m), 6.64-8.30 (6H, m), 10.00-12.18 (2H, m) MASS: 613 (M + H) + (free) Elemental analysis calculated for C31H38F6N402 • 2HC1 • 2H20 : C 51.60, H 6.15, N 7.76 Found: C 51.82, H 6.49, N 7.29 Example 65 To a stirred mixture of 100 mg of 4-aminohomomorpholine dihydrochloride in 5 ml of dichloromethane is added 107 mg of triethylmethyl at an ice bath temperature. A solution of 200 mg of (2R) -1- [3 is added, 5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- (2-formylethyl) piperazine in 2 ml of dichloromethane and the resulting mixture is stirred at room temperature. After 30 minutes the reaction mixture is concentrated under reduced pressure. The resulting residue is chromatographed on silica gel using a mixture of hexane and ethyl acetate as eluent to give 110 mg of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3, 4 - dimethylbenzyl) -4- [3- (homomorpholinoimino) propylTiperazine and an intermediate. This compound is dissolved in 5 ml of methanol and 17 mg of sodium borohydride is added at ice bath temperature. After 2 hours, an additional 40 mg of sodium borohydride is added and the reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with water and then extracted with dichloromethane. The extract is washed with brine and dried over magnesium sulfate. After evaporation of the solvent, the resulting residue is purified by silica gel column chromatography using a mixture of dichloromethane and methanol (50: 1) as eluent to provide the desired product, which is dissolved in ethyl acetate and Treat with 4N hydrogen chloride in ethyl acetate to provide 66 mg of the (2R) -1- [3,5-bis- (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [3-dihydrochloride] - (homomorfolinoamino) propyl] piperazine. [a] D27: -13.7 ° (C = 0.50, MeOH) ~ IR (KBr): 3450-2700, 2620.1645, 1430, 1280, 1185, 1135 c "1" _ MASS: 601 (M + H) + (free) Elemental analysis calculated for C30H3gF6N4O2 • 2HC1 - 0.7H20: C 52.51, H 6.08, N 8.17 Found: C 52.51, H 6.05, N 7.86 Preparation 32 29.4 g of diterbutyl dicarbonate are added to a mixture of 45.0 g of (2R) -2- (3,4-dimethylbenzyl) -4-benzylpiperazine dihydrochloride and 59.6 ml of triethylamine in 900 ml of tetrahydrofuran under cooling with ice. After 3 hours of stirring at the same temperature, stirring is continued at room temperature for 9 hours. The mixture is poured into 1 liter of ice water and extracted with 2.5 l of ethyl acetate.The extract is washed successively with 1N hydrochloric acid and brine, dried over sodium sulfate and evaporated under reduced pressure to provide a Crude oil of 49.6 g of (2R) -4-benzyl-l-tert-butoxycarbonyl-1- (3,4-dimethylbenzyl) piperazine. NMR (DMS0-ds, d): 1.40 (9H, s), 1.90-2.06 (2H, m), 2.15-2.17 (6H, m), 2.60-4.4 (9H, m), 6.86-7.05 (3H, m), 7. 20-7.39 (5H, m), ~ MASS (APCI): 395 (M + H) +, 339, 295 Preparation 33 ~ A solution of 48.5 g of (2R) -4-benzyl-l-tert-butoxycarbonyl-2- (3,4-dimethylbenzyl) piperazine in 730 ml of methanol is hydrogenated on palladium hydroxide 20% -carbon (0.3 g) at room temperature under atmospheric pressure. After removal of the catalyst by filtration, the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (10: 1). The fractions containing the objective compound are collected and evaporated under reduced pressure to provide 33.7 g of a (2R) -l-tert-butoxycarbonyl-2- (3,4-dimethylbenzyl) piperazine oil.

* ~ NMR (DMS0-d6, d): 1.26 (9H, s), 2.15-2.17 (6H, m), 2.30-4.05 (10H, m), 6.86-7.05 (3H, m) MASS (APCI): 305 (M + H) +, 249, 205 Preparation 34 A mixture of 29.0 g of (2R) -l-tert-butoxycarbonyl-2- (3,4-dimethylbenzyl) piperazine, 22.7 g of 3,3-dimethyl-4- (4-chloro-2-butynyl) morpholinin dihydrochloride , 39.5 g of potassium carbonate and 1.58 g of potassium iodide in 145 ml of N, N-dimethylformamide are stirred at room temperature for 2 hours, followed by 53 ° C for 3 hours. After cooling to room temperature, the mixture is poured into 1.2 liter of ice-water and extracted with 1.2 l of ethyl acetate. The extract is washed with 1 l of water and reextracted with 190 ml of 1 N hydrochloric acid. The aqueous acid layer is separated and the weight of the solution is converted to 1N sodium hydroxide. The alkaline solution is extracted with 1.1 l of ethyl acetate and the extract is washed with brine, dried over sodium sulfate and evaporated under reduced pressure to provide 43.1 g of a (2R) -1-tert-butoxycarbonyl- 2- (3,4-dimethylbenzyl) -4- [4- (3,3-dimethylmorpholino) -2-butinyl] -piperazine.

NMR (DMSO-dg, d): 0.95 (6H, s), 1.26 (9H, s), 2.03- L. 4.20 (25H, m), 6.80-7.05 (3H, m) - ^ MASS (APCI): 470 (M + H) + Preparation 35"" A solution of 4N hydrogen chloride in ethyl acetate is added to a solution of 40.0 g of (2R) -1-tert-butoxycarbonyl-2- (3,4-dimethylbenzyl) -4- [4- (3, 3 dimethylmorpholino) -2-butynyl] -piperazine in 120 ml of ethanol at room temperature and the whole is stirred for 12 hours.The reaction mixture is concentrated under reduced pressure and the residue is divided between 500 ml of ethyl acetate and a potassium carbonate solution The organic layer is separated and the aqueous layer is extracted with 300 ml of ethyl acetate.The combined extract is dried over sodium sulphate and evaporated under reduced pressure, and the residue is purified by column chromatography. on silica gel using a mixed solvent of n-hexane and ethyl acetate (3: 1) Fractions containing a target compound are collected and evaporated under reduced pressure and treated with 4N hydrogen chloride in ethyl acetate to provide 37.7 g of (3R) -3- (3,4-dimethylbenzyl) -1- trichlorohydrate. [4- (3,3-dimethylmorpholino) -2-butinyl] piperazine. p.f. : 264-272 ° C [a] D27: -23.6 ° (C = 0.5, MeOH) IR (KBr): 3500-3400, 2900, 2570, 2480, 1637, 1626, 1508, 1455, 1180 cm "1 - NMR (DMSO-dg, d): 1.33 (3H, s), 1.39 (3H, s), 2.21 (6H, S), 2.80-4.60 (20HJL m), 6.90-7.20 (3H, m), 9.90- 10.40 ( 3H, m) MASS (APCI): 370 (M + H) + (free) Preparation 36 0.22 ml of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide is added over 5 minutes to a mixture of 0.48 g of (3R) -3- (3,4-dimethyl-triebenzyl) -1- [4 - ( 3, 3dimethylmorpholino) -2-butinyl] -piperazine and 0.27 g of 3,5-bis (trifluoromethyl) enzoic acid, and 0.15 g of 1-hydroxybenzotriazole and 0.35 ml of triethylamine in 10 ml of dichloromethane. After 2 hours of stirring at room temperature, the reaction mixture is purified directly by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (40: 1). The fractions containing the objective compound are collected and evaporated under reduced pressure. The residue is treated with 4N hydrogen chloride in ethyl acetate and recrystallized from a mixture of acetone and water to provide 525 g of colorless crystals of (2R) -l- [3,5-bis (trifluoromethyl) dihydrochloride. ) enzoyl] -2- (3,4-dimethylbenzyl) -4- [4- (3, 3dimethylmorpholino) -2-butynyl] -piperazine mp: 180-190 ° C [CÍ-D28-3: -7.24 ° (C = 1.05, MeOH) ^ IR (Nujol): 3300, 2700-2400, 1635 cm "1-NMR (DMSO-d6, d): 1.30-1.40 (6H, m), 2.00-5.22 (25H, 7 m), 6.60-8.20 (6H, m), 12.05-12.20 (2H,) _7 MASS (APCI): 610 (M + H) + _ (free) Elemental analysis calculated for C32H37FgN302 • 2HC1 • 2.5H20: C 52.82, H 6.09, N 5.68 = Found: C 52.84, H 5.89, N 5.78 Preparation 37 .3 g of 3,3-dimethylmorpholine hydrochloride are added in small portions, for 1 hour to 6.9 ml of a mixture of 1,4-dichloro-2-butyne and 9.8 g of potassium carbonate in 100 ml of N, N- dimethylformamide. After stirring for 20 hours, the mixture is poured into 200 ml of ice-water and extracted with 100 ml of isopropyl ether twice. The extract is washed with 100 ml of brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel using a mixed solvent of n-hexane and ethyl acetate (4: 1). The fractions containing the objective compound are collected and evaporated under reduced pressure, and treated with 4N hydrogen chloride in ethyl acetate to provide 5.32 g of brown powder of 3, 3-dimethyl-4- (4-dihydrochloride) -chloro-2-butynyl) morpholinin. NMR (DMSO-dg, d): 1.35-1.39 (6H, m), 3.20-4.40 (8H, m), 4.56 (2H, s), 11.50-11.90 (1H, m) MASS: 202 (M + H) + (free) 204 Preparation 38"A mixture of 3.0 g of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) piperazine, 0.84 of propargyl bromide and 1.17 g of potassium carbonate in 300 g. ml of N, N-dimethylformamide is stirred at room temperature for "1.5 hours. The mixture is poured into ice water and extracted It is ethyl acetate. The extract is washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to provide 3.80 g of a syrup of (2R) -1- [3,5-bis- (trifluoromethyl) benzoyl] -2- (3 , 4-dimethylbenzyl) -4- (2-propynyl) piperazine. NMR (DMSO-dg, d): 2.00-5.00 (18H, m), 6.66-8.20 (6H, m) - MASS (APCI): 483 (M + H) + Preparation 39 A mixture of 0.49 g of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- (2-propynyl) piperazine, 0.185 g of hydrochloride 3,3-dimethylmorpholine, 62 mg of paraformaldehyde, 0.21 ml of diisopropylethylamine and 20 mg of copper iodide (I) in 5 ml of 1,4-dioxane is stirred at 70 ° C for 1.5 hours. After removal of the solvent by evaporation, the residue is purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (40: 1). The fractions containing the target compound are collected and evaporated under reduced pressure to provide a syrup of 0.45 g of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [4- (3,3-Dimethylmorpholino) -2-butinyl] -piperazine. NMR (CDCl 3, d): 0.97 (6H, s), 2.03-5.00 (25H, m), 6. © -8.23 (6H, m) MASS (APCI): 610 (M + H) +, 513 £ its hydrochloride Z pf : 185-188 ° C [] D28: -8.6 ° (C = 0.18, MeOH) IR (KBr): 2928, 2585, 2515, 1633, 1433, 1279, 1180, 1132 cm * 1 NMR (DMSO-dg, d): 1.33-1.40 (6H, m), 2.09-2.18 (6H, m), 2.50-5.20 (19H, m), 6.66-8.15 (6H,) MASS: 610 (M + H) + (free) Preparation 40 A mixture of 0.21 g of 37% aqueous formaldehyde, 0.75 g of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -piperazine, 0.11 mm of propargyl alcohol , 1. 3 mg of copper (II) substrate pentahydrate and 2.8 mg of potassium iodide in 1,4-dioxane is stirred at 100 ° C for 2 hours. After cooling to room temperature, the mixture is made basic with a saturated aqueous solution of sodium hydrogen carbonate. The resulting mixture is filtered and the filtrate is extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel using a mixed solvent of n-hexane and ethyl acetate (4: 1). "Fractions containing the target compound are collected and evaporated under reduced pressure to provide 0. 78 g of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- (4-hydroxy-2-butyl) piperazine as a syrup. ~ 7 NMR (CDC13, d): 1.99-5 ^ 00 (19H, m), 5.15 (1H, t, J = - 5.9Hz), 6.66-8.23 (6H, m) MASS (APCI): 513 (M + H) +, 499, 483 Preparation 41 The following compound is obtained according to a similar manner to that of Example 39. (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [4- (3, 3dimethylmorpholino) -2-butinyl] -piperazine. J NMR (CDC13, d): 0.97 (6H, s), 2.03-5.00 (25H, m), * 6.66-8.23 (6H, m) MASS (APCI): 610 (M + H) + \ 513 Preparation 42 A mixture of 30.0 g of 3,3-dimethylmorpholine hydrochloride, 16.4 ml of propargyl bromide and 63 g of potassium carbonate in 300 ml of N, N-dimethylformamide is stirred at 45-48 ° C for 1.5 hours. After cooling to room temperature, the mixture is poured into 800 ml of ice-water and extracted with 500 ml of ethyl acetate, twice. The extract is washed with 400 ml of brine, dried over magnesium sulfate and filtered. The filtrate is treated with 4N hydrogen chloride in 98 ml of ethyl acetate under cooling with ice. The solution is concentrated under reduced pressure to provide a crude solid which is collected by filtration and washed with isopropyl ether to provide 35 g of brown crystals of 3, 3-dimethyl-4- (2-propynyl) hydrochloride. morpholine - IR (KBr): 3500-3400, 2900, 2570, 2480, 1637, 1626, 1508, 1455, 1180 cm'1 NMR (DMSO-dg, d): 1.20-1.50 (6H, m), 3.20- 4.20 (9H, m), 11.91 (1H, S) MASS (APCI): 154 (M + H) + (free) Preparation 43 A mixture of 0.24 g of 3,3-dimethyl-4- (2-propynyl) morpholine hydrochloride, 0.26 ml of 37% aqueous formaldehyde, 0.57 g of (2R) -1- [3,5-bis (trifluoromethyl) enzoyl] -2- (3,4-dimethylbenzyl) piperazine, 5 mg of copper (II) sulphate pentahydrate and 20 mg of potassium iodide in 0.7 ml of 1,4-dioxane is stirred at 90 ° C for 1 hour. After cooling to room temperature, the mixture is poured into ice water and the aqueous mixture is made alkaline with a saturated aqueous solution of sodium hydrogencarbonate. The resulting mixture is extracted with ethyl acetate. The extract is washed with brine, dried over sodium sulfate and evaporated under reduced pressure.The residue is purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (40: 1). fractions containing the target compound and evaporated under reduced pressure, and treated with 4N hydrogen chloride in ethyl acetate solution.The resulting mixture is evaporated under reduced pressure and the residue is recrystallized from a mixture of acetone and water to provide 0.64 g of colorless dichlorohydrate crystals of (2R) -1- [3,5-bis (trifluoromethyl) -benzoyl] -2- (3,4-dimethylbenzyl) -4- [4- (3,3-dimethylmorpholino) -2-butinyl] piperazine. p.f. : 180-190 ° C [] D283: -7.24 ° (C = 1.05, MeOH) IR (Nujol): 3300, 2700-2400, 1635 cm * 1 NMR (DMSO-dg, 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 + H) + (free) _ Elemental analysis calculated for C32H37F6N302 • 2HC1 • 2. 5H20: C 52. 82, H 6. 09, N 5 68 Found: C 52. 84, H 5. 89, N 5. 78 Preparation 44 _ The following compounds are obtained according to a manner similar to Preparation 1. (1) 3- [2- (4-methoxy) iridyl] -2-propin-1-ol IR (KBr): 3130, 1598, 1562, 1471, 1425 cm "1 NMR (DMSO-dg, d): 3.84 (3H, s), 4.31 (2H, d, J = 6.0 Hz, 5.41 (1H, t, J = 6.0Hz), 6.97 (1H, dd , J = 2.6, 5.8Hz), 7.06 (1H, d, J = 2.6Hz), 8.35 (1H, d, J = 5.8 Hz) MASS (APCI): 164 (M + H) + 134 (2) 3- [2- (4-methoxycarbonyl) pyridyl] -2-propin-l-ol IR (KBr): 3133, 1598, 1568, 1430 cm "1 NMR (DMSO-d6, d): 3.91 (3H, s), 4.35 (2H, d, J = 6.0Hz), 5.75 (1H, d, J = 6.0Hz), 7.70-7.80 (1H,), 8.68 (1H, d, J = 5.0Hz), 8.78 (1H, d, J = 5.0Hz) MASS (APCI): 192 (M + H) + Preparation 45"(1) To a stirred solution of 1.14 g of chloropyrazine and 106 mg of [1,2-bis (diphenylphosphino) ethane] nickel (II) chloride in 40 ml of dry tetrahydrofuran is added a solution of chloride of 3, 4 -methylenedioxybenzylmagnesium (0.6 M in tetrahydrofuran, 29 ml) at 5 ° C under a nitrogen atmosphere for 15 minutes.After 1 hour of stirring at 5 ° C, 3N hydrochloric acid is slowly added under a nitrogen atmosphere and the mixture The mixture is stirred for 1 hour, the organic layer is separated and the aqueous layer is extracted with ethyl acetate.The organic extract is washed with water and dried over magnesium sulfate, the usual treatment followed by flash chromatography on silica gel with an mixture of n-hexane and ethyl acetate (10: 1-4: 1) gives 454 mg of 2- (3,4-methylenedioxybenzyl) piperazine as a colorless oil NMR (CDC13; d): 4.59 (2H, s) , 5.93 (2H, s), 6.75-6.88 (3H, m), 8.44-8.56 (3H, m) MASS (APCI): 215 (M + H) + (2) To a stirred solution of 317 mg of 2- (3,4-methylenedioxybenzyl) pyrazine in 12 ml of dry tetrahydrofuran is added a solution of diisobutylaluminum hydride (0.95 M in n-hexane, 15.6 ml) at 5 ° C. under a nitrogen atmosphere. After stirring for 1 hour at 5 ° C, a saturated solution of sodium sulphate is added to the mixture until gas production ceases. The insoluble materials are removed by filtration through Celite ™ and the organic layer is separated, ~ * dry over magnesium sulfate and concentrate under reduced pressure. The residue is dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to give 125 mg of 2- (3,4-methylenedioxybenzyl) piperazine dihydrochloride as a powder. NMR (DMSO-dg, d): 2.79-3.66 (9H, m), 6.02 (2H, s), 6.74-6.94 (3H, m), 9.79 (4H, broad s)] MASS (APCI): 221 (M + H) + (free) Preparation 46 (1) To a stirred solution of 10.75 g of 4-bromo-2-methylbenzoic acid in 50 ml of tetrahydrofuran is added a complex of borane-tetrahydrofuran (1 M in tetrahydrofuran, 150 ml) by means of a syringe, under an atmosphere of nitrogen at 5 ° C and the mixture is heated under reflux for 18 hours. After cooling, 50 ml of water and 20 g of potassium carbonate are added to the solution at 5 ° C. The organic layer is separated and the aqueous layer is extracted with ethyl acetate. The combined extract is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to provide 9.55 g of 4-bromo-2-methylbenzyl alcohol. This compound is used in the next reaction without further purification. (2) 13.06 g of tert-butylchlorodiphenylsilane and 9.7 g of imidazole are added to a solution of 9.55 g of 4-bromo-2-methylbenzyl alcohol in 80 ml of N, N-dimethylformamide at 5 ° C and the mixture is allowed to warm to room temperature, and stir for 18 hours. The mixture is extracted with ethyl acetate and the extract is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to provide 20.5 g of l-bromq ^ 4- (tert-butyldiphenylsilyloxymethyl) -3-methylbenzene as a colorless oil. NMR (DMSO-dg, d): 1.03 (9H, s), 2.14 (3H, s), 4.70 (2H, s), 7.34-7.71 (13H, m) (3) To a stirred solution of 2.19 g of l-bromo-4- (tert-butyldiphenylsilyloxymethyl) -3-methylbenzene in 30 ml of tetrahydrofuran is added 1.6 M butyllithium in 4.69 ml of hexane by means of a syringe under an atmosphere of nitrogen at -78 ° C.

After 30 minutes of stirring at -78 ° C, 1.16 ml of N, N-dimethylformamide is added to the solution at -78 ° C and then the mixture is allowed to warm at 5 ° C for 1.5 hours. 10 ml of a saturated solution of ammonium chloride is added to the mixture and the organic layer is separated, and the aqueous layer is extracted with ethyl acetate. The combined extract is washed with water, dried over magnesium sulfate and concentrated under reduced pressure to provide 1.90 g of 4- (tert-butyldiphenylsilyloxymethyl) -3-methylbenzaldehyde as a colorless oil. NMR (DMSO-dg, d): 1.06 9H, s), 2.20 (3H, s), 4.38 (2H, S), 7.37-7.83 (13H, m), 9.97 (1H, s) MASS (APCI): 389 (M + H) + (4) To a stirred mixture of 1.94 g of 4- (tert-butyldiphenylsilyloxymethyl) -3-methylbenzaldehyde in 991 mg of 1,4-diacetyl-2, 5-piperazinedione in a mixture of 10 ml of N, N-dimethylformamide and 10 ml of terbutanol, add 561 mg of potassium terbutoxide at 5 ° C. The mixture is stirred for 1 hour at room temperature and then poured into 300 ml of water, and stirring is continued for 18 hours at room temperature.

