AU2774500A - Piperazine derivatives as tachykinin antagonists - Google Patents

Description

1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

(ORIGINAL)

r r ee o r ea Name of Applicant: Actual Inventors: Address for Service: Fujisawa Pharmaceutical Co., Ltd.

Masaaki Matsuo; Takashi Manabe; Nobukiyo Konishi; Kazuhiko Take; Norihiro Igari; Shinji Shigenaga; Hiroshi Matsuda; Tadashi Terasaka.

DAVIES COLLISON CAVE, Patent Attorneys, 1 Little Collins Street, Melbourne, 3000 Piperazine derivatives as tachykinin antagonists Invention Title: The following statement is a full description of this invention, including the best method of performing it known to us: \\ABBOTSFORD\PATTEMP\OPER\PDB\2283768.DOC 13/4/00 P:\OPER\PDB\11106-97.SPE- 12/4/00 1A TECHNICAL FIELD This application is a divisional application derived from Australian Patent Application No.11106/97, the entire contents of which are incorporated herein by reference.

The present invention relates to new piperazine derivatives and a pharmaceutically acceptable salt thereof.

More particularly, it relates to new piperazine derivatives and a pharmaceutically acceptable salt thereof which have pharmacological activities such as Tachykinin antagonism, especially Substance P antagonism, Neurokinin A antagonism, Neurokinin B antagonism, and the like, to a process for preparation thereof, to a pharmaceutical composition comprising Sthe same, and to a use of the same as a medicament.

BACKGROUND ART Some piperazine derivatives having pharmaceutical activities such as Tachykinin antagonism have been known as described in EP 0655442 Al.

DISCLOSURE OF INVENTION o The object compound of the present invention can be represented by the following general formula

Y-R

2 3R-- R'-C-N N-R 4 P:\OPER\PDB\l 1106-97-SPE 15/11/99 wherein Y is Cl-CE alkylene, R' is phenyl which may have 1 or 2 mono (or di or tri) halo Cl-C 6 alkyl, RI is phenyl which may have 1 or 2 suitable substituent(s) selected from the group consisting of Cl-C6 alkyl, Cl-C 6 alkoxy, mono(or di or tri) halo(C 1

-C

6 alkyl and halogen, naphthyl or indolyl, 009 RI is hydrogen, and RI is morpholinyl alkyl which may have 1 or 2 Cl-C 6 alkyl; hooopoiy 0lC)akl homorpholinyl (Cl-C 6 alkyl; (hexamethyleneimino) (C 1

-C

6 alkyl; (3-azabicyclo[3.2.2]non-3-yl) (Cl-C 6 alkyl; piperazinyl (Cl-C 6 alkyl which may have phenyl. or cyclo (Cl-C 6 alkyl; morpholinyl (C 2

-C

6 alkenyl which may have 1 or 2 (Cl-C 6 **.alkyl; 0:...:morpholinyl (C 2 -C,)alkynyl which may have 1 or 2 (Cl-C 6 alkyl, (Cl-C 6 alkoxy (Cl-C 6 alkyl or mono (or di or tri)halo (Cl-C 6 alkyl; thiomorpholinyl (C 2

-C

6 alkenyl; thiomorpholinyl ((7 2

-C

6 alkynyl; pyrrolidinyl (C 2 -zC 6 alkynyl which may have (C 1

-C

6 alkoxy (Cl-C 6 alkyl; piperazinyl. (C 2

-C

4 alkynyl which may have cyclo-(C 3

-C

6 alkyl; morpholinylamino (Cl-C 6 alkyl; morphol1inyl amino (C 2

-C

6 alkyenyl; morphol inyl amino (C 2 alkynyl; [spirolindan-1, 4'-piperidinel -1 1-yl] (Cl-C 6 alkyl; piperidyl (Cl-C 6 alkyl. which has phenyl, (Cl-C6) P:\OPER\PDB\11106-97.SPE- 15/11199 -3alkoxy, (Cl-C 6 alkanoyl, piperidyl or oxo; or piperidyl (CI-C 6 alkyl which has phenyl and cyano and a pharmaceutically acceptable salt thereof.

and a pharmaceutically acceptable salt thereof.

It is to be noted that the object compound may include one or more stereoisomers due to asymmetric carbon atom(s) and double bond, and all of such isomers and a mixture thereof are included within the scope of the present invention.

It is further to be noted that isomerization or rearrangement of the object compound may occur due to the effect of the light, acid, base or the like, and the compound obtained as the result of said isomerization or rearrangement is also included within the scope of the present invention.

It is also to be noted that the solvating form of the compound hydrate, etc.) and any form of the crystal of the compound are included within the scope of the present invention.