The resulting precipitates are collected by filtration and washed with water and isopropyl ether, and dried under reduced pressure to provide 1.88 g of l-acetyl-3- (4-tert-butyldiphenylsilyloxymethyl-3-methylphenyl) -methylene-2, 5 -piperazinedione as a powder.

NMR (DMSO-dg, d): 1.05 (9H, s), 1.99 (3H, s), 2.19 (3H, S), 4.37 (2H, s), 4.77 (2H, s), 6.93 (1H, s) , 7.40-7.69 (13H, m), 10.37 (1H, s) MASS (APCI): 527 (M + H) + (5) A solution of 6.3 g of l-acetyl-3- (4-tert-butyl-butyldiphenylsilyloxymethyl-3-methylphenyl) methylene-2,5-piperazinedione in 300 ml of methanol is hydrogenated on 10% palladium-carbon (50%). % wet) for 4 hours at atmospheric pressure. After removing the catalyst by filtration, 721 mg of hydrazine monohydrate is added to the filtrate. The mixture is stirred for 1 hour at room temperature and concentrated under reduced pressure. The residue is triturated with a mixture of 200 ml of isopropyl ether and 400 ml of n-hexane and the precipitates are collected by filtration and washed with isopropyl ether to give a crude product. This is purified by flash column chromatography on silica gel using ethyl acetate and a mixture of dichloromethane and methanol (15: 1) as an eluent to provide 4.67 g of 3- (4-tert-butyldiphenylsilyloxymethyl-3-methylbenzyl) - 2,5-piperazinedione as a powder. NMR (DMSO-dg, d): 1.02 (9H, s), 2.12 (3H, s), 2.77- 3.18 (3H, m), 3.37 (1H,), 4.04 (1H, m), 4.72 (2H, s) ), 6. 97-7.04 (2H, m), 7.29-7.66 (11H, m), 7.94 (1H, m), 8.14 (1H, m) MASS (APCI): 487 (M + H) + (6) To a stirred solution of 1.46 g of 3- (4-tert-butyldiphenylsilyloxymethyl-3-methylbenzyl) -2,5-piperazinedione in a mixture of 40 ml of tetrahydrofuran and 40 ml of 1,2-dimethoxyethane is added 683 mg of lithium aluminum hydride under a nitrogen atmosphere at 5 ° C and the mixture is heated under reflux for 6 hours. After cooling, the reaction mixture is suspended by the sequential addition of 1.5 ml of water, 1.5 ml of a 15% sodium hydroxide solution and 4.5 ml of water. The insoluble materials are removed by filtration through Celite ™. Dry the organic layer over magnesium sulfate and concentrate under reduced pressure to provide an oil which is purified by flash chromatography on silica gel using a mixture of dichloromethane and methanol (50: 1-20: 1) to provide 242 mg of 1,4-bis (benzyloxycarbonyl) -2- (4-hydroxymethyl-3-methylbenzyl) piperazine as a powder. . NMR (DMSO-dg, d): 2.09 (3H, m), 2.58-3.22 (5H, m), 3.64-4.50 (6H, m), 4.82-5.21 (5H, m), 6.86-7.72 (13H, 7 m) " (7) A solution of 6.3 g of 1,4-bis (benzyloxycarbonyl) -2- (4-hydroxymethyl-3-methylbenzyl) iperazine in 5 ml of methanol is hydrogenated over 10% palladium-carbon (50% wet, 22 mg ) for 6 hours at atmospheric pressure. After removal of the catalyst by filtration, the filtrate is treated with 4N hydrogen chloride in ethyl acetate and concentrated under reduced pressure to provide 96 mg of 2- (4-hydroxymethyl-3-methylbenzyl) piperazine dihydrochloride as a dust. "= MASS (APCI): 221 (M + H) * (free) Preparation 47 (1) The following compound is obtained according to a manner similar to that of Preparation 46- (4). - l-acetyl-3- [1,4-benzodioxan-6-yl) methylene] -2,5-piperazinedione X-NMR (DMSO-d6, d): 2.48 (3H, s), 4.28 (4H, s) , 4.35 * (2H, s), 6.86-7.16 (4H, m), 10.30 (1H, s) JE. MASS (APCI): 303 (M + H) + (2) The following compound is obtained according to a manner similar to Preparation 46- (5). * 3- [(1,4-benzodioxan-6-yl) methyl] -2,5-piperazinadioan - "NMR (DMSO-dg, d): 2.75 UH, dd, J = 13.6, 4.9Hz), 2.94 (1H , m), 3.00 (1H, m), 3".43 (1H, dd, J = 17.4, 2.7Hz), 3.97 (1H, m), 4.20 (4H, s), 6.57-6.77 (3H, m) , 7.93 (1H, s), 8.10 (1H, m) MASS (APCI): 263 (M + H) + (3) To a stirred suspension of 564 mg of 3 - [(1,4-benzodioxan-6-yl) methyl] -2,5-piperazinedione in 100 ml of tetrahydrofuran is added a borane-tetrahydrofuran complex. (1 M in tetrahydrofuran, 21 ml) by means of a syringe under a nitrogen atmosphere at room temperature and the mixture is heated under reflux for 18 hours. After cooling, the reaction mixture is filtered and the filtrate is slowly added with 12% hydrogen bromide in 10 ml of acetic acid. To the mixture is added 100 ml of n-hexane and a total is stirred for 1 hour at 5 ° C. The resulting precipitates are collected by filtration and dried under reduced pressure to provide 831 g of 2- [(1,4-beñzodioxan-6-yl) methyl] piperazine dibromhydrate as a p > olvo. = - NMR (DMSO-dg, d): 2.62-3.80 (9H, m), 4.23 (4H, s), 7 6.71-6.88 (3H, m) MASS (APCI): 235 (M + H) + ~ ( free) Preparation 48 _ (1) The following compound is obtained according to a manner similar to that of Preparation 46- (4). l-Acetyl-3- [(4-methoxy-3-methylphenyl) methylene] -2,5-piperazinedione i- NMR (DMSO-dg, d): 2.17 (3H, s), 2.49 (3H, s), 3.83 (3H, s), 4.35 (2H, S), 6.90 (1H, s), 6.94 (1H, d, J = 7 15.7Hz), 7.32 (2H, m), 10.28 (1H, s) "" MASS (APCI): 289 (M + H) ^ "~~ (2) The following compound is obtained according to a similar manner to that of Preparation 46- (5). r ~ 3- (4-methoxy-3-methylbenzyl) -2,5-piperazinedione? -NMR (DMS0-ds, d): 2.09 (3H, s), 2.73- 3.04 (3H, m), "3.34 (1H, m), 3.75 (3H", s), 3.99 (1H, m), 6.81-6.97 (3H, m), 7.89 (1H, s), 8.11 (1H, m). "MASS (APCI): 249 (M + H) + (3) The following compound is obtained according to a manner similar to that of Preparation 47- (3). Dihydrobromide of 2- (4-methoxy-3-methylbenzyl) piperazine NMR (DMSO-d6, d): 2.09 (3H, s), 2.60-3.72 (9H, m), "- 3.78 (3H, s), 6.55 (2H, m), 6.87-7.14 (3H, m), 9.09 7 (2H, m) "MASS (APCI): 221 (M + H) + (free) Preparation 49 (1) The following compound is obtained according to a manner similar to that of Preparation 46- (4). l-Acetyl-3- [(2,3-dimethyl phenyl) methylene] -2,5-piperazinedione IR (KBr): 1712, 1697, 1685, 1647, 1624, 1373, 1271, 1225 cm "1 ^ NMR ( DMSO-dg, d): 2.51 (3H, s), 3.74 (3H, s), 3.83 (3H, s), 4.35 (2H, s), 7.03-7.16 (4H, m), 10.07 (1H, s) MASS (APCI): 305 (M + H) + (2) A solution of 2.40 g of l-acetyl-3- [(2, 3-dimethoxyphenyl) -methylene] -2,5-piperazinedione in a mixed solvent of 120 ml of tetrahydrofuran and 80 ml of methanol is hydrogenated using palladium 10% -carbon (50% wet, 0.55 g) at atmospheric pressure for 3 hours. The catalyst is removed by filtration and the filtrate is concentrated under reduced pressure. The resulting precipitates are collected by filtration to give a gray solid of 2.55 g of l-acetyl-3- (2,3-dimethoxybenzyl) -2,5-piperazinedione. IR (KBr): 3265, 1726, 1711, 1689, 1487, 1460, 1358, 1275, 1257 cm "1 NMR (DMSO-dg, d): 2.42 (3H, s), 2.90-3.20 (2H, m), 3. 57-3.83 (1H, m), 3.72 (3H, s), 3.79 (3H, s), 4.14- 4.23 (2H, m), 6.74-7.04 (3H, m), 8.34 (1H, s) MASS (APCI) ): 307 (M + H) + - "" (3) To a suspension of 2.49 g of l-acetyl-3- (2,3-dimethoxybenzyl) -2,5-piperazinedione in 38 ml of tetrahydrofuran is added 0.43 ml of hydrazine monohydrate at room temperature and the mixture is stirred at the same temperature for 30 minutes. The resulting precipitates are collected by filtration and washed with tetrahydrofuran to provide 1.40 g of 3- (2) powders., 3-dimethoxybenzyl) -2,5-piperazinedione. -_ IR (KBr): 3195, 3053, 1682, 1658, 1460, 1271, 1078 cm "1 * J NMR (DMSO-dg, 6): 2.87-3.09 (3H, s), (2H, m), 3.42 - "" 3.54 (2H, m), 3, .73 (3H, s), 3.79 (3H, s), 3.88-3.96 (1H, m), 6.73-7.02 (3H, m), 7.94-8.00 (2H , m) MASS (APCI): 265 (M + H) + (4) A suspension of 1.26 g of 3- (2,3-dimethoxybenzyl) -2,5-piperazinedione in a mixed solvent of 50 ml of tetrahydrofuran and 50 ml of 1,2-dimethoxyethane is heated to 60 ° C with stirring and 0.905 g of lithium aluminum hydride is added thereto in portions and with caution. Then, the reaction mixture is heated to 70 ° C with stirring for 3 hours, again 0.20 g of lithium aluminum hydride and 30 ml of tetrahydrofuran are added thereto, and the suspension is stirred at the same temperature for 2 hours. . After cooling with ice-water, the mixture is suspended by sequential addition of 1. 3 ml of water, 1.3 ml of 15% aqueous sodium hydroxide, 3.8 ml of water and the whole is stirred at room temperature for 2 hours. The resulting insoluble materials are removed by filtration and the filtrate is dried over sodium sulfate and evaporated under reduced pressure to give 0.97 g of a S "light yellow oil of 2- (2,3-dimethoxybenzyl) piperazine." IR (KBr): 2941, 1481, 1475, 1275, 1080 cm "1 ** NMR (DMSO-dg, d): 2.07-3.60 (9H, m), 3.69 (3H, s), _ 3.78 (3H, s ), 6.71-7.00 (3H, m) MASS (APCI): 237 (M + H) + (5) A solution of 0.59 g of benzoyloxycarbonyl chloride in 3.0 ml of dichloromethane is added dropwise to a solution of 0.91 g of 2- (2,3-dimethoxybenzyl) piperazine and 0.64 ml of triethylamine in 18 ml of dichloromethane underneath at 5 ° C, for "5 minutes under ice-cooling, and the reaction mixture is stirred at the same temperature for 15 minutes." After 2 hours of stirring at room temperature, the mixture is poured into a mixed solvent of 40 ml. of water and 25 ml of dichloromethane and the total is adjusted to pH 9 with an aqueous solution of sodium hydrogencarbonate The organic layer is separated, washed with brine, dried over sodium sulphate and evaporated under reduced pressure. The residue is purified by column chromatography on 20 g of silica gel using a mixed solvent of dichloromethane and methanol (40: 1). Fractions containing the target compound are collected and evaporated under reduced pressure to provide 0.68 g of an oil. in coloro of 1- (benzyloxycarbonyl) -3- (2,3-dimethoxybenzyl) piperazine. ~ - IR (KBr): 1714, 1699, 1685, 1273, 1244, 1225 cm "1 NMR (CDC13, d): 1.71 (1H, s), 2.23-3.00 (9H, m), 3.82 (3H, s) , 3.86 (3H, s), 5.13 (2H, s), 6.74-7.03 (3H,), '7.34 (5H, s) MASS (APCI): 371 (M + H) + Preparation 50 A solution of 0.81 g of l- [3,5-bis (trifluoromethyl) benzoyl] -4- (benzyloxycarbonyl) -2- (2,3-dimethoxybenzyl) piperazine in 20 ml of methanol is hydrogenated on palladium 10% -carbon ( 50% wet, 0.30 g) at room temperature under atmospheric pressure for 90 minutes. After removal of the catalyst by filtration, the filtrate is evaporated under reduced pressure to provide 0.64 g of colorless oil of 1- [3,5-bis (trifluoromethyl) benzoyl] -2- (2,3-dimethoxybenzyl) -piperazine. "IR (KBr): 1645, 1635, 1281, 1184, 1134 cm * 1 NMR (CDC13, d): 2.60-5.30 (10H, m), 3.81 (3H, s), 3.82 (3H, s), 6.40- 7.10 (3H, m), 7.20-8.49 (3H, m) MASS (APCI): 477 (M + H) + Preparation 51 (1) The following compound is obtained according to a manner similar to that of Preparation 46- (4). l-Acetyl-3- [(lH-indol-2-yl) methylene] -2,5-piperazinedione IR (KBr): 3332, 1714, 1685, 1668, 1419, 1221 cm "1 NMR (DMSO-dg, d ): 2.50 (3H, s), 4.38 (2H, s), 6.52- 8.21 (6H, m), 9.84-12.00 (2H, broad) MASS (APCI): 284 (M + H) + - (2) The following compound is obtained according to a manner similar to that of Preparation 46- (2). l-Acetyl-3- [(lH-indol-2-yl) methyl] -2,5-piperazinedione IR (KBr): 3325, 1730, 1697, 1682, 1653, 1456, 1205 cm "1 NMR (DMSO-dg , d): 2.43 (3H, s), 2.80-5.25 (5H, m), 6. 18-8.73 (6H, m), 10.96 (1H, s) MASS (APCI): 286 (M + H) + (3) The following compound is obtained according to a manner similar to that of Preparation 46- (3). 3- [(lH-indol-2-yl) methyl] -2,5-piperazinedione-IR (KBr): 3363, 3317, 1682, 1645, 1456, 1323 c "1 NMR (DMSO-dg, d): 3.03 -3.61 (4H, m), 4.09-4.15 (1H, m), 6.18 (1H, s), 6.89-7.05 (2H, m), 7.31 (1H, d, J = 7.9Hz), 7.43 (1H, d) , J = 7.2Hz), 7.99 (1H, s), 8.11 (1H, s), 10.85 (1H, s) MASS (APCI): 244 (M + H) + "" (4) The following compound is obtained according to a manner similar to that of Preparation 49- (4). 2- [(lH-indol-2-yl) methyl] iperazine IR (KBr): 3305, 2941, 1653, 1456 cm "1 NMR (DMSO-dg, d): 1.80-3.70 (11H, m), 6.12 ( 1H, s), 6.87-7.02 (2H, m), 7.27 (1H, d, J = 7.9Hz), 7.40 (1H, d, J = 6.9Hz), 10.89 (1H, s) "MASS (APCI): 216 (M + H) + (5) The following compound is obtained according to a manner similar to that of Preparation 49- (5). 1- (benzyloxycarbonyl) -3- [(1H-indol-2-yl) met il] -piperazine IR (KBr): 3303, 2908, 1697, 1684, 1456, 1433, 1248 cm * 1 NMR (DMSO-dg, d): 2.34-2.90 (8H, m), 3.78-3.89 (2H, - m), 5.03 (2H, s), 6.17 (1H, s), 6.90-7.04 (2H, m), 7.26-7.43 (7H , m), 10.93"(1H, s) ._ MASS (APCI): 350 (M + H) + Preparation 52 The following compound is obtained according to a manner "similar to that of Preparation 50. 1- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1H-indol-2-yl) -methyl] iperazine IR (KBr): 1653, 1647, 1635, 1281, 1184, 1136 cm "1 NMR (DMSO-dg, d): 2.50-4.90 (10H, m), 5.98-6.28 (1H, m), 6.90-7.42 (5H , m), 7.76-8.48 (2H, m), 10.59-11.03 (1H, m) MASS (APCI): 456 (M + H) * Preparation 53 (1) The following compound is obtained according to a manner "similar to that of Preparation 46- (4). 1-Acetyl-3- (3-methoxyphenyl) methylene-2, 5-piperazinedione NMR (DMSO-dg, Ó): 2.50 (3H, s), 3.79 (3H, s), 4.36 (2H, s), 6.9-7.0 (2H, m), 7.1-7.2 (2H, m), 7.3-7.4 (1H, m) , 10.4 (1H s broad) MASS (APCI): 275 (M + H) + (2) The following compound is obtained according to a manner similar to that of Preparation 49- (2). ° l-acetyl-3- (3-methoxybenzyl) -2,5-piperazinedione NMR (DMSO-dg, Ó): 2.42 (3H, s), 2.9-3.1 (2H, m), 3.33 (1H, d, J = 17Hz), 3.71 (3h, s), 4.02 (1H, d, J = 17Hz), 4.3-4.4 (1H, m), 6.7-6.9 (3H, m), 7.1-7.3 (1H, m), 8.43 (1H, broad s) "~ MASS (APCI): 277 (M + H) + ' (3) The following compound is obtained according to a manner similar to that of Preparation 49- (3). 3- (3-methoxybenzyl) -2,5-piperazinedione ~ NMR (DMSO-dg, d): 2.8-3.5 (4H, m), 3.71 (3H, s), 4.0- __ 4.1 (1H, m), 6.7 -6.9 (3H, ra), 7.1-7.3 (1H, ra), 7.91 ~ - (1H, broad s), 8.13 (1H, broad s) MASS (APCI): 235 (M + H) + _ (4) The following compound is obtained according to a manner similar to that of Preparation 49- (4). - 2- (3-methoxybenzyl) piperazine NMR (DMSO-dg, d): 2.2-2.9 (9H, m), 3.5-3.8 (2H, m), 3.73 (3H, s), 6.7-6.8 (3H, m ), 7.1-7.3 (1H, m) "" MASS (APCI): 207 (M + H) + (5) A solution of 1.99 g of diterbutyl dicarbonate in 20 ml of tetrahydrofuran is added dropwise to a mixture of 1.88 g of 2- (3-methoxybenzyl) piperazine and 1.90 ml of triethylamine in 19 ml of tetrahydrofuran with cooling with ice water. After stirring for 1 hour, 100 ml of ethyl acetate and 50 ml of water are added to the mixture, the organic layer is separated, washed with brine, dried over sodium sulphate and evaporated in vacuo. it is purified by column chromatography on silica gel using a mixture of dichloromethane and methanol (40: 1) to give 1.18 g of 2- (3-methoxybenzyl) -4- (tert-butoxycarbonyl) -piperazine as an oil. DMSO-dg, d): 1.34 (9H, s), 2.1-2.9 (8H, m), 3.6- 3.8 (2H, m), 3.73 (3H, s), 6.7-6.8 (3H, m), 7.1- 7.3 (1H, m) MASS (APCI): 307 (M + H) + (6) The following compound is obtained according to a manner "Similar to that of Example 86. 1- [3,5-bis (trifluoromethyl) benzoyl] -4-tert-butoxycarbonyl-2- (3-methoxybenzyl) piperazine. NMR (DMSO-dg, d): 1.44 (9H, s), 2.5-5.0 (12H, m), 6.5- 8.3 (7H, m) MASS (APCI): 447 (M + H) + (7) The following compound is obtained according to a manner similar to that of Preparation 35. _ 1- [3,5-bis (trifluoromethyl) benzoyl] -3- (3"-methoxybenzyl) piperazine-1H-NMR hydrochloride ( DMSO-dg, d): 2.7-5_.2 (12H, m), 6.4-8.3 (7H, m), 9.4-10.2 (2H, m) _ MASS (APCI): 447 (M + H) + (free ) Preparation 54 (1) 10.2 g of chloride of 3 are added successively, 4-dimethylbenzyl and 14.3 g of diethyl acetamidomalonate, to a solution of 4.94 g of sodium ethoxide in ethanol. The mixture is stirred under reflux for 2 hours and filtered through Celite ™. The filtrate is concentrated under reduced pressure to provide crystals which are collected by filtration and washed with isopropyl ether to provide 11.8 g of colorless crystals of diethyl 2-ac eti 1 amino-2- (3,4-dimethylbenzyl) malonate, pf : 107-109 ° C. "IR (KBr): 3335, 3275, 1750, 1645, 1520, 1460, 1380, 1280, 1185 cm" 1 NMR (DMS0-d6, d): 1.17 (6H, t, J = 7.2Hz), 1.90-1.93 (3H, m), 2.02-2.20 (6H *, m), 3.30-3.50 (3H, m), 4.14 (2H, c, J = 7.2Hz), 6.6CÍ-7.05 (3H, m), 7.97, 8.07 (1H, 2s) MASS (El): 335 (M) +, 276, 119 (2) Dissolve 13.8 g of 2-acetylamino-2- (3,4-dimethylbenzyl) malonate of diethyl and 2.76 g of potassium hydroxide in a mixed solution of 138 ml of ethanol and 138 ml of water, and the solution is stirred under reflux for 8.5 hours. After cooling to room temperature, the solution is concentrated under reduced pressure and the resulting aqueous solution is adjusted to pH 10 with a saturated aqueous solution of sodium hydrogen carbonate. The solution is washed with ethyl acetate and made acidic with dilute hydrochloric acid and extracted with ethyl acetate. The extract is dried over magnesium sulfate and evaporated under reduced pressure to provide 5.42 g of crystals of N-acetyl-3,4-dimethyl-DL-phenylalanine. p.f. : 136-139 ° C. IR (KBr): 3337, 2700-2400, 1710, 1610, 1540, 1450, 1380, 1355 cm "1 NMR (DMSO-dg, d): 1.67 (3H, s), 2.17-2.21 (6H, m), 2.60-3.15 (2H, m), 4.25-4.40 (1H, m), 6.90-7.05 (3H, m), 8.10-8.25 (1H, m) MASS (El): 235 (M) +, 176, 119 (3) 498.0 g of N-acetyl-3,4-dimethylphenyl-DL-alanine are dissolved in a mixture of 2.12 1 of 1N sodium hydroxide and 2.49 1 of water. 