Advantageously, one or more embodiments of the present invention may provide new and useful piperazine derivatives and a pharmaceutically acceptable salts thereof which have pharmacological activities such as Tachykinin antagonism, especially Substance P antagonism, Neurokinin A antagonism, Neurokinin B antagonism, and the like.

In another aspect, certain embodiments of the present invention may also provide a process for the preparation of said piperazine derivatives and a salt thereof.

Further embodiments of the present invention may advantageously provide a pharmaceutical composition comprising, as an active ingredient, said piperazine derivatives and a pharmaceutically acceptable salt thereof.

Advantageously, one or more of said piperazine P:\OPER\PDB\I 106-97.SPE- 15/11/99 -4derivatives or a pharmaceutically acceptable salt thereof may be useful as a Tachykinin antagonist, especially Substance P antagonist, Neurokinin A antagonist of Neurokinin B antagonist, or may be useful for treating or preventing Tachykinin-mediated diseases, for example, respiratory diseases such as asthma, bronchitis, rhinitis, cough, expectoration, and the like; ophthalmic diseases such as conjunctivitis, vernal conjunctivitis, and the like; cutaneous diseases such as contact dermatitis, atopic dermatitis, urticaria, and other eczematoid dermatitis, and the like; inflammatory diseases such as rheumatoid arthritis, osteoarthritis, and the like; pains or aches migraine, headache, toothache, cancerous pain, back pain, etc.); and the like in human being or animals.

9 ~According to the present invention, the object compound or a salt thereof can be prepared by processes which are illustrated in the following schemes.

Process i

Y-R

2

Y-R

2 -H

-R

4 (iv) R 3 or a salt thereof \-3 or its reacrLIVe aerivat-'-ve at t'oe 4mlno group or a salt thereof

(T)

or a salt thereof S *5 S

S

a St.

.Process 2 a-C-N N-I-

R

3 5

HO-C-K

or its reactive d er ivat iv e at the carboxv group or a salt thereof

Y-R

2 0 R--c-N N-C-K

R

3 (I I) or its reactive derivative at t: -i mino groun Or a salt thereatf (I a) oa salt thereof Process R K 2 0 ~H-K 6 0 R-C-N or a salt

Y

R-thereof

RK

3 or its reactive derivative at the carboxy group ca salt thereof (Ib) or a salt thereof Process 4 V v-R 2 0 0 1 N /\N-XO acv 1 at-c H C R--N \N-X-R or~ a zalt thereof (Id) of2 a salt thereof Process

Y-Y-R

2 NXR--C-N N-X-R 3 (Vii) 3 or a salt t hereof

R

3 a a (id) or a salt thereof (ITe) or a salt thereof ec a.

a p a Process 6 Y-R2 Y-R 2

NO

2 -eduiction 0

NH

R

3 or a salt thereof (Ig) or a salt thereof Process 7

Y-R

2

Y-R

2

R

1 CN N-X NH 2

W

2 -R R1 -x NHR 9 (VI II) or a saltIt Rthereof

R

3 (Ig) (Ih) or a salt thereof or a salt thereof is.* wherein Ga.Y, R R, R 3 and R are each as defined above, X is lower alkylene,

R

5 is lower alkoxyphenyl(lower)alkyl or lower alkanoylphenyl,

R

6 is piperazinyl which has cyclopentyl or halophenyl; or thiomorpholinyl,

*R

7 is acyloxy,

R

8 is pyridyl(lower)alkylauino; N- (lower alkyl)-N-[pyridyl (lower) alkyllamino; triazolylamino; morpholinoamino; lower alkoxy(lower)alkylamino; bis Ii(lower) alkoxy(lower) alkyll amino; N- (lower alkyl) (lower) alkoxy(lower) alkyl]amino; imidazolyl; pyrazolyl; or 1,2,3, 6-tetrahydropyridyl, 1,2,3, 4-tetrahydroisoquinolyl, 4,5, 6,7-tetrahydrothieno[3,2-c]pyridinyl or saturated heterocyclic, each of which may have suitable substituent

R

9 is lower alkanoyl, and W, and W2are each a leaving group.

8 s othe starting compounds (I(IIT) (V)l and ,VITI), some of then. are novel and can be prepared by the procedures described in the Preparations and 7xamples _mentaonea later or similar manners thereto.

S~tb~esa-s and nharmaceutica:llv acceptable salts of ne s tartlog and object compounds are Conventional non-toxic salt- a:nd incude an acid addition salt such as an organic ac t, Sa It acetate, tcilf iuo roacetaze, fumarate, maleate, IC-rate, maethanesul-Fonate, benzenesulfonate, formate, oluenesulf-onate, etc.), an iroraanic cid salt (e.g.

hvdrocchlorcie, hnydrobromide, hydroiodide, sulfate, nitrate, phosphate, etc.), or a salt with an amino acid (e.g.

arginine, aspartic acid, glutan c acid, etc.), or a metl salt such as an alkali metal salt sodium salt, _oozassium salt, etc.) and an alkaline ea;rth metal salt (e.g.

calciumn salt, magnesiu-m salt, etc.) an ammonium salt, an organic base salt trimethylamiLne salt, triethylamine salt, pDyridine salt, picolirne salt, dicvclohexylamine salt, N' T'dbenzylethvlenediamine salt, etc.), or the li'ke.