2.49 g of cobalt hexahydrate dichloride and acylase (Acylase Amano 15000, 24.9 g) are added to the solution, and the mixture is stirred at 37 ° C for 20 hours with control of the pH of the reaction mixture at 7.5 with sodium hydroxide. 1N. The resulting precipitates are collected by filtration and washed with water (500 ml x 2) to provide 120.7 g of crystals of L-3, 4-dimethylphenylalanine. The pH of the filtrate is adjusted to 1 with dilute aqueous hydrochloric acid and the solution is extracted with ethyl acetate. The extract is dried over magnesium sulfate and evaporated under reduced pressure to provide 160.72 g of a solid of N-acetyl-3,4-dimethylphenyl-D-alanine. p.f. : 156-159 ° C. IR (KBr): 3400, 3350, 2500-2400, 1710, 1620, 1560, 1450 cm "1 7 NMR (DMS0-ds, d): 1.78_ (3H, s), 2.16 (6H, s), 2.68- - 3.20 (2H, m), 4.28-4.40 (1H, m), 6.90-7.05 (3H, m), 8.18 (1H, d, J = 8.0Hz), 12.61 (1H, s) MASS (El): 235 (M) +, 176, 119 (4) A solution of 5.0 g of N-acetyl-3,4-dimethylphenyl-D-alanine in a mixture of 50 ml of concentrated hydrochloric acid and 50 ml of acetic acid is stirred under reflux for 20 hours. After cooling to room temperature, the resulting precipitate is collected by filtration and washed with ethyl acetate to provide 3.75 g of colorless crystals of 3,4-dimethylphenyl-D-alanine hydrochloride. p.f. : > 250 ° C. [a] D26: -3.3 ° (C = 1.0, MeOH) IR (Nujol): 2800-2400, 1730, 1600, 1500, 1480 crn "1 NMR (DMSO-dg, d): 2.19 (6H, s), 3.07 (2H, d, J = 6.2Hz), 4.07 (1H, t, J_ = 6.2Hz), 6.90_-7.10_ (3H, m), 8.30-8.60 (3H, m) MASS (APCI): 194 ( M + H) + (free) (5) 5.4 ml of thionyl chloride is added dropwise to 60 ml of methanol, below 5 ° C, with cooling with an ice-salt bath and stirring is continued for 10 minutes at the same temperature. 5.0 g of 3,4-dimethylphenyl D-alanine hydrochloride is added to the mixture in small portions for 20 minutes at -15 ° C and the whole is stirred at room temperature for 6 hours, and evaporated under reduced pressure. The resulting solid is triturated with isopropyl ether to give 5.10 g of colorless crystals of 3,4-dimethylphenyl-D-alanine methyl ester hydrochloride. p.f. : 190.0-190.5 ° C. [a] D30: -10.36 ° (C = 0.55, MeOH) 1. IR (Nujol): 3400, 1735_cm "1 ^ NMR (DMSO-dg, d): 2.19 (6H, s), 3.03 (1H, dd, J = 7.3, 14. 0Hz), 3.15 (1H, dd, j "= 5.7, 14.0Hz), 3.66 (3H, s), 4. 16 (1H, dd, J = 7.3, 5.7 Hz), 6.93 (1H, d, J = 7.6 Hz), 6.99 (1H, s), 7.08 (1H, d, J = 7.6 Hz), 8.78 (3H, "s) - MASS (APCI): 208 (M + H) +" (free) Z- (6) Add 5.45 g of potassium carbonate in small portions with ice cooling to a mixture of 4.81 g of 3,4-dimethylphenyl-D-alanine methyl ester hydrochloride in a mixed solvent of dichloromethane and water . 2.20 ml are added. of chloroacetyl chloride to the mixture, below 5 ° C for 10 minutes and the total is stirred for 30 minutes. The organic layer is separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure to provide 6.01 g of a (2R) -2- (2-chloroacetylamino) -3- (3, 4-) oil. methyl dimethylphenyl) propionate (6.01 g) IR (Pure): 3400, 1735, 1650, 1460 cm "1 .. NMR (DMSO-dg, d): 2.22 (6H, s), 3.08 (1H, d , J = .. 5.7 Hz), 3.74 (3H, s), 4.02 (2H, s), 4.77-4.87 (1H, m), _ 6.80-7.10 (4H, m) MASS (APCI): 283 (M + H) +, 441 (7) 5.4 ml of benzylamine and 4.08 g of potassium carbonate are successively added to a solution of 5.33 g of methyl (2R) -2- (2-clproacetylamino) -3- (3,4-dimethylphenyl) propionate in 25 g. ml of N, N-dimethylformamide at 20 ° C. After 3 hours of stirring at 35 ° C, the mixture is poured into a mixture of 40 ml of ice-water and 40 ml of dichloromethane. The mixture is then adjusted to pH 6 with about 1.4 ml of concentrated hydrochloric acid, the organic layer is separated, washed with 20 ml of brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue is triturated with n-hexane and filtered to provide 1.51 g of colorless powders of (3R) -l-benzyl-3- (3,4-dimethylbenzyl) -2,5-piperazinedione (1.51 g). The filtrate is evaporated under reduced pressure to provide 5.67 g of a methyl (2R) -2 - [(2-benzylaminoacetyl) amino] -3- (3, 4-dimethylphenyl) propionate oil. IR (Pure): 3400, 1735, 1650, 1460 cm * 1 NMR (CDC13 / d): _2.12-2._21 (6H, m), 3.04-3.10 (2H, m), 3. 29 (2H, d, J = 2.0Hz), 3.66 (2H, s), 3.74 (3H, s), ^ 4.80-4.90 (1H, m), 6.80-7.40 (9H, m), 7.90-8.05 (1H , m) 1 MASS (APCI): 355 (M + H) + (8) A mixture of 2.5 g of (2R) -2 - [(2-benzylaminoacetyl) amino] -3- (3,4-dimethylphenyl) propionatemethyl and 0.2 ml of acetic acid in 8.8 ml of isopropyl alcohol is stirred during 5 hours under reflux. After cooling to room temperature, isopropyl ether is added to the mixture. The resulting precipitates are collected by filtration and washed with isopropyl ether to provide 1.26 g of colorless crystals of (3R) -l-benzyl-3- (3,4-dimethylbenzyl) -2,5-piperazinedione. __ p.f. : 191-192 ° C. "[a] D2S: -23.3 ° (C = l, DMF) IR (Nujol): 3180, 1640, 1500, 1340 cm * 1 NMR (DMSO-dg, d): 2.11 and 2.16 (3H, 2s), 2.82 (1H, dd, J = 4.8, 13.5Hz), 3.13 (1H, dd, J = 4.2, 13.5Hz), 2.76 (1H, d, J = 17.1Hz), 3 ^ 46 (1H, d, J = 17.1 Hz), 4.22 (1H, d, J = 14.5Hz), 4.55 (1H, d, J = 14.5Hz), 4.2-4.3 (1H, m), 6.7-6.9 (3H, m), 7.0-7.1 (2H, m), 7.2-7.3 (3H, m), 8.31 (1H, s) MASS: 323 (M + l) (9) The following compound is obtained according to a manner similar to that of Preparation 49- (4). (3R) -l-benzyl-3- (3,4-dimethylbenzyl) piperazine IR (Pure): 3000-2750, 1670, 1500, 1450, 1360, 1320 cm * 1 NMR (CDC13, d): 2.26 (6H, m), 1.8-3.0 (9H, m), 3.4-3.6"(2H,), 6.9-7.1 (3H, m), 7.2-7.5 (5H, m) MASS : 295 (M + l) its hydrochloride p.f. : 186-188 ° C. [< X] D29'2: + 12.72 ° (C = 0.55, MeOH) IR (Nujol): 3500, 2350 cm "1 NMR (DMSO-dg, d): 2.20 (6H, s), 2.73-3.90 (9H, m ), 4. 34 (1H, d, J = 13.1Hz), 4.42 (1H, d, J = 13.1Hz), 6.97 (1H, d, J = 7.6Hz), 7.02 (1H, s), 7.11 (1H, d, J = 7.6 Hz), 7.36-7.65 (5H, m) MASS (APCI): 295 (M + H) + (free) (10) The following compound is obtained according to a manner similar to that of Example 86. "(2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) - 4-benzylpiperazine IR (Pure): 3000-2700, 1640, 1500, 1430, 1350 cm "1 fc NMR (CDC13, d): 2.1-2.3 (6H, m), 2.1-2.2 (2H, m), 2.6- 3.7 (8H, m), 4.5-5.1 (1H, m), 6.5-6.7 (2H, m), 6.9-7.6 (7H, m), 7.8-7.9 (2H, m) MASS: 535 (M + l) (11) A mixture of 2.94 g of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4-benzylpiperazine, 1.74 g of ammonium formate and 0.58 g of palladium 10% -carbon in a mixed solvent of 11.8 ml of methanol, 5.9 ml. of water and 10 ml of tetrahydrofuran is stirred for 5.5 hours at 50 ° C under a nitrogen atmosphere. The reaction mixture is cooled to room temperature and filtered through a pad of Celite ™. The filtrate is concentrated under reduced pressure and the residue is dissolved in ethyl acetate. The solution is washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue is dissolved in methanol 468 mg of fumaric acid to provide 0.24 g of a colorless powder of the fumaric acid salt (1: 1) of (2R) -1- [3,5-bis (trifluoromethyl) behzoyl] -2 - (3,4-dimethylbenzyl) -piperazine. p.f. : 186-188 ° C. _ [Cí] D31 i -23.99 ° (C = 0.55 ^ MeOH) IR (Nujol): 2320, 1720, 1705, 1630, 1270 cm "1 NMR (DMSO-dg, d): 1.57-2.34 (6H, m) , 2.56-5.08 (9H, ^ m), 6.10-8.52 (11H, m) -_ MASS (APCI): 445 (M + H) + (free) Preparation 55 (1) 17.4 ml of benzaldehyde are added dropwise to a solution of 20 g of 2-amino-2-methyl-1,3-propanediol in 200 ml of methanol-at 0 ° C and the whole is stirred at room temperature for 2 hours Z 11.5 g of sodium borohydride are added in portions, at 0 ° C and the mixture is stirred for 10 minutes. A 1N sodium hydroxide solution is added and the organic layer is separated, dried over magnesium sulfate and evaporated in vacuo to provide 28.54 g of 2-benzylamino-2-methyl-1,3-propanediol. __ NMR (CDC13, d): 1.08 (3H, s), 3.54 (4H, s), 3.73 (2H,% s), 7.20-7.45 (5H, m) MASS (APCI): 196 (M + H) ( 2) 14.0 ml of chloroacetyl chloride is added dropwise to a mixture of 28.5 g of 2-benzylamino-2-methyl-1,3-propanediol, 30.3 g of potassium carbonate in 150 ml of dichloromethane and 150 ml of water, at 0 ° C, and the whole is stirred at room temperature for 2 hours. The mixture is extracted with dichloromethane and the extract is washed successively with water, 1 N hydrochloric acid and brine, dried over sodium sulfate and evaporated in vacuo. The residue is dissolved in 400 ml of terbutanol and to the solution 16.38 g of potassium tert-butoxide are added in portions and the whole is refluxed for 30 minutes. After cooling, the solvent is removed by evaporation and ethyl acetate and water are added thereto. The organic layer is separated, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (1: 1) as an eluent to provide 10.89 g of 4-benzyl-5-hydroxymethyl-5-methyl-3 - morpholinone. NMR (CDC13, d): 1.12 (3H, s), 2.50 (1H, broad s), 3.44 (1H, d, J = 11.7Hz), 3.56 (1H, d, J = 11.9Hz), 3.67 (1H, d, J = 11.7Hz), 3.98 (1H, d, J = 11.9 Hz), - 4.29 (2H, s), 4.67 (2H, s), 7.10-7.40 (5H, m) _ MASS (APCI): 236 (M + H) + (3) Sodium hydride and bis (2-methoxyethoxy) aluminum (3.46 M solution in toluene, 42 ml) is added to a solution of 10.77 g of 4-benzyl-5-hydroxymethyl-5-methyl-3-morpholinone in 100 ml. ml of toluene at 0 ° C under a nitrogen atmosphere and the whole is stirred at room temperature for 1 hour. "20 ml of ethanol 'are added to the mixture at 0 ° C and the weight of the mixture is stirred at 12 ° C. a 1N sodium hydroxide solution The organic layer is separated, 1N hydrochloric acid is added and the aqueous acid layer is separated.This procedure is repeated twice and the combined aqueous layer is made alkaline with a 4 M sodium hydroxide solution. Extract with ethyl acetate, dry over magnesium sulfate and evaporate in vacuo to provide 9.35 g of as an oil NMR (CDC13, d): 1.12 (3H, s), 2.50-2.64 (2H, m). , 3.10- 4.05 (8H, m), 7.20-7.50 (5H, m) MASS (APCI): 222 (M + H) * 77 (4) A solution of 1 g of 4-benzyl-3-hydroxymethyl-3-methylmorpholine in 10 ml of tetrahydrofuran is added dropwise to a suspension of sodium hydride (suspension 60% in oil, -0.27 g in 20%). ml of tetrahydrofuran at room temperature under a nitrogen atmosphere and the whole is stirred at 70 ° C for 1 hour.After cooling, 0.34 ml of methyl iodide is added to the mixture and the whole is stirred at 40 ° C for 1 hour. After cooling, ethyl acetate and water are added to the mixture Z and the organic layer is separated, dried over magnesium sulfate and evaporated in vacuo.The residue is purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (1: 4) as an eluent to give 0.77 g of 4-benzyl-3-methoxymethyl-3-methylmorpholine as an oil NMR (CDC13, d): 1.15 (3H, s) , 2.30-2.64 (2H, m), 3.20- _r 3.70 (8H, m), 3.36 (3H, s), 7.14-7.40 (5H, m) MASS (APCI): 236 (M + H) + 7 (5) A solution of 0.77 g of 4-benzyl-3-methoxymethyl-3-methylimorpholine in 20 ml of methanol is hydrogenated in the presence of 80 mg palladium 10% -carbon at room temperature. After 1 hour, the palladium-carbon is removed by filtration and the filtrate is evaporated in vacuo. The residue is dissolved in 20 ml of ethyl acetate and 4.08 ml of 4N hydrogen chloride in ethyl acetate is added to the solution. The mixture is evaporated in vacuo to provide 0.4 g of 3-methoxymethyl-3-methylmorpholine hydrochloride as a white solid. - p.f. : 80-90 ° C. IR (KBr): 3240-3270, 2976, 1090, 1049 cm "1" NMR (DMSO-dg, d): 1.29 (3H, s), 3.00-3.92 (8H, m), 3.36 (3H, s) MASS (APCI): 146 (M + H). + (Free) Preparation 56 (l) A solution of 0.94 g of (3R) -4-benzyl-3-hydroxymethylmorpholine in 10 ml of tetrahydrofuran is added dropwise to a suspension of sodium hydride (suspension in 60% oil, 0. 22 g) in 20 ml of tetrahydrofuran at room temperature under a nitrogen atmosphere and the whole is stirred at 70 ° C for 1 hour. After cooling, 0.31 ml of methyl iodide is added thereto and the mixture is stirred at 40 ° C for 1 hour. After cooling, the mixture is poured into ice water and extracted with ethyl acetate. The extract is dried over magnesium sulfate and evaporated in vacuo. The residue is purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (3: 7) as an eluent to provide 0.88 g of (3R) -4-benzyl-3-methoxymethylmorpholine as an oil. . NMR (CDC13, d): 2.20 (1H, m), 2.56-2.86 (2H, m), 3.26- 4.26 (8H, m), 3.34 (3H, s), 7.20-7.48 (5H, m) MASS (APCI ): 222 (M + H) + (2) The following compound is obtained in a manner similar to that of Preparation 55 ~~~ (5). (3R) -3-methoxymethylmorpholine hydrochloride mp: 150-152 ° C [] +16.31 ° ( C = 0. 42, MeOH) IR (KBr): 2964, 2947, ^ 2929, 2897, 2887, 2835, 2810, 2789, 2765, 2727, 2698, 2490, 1450, 1311, 1194, 1136, 1111, 1095 cm "1 NMR (DMSO-dg, d): 2.94-3.24 (2H, m), 3.31 (3H, s), 3.36-3.78 (5H, m), 3.80-3.98 (2H, m), 9.52 (2H, s) broad) MASS (APCI): 132 (M + H) + (free) Preparation 57 _ (1) The following compound is obtained according to a manner similar to that of Preparation 56- (1). (3S) -4-benzyl-3-methoxymethylmorpholine NMR (CDC13, d): 2.15-2.34 (1H, m), 2.54-2.72 (2H, m), 3.33 (3H, s), 3.33 (lH, _d, J = 13.5Hz), 3.40-3.90 (6H, * _ m), 4.07 (1H, d, J = 13 ~ .5 Hz), 7.18-7.40 (5H, m) MASS (APCI): 222 (M + H) + * (2) The following compound is obtained according to a manner similar to that of Preparation 55- (5). (3S) -3-methoxymethylmorpholine hydrochloride p.f. : 150-152 ° C [a] D27: -14.70 ° (C = 0.50, MeOH) IR (KBr): 2964, 2947, 2929, 2887, 2833, 2810, 2789, 2765, 2727, 2698, 2490, 1450, 1311, 1194, 1136, 1111, 1095 104 cm "1 NMR (DMSO-dg, d): 2.94-3.24 (2H, m), 3.31 (3H, s), 3.38-3.75 (5H, m), 3.84-3.96 (2H, m), 9.45 (2H, broad s) MASS (APCI): 132 (M + H) + (free) Preparation 58 (1) The following compound is obtained according to a manner similar to that of Preparation 56- (1). (3S) -4-benzyl-3-ethoxymethylmorpholine NMR (CDC13, d): 1.20 (3H, t, J = 7.0Hz), 2.15-2.40 I (1H, m), 2.54-2.84 (2H, _m) , 3.24-4.20 (10H, m), 7.20- 7.45 (5H, m) MASS (APCI): 236 (M + H) + (2) The following compound is obtained according to a manner similar to that of Preparation 55- (5). (3S) -3-ethoxymethylmorpholine hydrochloride p.f. : 100-115 ° C [] -13.07 ° (C = 0.505, MeOH) IR (KBr): 2976, 2922, 2900, 2866, 2790, 2767, 2746, 2721, 2468, 1458, 1450, 1435, 1309, 1176 , 1147, 1126, 1101, 1043, 1030 cm "1 NMR (DMSO-dg, d): 1.15 ~ (3H, t, J = 7.0Hz), 2.94-3.28 (2H, m), 3.28-3.80 (7H, m), 3.80-4.00 (2H, m), 9.47 (2H, broad s) MASS (APCI): 146 (M + H) + (free) Preparation 59 The following compound is obtained according to a manner similar to that of Preparation 55- (5). (3S) -3-hydroxymethylmorpholine hydrochloride p.f. : 123-126 ° C [] D27: -15.80 ° (C = 0.44, MeOH) _ IR (KBr): 3290-3480, 2945, 1105, 1047 cm * 1 NMR (DMSO-dg, d): 2.86-4.00 (9H, m), 5.41 (1H, s "" broad), 9.25 (1H, broad s), 9.56 (1H, broad s) MASS (APCI): 118 (M + H) + (free) Preparation 60 (1) 1.58 ml of a complex of hexafluoro-propene and diethylamine is added dropwise to a solution of 1.5 g of (3R) -4-benzyl-3-hydroxymethylmorpholine in 100 ml of dichloromethane at -30 ° C under a nitrogen atmosphere and The whole is stirred at room temperature for 3 hours. The solution is washed with water and a saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue is dissolved in 100 ml of methanol and 2.9 ml of a 30% solution of sodium methoxide in methanol is added to the solution. After 30 minutes of agitation0.9 ml of acetic acid is added to the mixture and the whole is evaporated in vacuo. Dichloromethane and water are added to the residue