In the above and subseauent descri-otions of the oresent *specification, suitable exampcles andi illustrations of the va=riousz def initi-ons w-'ch -oresent invention intends to incl ude with-_in the scoce thereo f are expolained in detail as ollows.

The Term loe"is intended tLo mean I to 6, oreferabl, Ito 4, carbon atom(s), unless otherwise indicated.

Suitable "lower alkylene" may include straight or branched one- having 1 to 6 carbon atom(s), such as methylene, ethyle-ne, trimethylene, propylene, tet:ramethylene, aie thylmethylene, methyltrimethylene, hexamethyle ne, and the _-ike, ln whch thne oreferred one is methylene, ethylene, riLmethvierie or methylmethylene.

Siale "halogen" and "halogen moi'etv" in the term "di- lcbenzcvl (lower) a 2 Vy' 1 and m ray include SneInhlorine, bromine and ioo-ne.

Suitable "lower alkyl" and "lower alkyl moiety" in the terms "ord'(,Iwrakyain~oe~ly" Ipvfi dvl (lowe r) aYlylarri1no (lower) alkeny tt "N!W (lower a I' -lyl) Fryridvl (lowe r) a!lkv! J amino (lower) a!lkvrl1 7 t r acv4oloe~ly" "lower alkoxy(liower)alkylamino- (lower) alkyl", "bis[ (lower) alkoxy(lower) alkyllamino (lowe-) alkyl 7 "-N-(l'ower- alkyl)-N-,((l-ower)a'Ikoxy(lower)al-kylli-.ipno- (loer) lkvl!, Fhdroxv(lower)aIkvllI, "lower alkv-lsulfonyloxy(lower)alkl!', "phenyl (lower) alkylir, "di(lower) alk: ylaminocarbony-L' T "lower a'lkoxyphenyl ,(lower) a ky ca rbonyl", "benzoyl (lower) alkyl", "di (lower) alkylaminovr, "benzovl (lower) alkyl", "d-'ihal obenzovl (l-ow ,er) alkyl 1 "di (lower) al'kvlbenzoyl (lower) alkvl".

2 -fl 1 uorobenzovl (lower) alkyl", "Piperazinylcarbonyl (lower) al f" U2-yridvl) (Ilowe r)alk v!r _'TJdaz o 1l(1lowe r)al kyl", "pyrazolyl (lower)alkyl", "thiomorpholin.vlcarbonyl (lower) ~20 alkvl", 13-azab icyclo 2. 2]non- 3-yl) carbonyl (lower) al kyl" "thi eny'icarbonyl (lower) alkyl", 2, 3, 6--et rahvdropyriLdylllower) alkyl-", t-t"ahvdroisoquinolyl(lower)alkylf 7-tetrahydrot-hieno 2-clpyri-din'l (lower) alkyl", "s3aturated heterocyclic(lower)alkyl", "saturated hieterocyclicamino (lower) a 2 and "lower alIkoxvphenvl (lower) alkyl" may Include straiaht or branched one having 1 to 6 carbon atom(s), such as -methyl, ethyl, p rooyl, i'sopropyl, butyl, isobutyl, pentyl, hexyl and the like, -oref'erablv one having 1 to 5 carbon atom(s).

Sui,_table "lower alkenyl moiety" in the terms "chi-',oro (lower) alkenyl", "pyridvi alkylamoino (lower) alkenyl", "saturated hetLerocycli4c (lower) alkenyl" and I'saturated hneterocyclbcamrro (lower) alkenyl"f may include vinyl, (or 2-)propenyl, l-(or 2- or 3-)butenyl, 2- or 3- or 4-)oentenyl, l-(or 2- of 3- or 4- or mrethvl-,inI ezhylvinvl, 2- or 3-)-methyvl-l'-(or o_ op-nVl, c 2- or ethvl- !or 2-'propenyl, l-(or 2- or 3- or 4-):methvi-1-(or 2- or 3-)bu7-enyi, and the like, in E which. more oreferable example may be C- 4 alkenyl.