and the organic phase is separated, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by column chromatography on silica gel to provide 2.26 C of a crude mixture containing mainly (3R) -4-benzyl-3-fluoromethylmorpholine and 4-benzyl-6-fluorperhydro-1,4-oxazepine. The resulting mixture is used in the next reaction and additional purification. (2) Dissolve (2.2 g) of crude mixture obtained by the previous procedure, which contains mainly (3R) -4-benzyl-3-fluoro-methylmorpholine and 4-benzyl-6-fluorperhydro-1,4-oxazepine, in 50 ml of methanol. The solution is hydrogenated in the presence of 200 mg palladium 10% -carbon at room temperature. After 1 hour of stirring, the palladium-carbon is removed by filtration and the filtrate is evaporated under reduced pressure. Two isomers are separated by column chromatography using 2% methanol in dichloromethane as an eluent to provide (3R) -3-fluoromethylmorpholine and 6-fluoroperhydro-l, 4-oxazepine (the first is less polar). The products are converted to their hydrochloride in a conventional manner using 4N hydrogen chloride in ethyl acetate, respectively. (3R) -3-fluoromethylmorpholine hydrochloride (0.21 g) NMR (DMSO-dg, d): 3.02-3.34 (2H, m), 3.48-3.82 (3H, m), 3.82-4.10 (2H, m), 4.57 (1H, d, J = 4.0 hz), 4.80 (1H, d, J = 4.0 Hz), 9.84 (2H, broad s) MASS (APCI): 120 (M + H) + (free) 6-Fluoroperhydro-1,4-oxazepine hydrochloride (0.26 g) NMR (DMSO-dg, d): 3.10-3.32 (2H, m), 3.40-3.60 (2H, m), 3.68-4.16 (4H, m) , 4.94-5.30 (1H, m) _ MASS (APCI): 120 (M + H) "+ (free) Preparation 61 7.31 g of triphenylphosphine are added to a solution of 4.62 g of carbon tetrabromide in 15 ml of dichloromethane at 0 ° C and the mixture is stirred at 0 ° C for 15 minutes. A solution of 1.5 g of (3S) -4-tert-butoxycarbonyl-3-formylmorpholine in 15 ml of dichloromethane is added dropwise to the solution for 10 minutes at 0 ° C, and stirred for 3 hours, and to the mixture a saturated solution of sodium hydrogen carbonate is added. The organic layer is separated and the aqueous layer is extracted with ethyl acetate three times. The combined organic layer is washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by column chromatography ~~ on silica gel using a mixture of ethyl acetate and n-hexane (4: 6) to provide (3R) -4-tert-butoxycarbonyl-3- (2,2-dibromoethenyl) ) -morpholine as an oil. This oil is dissolved in 15 ml of tetrahydrofuran and butyllithium (1.62 M in hexane, 9.45 ml) is added to the solution at -78 ° C. After 30 minutes of stirring at -78 ° C, the mixture is suspended with water and extracted with ethyl acetate twice. The combined organic layer is washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel using a mixture of ethyl acetate and hexane (2: 8) to provide 1385 g of (3R) -4-tert-butoxycarbonyl-3-ethynylmorpholine as a yellow oil. pale. - NMR (CDC13, d): 1.48 (9H, s), 2.31 (1H, d, J = 2.3Hz), 3.19-3.96 (6H, m), 4.74 (1H, broad s) MASS (APCI): 112 ( MB? C) + Preparation 62 - (1) The following compound is obtained according to a manner similar to that of Preparation 55- (5). (3S) -3-ethoxycarbonylmorpholine hydrochloride NMR (CDC13, d): 1.33 ~ (3H, t, J = 7.1Hz), 3.20-3.75 (2H, m), 3.90-4.30 (5H, m), 4.32 (2H) , c, J = 7.1 Hz), 10.04 (1H, broad s), 10.74 (1H, broad s) MASS (APCI): 160 (M + H) + (free) (2) A mixture of 0.3 g of (3S) -3-ethoxycarbonylmorpholine hydrochloride, 0.34 ml of propargyl bromide and 0.91 g of potassium carbonate in 10 ml of N, N-dimethylformamide is stirred at room temperature for 1 hour and then the solvent is removed under reduced pressure. Ethyl acetate and a sodium acid carbonate solution are added to the residue, and the organic layer is separated, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (3: 7) as an eluent to provide 0.22 g of (3S) -3-ethoxycarbonyl-4- (2-propynyl) ) morpholine as an oil. NMR (CDC13, d): 1.29 (3H, t, J = 7.1 Hz), 2.28 (1H, t, * J = 2.5 Hz), 2.70-2.95 (2H, m), 3.40-4.05 (7H, m), 4.21"(2H, c, J = 7.1 Hz) * ~ MASS (APCI): 198 (M + H) + Preparation 63 (1) 4.63 g of sodium triacetpxiborohydride are added in portions to a mixture of 1.5 g of (R) -l - (-) -2-amino-1-butanol and 1.79 g of benzaldehyde in 50 ml of 0 ° dichloromethane C and the whole is stirred at room temperature overnight. The mixture is washed with a sodium carbonate solution and brine, dried over sodium sulfate and evaporated in vacuo to provide 2.69 g of (R) -2-benzylamino-1-butanol [IR (Pure): 3292, 1460 , 1350, 1136, 1061 cm "1). A solution of 2.1 g of chloroacetyl chloride in 4 ml of tetrahydrofuran is added to a mixture of 2.69 g of the obtained oil and 4.6 g of potassium carbonate in a mixture of 20 ml of acetone and 20 ml of water at 0 ° C. After 1 hour * of stirring, the solvent is replaced with ethyl acetate.The organic layer is separated, washed with brine, dried over sodium sulfate and Evaporate in vacuo The residue is purified by column chromatography on silica gel to provide 2.73 g of N-benzyl-N- [(2R) -2- (1-hydroxybutyl)] -2-chloroa-ethamide [IR (Pure ): 3430, 1640, 1450, 1420, 1355, 1045 cm "1, MASS (APCI): 256 (M + H) +, 220] as an oil. 1.22 g of potassium terbutoxide are added to a solution of the 2.7 g of the oil obtained above in 20 ml of tert.-butanol, in portions, at room temperature, and the whole is stirred overnight. The mixture is evaporated in vacuo, and ethyl acetate and water are added to the residue. The organic layer is separated, washed with brine, dried over sodium sulfate and evaporated in vacuo to provide 2.33 g of (5R) -4-benzyl-5-ethyl-3-morpholinone as an oil. "" IR (Pure): 1655, 1640, 1450, 1430, 1360, 1340, 1260, 1155, 1128 cm * 1 - z NMR (CDCI3, d): 0.91 (3H, t, J = 7.5 Hz), 1.60-1.96 (2H , m), 2.94-3.14 (1H7 m), 3.55-3.94 (2H, m), 3.92 (1H, d, J = 15.0Hz), 4.21 (1H, d, J = 16.7Hz), 4.31 (1H, d, J = 16.7 Hz), 5743 (1H, d, J = 15.0 Hz), 7.20-7.444 (5H, m) MASS (APCI): 220 (M + H); (2) A 2.3 g solution is added in portions (5R) -4-benzyl-5-ethyl-3-morpholinone in 7 ml of tetrahydrofuran to a suspension of 0.4 g of lithium aluminum hydride in 15 ml of tetrahydrofuran and the whole is refluxed for 2 hours. After cooling, 4 ml of a 50% aqueous tetrahydrofuran solution are added thereto and stirring is continued for 15 minutes, the mixture is filtered through a pad of Celite ™ and the pad washed with tetrahydrofuran. The combined filtrate is evaporated in vacuo and the residue is purified by column chromatography on silica gel to provide 1.44 g of (3R) -4-benzyl-3-ethylmorpholine as an oil. IR (Pure): 1495, 1450, 1355, 1130, 1060 cm "1 NMR (CDC13, d): 0.93 (3H, t, J = 7.5 Hz), 1.44-1.94 * (2H, m), 2.08-2.45 ( 2H, m), 2.54-2.70 (1H, m), 3.15 (1H, d, J = 13.3 Hz), 3.55-3.86 (4H, m), 4.06 (12H, d, J = 13.3 Hz), 7.15-7.40 (5H, m) MASS (APCI): 205 (M + H ) + * A solution of 1.44 g of the oil obtained in 15 ml of ethanol is hydrogenated using 200 mg of palladium 10% -carbon at atmospheric pressure. After the reaction is complete (7 hours), the catalyst is removed by filtration. To the filtrate, 4 N hydrogen chloride in 2.5 ml of ethyl acetate is added and the whole is evaporated in vacuo. The residue is triturated with ethyl acetate and the resulting precipitates are collected by filtration and dried to provide 1.0 g of (3R) -3-ethyl-morpholine hydrochloride. p.f. : 223-225 ° C [] D28: + 9.5 ° (C = 0.5, MeOH) IR (KBr): 2729, 2696, 2472, 1458, 1427, 1360, 1313, 1109, 1061 c * 1 NMR (DMSO-dg , d): 0.93 (3H, t, J = 7.5 Hz), 1.40-1.78 (2H, m), 2.88-3.55 (4H, m), 3.60-4.04 (3H, m), 9.60 (2H, broad s) - MASS (APCI): 116 (M + H) + ^ (free) Preparation 64 (1) The following compound is obtained according to a manner similar to that of Preparation of Preparation 63- (1). (3S) -4-benzyl-5-ethyl-3-morpholinone-IR (Pure): 1653, 1462, 1348, 1263, 1155, 1122 c "1 7. NMR (CDC13, d): 0.91 (3H, t, J = 77.5 Hz), 1.60-1.96 (2H, m), 2.95-3.14 (1H, m), 3.58-3.94 (2H, m), 3.92 (1H, d, J = 15.0Hz), 4.21 (1H, d, J = 16.7Hz), 4.30 (1H, d, J = 16.7 Hz), 5.43 (1H, d, J = 15.0 Hz), 7.15-7.44 (5H, m) MASS (APCI): 220 (M + H) + (2) The following compound is obtained according to a manner similar to that of Preparation of Preparation 63- (2). (3S) -ethylmorpholinone hydrochloride p.f. : 221-224 ° C "[a] D26: -11.2 ° (C = 0.5, MeOH) IR (KBr): 2729, 2625, 2472, 1454, 1356, 1313, 1109, • __ 1061 cm" 1 NMR (DMSO) -dg, d): 0.93 (3H, t, J = 7.5 Hz), 1.40-1.78 (2H, m), 2.90-3.54 (4H, m), 3.60-4.04 (3H, m), 9.57 (2H, s) ampliio) - MASS (APCI): 116 (M + H) + "~ (free) Preparation 65 ~ A mixture of 200 mg of 7-oxa-4-azaspiró [2.5] octane hydrochloride, 0.28 ml of "2-bromoethanol and 550 mg of potassium carbonate in 2 ml of N, N-dimethylformamide are stirred at 90 ° C The mixture is poured into brine and extracted with dichloromethane.The extract is dried over magnesium sulphate and evaporated under reduced pressure and purified by column chromatography on silica gel using a mixture of methanol and chloroform (2:98) to give 4- (2-hydroxyethyl) -7-oxa-4-azaspiro [2.5] ocatane as an oil.This oil is dissolved in 5 ml of ethyl acetate and to the solution 0.16 ml of methanesulfonyl chloride and 0.3 ml "of triethylamine. After 30 minutes of stirring at room temperature, the mixture is filtered, evaporated and purified by column chromatography on silica gel using a mixture of ethyl acetate and n-hexane (20:80 30:70) to provide mg of 4- (2-chloroethyl) -7-oxa-4-azaspiro [2.5] octane as an oil. NMR (CDC13, d): 0.61-0.67 (2H, m), 0.95-1.05 (2H, m), ! 3.10-3.15 (2H, m), 3.22 (2H, t, J = 6.9 Hz), 3.50 (2H, s broad), 3.54-3.64 (2H, m), 3.80 (2H, t, J = 4.7 Hz MASS (APCI): 176 (M + H) + Preparation 66 A mixture of 0.2 g of (3R) -3-ethylmorpholine hydrochloride, 0.5 ml of 1,4-dichloro-2-butyne and 0.71 g of potassium carbonate in 10 ml of N, N-dimethylformamide is stirred at room temperature for 2 hours . After removal of the solvent, ethyl acetate and sodium hydrogen carbonate are added thereto. The organic layer is separated and the aqueous layer is extracted with ethyl acetate twice. The combined organic layer is dried over magnesium sulfate and evaporated in vacuo. The residue is purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (1: 1) as an eluent to provide (3R) -4- (4-chloro-2-butynyl) -3 -ethylmorpholine (0.2 g) as an oil. _ NMR (CDC13, d): 0.89 (3H, t, J = 7.5 Hz), 1.20-1.74 (2H, m), 2.95-3.14 (3H, 'm), 3.20-3.90 (6H, m), 4.18 (2H, t, J = 2.0Hz) __ MASS (APCI): 202 (M + H) + Preparation 67 _ (1) A mixture of 8.3 g of (3S) -3,5-dimethylmorpholine hydrochloride, 14.34 g of diterbutyl dicarbonate and 5.48 g of sodium hydroxide in 30 ml of water is stirred at room temperature overnight. 50 ml of water and isopropyl ether are added to the mixture and the organic layer is separated, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (1: 9) as an eluent to provide 3.55 g of (3S, 5S) -4-tert-butoxycarbonyl-3, 5-dimethylmorpholine and 2.84 g meso-4-tert-butoxycarbonyl-3,5-dimethylmorpholine (the first is less polar). 3.55 g of (3S, 5S) -4-tert-butoxycarbonyl-3,5-dimethylmorpholine are dissolved in a mixture of 20 ml of dichloromethane and 20 ml of trifluoroacetic acid, and the mixture is stirred at room temperature for 2 hours. After removal of the solvent under pressure, 20 ml of a sodium hydroxide solution are added thereto. 1N and dichloromethane. The organic phase is separated, dried over magnesium sulfate and 4N hydrogen chloride in 20 ml of ethyl acetate is added. The mixture is evaporated in vacuo and the residue is triturated with a mixture of dichloromethane and isopropyl ether to provide 1.56 g of (3S, 5S) -3,5-dimethylmorpholine hydrochloride as a white solid. p.f. : 172-173 ° C [] D2S: + 16.37 ° (C = 0.333, MeOH) IR (KBr): 3049, 2993, 2978, 2970, 2935, 2916, 2873, 2829, 2817, 2800, 2785, 2742, 2723 , 1460, 1433, 1385, 1136, 1107, 1028 cm "1 NMR (CDC13, d): 1.50 (6H, d, J = 6.5 Hz), 3.44-4.08 (6H, m), 9.97 (2H s broad) MASS (APCI): 116 (M + H) + (free) 2.84 g of meso-3,5-dimethylmorpholine hydrochloride are prepared from meso-4-terbutoxycarbonyl-3,5-dimethylmorpholine in a manner similar to the preparation of (3S, 5S) -3,5-dimethylmorpholine hydrochloride ( 1.84 g). p.f. : 85-90 ° C IR (KBr): 2981, 2945, "2929, 2873, 2860, 2808, 2802, 2773, 2748, 2735, 2727, 1672, 1624, 1205, 1182, 1138, 1117, 1057 cm * 1 NMR (CDC13, d): 1.35 (6H, d, J = 6.6 Hz), 3.22-4.00 (6H, m), 9.44 (1H s broad), 10.22 (1H, broad s), - MASS (APCI): 116 (M + H) + (free) (2) The following compound is obtained according to a manner similar to that of Preparation 66. (3S, 5S) -4- (4-chloro-2-butinyl) -3,5-dimethylmorpholine NMR (CDCl 3, d) : 1.06 (6H, d, J = 6.5 Hz), 2.95-3.14 (2H, m), 3.34-3.54 (4H, m), 3.72 (2H, dd, J = 11.0, 3.1Hz), 4.16 (2H, t , J = 2.1 Hz) MASS (APCI): 202 (M + H) + Preparation 68 (1) The following compound is obtained according to a manner similar to that of Preparation 65. 2- (3, 3-dimethylmorpholin-4-yl) ethanol * NMR (DMSO-dg, 8): 0.91 (6H, s) ), 2.3 (2H, t, J = 6.7Hz), 2.4-2.5 (2H, m), 3.19 (2H, s), 3.3-3.4 (2H, m), 3.5-3.6 (2H, m), 4.27 flH , t, J = 5.4 Hz) MASS (APCI): 160 (M + H) + (2) The following compound is obtained according to a manner similar to that of Preparation 65. Ethylene methanesulfonate 2- (3, 3-dimethylmorpholin-4-yl) The compound is used in the next step without further purification.

Preparation 69 The following compound is obtained according to a manner similar to that of Preparation 62- (2). 4- (3-chloropropyl) -3,3-dimethylmorpholine NMR (DMSO-dg, d): 0.92 6H, s), 1.77 (2H, qui, J = 6.4 _ Hz), 2.3-2.5 (4H, m), 3Tl9 (2H, s), 3.55-3.60 (2H, m), 3.67 (2H, t, J = 6.4 Hz) MASS (APCI): 192 (M + H) + Preparation 70 * "" (1) The following compound is obtained according to a manner similar to that of Preparation 53- (5) starting from (3R) -l-benzyl-3- [(1H-indol-3-yl) ) methyl] piperazine. (2R) -4-Benzyl-1-tert-butoxycarbonyl-2- [(1H-indol-3-yl) -methyl] piperazine m.p. : 143-145 ° C IR (KBr): 3305, 2976, 2922, 2810, 1664, 1454, 1425, 1367, 1336, 1299, 1261, 1223 crn * 1 NMR (CDC13, d): 1.00-1.50 (9H, m), 1.80-2.10 (2H, m), - 2.60-4.30 (9H, m), 6.80-7.70 (10H, m), 10.72 (1H, broad s) _ MASS (APCI): 406 (M + H ) + ^ (2) The following compound is obtained according to a manner similar to that of Preparation 33. (2R) -l-tert -butoxycarbonyl-2- [(1H-indol-3-yl) -methyl] iperazine IR ( KBr): 3410, 3311, 2976, 2924, 1672, 1454, 1417, ~ 1365, 1259 cm "1 NMR (DMSO-d5, d): 1.22 (9H, broad s), 2.25-4.20 (10H, m), 6.88-7.70 (5H, m), 10.78 (1H, broad s) MASS (APCI): 316 (M + H) + (3) The following compound is obtained according to a manner similar to that of Preparation 34. ( 2R) -1- tert -butoxycarbonyl-4- [4- (3, 3-dimethyl-morpholino) - ~ 2-butynyl] -2- [(lH-indol-3-yl) -methyl] piperazine IR (KBr ): 3500-3300, 2972, 2935, 1687, 1456, 1417, 1365, 1333, 1227 cm * 1 NMR (DMSO-ds, d): 0.94 (6H, s), 1.21 (9H, s), 1.82-2.20 (2H, m), 2.50-4.30 (17H, m), 6.85 -7.66 (5H, m), 10.81 (1H, broad s) MASS (APCI): 481 (M + H) + (4) The following compound is obtained according to a manner similar to that of Preparation 35. (3R) -1- [4- (3,3-dimethylmorpholino) -2-butynyl] -3- [(1H-trichlorohydrate. -indol-3-yl) -methyl] piperazine - = pf : 209-230 ° C ~ "[a] D2S: -10.9 ° (C = 0.5, MeOH) IR (KBr): 3600-3300, 2900, 2700-2400, 1645, 1628, 1539, 1516, 1454, 1429, 1344 cm "1 NMR (DMSO-dg, d): 1.20-1.50 (6H, m), 3.10-4.42 (20H, m), 6.95-7.80 (5H, m), 9.90- 10.25 (2H, m), 11.15 (1H, broad), 11.90 (1H, broad s) ~ MASS (APCI): 381 (M + H) + (free) Preparation 71 (1) 5.4 ml of acetic acid are added to a solution of 8.4 g of 2-amino-2-methyl-1-propanol and 10 g of benzaldehyde in 140 ml of 1,2-dichloroethane, under cooling with ice. After 30 minutes of stirring at the same temperature, 26 g of sodium triacetoxyborohydride are added in small portions to the solution for 10 minutes. After 2 hours of stirring at room temperature, the mixture is poured into a solution of 48.0 g of sodium acid carbonate in 300 ml of water. The aqueous layer is separated and adjusted to pH 12 with an aqueous solution of 24% sodium hydroxide. The alkaline solution is extracted with ethyl acetate (2 times). The extract is dried over sodium sulfate and evaporated under reduced pressure to provide 13.2 g of colorless crystals of 2-benzylamino-2-methyl-1-propanol.