Suitable "lower alkynyl mciety" the terms "chlorc7olower)a" kvnyI-", "r 3-c\roIvlyl (]ower)aikvnvl", 3, E-rezrahvdropyridyl (lower) alkvnyl", "saturated !he-e_-orvclI (ower) al kynvI" arid "saturated 0 her-erocy<cl--I :4n-io (lowier)a'lkv-nvl," mav i=nclude etnvnv l-3rocynv±, orocrgy 1 1 -methylprocargyl, I or 2 or 3butynyl, I or 2 or 3 or 4-pentynyl, I or 2 or 3 or 4 or nexvnyl' and the like, in which more oreferable example may be C-Cr; akyny 2 SuLitrable "aryl" may include chenyl, naphthvl-, and t-he like, in which the preferred one J s C 6

C

0 aryl and the most oDreferred one is phenyl.

Suitable "lower alkanoyl" and "lower alkanoyl moiety" in 20 the terms "lower alkanoylamino", "lower alkanoylbenzoyl" and "lower alkanoylohenyl" may include formyl, acetyl, propanoyl, butanovl, 2-meohl-ropanoyl, pentanoyl, 2,2-dimethylprooanovi, hexanoyl and the like.

Suitable "lower alkoxy moiety" in the terms "lower a! koxypbeny 2 I I Iower) alIkylIcarbonyl and "lower rlkoxyp'h-en-f K olwer) alkyl" may Jnc u- ne-hoxv,eho, cropDoxy, -soor ocoxy, butoxy, isobu,_toxy, t-butoxy, pentyloxy, t-oentyloxy, hexyl'oxy and the like.

Suitable "saturated heterocyclic" and "saturated heterocyclic moiety" in the terns "saturated heterocvcolicower alkv 11 "saturated he t-eocvc 1 4-c( 1 -ower)alkynyl", "saturated het e-ocyc 1 i.camino (lowe r) al kylI", "saturated n-eterocyclicamino( -wer) alikenvl" and "sazurated neterocyclicami-no(lower) alikynyl" -may include satu.rated 3 to 8-membered (more oreferably S to 7me-mber-ed) heteromonocyclic group containing 1 to 4 nitrogen atom(s), f'or example, pyrrolidinvl, imidazolidinyl, C'cperidy 1 -iperazinyl, hexa-methylenernino, etc.; satuarated 3 to 8-membered (-nore preferably 5 or 6membered) hezeromTono-cyclic group contain 4ng 1 or 2 oxygen acorn(s) and I cc 3 nitrogen atom(s), for example, mior=hoc--ny-', syvdnonyl, etc., saturated 3 to 8-membered (more -creferably -I or 6rnemoered) heteromonocyclic group containing 1 or 2 sulfur atorn(s) and 1 to 3 nitrogen atom for example, I-I -azolidinyi, thiomorpholinyl, etc.; saturated heterobicyclic group of the formula 9.

9.

9 *9 9 9* *9 (OH 2

N

CH?)

CH

2 (wherein i, mT and n are each integer of 1 to 6); p.

S

9 9 9 saturated heterobicyclic group of the formula:

-N

(C K (wherein- q, r, s and t are each integer of1 to and the like.

Suitable "substituent" in the t-erm.s "arvl which may have suitale sbstiuent(s)", "ary 1 or indolvl each of which may have suitable substituent(s)", "thienylcarbonyl (lower) alkyl, 1,2,3,6-tetrahydropyridyl(lower)alkyl, 1,2,3,6-tetrahydropyridyl(lower)alkynyl, 1,2,3,4-tetrahydroisoquinolyl(lower)alkyl, 4 5 ,6, 7 -tetrahydrothieno[3,2-cpyridinyl(lower)alkyl, saturated heterocyclic(lower)alkyl, saturated heterocyclic- (lower)alkenyl, saturated heterocyclic(lower)alkynyl, saturated heterocyclicamino(lower)alkyl, saturated heterocyclicamino(lower)alkenyl or saturated heterocyclicamino(lower)alkynyl, each of which may have suitable substituent(s)" and "1,2,3,4-tetrahydroisoquinolyl, 4,5, 6,7-tetrahydrothieno- [3,2-c]pyridinyl or saturated heterocyclic each of which may have suitable substituent(s)" may include lower alkyl is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, :9::,tert-butyl, pentyl, neopentyl, tert-pentyl, hexyl, etc.), cyclo(lower)alkyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), lower alkoxy methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, tert-butoxy, *9*9 pentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy, etc.), lower alkoxy(lower)alkyl methoxymethyl, ethoxymethyl, 91-methoxyethyl, 2-methoxyethyl, 1-ethoxyethyl, 2-ethoxyethyl, etc.), lower alkanoyl formyl, acetyl, propionyl, butyryl, isobutyryl, etc.), lower alkenyl vinyl, 1-propenyl, allyl, 1-methylallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, etc.), lower alkynyl ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5-hexynyl, etc.), mono(or di or tri)halo(lower)alkyl 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 chlorine, bromine, fluorine and iodine), carboxy, protected 13 carboxy, hydroxy, protected hydroxy, aryl phenyl, naphthyl, etc.), ar(lower)alkyl such as phenyl(lower)alkyl benzyl, phenethyl, phenylpropyl, etc.), carboxy(lower)alkyl wherein lower alkyl moiety can be referred to the ones as exemplified above, protected carboxy(lower)alkyl wherein lower alkyl moiety can be referred to the ones as exemplified above, nitro, amino, protecEed amino, di(lower)alkylamino dimethylamino, diethylamino, diisopropylamino, ethylmethylamino, isopropylmethylamino, ethylisopropylamino, etc.), hydroxy(lower)alkyl, protected hydroxy(lower)alkyl, acyl, cyano, oxo, mercapto, lower alkylthio methylthio, ethylThio, propylthio, isopropylthio, butylthio, etc.), lower alkylsulfinyl methylsulfinyl, ethylsulfinyl, 15 propylsulfinyl, isopropylsulfinyl, butylsulfinyl, etc.), imino, morpholinyl 2-morphoiinyl, 3-morpholinyl, morpholino), bivalent group of the formula and the like.

Suitable "leaving group" may include lower alkoxy (e.g.

methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, etc.), aryloxy phenoxy, naphthoxy, etc.), an acid residue or the like.

Suitable "acid residue" may be halogen chlorine, bromine, iodine, etc.), sulfonyloxy methylsulfonyloxy, phenylsulfonyloxy, mesitylenesulfonyloxy, toluenesulfonyloxy, etc.) or the like.

Suitable "acyloxy" may include hydroxysulfonyloxy, lower alkylsulfonyloxy methylsulfonyloxy, ethylsulfonyloxy, etc.), phosphonooxy, and the like.

Preefre emoodi-ments of the object compound are as 7OjlIcw i s lower a=_kylene (more preferably CI-CA alkylene, most ore ferablv methylene); arv '~orepreeraly 6

-C

1 0 aryl, most prefferably prienvi) whi:ch may have I to 3 (mcore preferably 1 or 2, mqoss- cre ferab'ly salitable szubsti'tuent(s) [more ::)eferaicy -ono (or di- or tri)halo!ower-)alkyl (more _rrraL :rn ~oe)alkyvl, most )referablv __ry'1 (more pre ferably 6-C 1 0 aryl, most preferably p henyl or naphth1-yl,) or indolyl each of which may nave i 0 to3 (more preferably I or 2, most preferably 2 sui table substi tuent T-more preferably substituent selected.1 from the group consisting of lower alkyl (more creferab-ly C 1 -O4 alkvl1, most preferablyv methyl), lower alkoxy (_more preferatly CI 1

-C

4 alkoxy, most preferaly methoxy), mono(or di or triJ)halo(lower)alkvl (more preferably1 mono (or di. or tri)halo(C 1 C,,alkyl -most oreeraly rifuorom,,ethyl) and hralogen (more preferably chLor___ or fluorine) 1; I's hydrogen; and ischor~lwe~akenyl, (more preferably chloro(C 2

-C

4 eny±, most_ oreferabl]v chlo_'ro-2-butenvl); cloro' (Lowerf) a lkyvnyl (more pcreferablh hoo C- 4 aikyny-,, most preferably 4-chloro-2-butynyl) cyri-dy'l(lower) alkcylamino (lower) alkyl [more, preferably pyrdyll' 1 C~lyaioC- 4 akl most preferably 2-!'(3-pyri dylmerh,vl) aminol ethyl, (4-Dyridylmethv.L) anoethyl or 3- F (3-pyridylm-ethvl) amino] propyl] pyridvyl (l-ower) alkya-mino (lower)alkenyl (more preferably pyiv-CC~]Kl-'O--') mev,-ost prefferably 4T(3-pyvridylmethyl) amino] -2-butenvl) N- (lower alkyl) [pyridyl (lower) alkylamino(lower) alkyl m, .re oreferah!lv (C 1 aI j prdyl (C-C a -7 ar~n-(C-C)a'lky1, more preferably 2-[IN -methyl-Nvrid--v 7e zhvl1) ami no]I e T-~ 1 i ~azc-' lamino (lower) al kyl nore ore -ferabl y crlaoivlamno(C 1

C

4 )alkvl, mrost preferably 3-(i,2,4- _rta7z3I-3-ylamlno)propyl); lower al-koxy(lower) alkylamin4no (o--wer)alkvl (more reterably Cl-Cd allkoxy(C,-C, alky, amino (C 1

-C

4 )alky1, MoSt preferably 2- (2-methoxveTrhvi' )arqinoethyl) I. b iS iow7.,er alkoxv(Ilower) a I yl 1amino( lower) alkyl Imore ot preferably 3- [bis (2-mTe-Lhoxyet-hvl) amirno 2 procpyl; N- (lower a'lkvl)-N-F (lower) alkoxv(lower) aikyilmio 5(ower) a lkvl [mrore oref e-ab--y N- (C,-C 4 alIkyl)