The following compound is obtained according to a manner similar to that of Preparation 34. p.f. : 46.0-47.0 ° C IR (Nujol): 3330, 3100, 2900, 1450, 1380, 1355 cm "1 0 NMR (DMSO-dg, ß): 0.99 (6H, s), 3.23 (2H, d, J = 3.9Hz), 3.62 (2H, s), 4.50-4.60 (1H, m), 7.16-7.36 (5H, m) - - MASS (APCI): 180 (M + H) "+; (2) 6.0 g of 2-benzylamino-2-methyl-1-propanol and 6.95 g of potassium carbonate are dissolved in a mixture of 30 ml of dichloromethane and 30 ml of water, under cooling with ice. 2.95 ml of chloroacetyl chloride are added to the mixture for 25 minutes and the whole is stirred for 2 hours at room temperature, the organic layer is separated, washed with dilute hydrochloric acid and brine, and dried over sodium sulfate. magnesium and evaporated under reduced pressure, the residue is dissolved in 40 ml of tert.-butyl alcohol and 3.76 g of potassium tert-butoxide are added to the solution, the whole is stirred for 4 hours under reflux under a nitrogen atmosphere. at room temperature, the insoluble mass is filtered off and washed with ethyl acetate.The filtrate and the washing are combined and the whole is washed with dilute hydrochloric acid and with brine, successively, and dried over magnesium sulfate and evaporate under reduced pressure The residue is triturated with a mixture of hexane and disopropyl ether (1: 1) and the resulting crystals are collected by filtration and washed with a mixed solvent. of hexane and diisopropyl ether (1: 1) to provide colorless crystals of 4.53 g of 4-benzylamino-5,5-dimethyl-3-morpholinone. The following compound is obtained according to a manner similar to that of Preparation 34. p.f. : 76-77 ° C IR (Nujol): 1635, 160? "1490, 1460, 1380, 1355 cm" 1 NMR (CDCI3, 6): 1.20 (6H, s) 3.61 (2H, s), _ 4.32 ( 2H, s), 4.64 (2H, s), 7.18-7.36 (5H, m) MASS (APCI): 220 (M + H) + (3) 4.45 g of 4-benzyl-5,5-dimethyl-3-morpholinone are added to an ice-cooled suspension of 0.77 g of lithium aluminum hydride in 2 JD ml of dry tetrahydrofuran under a nitrogen atmosphere. After 5 hours of stirring at 50 ° C, the reaction mixture is cooled to below 5 ° C and 0.36 ml of water, 0.36 ml of an aqueous solution of sodium hydroxide 12% and 1 ml are successively added thereto. of water. After 30 minutes of stirring, the mixture is filtered through a pad of Celite ™ and the pad washed with ethyl acetate. The filtrate and the washing are combined and the whole is dried over magnesium sulphate and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel using a mixture of n-hexane and ethyl acetate. The fractions containing the objective compound are collected and evaporated under reduced pressure to provide 4-benzyl-3,3-dimethylmorpholine as an oil. The oil obtained and 5.7 g of ammonium formate are dissolved in a mixed solvent of 35 ml of ethanol and 5 ml of water, and the whole is stirred under reflux for 1 hour under a nitrogen atmosphere. The mixture is filtered through a pad of Celite ™ The filtrate is evaporated under reduced pressure The residue is dissolved in methanol and a solution of 4N hydrogen chloride in ethyl acetate is added thereto The whole mixture is evaporated and the residue The mixture is triturated with a mixture of ethanol and n-hexane (1: 1) .The resulting crystals are collected by filtration and washed with a mixed solvent of ethanol and n-hexane (1: 1) to provide 1.56 g of colorless crystals of 3, 3-dimethylmorpholine hydrochloride mp: 196-197 ° C IR (Nujol): 3300, 2750, 2650, 2500, 1590, 1460 cm "1 NMR (DMSO-dg, d): 1.21 (6H, s), 3.05-3.11 (2H, m), 3. 51 (2H, s), 3.76-3.81 (2H, m), 9.66 (2H, broad s).

Example 66"" 30 mg of paraformaldehyde and 9 mg of copper iodide (I) are added to a mixture of 0.16 g of (2R) -l- [3,5-bis (trifluoromethyl) -benzoyl] -2- (3, 4) -dimethylbenzyl) piperazine0.08 g of (3S) -3-ethoxycarbonyl-4- (2-propynyl) morpholine and 0.09 ml of N, N-diisopropylethylamine in 10 ml of 1,4-dioxane and the whole is stirred at room temperature for 30 minutes, and then it is heated at 90 ° C for 30 minutes. After cooling, ethyl acetate and a sodium acid carbonate solution are added to the mixture. The organic layer is separated, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (1: 1) as an eluent to provide 0.21 g of (2R) -1- [3,5-bis (trifluoromethyl) benzolyl] -2- (3,4-dimethylbenzyl) -4- [4- ((3S) -3-ethoxycarbonylmorpholino) -2-butynyl] piperazine. _ - NMR (CDC13, d): 1.20-5.30 (31H, m), 6.55-7.90 (6H, m) "" MASS (APCI): 654 (M + H) + Example 67 The following compound is obtained according to a manner similar to that of Example 66. (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [3- [(3R) - (4-tert-butoxycarbonyl) morph olin-3-yl] -2-propynyl] piperazine NMR (DMSO-dg, d): 1.39 (9H, s), 2.09-2.17 (6H, m), 2. 30-5.00 (18H, m), 6.60-8.15 (6H, m) MASS (APCI): 668 (M + H) + (free) Example 68 To a solution of 1,607 g of (2R) -l- [3,5-bis (trifluoromethyl) -benzoyl] -2- (3,4-dimethylbenzyl) -4- [3- [(3R) - (4-ter -butoxycarbonyl) morpholin-3-yl] -2-propynyl] piperazine in 16 ml of ethyl acetate is added hydrogen chloride (4N in ethyl acetate, 3 ml). After 8 hours of stirring at room temperature, the mixture is evaporated under reduced pressure to provide 1.43 g of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl dihydrochloride. ) -4- [3- [(3R) -morpholin-3-yl] -2-propynyl] -piperazine as a solid ^ pf : 190-191 ° C [] -14.0 ° (C = 0.5, MeOH) IR (KBr): 2927, 1643 crn "1 NMR (DMSO-dg, d): 2.10-2.18 (6H, m), 2.80-5.25 (18H, m), 6.65-8.25 (6H, m) MASS (APCI): 568 (M + H) + (free) Example 69 0.034 g of paraformaldehyde and 12 mg of copper iodide (I) are added to a mixture of 0.21 g of (2R) -l- [3,5-bis (trifluoromethyl) -benzoyl] -2- (3, 4 -dimet ilbenzyl) -4- (2-propynyl) iperazine, 0.09 g of (3S) -3-methoxymethylmorpholine and 0.1 ml of N, N-diisopropylethylamine in 5 ml of 1,4-dioxane and the whole is stirred at room temperature for 30 minutes. minutes and then heated at 70 ° C for 2.5 hours. After cooling, ethyl acetate and a sodium acid carbonate solution are added to the mixture. The organic layer is separated, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by column chromatography on silica gel with 3% methanol in chloroform as an eluent to provide (2R) -1- [3,5-bis- (trifluoromethyl) benzoyl] -2- (3, 4- dimethylbenzyl) -4- [4- ((3S) -3'-methoxymethylmorpholino) -2-butynyl] piperazine. Dissolve in ethyl acetate and add 4N hydrogen chloride in ethyl acetate to the solution. The mixture is evaporated in vacuo and the residue is triturated with a mixture of ethyl acetate and isopropyl ether to give 0.16 g of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3-dihydrochloride. , 4-dimethylbenzyl) -4- [4- ((3S) -3-methoxymethylmorpholino) -2-butyl] piperazine. ~ p.f. : 60-70 ° C [] D28: -1.8 ° (C = 0.25, MeOH) IR (KBr): 1684, 1645, "1512, 1460, 1448, 1431, 1371, 1365, 1325, 1281, 1184, 1136, 1072 cm "1 NMR (DMSO-d6, d): 2.00-2.28 (6H, m), 2.60-5.30 (25H, m), 6.60-8.30 (6H, m) MASS (APCI): 626 (M + H) + (free) Example 70 The following compounds are obtained according to a manner similar to that of Example 69. (1) (2R) -1 - [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [4- ((3R) -3-f-luoromethylmorpholine) - hydrochloride 2-butynyl] piperazine pf : 118-128 ° C [a] D28: -6.8 ° (C = 0.25, MeOH) IR (KBr): 1645, 1502, 1435, 1365, 1321, 1282, 1182, 1136, 1049 cm * 1 NMR (DMSO- dg, Ó): 2.00-2.30 (6H, m), 2.60-5.30 (22H, m), 6.60-8.30 (6H, m) MASS (APCI): 614 (M + H) ^ (free) (2) (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [4- (tetrahydro-6-fluoro-1,4) dihydrochloride -oxazepin-4 (5H) -yl) -2-butinyl] piperazine pf : 90 -100 ° C [a] D28: + 1.6 ° (C = 0.25, MeOH) IR (KBr): 1645, 1504, 1433, 1373, 1365, 1323, 1282, 1219, 1182, 1136 cm "1 NMR (DMSO-dg, d): 2.00-2.30 (6H, m), 2.60-5.30 (22H, m), 6.60-8.28 (6H, m) MASS (APCI): 614 ( M + H) + (free) 71 The following compounds are obtained according to a manner similar to that of Example 31. (1) Dichl orhydrate of (2 R) -l - [3,5-bis (trifluoromethyl) enzoyl] -2- (3,4-dimethylbenzyl) -4- [4- (3-methoxymethyl-3-methylmorph olino) -2-butinyl] piperazine pf : 155-160 ° C [a] D28: -11.6 ° (C = 0.25, MeOH) IR (KBr): 1645, 1437, ^ 1362, 1323, 1281, 1219, 1182, 1138, 1055 cm "1 NMR (DMSO-dg, d): 1.20-1.50 (3H, m), 2.05-2.26 (6H, m), 2.60-5.20 (24H, m), 6.60-8.30 (6H, m) MASS (APCI): 640 (M + H) + (free) (2) (2R) -1 - [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [4- ((3S) -3-ethoxymethylmorpholino) -2 - butinyl] piperazma pf : 155-160 ° C [al: + 0.6 ° (C = 0.25, MeOH) IR (KBr): 1645, 1439, 1371, 1281, 1217, 1182, 1136, 1072, 1032 cm * 1 - NMR (DMSO-dg , d): 1.13 (3H, t, J = 7.0Hz), 2.02-5.24 (30H, m), 6.60-8.28 (6H, m) MASS (APCI): 640 (M + H) + (free) (3) D iclo rhi dra to of (2 R) - l - [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [4- ((3S, 5S) - 3, 5 -dimethylmorpholine) -2-butinyl] piperazine pf : 160-165 ° C [] D28: + 14.2 ° (C = 0.25, MeOH) IR (KBr): 1657, 1649, _1643, 1433, 1356, 1281, 1186, 1136, 1109 crn * 1 NMR (DMSO-dg , d): 1.10-1.45 (6H, m), 2.00-2.28 (6H, m), 2.60-5.20 (19H, m), 6.60-8.28 (6H, "m) MASS (APCI): 610 (M + H ) + (free) (4) (2R) -1 - [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [4- ((3S) -3-hydroxymethylmorpholino) -2 - butinyl] piperazine pf : 130-150 ° C [a] D28: -2.6 ° (C = 0.25, MeOH) IR (KBr): 1691, 1645, 1512, 1458, 1442, 1433, 1371, 1365, 1325, 1281, 1217, 1182, 1136, 1059 cm "1 NMR (DMSO-dg, d): 2.00-2.30 (6H, m), 2.60-5.30 (22H, m), 6.60-8.28 (6H, m) MASS (APCI): 612 (M + H) + (free) (5) Dichl orhydrate of (2 R) -1 - [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [4- ((2S) -3-methoxymethylmorph olino) -2-butinyl] piperazine pf : 85-95 ° C ~ [a] D2S: -4.71 ° (C = 0.25, MeOH) IR (KBr): 1641, 1631, 1442, 1281, 1134 cm * 1 NMR (DMSO-dg, d): 2.00- 2.30 (6H, m), 2.60-5.28 (25H, m), 6.60-8.30 (6H, m) MASS (APCI): 626 (M + H) + (free) (6) D i cl (2 R) -1 - [3,5-bis (trifluoromethyl) enzoyl] -2- (3,4-dimethylbenzyl) -4- [4- ((2R) -2-methoxymethylmorpholinohydrate ) -2-butinyl] piperazine pf : 80-90 ° C [] D28: -15.00 ° (C = 0.24, MeOH) IR (KBr): 1657, 1649, 1641, 1631, 1441, 1431, 1281, 1186, 1176, 1136, 1109 cm "1 NMR (DMSO-dg, d): 2.00-2.30 (6H, m), 2.60-5.20 (25H, m), 6.60-8.30 (6H, m) MASS (APCI): 626 (M + H) + (free) (7) D i cl orhydrate of (2 R) -1 - [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [(E) -4 - (3R) -3-methoxymethylmorpholino) -2-butenyl] piperazine pf : 240-250 ° C [a] D28: -19.47 ° (C = 0.19, MeOH) IR (KBr): 1647, 1635, 1618, 1456, 1435, 1379, 1281, 1186, 1132, 1108 cm "1 NMR (DMSO-dg, d): 2.00-2.28 (6H, m), 2.60-5.20 (25H, m), 5.80-8.30 (8H, m) MASS (APCI): 628 ( M + H) + (free) Example 72 A mixture of 1.2 g of (2R) -1-3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [4-chloro-2-butynyl] piperazine and 0.43 g of hydrochloride of (3S) -3-ethoxycarbonylmorpholine, 1.09 g of potassium carbonate and a trace of potassium iodide in 50 ml of N, N-dimethylformamide is stirred at 55 ° C for 12 hours. After cooling, the solvent is removed by evaporation and ethyl acetate and water are added thereto. The organic layer is separated, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (2: 3) as an eluent to give 0.29 g of (2R) -1- [3,5-bis (trifluoromethyl) ) benzoyl] -2- (3,4-dimethylbenzyl) -4- [4- ((3S) -3-ethoxycarbonylmorpholino) -2-butinyl piperazine as an oil. NMR (CDC13, d): 1.20-5.30 (31H, m), 6.55-7.90 (6H, m) MASS (APCI): 654 (M + H) "" + Example "73 The following compounds are obtained according to a manner "similar to that of Example 72. (1) D i cl orhydrate of (2 R) -1 - [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [4- ((3R) -3- ethylmorpholino) -2-butynyl] piperazine [a] D27: -22.7 ° (C = 0.5, MeOH) IR (KBr): 3600, 1645, 1460, 1280, 1180, 1135 cm * 1 NMR (DMSO-dg, d): 0.83-5.17 (31H, m), 6.62-8.24 (6H, m) MASS (APCI): 610 (M + H) + (free) (2) (2R) -1- [3,5-bis (trifluoromethyl) -4- [4- ((3S) -3-ethylmorpholino) -2-butynyl-2- [(lH-indole-3-) dihydrochloride] il) methyl] piperazine [a] D28: + 11.2 ° (C = 0.5, MeOH) IR (KBr): 3365, 2600, 1645, 1430, 1280, 1180, 1135 cm "1 NMR (DMSO-dg, d): 0.67-5.20 (25H, m), 6.60-8.28 (8H, m), 10.96 (1H, S) MASS (APCI): 621 (M + H) + (free) (3) Dichl orhydrate of (2 R) -1 - [3,5-bis (trifluoromethyl) enzoyl] -2- (3,4-dimethylbenzyl) -4- [(E) -4 - (3S) - 3-methoxymethylmorpholino) -2-butenyl] piperazine pf : 130-140 ° C [a] D27: + 2.0 ° (C = 0.25, MeOH) IR (KBr): 1653, 1647, 1637, 1282, 1188, 1134 cm "1 NMR (DMSO-dg, d): 2.00 -2.28 (6H, m), 2.70-5.28 (25H, m), 6.00-8.32 (8H, m) MASS (APCI): 628 (M + H) + (free) Example 74 To a solution of 0.42 g of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [4 - ((3S) -ethoxycarbonyl-morpholino) - 2-butynyl] piperazine in 30 ml of ethanol is added 30 ml of a 1N sodium hydroxide solution and the whole is stirred at room temperature for 2 hours. The solvent is removed under reduced pressure and the residual aqueous solution is neutralized with concentrated hydrochloric acid. The solution is extracted with dichloromethane. The extract is dried over magnesium sulfate and evaporated in vacuo to provide 0.26 g of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethyl-benzyl) -4- [4- ((3S-3-carboxymorpholino) -2-butynyl] piperazine as an oil NMR (CDClg, d): 2.00-5 ^ 28 (26H, m), 6.50-7.90 (6H, m) MASS (APCI) ): 626 (M + H) + Example 75 A solution of tetrahydrofuran of dimethylamine (2M, 0.32 ml) is added to a mixture of 0.13 g of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4 - [4- ((3S) -3-carboximorpholino) -2-butyl] piperazine, 85 mg of 1-hydroxybenzotriazole and 0.12 g of l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride in 5 ml of N, N dimethylformamide, and the whole is stirred at room temperature for 5 hours. The solvent is then removed by evaporation, and dichloromethane and a sodium acid carbonate solution are added to the residue. The organic layer is separated, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by column chromatography on silica gel with 3% methanol in dichloromethane as an eluent to provide (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) ) -4- [4- ((3S) -3-dimethylcarbamoylmorpholino) -2-butyl] piperazine. It dissolves in ml of ethyl acetate and to the solution are added 4N hydrogen chloride in ethyl acetate (0.26 ml). The mixture is evaporated in vacuo and the residue is triturated with a mixture of ethyl acetate "and isopropyl ether to provide 0.12 g of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- dihydrochloride ( 3, 4-dimethyl-ylbenzyl) -4- [4- ((3S) -3-dimethylcarbamoylmorpholino) -2-butynyl] -perazine as a solid. ^ Pp: 150-160 ° C [a] D27: -33.2 ° ( C = 0.25, MeOH) IR (KBr): 1653, 1506, ~ 1433, 1371, 1325, 1281, 1182, 1136, 1063, 1026 cm "1 NMR (DMSO-dg, d): 2.00-2.30 (6H, m), 2.60-5.20 (26H, m), 6.60-8.38 (6H, m) _ MASS (APCI): 653 (M + H) + (free) Example 76 The following compounds are obtained according to a manner similar to that of Example 5 (1) (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1H-indol-3-dihydrochloride]] il) methyl] -4-. { 3- [2- (4-methoxy) pyridyl] -2-propynyl} piperazine p.f. 130-135 ° C [a] D28: + 2.8 ° (C = 0.5, MeOH) IR (KBr): 3600, 3314, 1640, 1625, 1430, 1280, 1180, 1135 cm "1 NMR (DMSO-dg, d ): 3.95 (3H, s), 2.74-5.24 (11H, m), 6. 60-8.60 (11H, m), 10.92 (1H, s) MASS (APCI): 601 (M + H) + (free) (2) (2R) -1 - [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- dihydrochloride. { 3- [2- (4-methoxy) pyridyl] -2-propynyl} -piperazine p.f. : 95-100 ° C [] D28: -6.2 ° (C = 0.5, MeOH) IR (KBr): 3405, 2930, 2590, 1625, 1430, 1280, 1180, 1135 cm "1 - NMR (DMSO-dg, d): 2.51 (3H, s), 2.03, -5.20 (17H, m), 6.66-8.66 (9H, m) MASS (APCI): 590 (M + H) ¥ (free) (3) (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1H-indol-3-yl) methyl] -4- dihydrochloride. { 3- [2-methyl) pyridyl] -2-propynyl} piperazine p.f. : 150-155 ° C [] D27: -3.3 ° (C = 0.5, MeOH) IR (KBr): 3335, 1645, 1498, 1430, 1280, 1185 cm * 1 NMR (DMSO-dg, d): 2.37 ( 3H, s), 2.10-5.24 (11H, m), 6.60-8.67 (11H, m), 10.93 (1H, s) MASS (APCI): 585 (M + H) + (free) (4) D i c l or (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- orchid. { 3- [2- (4-methoxycarbonyl) pyridyl] -2-propynyl} piperazine p.f. : 125-130 ° C [a] D27: -30.3 ° (C = 0.5, MeOH) IR (KBr): 2600, 1740, 1645, 1430, 1280, 1180 cm "1 NMR (DMSO-dg, d): 3.93 (3H, s), 2.00-5.20 (17H, m), 6. 60-8.90 (9H, m) MASS (APCI): 618 (M + H) + (free) Example 77 A mixture of 0.20 g of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- [(lH-indol-3-yl) methyl] piperazine, 0.11 g of (3S, 5S) -3 , 5-dimethyl-4- (4-chloro-2-butynyl) morpholine and 0. 31 g of potassium carbonate in 4 ml of N, N-dimethylformamide is stirred at 60 ° C for 3 hours. After cooling, the solvent is removed under reduced pressure and the residue is partitioned between ethyl acetate and a sodium hydrogen carbonate solution.The organic layer is separated, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by column chromatography on silica gel with 3% methanol in ethyl acetate as an eluent to give (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -4- [4 - ((3S, 5S) -3,5-dimethylmorpholino) -2-butynyl-2 - [(1H-indol-3-yl) methyl] -piperazine. Dissolve in ethyl acetate and add hydrogen chloride to the solution. 4N in ethyl acetate The mixture is evaporated in vacuo and the residue is triturated with isopropyl ether to give 0.11 g of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -4- [4- ((3S, 5S ") -3,5-dimethyl-morpholino) -2-butyl] -2- [(1H-indol-3-yl) methyl] -piperazine. s- p.f. : 170-180 ° C [< ?] D27: +21. 57 ° (C = 0. 255, MeOH) IR (KBr): 1645, 1637, 1458, 1431, 1360, 1281, 1184, "1136, 1111 cm" 1 NMR (DMSO-dg, d): 1.10-1.45 ( 6H, m), 2.70-5.30 (19H, m), 6.60-8.28 (8H, m) MASS (APCI): 621 (M + H) + (free) Example ^ 78 The following compounds are obtained according to a manner similar to that of Example 77. (1) Dichl orhydrate of (2R) -1 - [3, 5-bis (trifluoromethyl) benzoyl] -4- [4- ((3R) -3-ethylmorpholino) -2-butinyl] -2- [ (lH-indol-3-yl) methyl] -piperazine pf 176-180 ° C [a] D26: -12.2 ° (C = 0.25, "MeOH) IR (KBr): 1635, 1454, L437, 1358, 1333, 1281, 1223, 1182, 1138, 1068 cm "1 NMR (DMSO-dg, d): 0.68-5.30 (25H, m), 6.55-8.30 (8H, m), 10.95 (1H, s) MASS (APCI): 621 (M + H) + (free) (2) D iclo rhidrat o of (2 R) -1 - [3, 5 bis (trifluoromethyl) benzoyl] -4 - [3 - (3,3-dimethylmorphino) propyl] -2- [(1H-indol- 3-yl) methyl] piperazine pf : 107 ~ ° C [a] D28: -7.0 ° (C = 0.5, MeOH) IR (KBr): 3500-3400, 2933, 2599, 1645, 1637, 1458, 1435, 1362, 1280 cm "1 NMR (DMSO) -dg, d): 1.2-1.4 (6H, m), 2.1-1.6 (2H, m), 2.7-5.2 (19H, m), 6.6-8.3 (8H, m), 10.9-11.8 (3H, m) MASS (APCI): 611 (M + H) + (free) (3) (2R) -1 - [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- dihydrochloride. { 2- [7-oxa-4-azaspiro [2.5] octan-4-yl] -ethyl} } -piperazine p.f. : 110-113 ° C [] D27: -13.8 ° (C = 0.5, MeOH) IR (KBr): 3435, 1645 cm * 1 NMR (DMSO-dg, d): 0.80-0.95 (2H, m), 1.20 -1.50 (2H, m), 2.11-2.19 (6H, m), 3.00-5.15 (19H, m), 6.65-8.17 (6H, m) MASS (APCI): 584 (M + H) + (free) (4) (2R) -1 - [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [3- (3, 3-dimethylmorpholino) propyl] piperazine dihydrochloride m.p. .- 197 ° C [] D27: -17.8 ° (C = 0.5, MeOH) IR (KBr): 3500-3400, 2933, 2692, 1645, 1637, 1456, 1430, 1435, 1280 cm * 1 NMR (DMSO- d6, d): 1.33 (6H, s), 1.92-5.2 (27H, m), 6.6-8.3 (6H, m), 11.0-11.5 (2H, m) MASS (APCI): 600 (M + H) + (free) Example 79 The following compounds are obtained according to a manner similar to that of Example 5. (1) Dichl orhydrate of (2R) -1 - [3, 5-bis (trifluoromethyl) benzoyl] -4 - [2 - (3, 3-dimethemorpholino) ethyl] -2 - [(lH- mdol-3-yl) methyl] -piperazine pf 247-258 ° C [] D27: -4.5 ° (C = 0.5, MeOH) IR (KBr): 3500-3400, 1645, 1637, 1280 cm "1 NMR (DMSO-dg, d): 1.2-1.5 (6H , m), 2.8-5.3 (19H, m), 6. 6-8.3 (8H, m), 11.0 (1H, broad s), 11.5-12.1 (2H, m) MASS (APCI): 597 (M + H) + (free) (2) D iclo rhi drat o de (2 R) - l - [3, 5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [2- (3, 3-dimethylmorphine) ) ethyl] -piperazine pf : 190-210 ° C [a] D27: -13.9 ° (C = 0.5, MeOH) IR (KBr): 3500-3400, 1643, 1450, 1430, 1384, 1363, 1280, 1185 cm * 1 NMR (DMSO-dg, d): 1.40 (6H, m), 2.10-2.2 (6H, m), 2.7-2.2 (19H, m), 6.6-8.2 (6H, m), 11.6 -12.2 (2H, m) MASS (APCI): 586 (M + H) + (free) Example 80 The following compounds are obtained according to a manner similar to that of Example 39. (1) D iclo rh a ra to (2 R) - 1 - [3, 5-bis (trif luoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [2- ((3R) -3 Ethylmorpholino) ethyl] piperazine [] D28: -23.6 ° (C = 0.5, MeOH) IR (KBr): 3425, 2600, 1645, 1640, 1280, 1185, 1135 cm "1 NMR (DMS0-d6, d): 0.95 (3H, t, J = 7.2Hz), 1.57-5.20 (28H, m), 6.66-8.28 (6H, m) MASS (APCI): 586 (M + H) + (free) (2) Dihydrochloride ( 2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [2- ((3S) -3-hydroxymethylmorpholino) -ethyl] piperazine mp: 150-160 ° C [] D26: -8.4 ° (C = 0.25, MeOH) IR (KBr): 1643, 1437, 1375, 1323, 1282, 1221, 1184, 1138, 1047 cm "1 NMR (DMSO-ds, d): 2.00-2.28 (6H, m), 2.60-5.20 (23H, m), 6.58-8.28 (6H, m) MASS (APCI): 588 (M + H) + (free) (3) J2R-Dihydrochloride) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [2- ((2S) -2-methoxymethylmorpholino) -ethyl] piperazine pf : 180-190 ° C [a] D26: -12.36 ° (C = 0.275, MeOH) IR (KBr): 1653, 1647, 1635, 1282, 1182, 1136 cm "1" NMR (DMSO-dg, d): 2.00-5.20 (31H, m), 6.60-83.0 (6H, m > MASS (APCI): 602 (M + H) + (free) (4) D iclo rh i drat o of (2 R) -1 - [3, 5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [4- ((3S) -3 -methoxymethylmorpholino) -ethyl] piperazine pf : 90-100 ° C [] D27: -9.8 ° (C = 0.25, MeOH) IR (KBr): 1645, 1512, 1506, 1460, 1433, 1371, 1325, 1282, 1223, 1184, 1136, 1053 cm * 1 NMR (DMSO-dg, d): 2.00 ^ 2.30 (6H, m), 2.60-5.20 (25H, m), 6.60-8.40 (6H, m) MASS (APCI): 602 (M + H) + (free ) (5) (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [2- (2-methoxymethylmorpholino) ethyl] piperazine dichlorohydrate m.p. : 150-154 ° C [a] D28: -5.8 ° (C = 0.5, MeOH) IR (KBr): 3463-3406, 1647 cm "1 NMR (DMSO-dg, d): 2.10-2.18 (6H, m ), 2.40-5.10 (25H, m), 6.55-8.16 (6H, m) MASS (APCI): 602 (M + H) + (free) (6) Hydrochloride of (2 R) -1 - [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [3- ((3S) -3-methoxymethylmorpholino) ) -propyl] piperazine pf : 55-60 ° C [] D27: -1.4 ° (C = 0.25, MeOH) IR (KBr): 1653, 1647, 1635, 1282, 1182, 1134, 1109 cm * 1 NMR (DMSO-dg, d): 1.80-5.22 (3H, m), 6.60-8.30 (6H, m) MASS (APCI): 616 (M + H) + (free) (7) D iclo rh idratode (2 R) - 1 - [3, 5 Bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [3- (2-methoxymethylmorphine-fpropyl) -perazine mp: 145-155 ° C [a] D28: -11.9 ° (C = 0.5 , MeOH) IR (KBr): 3455-3407, 1645 cm "1 NMR (DMSO-dg, d): 2.10 2.19 (6H, m), 2.10-5.10 (27H, m), 6.68-8.17 (6H, m) "" MASS (APCI): 616 (M + H) + (free) (8) D iclo rh idratode (2 R) - 1 - [3,5-bis (trifluoromethyl) benzoyl] -2- [(lH-indol-3-yl) methyl] -4- [2- ((3) -3-methoxymethylmorpholine) ethyl] piperazine pf. : 175-185 ° C [] D27: -0.6 ° (C = 0.25, MeOH) IR (KBr): 1645, 1637, 1458, 1431, 1383, 1362, 1281, 1184, 1138, 1111 cm "1 NMR (DMSO) -dg, d): 2.80-5.28 (25H, m), 6.60-8.30 (8H, m), MASS (APCI): 613 (M + H) + (free) (9) D iclo rh idratode (2 R) - 1 - [3,5-bis (trifluoromethyl) benzoyl] -2- [(lH-indol-3, 3-yl) methyl] -4- [2- (( 3R) -3-methoxymethylmorpholine) ethyl] iperazine pf : 130-150 ° C [] DS: -15.8 ° (C = 0.25, MeOH) IR (KBr): 1653, 1645, 1635, 1281 cm * 1 NMR (DMSO-dg, d): 2.60-5.25 (25H, m), 6.60-8.32 (8H, m), 10.96 (1H, s) MASS (APCI): 613 (M + H) + (free) (10) (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [3- ((3R) -3-methoxymethylmorpholino) -propyl] -hydrochloride piperazine pf : 80-100 ° C [] D28: -21.59 ° (C = 0.22, MeOH) IR (KBr): 1653, 1647, 1637, 1618, 1508, 1473, 1464, 1456, 1448, 1435, 1431, 1385, 1373 , 1363, 1281, 1215, 1184, 1136, 1109 cm "1 NMR (DMSO-ds, d): 2.00-5.40 (33H, m), 6.55-8.30 (6H, ra) MASS (APCI): 616 (M + H) + (free) Example 81 The following compounds are obtained according to a manner similar to that of Example 37. (1) D iclo rhidrat o de (2 R) - l - [3, 5-bis (trif luoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [2- ((3R) -3- fluoromethylmorpholino) ethyl] piperazine pf : 145-155 ° C [a] D2S: -19.2 ° (C = 0.25, MeOH) IR (KBr): 1643, 1437, 1367, 1321, 1281, 1221, 1184, 1138, 1034 cm * 1 NMR (DMSO-dg, d): 2.00-2.28 (6H, m), 2.60-5.20 (22H, m), 6.60-8.32 (6H, m) MASS (APCI): 590 (M + H) + (free) (2) (2R) -1 - [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [2- (3-methoxymethyl-3-methylmorpholino) ethyl] piperazine dihydrochloride pf : 60-70 ° C [] D27: -15.5 ° (C = 0.3, MeOH) IR (KBr): 1643, 1469, 1439, 1375, 1369, 1360, 1323, 1282, 1225, 1184, 1138 cm "1 NMR (DMSO-dg, d): 1.10-1.50 (3H, m), 2.00-5.22 (30H, m), 6.60-8.30 (6H, m) MASS (APCI): 616 (M + H) "+ (free) (3) Dichl orhydrate of (2 R) -1 - [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [2- ((3S) -3-ethoxymethylmorph olino) -ethyl] piperazine pf 60-65 ° C ~ [Cí] D27: -8.2 ° (C = 0.25, MeOH) * 7 IR (KBr): 1643, 1437, "1369, 1321, 1281, 1221, 1182, - 1138, 1072, 1051 cm * 1 NMR (DMSO-dg, d): 1.10-1.30 (31H, m), 2.00-5.25 (30H, - m), 6.60-8.40 (6H, m) - MASS (APCI): 616 (M + H) + (free) (4) (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [2- ((3R) -3-methoxymethylmorpholino) ethyl] -hydrochloride] piperazine pf : 90-100 ° C [] D27: -26.48 ° (C = 0.287, MeOH) IR (KBr): 1635, 1469, 1454, 143y, 1375, 1369, 1360, 1321, 1282, 1221, 1184, 1136, 1074 cm "1 NMR (DMSO-dg, d): 2.00-5.22 (31H, m), 6.60-8.28 (6H, m) MASS (APCI): 602 (M + H ) + (free) (5) D iclo rh i drat o of (2 R) - 1 - [3, 5 - - "" bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [2- ((2R ) -2-methoxymethylmorpholine) ethyl] piperazine pf : 160-170 ° C [Cí] D27: -17.40 ° (C = 0.27, MeOH) IR (KBr): 1645, 1454, 1431, 1383, 1363, 1321, 1281, 1215, 1184, 1138, 1109 cm "1 NMR (DMSO-dg, d): 2.00-2.28 (6H, m), 2.60-5.22 (25H, m), 6.60-8.28 (6H, m) MASS (APCI): 602 (M + H) + (free) (6) D iclohydrate of (2 R) -1 - [3,5-bis (trifluoromethyl) benzoyl] -2- (naphthylmethyl) -4- [2- ((3S) -3-ethylmorpholino) -propyl] piperazine [a] D28: -16.2 ° (C = 0.5, MeOH) IR (KBr): 3400, 2610, 1430, 1280, 1185, 1135 cm "1 NMR (DMSO-dg, d): 0.86-5.31 (25H, m), 7.00-8.20 (10H, m) MASS (APCI): 608 (M + H) + (free) (7) Dichl orhydrate of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1H-indol-3-yl) met? L] -4- [2- ( (2S-2-methoxymethylmorpholino) -ethyl] piperazine mp: 160-170 ° C [a] D27: -3.0 ° (C = 0.25, MeOH) IR (KBr): 1645, 1637, "l618, 1458, 1429, 1362 , 1281, 1184, 1138, 1109, 1099 cm "1 NMR (DMSO-dg, d): 2.60-5.30 (25H, m), 6.60-8.30 (8H, m) MASS (APCI): 613 (M + H) + (free ) (8) (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- [(lH-indol-3-yl) methyl] -4- [2- ((2R) -2 -dihydrochloride] -methoxymethylmorpholino) ethyl] piperazine mp: 190-200 ° C [0C] D27: -15.0 ° (C = 0.24, MeOH) IR (KBr): 1641, 1458, 1421, 1362, 1282, 1176, 1130, 1113, 1099 , 1074 c "1 NMR (DMSO-dg, d): 2.60-5.28 (25H, m), 6.60-8.28 (8H, m), 10.94 (1H, s) MASS (APCI): 613 (M + H) + (free) (9) D iclo rh i dra to (2 R) - 1 - [3,5-bis (trif luoromethyl) benzoyl] -2- [(lH-indol-3-yl) methyl] -4- [2- ((3S, 5S) -dimethylmorpholino) -ethyl] piperazine pf : 170-180 ° C [] D27: + 13.49 ° (C = 0.315, MeOH) IR (KBr): 1645, 1637, 1458, 1448, 1429, 1362, 1281, 1184, 1136, 1111 cm "1 NMR (DMSO-dg, d): 1.08-1.50 (6H, m), 2.60-5.20 (19H, m), 6.55-8.30 (8H, m) MASS (APCI): 597 ( M + H) + (free) (10) D iclo rhi drat o of (2 R) -1 - [3, 5-bis (trifluoromethyl) benzoyl] -4- [2- ((3R) -3-ethylmorpholino) ethyl] -2- [(lH -indol-3-yl) methyl] -piperazine [a] D28: -14.9 ° (C = 0.5, MeOH) IR (KBr): 3365, 2590, 2470, 1645, 1430, 1280, 1185, 1140 cm * 1 NMR (DMSO-dg, d): 1.53-5.20 (25H, m), 6.60-8.28 (8H, m), 10.95 (1H, s) MASS (APCI): 597 (M + H) + (free) (11) D iclo rhi dra to of (2 R) - 1 - [3, 5-bis (trifluoromethyl) benzoyl] -4- [2- ((3S) -3-ethylmorpholino) ethyl] -2- [( lH-indol-3-yl) methyl] -piperazine [] D28: + 6.0 ° (C = 0.5, MeOH) IR (KBr): 3300, 2670, 2610, 1645, 1430, 1280, 1180, 1140 cm "1 NMR (DMSO-ds, d): 0.84-5.20 (25H, m), 6.64-8.28 (8H, m), 10.94 (1H, s) MASS (APCI): 597 (M + H) + (free) Example 82 _ A solution of 0.09 g of (2R) -l- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [4- ((3S) -3-methoxymethylmorpholino) - 2-butynyl] piperazine in 10 ml of methanol is hydrogenated in the presence of 40 mg palladium 10% -carbon at room temperature. After 1 hour, the palladium-carbon is removed by filtration and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography and on silica gel with a mixture of methanol and ethyl acetate as an eluent to give (2R) -1- [3,5-bis- (trifluoromethyl) benzoyl] -2- (3 , 4-dimethylbenzyl) -4- [4 - (((3S) -3-methoxymethylmorpholino) butyl] piperazine. It is dissolved in 10 ml of ethyl acetate and 0.5 ml of 4N hydrogen chloride in ethyl acetate is added thereto. The mixture is evaporated in vacuo and the residue is triturated with a mixture of ethyl acetate and isopropyl ether to provide 0.03 g of (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3-dihydrochloride. , 4-dimethylbenzyl) -4- [4- ((3S) -3-methoxymethylmorpholino) butyl] piperazine as a solid. NMR (DMSO-dg, d): 1.60-2.00 (4H, m), 2.00-2.30 (6H, m), 2.60-5.20 (25H, m), 6.60-8.30 (6H, m), 10.40-11.60 (2H , m) - MASS (APCI): 630 (M + H) + (free) Example 83 The following compounds are obtained according to a manner similar to that of Example 82. (1) D i c l orhydrate of (2R) -1 - [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4-. { 3- [2- (4-methoxy) pyridyl] propyl} -piperazine p.f. : 130-140 ° C [a] D28: -10.4 ° (C = 0.5, MeOH) IR (KBr): 3425, 2400, 1640, 1500, 1430, 1280, 1180, 1135 cm "1 NMR (DMSO-dg, d): 4.08 (3H, s), 2.05-5.14 (21H, m), 6.60-8.72 (9H, m) MASS (APCI): 594 (M + H) + (free) (2) (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1H-indol-3-yl) methyl] -4- dihydrochloride. { 3- [2- (4-methyl) pyridyl] propyl Jpiperazine p.f. : 120-130 ° C [] D27: -5.0 ° (C = 0.5, MeOH) IR (KBr): 3420, 1645, 1498, 1430, 1280, 1135 cm "1 NMR (DMSO-dg, d): 2.55 ( 3H, s), 2.14-5.20 (15H, m), 6.64-8.74 (11H, m), 10.95 (1H, s) MASS (APCI): 589 (M + H) + (free) (3) Dichl orhydrate of (2 R) -1 - [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [2- (4-methoxycarbonyl) pyridyl] -propil} piperazine p.f. : 115-125 ° C [a] D28: -11.7 ° (C = 0.5, MeOH) IR (KBr): 2650, 2625, 1740, 1645, 1460, 1280, 1135 cm "1 NMR (DMSO-dg, d) : 3.92 (3H, s), 2.07-5.14 (21H, m), 6.60-8.78 (9H, m) MASS (APCI): 622 (M + H) + (free) Example 84 To a stirred suspension of 104 mg of 2- (3,4-melenedioxybenzyl) piperazine hydrochloride and 196 mg of potassium carbonate in 4 ml of N, N-dimethylformamide are added 84.5 mg of 4- (4-chloro) hydrochloride. -2-butynyl) -3,3-dimethylmorpholine at 5 ° C under a nitrogen atmosphere and the mixture is gradually warmed to room temperature overnight. To the above stirred suspension is added 98.2 mg of 3,5-bis (trifluoromethyl) benzoyl chloride at 5 ° C "and the mixture is stirred for 1 hour at this temperature.Mixing is extracted with ethyl acetate and the extract is washed with water and dried over magnesium sulfate The visual treatment followed by flash chromatography on silica gel with a mixture of dichloromethane and methanol (50: 1) gives 1- [3, 5-bis- (trifluoromethyl) benzoyl] -4- [4- (3", 3-dimethylmorpholino) -2-butinyl] -2- (3,4-methylenedioxybenzyl) piperazine, which is dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate to provide 107 mg of l- [3,5-bis- (trifluoromethyl) benzoyl] -4- [4- (3, 3"-dimethylmorpholine) -2 dihydrochloride -butinyl] -2- (3,4-methylenedioxybenzyl) piperazine as a powder. NMR (DMSO-dg, d): 1.32 (6H, m), 2.20-5.00 (19H, m), 5.96 (2H, s), 6.43-8.17 (6H, m) MASS (APCI): 626 (M + H ) + (free) Example 85 The following compounds are obtained according to a manner similar to that of Example 84. (1) D iclo rh i dra t "of (2 R) -1 - [3, 5-bis (trifluoromethyl) benzoyl] -4 - [4 - (3, 3-dimethylmorpholino) -2-butynyl] - 2- (4-hydroxymethyl-3-methylbenzyl) piperazine NMR (DMSO-dg, d): 1.32-1.38 (6H, m), 2.00-5.22 (25H, m), 6.55-8.17 (6H, m) MASS (APCI) ): 626 (M + H) + (free) (2) 2- [(1,4-Benzodioxan-6-yl) methyl] -1- [3, 5-bis- (trifluoromethyl) benzoyl] -4- [4- (3, 3-dimethylmorphino) dihydrochloride -2-butinyl] piperazine NMR (DMSO-dg, d): 1.21-1.23 (6H, m), 2.62-5.00 (23H, m), 6.37-8.48 (6H, m) MASS (APCI): 640 (M + H) + (free) (3) Dihydrochloride - [3,5-bis (trifluoromethyl) -benzoyl] -4- [4 - (3,3-dimethylfolphin) -2-butynyl] -2- (4-methoxy-3-methylbenzyl) piperazine NMR (DMSO-dg, d): 1.33-1.40 (6H, m), 2.00-5.22 (25H, m), 6.64-8.15 (6H, m) MASS (APCI): 626 (M + H) + (free ) Example 86 To a mixed solution of 0.65 g of 1- (benzyloxycarbonyl) -3- (2,3-dimethoxybenzyl) piperazine and 0.293 ml of triethylamine in 17 ml of dichloromethane are added dropwise a solution of 0.534 g of 3: 5 chloride. bis (trifluoromethyl) benzoyl in 2.5 ml of dichloromethane under cooling with ice. After stirring at the same temperature ^ "for 2 hours, the reaction mixture was poured into a mixed solvent of 40 ml of water and 25 ml of dichloromethane and the whole was adjusted to pH 9 with an aqueous solution of anhydrous acid carbonate. sodium. The organic layer is separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue is purified by column chromatography on 10 g of silica gel using a mixed solvent of n-hexane and ethyl acetate (2: 1). The fractions containing the objective compound are collected and evaporated under reduced pressure to provide 0.84 g of l- [3,5-bis (trj.fluorornethyl) benzoyl] -4- (benzyloxycarbonyl) -2 - (2,3-dimethoxybenzyl) piperazine.