_N-F(C

1 ,-C%)alkoxy(C 1 -Clkv-iami no (CI alkyl, most poreferab Iy 2 N-methv'L-N- (-me-_rioxvethvl amino] ethyl; h vdroxv(lower)alkyl (more preferably hvdroxy- (C~-C~alklmost preferably hvdroxypropyl) lowe-r alkvl!sulfonyloxy(lower)ai'kyl (more preferably C alylslfonloxyc 1 4 )aikyl, most nrfral mehvlsulfonyloxyoroovl); onerv ,ower)alkyl (more prefferably phenyl(C 1

-C

4 )alkyl most c9-feraIbly benzvl) which mnay have lower alkanoyl 257 (mor -e oref'erably C, -C 4 al'kanoyl, most preferably acetyl' amino, lower alkanovlamino (more preferably C- Ci alkanoylamino, most poreferablv acetylamino), c:(low, er).alkylamT-'inocarb onvyl (more Preferably di (C -C~ alkvlaminooarbonyl, most preferably dieuhvlaminocarbonyl) or ni~ tro; lower alkoxvphenyl(lower)alkv'lcarb)onyI (more preferably -CA alkoxvphenyl alylabonyl, most preferably sower alkanoylbenzoyl (more preferably C 1 -Ci alkanoylbenzoyl, most preferably acetvlbenzoyl) a a -en-oyL (lower) alkyl (more p-referablv benzoyl (C 1 -c) ::lkvl!, most preferably benzoyl-methvl) which haslower alKvl' (more creferably C- 1

-C

4 alkyl, most preferably m-e:hyl)/' chlorine or di (lower'alkvlam.ino (mrore ore ,era blv di (C -C~9lvaio most referably ~im~nvamino) 7nnoY owe'-)alkyl (more preferably benzoyl' (CC- ;zlkyl, m ,ost: preferably benzoylinethyl) which has ha::logen 'more ore ferablIy -uc r ion -nd loe alkyvl (more ,orefer-;bly CI-C4 alkvl, most preferably methyl); d Pi 1 obenzovl(l -ower)alkvl- [more ore ferably oz)enzoyl (C l-CI) alIkvlI, mo-st, -ore-ferably (difl uorobenzoyl) methv 1 1 do1(i owe--)alkylbenzoyl(lower)al'kyi1 fmore oreferablv oi( Z-C)alkylbenzovl-C, 1y most preferably diret__nyvi benzoylmethvl]; 3-f -Lu-orobenzoyl 1 ower) alkvyl (more preferably 3fluorobenzoyl (01-04) alkvl, most pcre ferably 3fluorobenzoylmethvI); 3- oorobenzo~vl) propyl; 4, 4'-ethyleneiioxv--- 4- fliorophenyl) )butyl; oierazinylcarbonvl (lower) alkyl- (more preferably Pi---eraz -nylcarbonyl(Cl-(>jal-kyl, most preferably papoeraz lnvlcarbonvylmethvI) which haas cyclopentyl7 or halophenyl (more preferably fluorophenyl); (2-vriyl)(lower)alkyl (-more preferably (2-pyridyl)-

(C

1

-C

4 )alkvi, mos, preferbly (2-pyrieyl)methyl); (3--oyr-idvl) oro-)vl (more pre ferab ly 3-1,3-pyridyl)pronvi) (3-pyriJdyl) (lower)alkynvl (more preferably (3y-idyl) (C 5

-C

4 )alkynvi, nost preferably 3-(3--pyridvl)-2propyny c7Olv 1 lowr~akvl(more preferably imidazolyl- (Cjl-CA-alk;yl, most oreferablv (lHI-±midazol-1-yl)metI-Lv 1 (!H-imi, dazol--yl)metuhy-L or 1 -H-iihdazol-4-yl)methyl) which may h-ave lower alkyl (more oreferably 01-04, alkyl, a. a a a most creferably m.Tethyli) ovrazo',l 2 (Iower)alIkvl (more oreferably pvrazolyl(C--C 4 ~lvmost oreferably r-Vrazo I---v 1 met-hvl or 2- (14- -ovrazoi1-4-yi) propyl which myhave lower alkyl (more o~referacDl CI-CL alkvl, most pre-ferably methyl); zhl'omorphol~nio-Y-arbonv'I owrly (more poreferabl y tn~morho 2 i rvlcrbnvl(C 1 -19a 1 >lmost preferably ohiomoroholi-nvicarbonvlm-ieth- l)i-aac~yc F 3 .2z. 2 noni-3-vi carbonyi (lower) aiky 1 (more referablv 3-azabi-cyolo, D,.2.2Q>-3-vl)carbonyl(C,-%,)- ~kimost preferablv (3-azablc-vclo[3.2.2Inon-3vI carbDonylmethyl) or thien y7lcarbonyl ,(lower) alkyl (more preferably :rhienycarbonyl(C-.-C 4 kyI', most: preferably t.hi:enyl7-carbonvlme-hvl,), 6-F-etErahvdropyri-dy1L ~(lower)a 1 lkyl (more preferably 1,2,3,6-tetrahydropyridyl- ',CI-CI) alkyl, most, Preferably 23-(1,2,3,6t eztrahvdropyridin-l-yl )propyl) 3, 6-tet-rahivdro1Dyri dv'(lower"akJ'yrlyl (more p)referably 1, 2, 3, 6-tet-rahydropyridyl (C 2 -C )alkvnyl, most preferably ±',2,3,4-tetrahvdroi-socru olyl,(cwer-)alkv1 (more o D~~referacly 1,2,3,4-tetrahvdrol-soauinol'-yl(C 1