IR (KBr): 1732, 1714, 1705, 1647, 1431, 1281, 1134 cm "1 NMR (CDC13, d): 2.60-4.70 (9H, m), 3.79 (6H, s), 5.20 (2H, s) , 6.40-8.60 (11H, m) MASS (APCI): 611 (M + H) + Example 87 A mixture of 0.192 g of l- [3,5-bis (trifluoromethyl) benzoyl] -2- (2,3-dimethoxybenzyl) piperazine, 0.106 g of 3,3-dimethyl-4- (4-chloro-2 hydrochloride -butynyl morpholinin, 0.167 g of potassium carbonate and 67 mg of potassium iodide in 1.3 ml of N, N-dimethylformamide is stirred at 65 ° C for 90 minutes and cooled.The mixture is poured into 30 ml of ice-water and The whole is adjusted to pH 9 with sodium bicarbonate and extracted with 30 ml of ethyl acetate.The extract is washed with 30 ml of brine, dried over sodium sulphate and evaporated under reduced pressure. column chromatography on 8 g of silica gel using a mixed solvent of dichloromethane and methanol (40: 1). Fractions containing the objective compound are collected and evaporated under reduced pressure to provide a colorless oil of 1- [3.5 Bis (trifluoromethyl) benzoyl] -2- (2,3-dimethoxybenzyl) -4- [4- (3,3-dimethylmorpholino) -2-butynyl] -piperazine. It is dissolved in 2 ml of ethyl acetate and the solution is treated with a solution of 4N hydrogen chloride in ethyl acetate (0.30 ml) under ice-cooling, and evaporated under reduced pressure to give 0.18 g of a colorless powder. 1- [3,5-bis (trifluoromethyl) benzoyl] -2- (2,3-dimethoxybenzyl) -4- [4- (3,3-dimethylmorpholino) -2-butynyl] piperazine dihydrochloride. _ p.f. : 170 ° C IR (KBr): 2933, 2575, 1647, 1637, 1433, 1281, 1186, - 1136 cm "1 NMR (DMSO-dg, d): 1.33 (3h, s), 1.41 (3H, s) , 2.60- 5.20 (19H, m), 3.75 (6H, s), 6.50-7.00 (3H, m), 7.50- ~ 8.20 (3H, m) MASS (APCI): 642 (M + H) + (free) Example 88 The following compound is obtained according to a manner similar to that of Example 86. 1- [3,5-bis (trifluoromethyl) benzoyl] -4- (benzyloxycarbonyl) -2- [(1H-indol-2-yl)] methyl] piperazine IR (KBr): 1714, 1699, 1684, 1647, 1635, 1458, 1281 cm "1 ^ NMR (DMSO-dg, d): 2.60-5.10 (9H, m), 5.15 (2H, s), - 5.98-8.48 (13H, m), 10.58-11.04 (1H, m) MASS (APCI): 590 (M + H) + Example 89 The following compounds are obtained according to a manner similar to that of Example 87. (1) Dichlorhydrate of 1 - [3,5-bis (trifluoromethyl) benzoyl] -2- [(1 H -indol-2-yl) -methyl] -4- [4- (3, 3-dimethylmorpholino) -2- butinyl] -piperazine pf : 185 ° C IR (KBr): 1651, 1647, 1637, 1281, 1188, 1136 cm "1 NMR (DMSO-dg, 6): 1.31 (3H, s), 1.40 (3H, s), 3.00-5.22 ( 19H, m), 6.02-6.40 (1H, m), 6.90-8.20 (7H, m), 11.70-11.17 (1H, m) MASS (APCI): 621 (M + H) + (free) (2) D iclo rh id ra to 1 - [3, 5-bis - (trifluoromethyl) benzoyl] -2- (3-methoxybenzyl) -4- [4- (3,3-dimethyl) morpholino) -2 - butinyl] piperazine pf : 223-225 ° C IR (KBr): 3600-3300, 2900, 2600-2300, 1647, 1635, 1458, 1435, 1280 cm "1 NMR (DMSO-dg, d): 1.32 (3H, s), 1.40 (3H, s), 2.8-5.2 (22H, m), 6.5-8.20 (7H, m), 12.1-12.6 (2H, m) MASS (APCI): 612 (M + H) + (free) Example 90 The following compounds are obtained according to a manner similar to that of Example 9. (1) (2R) -4- [4- (3, 3-Dimethyrylmorpholino) -2-butynyl] -2- [(lH-indol-3-yl) methyl] -1- [3- (methylamino)] -hydrochloride - 5- (trifluoromethyl) benzoyl] piperazine pf : 215-230 ° C [a] D27: + 41.8 ° (C = 0.5, MeOH) IR (KBr): 3600-3300, 2900, 2600-2300, 1645, 1624, 1614, 1458, 1419 cm "1 NMR (DMSO-dg, d): 1.20-1.50 (6H, m), 2.69 (3H, s), 2. 90-5.30 (19H, m), 6.55-7.90 (9H, m), 10.98 (1H, broad s), 11.90-12.60 (2H, m) MASS (APCI): 582 (M + H) + (free) (2) (2R) -1- [3- (dimethylamino) -5- (trifluoromethyl) benzoyl] -4- [4- (3, 3-dimethylmorpholino) -2-butynyl] -2- [(lH- indol-3-yl) methyl] piperazine pf : 210-225 ° C [«] • + 31.8 ° (C = 0.5, MeOH) IR (KBr): 3600-3300, 2900, 2600-2300, 1653, 1647, 1635, 1558, 1541, 1508, 1473, 1458 , 1419 cm "1 NMR (DMSO-dg, d): 1.20-1.50 (6H, m), 2.70-5.28 (19H, m), 2.94 (6H, s), 6.48-7.90 (8H, m), 10.99 ( 1H, broad s), 12.00-12.50 (2H, m) MASS (APCI): 596 (M + H) + (free) (3) (2R) -4- [4- (3,3-dimethylmorpholino) -2-butynyl] -2- [(1H-indol-3-yl) methyl] -1- [3-nitro-5-dimethyl] -hydrochloride. - (trifluoromethyl) -benzoyl] -piperazine pf : 198-220 ° C IR (KBr): 3600-3300, 2900, 2600-2300, 1645, 1635, 1543, 1471, 1458, 1421, 1358, 1331, c "1 NMR (DMSO-dg, d): 1.33 (3H, s), 1.41 (3H, s), 2.80-5.22 (19H, m), 6.50-8.62 (8H, m), 10.99 (1H, s), 11.80-12.60 (2H, m) MASS (APCI) : 598 (M + H) + (free) (4) (2R) -2- (3,4-dimethylbenzyl) -4- [4- (3,3-dimethylmorpholino) -2-butynyl] -1- [3- (methylamino) -5- (trifluoromethyl) dihydrochloride ) benzoyl] piperazine pf : 195-205 ° C [] D27: + 10.8 ° (C = 0.5, MeOH) IR (KBr): 3600-3300, 2900, 2600-2300, 1647, 1635, 1616, 1456, 1419 cm "1 NMR (DMSO) -dg, d): 1.32 (3H, s), 1.40 (3H, s), 2.00-2.30 (6H, m), 2.70 (3H, s), 2.90-5.20 (19H, m), 6.20-7.20 (7H , m), 12.22 (2H, broad s) MASS (APCI): 571 (M + H) "+ (free) (5) (2R) -1- [3- (dimethylamino) -5- (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [4- (3, 3-dimethylmorpholino) - dihydrochloride 2-butynyl] piperazine pf : 108-185 ° C [a] D27: + 8.80 ° (C = 0.5, "MeOH) IR (KBr): 3600-3300, 2900, 2600-2300, 1647, 1635, 1616, 1608, 1506, 1456, 1425 cm "1 NMR (DMSO-dg, d): 1.32 (3H, s), 1.40 (3H, s), 2.02-2.30 (6H, m), 2.95 (6H, s), 3.00-5.25 (19H, m) , 6.20-7.20 (6H, m), 12.28 (2H, broad s) MASS (APCI): 585 (M + H + _ (free) (6) (2R) -2- (3,4-dimethylbenzyl) -4- [4- (3,3-dimethylmorphino) -2-butyl] -1- [3-nitro -5- (trifluoromethyl) dihydrochloride ) -benzoyl] piperazine pf : 157-200 ° C [a] D26: + 19.5 ° (C = 0.5, MeOH) IR (KBr): 3600-3300, 2900, 2600-2300, 1647, 1637, 1543, 1456, 1423, 1356, 1330, 1319 cm "1 NMR (DMSO-dg, d): 1.33" (3H, s), 1.41 (3H, s), 1.95- 2.34 (6H, m), 2.62-5.20"(19H, m), 6.60-8.60 (6H, m), 12.10-12.50 (2H, m) MASS (APCI): 587 (M + H) + (free) Preparation 72 The following compounds are obtained in a manner similar to that of Preparation 38. (1) (2R) -1- [3,5-bis (trifluoromethyl) "benzoyl] -2- [(1H-indol-3-yl) methyl] -4- (2-hydroxyethyl) piperazine IR (Pure): 3300, 2930, 2800, 1623 cm "1 NMR (DMSO-dg, d): 2.00-5.00 (14H, m), 6.60-8.28 (8H, m), 10.86 (1H, s) MASS (APCI): 500 ( M + H) + (free) (2) (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- (2-hydroxyethyl) piperazine IR (Pure): 3400, 1640, 1430, 1280, 1170 cm * 1 NMR (DMSO-dg, d): 2.00-5.00 (20H, m), 6.60-8.20 (6H, m) Preparation 73 The following compounds are obtained in a manner similar to that of Example 39. (1) (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1H-indol-3-yl) methyl] -4- (2-methanesulfonyloxyethyl) piperazine IR (Pure): 3340 , 3300, 3000, 2930, 2800, 1624 cm "1 NMR (DMS0-ds, d): 2.10_-4.70 (13H, m), 3.24 (3H, s), 6.26-8.28 (8H, m), 10.90 ( 1H, s) MASS (APCI): 578 (M + H) + (2) (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- (2-methanesulfonyloxyethyl) piperazine IR (Pure): 1640, 1430, 1280, 1150 cm * 1 NMR (DMSO-dg, d): 2.00-5.00 (23H, m), 6.60-8.20 (6H, m) 'MASS (APCI): 567, 489 Preparation 74 The following compound is obtained in a manner similar to that of Preparation 37. (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1H-indol-3-yl) methyl] -4- (4-chloro-2-butynyl) piperazine IR (Pure): 3300, 3050, ^ 2800, 2600, 1630, 1430 cm "1 MN (DMSO-dg, d): 2.20-5.30 (13H, m), 6.75-8.20 (8H, m) MASS (APCI): 542 (M + H) + Preparation 75 (1) The following compounds are obtained in a manner similar to that of Preparation 46- (4). l-Acetyl-3- (3-methoxy-4-methylphenyl) methylene-2, 5-piperazinedione NMR (DMSO-dg, d): 2.17 (3H, s), 2.50 (3H, s), 3.83 (3H, s) ), 4.37 (2H, s), 6.95 (1H, s), 7.08-7.22 (3H, m), . 33 (1H, S) MASS (APCI): 289 (M + H) + (2) The following compounds are obtained in a manner similar to that of Preparation 46- (5). 3- (3-methoxy-4-methylbenzyl) -2,5-piperazinedione NMR (DMSO-dg, d): 2.11 (3H, s), 2.75 (1H, d, J = 17.4Hz), 2.84 (1H, m ), 3.05 (1H, dd, J = 13.4, 4.5Hz), 3.35 (1H, m), 3.73 (3H, s), 4.04 (1H, m), 6.63 (1H, d, J = 7.4Hz), 6.73 (1H, nd, 7.03 (1H, d, J = 7.4Hz), 7.88 (1H, m), 8.13 (1H, m) MASS (APCI): 249 (M + H) * (3) The following compounds are obtained in a manner similar to that of Preparation 46- (3). 2- (3-Methoxy-4-methylbenzyl) piperazine dihydromachihydrate NMR (DMSO-dβ, d): 2.13 (3H, s), 2.78-3.78 (9H, m), 3.81 (3H, s), 6.73-7.15 ( 3H, m), 9.11 (4H, m) MASS (APCI): 221 (M + H) + (free) (4) A stirred solution of 240 mg of 2- (3-methoxy-4-methylbenzyl) -piperazine dihydromihydrate in 8 ml of 48% hydrobromic acid is heated under reflux for 48 hours. After cooling, the mixture is concentrated under reduced pressure. The residue is triturated with ethyl acetate and the resulting precipitates are collected by filtration and washed with ethyl acetate to provide 175 mg of 2- (3-hydroxy-4-methylbenzyl) piperazine dihydromihydrate as a powder. _ NMR (DMSO-dg, d): 2.11 (3H, s), 2.67-3.78 (9H, m), 6.70-6.95 (3H, m), 9.09 (4H, m) MASS (APCI): 207 (M + H) + (free) Example 91 The following compounds are obtained in a manner similar to that of Example 84. (1) Dihydrochloride of 1 - [3, 5-bis (trifluoromethyl) benzoyl] -4- [4 - (3, 3-dimethylfolphin) -2-butynyl] -2- (3-hydroxy-4) - methylbenzyl) piperazine NMR (DMSO-d6, d): 1.32-1.38 (6H, m), 2.08 (3H, s), 2.68-5.03 (20H, m), 6.18-8.20 (6H, m) MASS (APCI) : 612 (M + H) + (free) (2) 1 - [3, 5-bis (trifluoromethyl) benzoyl] -4 - [4- (3, 3-dimethylmorpholino) -2-butynyl] -2- (3-methoxy-4-methylbenzyl) piperazine hydrochloride NMR (DMSO-dg, d): 1.33-1.38 (6H, m), 2.10 (3H, s), 2.73-5.10 (22H, m), 6.40-8.18 (6H, m) MASS (APCI): 626 (M + H) + (free) (3) Dichlorhydrate from 1 - [3, 5-bis (trifluoromethyl) benzoyl] -4 - [4 - (3, 3-dimethyl-imino-vinyl) -2-butynyl] -2- (4-hydr oxy-3 - methylbenzyl) piperazine NMR (DMSO-dg, d): 1.32-1.38 (6H, m), 2.09: 3H, 2.73-4.98 (20H, m), 6.55-8.20 (6H, m) MASS (APCI): 612 (M + H) + (free) Preparation 76 The following compound is obtained according to a manner similar to that of Preparation 75- (4). 2- (4-Hydroxy-3-methylbenzyl) piperazine-D-NMR (DMSO-dg, d): 2.10 (3H, s), 2.67-3.57 (9H, m), 6. 57-7.11 (3H, m), 9.12"-9.39 (5H, m) MASS (APCI): 207 (M + H) + (free) Preparation 77 (1) The following compound is obtained according to a manner similar to that of Preparation 46- (4). l-acetyl-3- (3-nitrophenyl) methylene-2, 5-piperazinedione = p.f. : 190-200 ° C NMR (DMSO-dg, 5): 2.51 (3H, s), 4.32 (2H, s), 7.03 (1H, s), 7.65 (1H, m), 7.94 (1H, d, J = 7.8Hz), 8.16 (1H, dd, J = 1.6, 7.8 Hz), 8.37 (1H, d, J = 1.6Hz), 10.80 (1H, broad s) MASS (APCI): 290 (M + H) + 79 (2) A mixture of 10.2 g of l-acetyl-3- (3-nitrophenyl) methylene-2, 5-piperazinedione, 6.43 ml of triethylamine and 23.5 g of diterbutyl dicarbonate in 50 ml of N, N-dimethylformamide Hydrogenated on 10% palladium-carbon (50% wet, 1 g) at room temperature under 2-3 atmospheres. After removal of the catalyst by filtration, the filtrate is concentrated by evaporation, the residue is partitioned between ethyl acetate and water. The organic layer is washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel using a mixture of dichloromethane and methanol (20: 1). The fractions containing the objective compound are collected and evaporated under reduced pressure. The resulting precipitates are collected by filtration and washed with methanol to give 1.3 g of l-acetyl-3- [3- (tert-butoxycarbonylamino) benzyl] -2,5-piperazinedione as colorless powders. -190 ° C IR (KBr): 3334, 1727, 1704, 1681, 1602, 1590, 1540 cm "1 NMR (DMSO-d6, d): 1.46 (9H, s), 2.43 (3H, s), 2.94 (1H, dd, J = 6.4, 14.2 Hz), 3.10 (1H, dd, J = 6.4, _ 14.2), 3.15 (1H, d, J = 17.4 hz), 3.96 (1H, d, J = 17.4Hz), 4.30-4.35 ( 1H, m), 6.58 (1H, d, J = 7.1Hz), 7.15 (1H, m), 7.23 (1H, d, J = 7.Hz), 7.43 (1H, s), 7.42 (1H, d) , J = 2.8 Rzj, 9.32 (1H, s) MASS (APCI): 306 (M- (CH3) 3) + ~ (3) The following compound is obtained according to a manner similar to that of Preparation 46- (5). 3- [3-tert-butoxycarbonylamino) benzyl] -2,5--piperazinedione ~ p.p. : 230-233 ° C IR (KBr): 3301, 3212, 3083, 2981, 1716, 1675, 1608 cm "1 NMR (DMSO-dg, d): 1.47 (9H, s), 2.89 (1H, dd, J = 5.3, 9.1Hz), 2.95 (1H, d, J = 17.0 Hz), 2.96 (1H, dd, J = 5.3, 9.1Hz), 3.36 (1H, dd, J = 3.8, 17.0Hz), 3.95-4.00 (1H, m), 6.78 / (1H, d, J = 7.8 Hz), 7.14 (1H, m), 7.30 - 7.35 (2H, m), 7.91 (1H, broad), 8.13 (1H, broad), 9. 30 (1H, s). ^ MASS (APCI): 320 (M + H) +, 264 (4) A solution of 0.75 g of 3- [3- (tert-butoxycarbonylamino) benzyl] -2,5-piperazinedione in 10 ml of trifluoroacetic acid is stirred for 4 hours at room temperature. After removal of the solvent by evaporation, the residue is dissolved in a mixture of 10 ml of dichloromethane and 3 ml of methanol and thereto are added 0.742 g of benzaldehyde and 2.11 g of sodium triacetoxyborohydride. The whole is stirred for 2 hours at room temperature and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel using a mixture of dichloromethane and methanol '(25: 1). The fractions containing the objective compound are collected and triturated with isopropyl alcohol to provide 0.43 g of 2- [3- (benzylamino) benzyl] -3,6-piperazinedione as colorless crystals. p.f. : 160-161 ° C IR (KBr): 3168, 3056, 2975, 2867, 1677, 1606, 1550 cm * 1 NMR (DMSO-d6, d): 2.86 (1H, d, J = 17.2Hz), 2.82 ( 1H, dd, J = 4.8, 13.3 Hz), 2.92 (1H, dd, J = 4.8, 13.3 Hz), 3.33 (1H, dd, J = 17.2Hz), 3.96 (1H, d, J = 3.0Hz), 4.21 (2H, d, J = 6.0Hz), 6.16 (1H, m), 6.33 (1H, d, J = 7.4Hz), 6.41-6.45 (2H, m), 6.92 (1H, m), 7.18-7.33 (5H, m), 7.78 (1H s broad), 8.04 (1H, d, J = 2.2Hz). MASS (APCI): 310 (M + H) + (5) A suspension of 0.45 g of 2- [3- (benzylamino) benzyl] -3,6-piperazinedione, 81 mg of aqueous formaldehyde at 37%, 0.62 g of sodium triacetoxyborohydride and 175 mg of acetic acid in a mixture of 15 ml of 1,2-dichloroethane and 5 ml of N, N-dimethylformamide is stirred for 5 hours at room temperature. Then an additional 0.1 ml of aqueous formaldehyde is added to 37%, 0.2 ml of acetic acid and 0.60 g of sodium triacetoxyborohydride to the reaction mixture, and the whole is stirred for an additional 2 hours. The mixture is concentrated under reduced pressure and the residue is purified by column chromatography on silica gel using a mixture of dichloromethane and methanol (10: 1). The fractions containing the objective compound are collected and evaporated under reduced pressure. The resulting precipitates are collected by filtration and washed with isopropyl alcohol to provide 0.46gde2- [3- (N-benzyl-N-methylamino) benzyl] -3,6-piperazinedione as colorless crystals. NMR (DMSO-dg, d): 2.71-3.03 (3H, m), 2.94 (3H, s), 3. 27-3.37 (1H, m), 4.00-4.05 (1H, "m), 4.53 (2H, s), 6.42 (1H, d, J = 7.5Hz), 6.57-6.61 (2H, m), 6.98-7.06 (1H, m), 7.16-7.34 (5H, m), 7.85 (1H, s), 8.09 (1H, d, J = 2.2Hz) MASS (APCI): 324 (M + H) 7 (6) obtain the following compound according to a manner similar to that of Preparation 49- (4) 2- [3- (N-benzyl-N-methylamino) benzyl] piperazine The compound is used in the next step without further purification. _ Preparation 78 The following compound is obtained according to a manner similar to that of preparation 50. 1- [3,5-bis (trifluoromethyl) benzoyl] -2- [3- (N-methylamino) -benzyl] piperazine 7 NMR (DMSO-dg, d): 2.20-5.20 (10H, m), 2.99 ( 3H, s), 6.00-7.40 (7H, m), 8.16_ (1H, s) ~ MASS (APCI): 446 (M + H) ~ + Example 92 The following compound is obtained according to a manner similar to that of Preparation 49- (5) through an Isirailar manner to that of Example 86. - 1- [3,5-bis (trifluoromethyl) benzoyl] -2 - [3- (N-Benzyl-N-methylamino) benzyl] -4- (benzyloxycarbonyl) piperazine IR (Pure): 1705, 1645, 1605, 1505 cm "1" NMR (CDC13, d): 2.60 ^ 4.80 (14H , m), 5.18 (2H, s), 6.10-7.40 (16H, m), 7.84 (1H, s) ~ MASS (APCI): 670 (M + H) + Example 93 The following compound is obtained according to a manner similar to that of Example 87. l- [3,5-bis (trifluoromethyl) benzoyl] -4- [4- (3, 3-t-dimethylmorphino) -2-butynyl ] - 2 - [3 - (N-methylamino) benzyl] piperazine IR (Pure): 3400, 1680, 1640, 1610 cm "1 NMR (CDC13, d): 1.06 (6H, broad S), 2.10-5.20 (20H , m), 3.34 (3H, s), 5.95-7.80 (7H, m) MASS (APCI): 611 (M + H) + ~ its trichlorhydrate - mp: 192-195 ° C IR (KBr): 3500-3300 , 3000-2800, 2700-2300, 1644 cm "1 NMR (CDCI3, d): 1.36 (6H, s), 2.71-2.81 (3H, m), 3.20- 5.20 (20H, m), 6.60-8.21 (7H , m) MASS (APCI): 611 (M + H) + (free) Example 94 - A suspension of 0.19 g of l- [3,5-bis (trifluoromethyl) benzoyl] -4- [4- (3,3-dimethylmorpholino) -2-butynyl] -2- [3- (N-methylamino) - benzyl] piperazine, 50 μl of 37% aqueous formaldehyde, 79 mg of sodium triacetoxyborohydride and 22 μl of acetic acid in 5 ml of dichloromethane are stirred for 2 hours at room temperature, then an additional 25 μl of 37% aqueous formaldehyde is added. , 10 μl of acetic acid and 40 mg of sodium triacetoxyborohydride, to the reaction mixture, and the whole is stirred for an additional 1 hour. The mixture is poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with dichloromethane. The extract is dried over magnesium sulfate * and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel using a mixture of dichloromethane and methanol (40: 1). The fractions containing the objective compound are collected and evaporated under reduced pressure and treated with 4N hydrogen chloride in an ethyl acetate solution to provide 0.21 g of l- [3,5-bis (trifluoromethyl) benzoyl trichlorohydrate] -2- [3- (N, N-dimethylamino) benzyl] -4- [4- (3,3-dimethylmorpholino) -2-butynyl] piperazine. p.f. : 205-210 ° C IR (KBr): 3500-3300, 2900-2500, 1644 cm "1 NMR (DMSO-dg, d): 1.32 (3H, s), 1.41 (3H, s), 2.91-3H, s), 3.03 (3H, s), 3.20-5.20 (19H, m), 6.40-8.25 (7H, m) MASS (APCI): 625 (M + H) + (free)