-C

4 )alkvl, o. ~~Most creferablv 1,2,3,4-t-et-ranyorot souinolylpropzyl), 4,5,6, 7-tet---:-h\drothi'eno[3,2-c]pyvri-dinyl(ower)alkvl (more oreferably 4,5,6,7-t-etraiycror:hieno[3,2-c]pvyr_,dlnyl(CI-C 4 )alkyl, most pre-ferably 7-tetrahydrothi-eno 2-c-i-v-4dinylorpyl) saturated heterocyclic (lower) alkyl (more poreferably satcur-ated h--eteroccycl-c (C 1 -09 ,alky 1 more preferably sat',iat-ed heterocyclicethyl or saturated heterocyclicpropyl, most prefferably sat urat:ed heterocycliJcpropyl)', saturatEed het-erocyclic(l-ower) alki-enyl (more preferably satur-ated hetLerocyclic_(C 2

-C

4 ,'al'kenvi, most preferably satu-rat-e 'ne7:erccvcii-cbu-,tenvi) sat.urated h--eterocyclic (lower) alkvnvl (more preferably satu,.ra--ed eeovlcC-:akn most preferably satura--ed nezerocycli cbutynvlI or s sa t crat:ead -e -erocvcli- 'cpentynv7I saturated net-erocyolicamiLno (I-ower)alkvl (more preferably sa- ur a r ed hnet erocycl icamino -04 )a 1 kv 1 most p~referably s-a t ur a -ed h-eterocvcli-'cami-nonrop.v'l), saturat:ed h-ete--ocyclic-ami, no (Iower)ai kenyl (more iC referazbv Saturated 'heterocyclicamino (C 9

-C

4 alkenyl", m ostu referablv saturated heterocyclicaminobutenyl) or sat-u-ra,-ed n,-e 7eroovc!icamino 1, ower) alkyn\/. (more reerablv saturated heterociclicamino(C9-C)aknl most pr-e -ferably saturated heterocyclicaminobutynyl) T,/-herein "saturated heterocyclic moiety" is saturated 3 to 8--mermbered (more -oreferablv 5 to 7-membered) het'-eromonocvc 1 ~ic group containing I to4(more preferably 1or 2) nitrogen atomn(s) (more pcreferably pyrrolidinyl', piperidyl, piperazinyl or -hexametUhyleneimino, most preferably piperidyl) saturated 3 to 8-membered (more oreferablIv 5 to 7menbered) heteromonocyclic group containing 1 or 2 (more preferably 1) oxygen atomr(s) and -1 to 3 (more preferably 1, trooen atom(s) (more -oreferably morpholinyl or homomor-oholinyl, most preferably morpholinyl) saturated 3 to S-membered (more are-fferably 5 or 6'meimbered) heteromonocyclic group containing 1 or 2 (more orefzerably 1) sulfur atom(s) and 1 to 3 (more preferably 1) nit-rogen atom(s) (more preferably thiomorpholinyl) or saturated heterocyclic group of the formula: 2'q (CYCQ) (C 2 (werin r, s and are each as def- ined above) a-o-e~f erablv 3-a;:zabicyclo[F3.2.21 non-3-yl) 11, eacn of IDwhich may have 1 to 3 (more pre-"Le-ablv 1 or 2) suitable S! sriuent- [more pref-"e rab ly subs ti4tuent s el1ect---ed f-rnm tne groupn consisting of cyclo (lower) alkvl' (more preferably cyclohexyl), lower alkanoyl (more preferably 0: C~C4alkanoyl, most preferably acet yl), lower alkyl (moe ne'erablv C 1 -CA alkvl, most oreferably methyl), -rono (or di or tri)halIo(lower)alJkyl (more preferably monoh--al'o (01-04)alkyl, most preferably fluoromethyl), lower alkoxy (more preferably 01-04 alkoxy, most pcreferably methoxy), lower alkoxy(lower)alkyl (more preferably C -C 4 alkoxy(CI-C 'alkyl, most preferably methI-oxym-ethvNl) halogen (more preferably chlorine) aryl (mr rfrhl hnlcyano, oxo and bivalent group f*o n ormula More -referred embodiments of th e object[- compound (I) are as follows Y I: ower alkylene (more preferably C-I-CA alkylene, most preferably methylene); 3 R 1 is oh',)enyl which may have 1 or 2 mono (or di or tri) halo- (lower) alkyl [more Dreferablyv biLs (trihalo(lower) alkyl) pnenyl, most preferably bis(trifluoromiethyl)phenyl; R sphenvl1 which may have I or 2 suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, mono(or di or tri)hal-o(lower)alkyl and halogen more pre ffera blv di lowe r) aikyl-henyl, lIowei) a lkoxyphenyl, F tr ihaio (lower) aikvl 1, phenyl, 'lower, e_.I,<v 2 ihalophenvl', hna-ophenyl or dihalophenyl, most orefera=blv dimethyiphenyl, 7m.ethoxyphenyl, (:rlluorme~hl~peyi, rethvl'fluorophenyl, :F -uoroPhenvl or di'fluorochliorophenyli, naphthyl or 4ndolvl"; R- ~s nvarcaen; and