Claims

^ CLAIMS

Z l. A compound of the "formula: represented by the following general formula (I) wherein Y is a bond or lower alkylene, R1 - is aryl which may have substituent or substituents R2R is aryl or indolyl, each of which may have substituent or substituents, R3 is hydrogen or lower alkyl, R4 is pyridylalkyl (lower) aminoalkynyl lower, - N- (lower alkyl) -N- [pyridylalkyl-lower] amino-lower alkyl; hydroxyalkoxy (lower) lower alkyl; lower alkoxy (lower) lower alkoxy lower alkyl; lower phenylalkyl which has lower hydroxyalkyl or lower morpholinylalkyl; aralkoxy (lower) carbonyl; (2-pyridyl) lower alkyl which may have 1 to 3 substituent or substituents which are selected from the group consisting of lower alkyl, lower alkoxy, lower alkoxycarbonyl, mono (or di or tri) lower haloalkyl, and halogen; (3-pyridyl) propyl which may have lower alkoxy or amino; (3-pyridyl) butyl which may have lower alkoxy or amino; lower pyridylalkenyl which may have lower alkoxy or amino; (2-pyridyl) lower alkynyl which may have 1 to 3 substituents which are selected from the group consisting of lower alkyl, lower alkoxy, lower alkoxycarbonyl, mono (or di or tri) lower haloalkyl, and halogen; (3-pyridyl) lower alkynyl which may have lower alkoxy or amino; pyridyl, thiazolyl, imidazolyl or pyrazolyl, each of which may have substituents or substituents; lower imidazolylalkyl which may have 1 or 2 substituent or substituents which are selected from the group consisting of lower alkyl, lower alkynyl, lower aralkyl, lower pyridylalkyl, 7 mono (or di or tri) haloalkyl lower and halogen; pyrazolyl lower alkyl which may have lower hydroxyalkyl, lower carboxyalkyl, . lower alkoxycarbonylalkyl, lower morpholinylalkyl or morpholinylcarbonylalkyl; thiazolyl lower alkyl which may have lower alkyl; piperidylalkyl lower which may have lower hydroxyalkyl or lower alkoxy; morpholinyl lower alkyl which may have 1 or 2 substituents which are selected from the group consisting 7 = ethyl, lower hydroxyalkyl, lower haloalkyl and lower alkoxy lower alkyl; t morpholinyl lower alkyl which has alkyl lower and lower alkoxy lower alkyl; - (3,5-dimethylmorpholinyl) lower alkyl; lower morpholinoalkenyl which may have lower alkyl or lower alkoxy lower alkyl; (2- or 3-morpholinyl) lower alkenyl which may have lower alkoxycarbonyl; lower pyrrolidinyl alkynyl which may have lower alkoxy lower alkyl; lower morpholinylalkyl which may have 1 or 2 substituents which are selected from the group consisting of ethyl, propyl, isopropyl, isobutyl, lower spirocycloalkyl, lower alkoxy, lower alkyl, lower hydroxyalkyl, lower carboxyalkyl, di (lower alkyl) carbamoyl, alkoxycarbonyl lower and lower haloalkyl; lower morpholinylquinoline which has methyl and lower alkoxy; (dimethylmorpholino) lower alkynyl; lower homomorpholinylalkynyl which has halogen; (morpholinylamino) propyl which may have lower alkanoyl; lower thiomorpholinylalkynyl which may have substituent or substituents; homomorpholinylamino lower alkyl; thiomorpholinylamino lower alkyl; or saturated lower heterocyclic oxamalkyl, saturated heterocyclic aminocarbonylalkyl or saturated lower heterocyclic alkoxy lower alkyl, each of which may have substituent or substituents, as when it is 2- [N-methyl-N- (3-pyridylmethyl) amino] ethyl , 3- (3-pyridyl) propyl, 3- (3-pyridyl) -2-propynyl, 4- [(2-methoxymethyl) pyrrolidino] -2-butynyl, 4-thiomorpholino-2-butynyl, 3- (morpholinoamino) propyl, 4- (morpholino-2-butenyl, 4-morpholino-2-butinyl, or 4- (3,3-dimethylmorpholino) -2-butinyl, then R 1 is not 3,5-bis (trifluoromethyl) phenyl. come out of it
2. The compound as described in claim 1, wherein: Y is lower alkylene, R1 is C6-C10 aryl which may have one or two substituents that are selected from the group consisting of mono (or di or tri) haloalkyl lower, halogen, lower alkylamino, dialkylamino lower and nitro, R2 is C6-C10 aryl or indolyl, each of which may have 1 to 3 substituents which are selected from the group consisting of lower alkyl, mono (or di or tri) lower haloalkyl, lower alkylenedioxy, hydroxy, lower hydroxyalkyl, lower alkoxy, lower alkylamino and lower dialkylamino, R3 is hydrogen, and R4 is lower pyridylalkyl (lower) aminoalkynyl; (2-pyridyl) ropyl which may have 1 to 3 substituents or substituents which are selected from the group consisting of lower alkyl, lower alkoxy, lower alkoxycarbonyl, mono (or di or tri) lower haloalkyl, and halogen; pyridyl, thiazolyl, imidazolyl or pyrazolyl, each of which may have 1 or 2 substituents which are selected from the group consisting of lower alkyl, lower aralkyl and lower pyridylalkyl, -imidazolylalkyl lower which has 1 or 2 substituents which are selected from the group consisting of a group consisting of lower alkyl, lower alkynyl, lower aralkyl, lower pyridylalkyl, mono (o or tri) lower haloalkyl, and halogen; (2-methyl-lH-imidazol-4-yl) lower alkyl which has 1 or 2 substituents which are selected from the group consisting of isopropyl, lower alkynyl, lower aralkyl, pyridylalkyl lower, mono (or di or tri) aralkyl lower and halogen; (5-methyl-lH-imidazol-4-yl) lower alkyl which has 1 or 2 substituents which are selected from the group consisting of isopropyl, lower alkynyl, lower aralkyl, pyridylalkyl lower, mono (or di or tri) lower haloalkyl and halogen; piperidylalkyl lower which may have lower hydroxyalkyl or lower alkoxy; morpholinyl lower alkyl which has 1 or 2 substituents which are selected from the group consisting of ethyl, lower hydroxyalkyl, lower haloalkyl and lower alkoxy lower alkyl; morpholinyl lower alkyl which has lower alkyl and lower alkoxy lower alkyl; (3, 5-dimethylmorpholino) lower alkyl; lower morpholinoalkynyl which may have lower alkyl or lower alkoxy) lower alkyl, - (2- or 3-morpholinyl) lower alkenyl which may have lower alkoxycarbonyl; lower pyrrolidinyl alkynyl which may have lower alkoxy lower alkyl; lower morpholinylalkyl which may have 1 or 2 substituents which are selected from the group consisting of ethyl, propyl, isopropyl, isobutyl, lower spirocycloalkyl, lower alkoxy lower alkyl, lower hydroxyalkyl, lower carboxyalkyl, di (lower alkyl) carbamoyl or, lower alkoxycarbonyl and lower haloalkyl; lower morpholinylalkynyl which "has methyl and lower alkoxy lower alkyl; (dimethylmorpholino) lower alkynyl; or lower homomorpholinylalkynyl which may have halogen.
3. The compound as described in claim 2, wherein Y "is lower alkylene, R1 - is phenyl which has 1 or 2 substituents which are selected from the group consisting of trihaloalkyl-lower, halogen, lower alkylamino, dialkylamino lower and nitro, R 2 is phenyl or indilyl, each of which has 1 or 2 substituents which are selected from the group consisting of lower alkyl, trihalo lower alkyl, lower alkylene, hydroxy, lower hydroxyalkyl, lower alkoxy , lower alkylamino and dialkyl (lower) amino, R3 is hydrogen, and R4 is (2-pyridyl) propyl which may have 1 to 3 substituents which are selected from the group consisting of lower alkyl, lower alkoxy, mono (or di- tri) lower haloalkyl and halogen; lower morpholinylalkyl which has 1 or 2 substituents which are selected from the group consisting of ethyl, lower hydroxyalkyl, lower haloalkyl and lower alkoxy lower alkyl; lower morpholinylalkyl which may have 1 or 2 substituents which are selected from the group consisting of ethyl, propyl, isopropyl, isobutyl, spirocycloalkyl, lower alkoxy, lower alkyl, hydroxyalkyl, carboxyalkyl, di (lower alkyl) carbamoyl , lower alkoxycarbonyl and lower haloalkyl.
4. The compound as described in the claim, which is selected from the group "consisting of: (1) (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4 - (( 3S) -3- ethylmorpholino) -2-butinyl] -2- [(1H-indol-3-yl) methyl] piperazine, (2) _ (2R) -1- [3, 5-bis (trifluoromethyl) benzoyl) ] -2- (3, 4- = d ime ti 1 b ene i 1) - 4 - [2 - ((2 S) -2-me t oxime ti 1-morpholino) ethyl] piperazine, (3) _ ( 2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- (3,4-dimethylbenzyl) -4- [2- ((3R) -3-methoxymethylmorphino) ethyl] piperazine (4) ) _ (2R) -1- [3, 5-bis (trifluoromethyl) benzoyl [-2- (3, 4-dimethylbenzyl) -4- [2 - ((2R) -2-methoxymethyl-morpholine) ethyl] piperazine, (5) _ (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -2- [(1H-indol-3-yl) methyl] -4 - [2 - (2S)] - 2-methoxymethyl-morpholine) ethyl] piperazine, and (6) "" (2R) -1- [3,5-bis (trifluoromethyl) benzoyl] -4- [2- ((3R) -3- ethylmorpholino) ethyl] -2- [(lH-indol-3-yl) -methyl] piperazine or a pharmacological salt pharmaceutically acceptable thereof.
5. A process for the preparation of the compound as described in claim 1 or a salt thereof, which comprises: (1) reacting a compound of the formula (II): wherein R1, R2, R3 and Y are each as defined in claim 1, or a salt thereof with a compound of the formula "(III): x-R4 (IV) wherein R4 is as defined in claim 1, and Wx is a leaving group, or a salt thereof, to provide a compound of the formula (I): wherein R1, R2, R3, R4 and Y are as defined in claim 1, or a salt thereof, (2) subjecting a compound of the formula (Ia): wherein R1, R2, R3 and Y are as defined above, R5 is 2-pyridyl which may have 1 to 3 substituents which are selected from the group consisting of lower alkyl, lower alkoxy, lower alkoxycarbonyl, mono (or di tri) lower haloalkyl and halogen; or 3-pyridyl which may have lower alkoxy or amino, -and Zx is lower alkylene, or a salt thereof to a reduction reaction to provide a compound of the formula (Ib): wherein R1, R2, R3, Y and Rs are each as defined above, and X x is lower alkylene, or a salt thereof, (3) reacting a compound of the formula (III): wherein R1, R2, R3 and Y are each as defined above, and X2 is lower alkylene, or its reactive derivative at the carboxy group or a salt thereof with a compound of the formula (V): H2N-Rs (V) wherein Rs is saturated heterocyclic which may have substituent or substituents or a salt thereof to provide a compound (le): wherein R1, R2, R3, R6, X2 and Y "are each as defined above, (4) reacting a compound of the formula (VI): wherein R1, R2, R3 and Y are each as defined above, X3 is lower alkylene, and 2 is a leaving group, or a salt thereof with a compound of the formula (VII): H-R7 (VII) wherein R7 is pyridylamino lower; N- (lower alkyl) -N- [pyridylalkyl] -amino, -l-imidazolyl which may have 1 or 2 substituents which are selected from the group consisting of lower alkyl, lower alkynyl, lower aralkyl, pyridylalkyl, mono ( or di or tri) lower haloalkyl and halogen, -1-pyrazolyl which may have lower hydroxyalkyl, lower carboxyalkyl, alkoxy (lower) carbonylalkyl lower, morpholinyl lower alkyl or morpholinylcarbonylalkyl lower; Piperidino which may have lower hydroxyalkyl or lower alkoxy; TZ morpholino which has 1 or 2 substituents which are selected from the group consisting of ethyl, lower hydroxyalkyl, lower haloalkyl and lower alkoxy lower alkyl; morpholino which has lower alkyl and lower alkoxy lower alkyl; 3, 5-dimethylmorphol, morpholinylamino which may have lower alkanoyl; homomorpholinylamino; or thiomorpholinylamino, or a salt thereof to provide a compound of the formula (Id): wherein R1, R2, R3, R7, X3 and Y are each as defined above, or a salt thereof, (5) reacting a compound of the formula (VIII): wherein R1, R2, R3 and Y are as defined in the foregoing, Z2 is lower alkenylene, and 3 is a leaving group, or a group thereof with a compound of the formula (IX). H-R8 (IX) wherein R8 is morpholino which may have lower alkyl or lower alkoxy lower alkyl, or a salt thereof to provide a compound of the formula (le): wherein R1, R2, R3, R8, Y and Z2 are as defined in the foregoing, or a s * to it, (6) reacting a compound of the formula (X): wherein R1, R2, R3 and Y are each as defined above, Z3 is a lower alkynylene, and 4 is a leaving group, or a salt thereof, with a compound of the formula (XI): H-R9 (XI) wherein R9 is pyrrolidino which may have lower alkoxy, lower alkyl, -morpholino which may have 1 or 2 substituents which are selected from the group consisting of ethyl, ~ propyl, isopropyl, isobutyl, spirocycloalkyl - lower, lower alkoxy, lower alkyl, lower hydroxyalkyl, lower carboxyalkyl, * "" "di (lower alkyl) carbamoyl, lower alkoxycarbonyl and lower haloalkyl; morpholino which has methyl and lower alkoxy, - dimethylmorpholino; or homomorpholino which has halogen, or a salt thereof to provide a compound of the formula (If) : _ wherein R1, R2, R3, R9, Y and Z3 are each as defined above, or a salt thereof.
6. A pharmaceutical composition, which comprises, as an active ingredient, a compound as described in claim 1, or a pharmaceutically acceptable salt thereof, in admixture with pharmaceutically acceptable carriers.
7. The compound as described in the claim 1, for use as a medication.
8. A method for treating or preventing diseases mediated by tachykinin, which comprises administering an effective amount of a compound as described in claim 1 or a pharmaceutically acceptable salt thereof to humans or animals.
9. The compound as described in claim 1, for use as a tachykinin antagonist.
10. The use of a compound as described in claim 1, for the manufacture of a medicament for treating or preventing diseases mediated by tachykinin.