R

4 -s morichol invl-(Iower)alkyl-I whichA may have I or 2 lower a-!kv! (more preferably methyl), homomroholnv, (lower) alkvl, th orrorpinol, nyl (lIower) alkvl, (hexme~hlene>o)(lower) a! kyl aza'-o cycl o[3.2.2]non-3-yl),' (lo(:wer) alkvl, oipoeraz4-v''( 1 ower)alkvl which, may have phenyl or cyclo (lower) alkvl (more oreferably Pperazlnyl(iower)alkyl which has phenyl or cyclohexyl), morpoholl-nyl(lower)alkenyl which may have 1 or 2 lower a-!kyl (more oreferably methyl), moroholi4nyl(lower)alkynyl which'r may have a substituent selected from the group consisting of lower alkyl (more ore r-roby m-ethyl-), lower alkoxy (lower) alkyl (more oreferabliv methoxvmethyl) and -mono (or di or 'i)halo(1ocwer'alky1l (more preferably fluoromethyl), t-h -ioorpholi nyl ower) a-lkenyl, tniomoroolinyl (lower) alkynyl, pyrrolidinvl---klower)alkynyI whic'n may have lower a_'koxv(_'ower) aIkyl (more preferably methoxymethyl), ou-'oeraz -nyl (lower) alkvnyl which may have cyclo,'ower)al-kyl, (more preferably cyclohexyl), -opoinvlamino (lower) alkyl, moLrloolinyamino (lower) alkenvl, mo rphol i -yl-am ino (lIowe r) alkynyl, o r pioeridvl(lower)alkyi' which-n may have 1 or 2 suitable substituent(s) selected from the group consisting of bivalent group of the formula K, phenyl, cyano, lower alkanoyl, lower alkoxy, piperidinyl, and oxo [more preferably [spiro[indan-1,4'-piperidine]-1'-yl] (lower)alkyl, piperidyl(lower)alkyl which has phenyl, acetyl, methoxy, piperidino or oxo, or piperidyl(lower)alkyl which has phenyl and cyano].

The Processes 1 to 7 for preparing the object compound of the present invention are explained in detail in the following.

Process 1 The object compound or a salt thereof can be prepared by reacting the compound (II) or its reactive 15 derivative at the imino group or a salt thereof with the compound (IV) or a salt thereof.

Suitable reactive derivative at the imino group of the compound (II) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (II) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide, bis(trimethylsilyl)urea or the like; a derivative formed by S 25 reaction of the compound (II) with phosphorus trichloride or phosgene and the like.

The reaction is usually carried out in a conventional solvent such as water, alcohol methanol, ethanol, etc.], acetone, dioxene, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These conventional solvents may also be used in a mixture with water.

The reaction may also be carried out in the presence of an inorganic or organic base such as alkali metal carbonate, alalli metal bicarbonate, tri (lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N-d il ower)aikyibenzylamine, or the like.

The reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.

Process 2 The object compound 7Ia) or a salt thereof can be prepared by reacting the compound or its reactive derivative at the carboxy group or a salt thereof with the compound (II) or its reactive derivative at the imino group or a salt thereof.

Suitable reactive derivative at the carboxy group of the 15 compound may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like. The suitable example of the reactive derivative may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid dialkylphosphoric acid, phenylospsphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.], dialkylphosphorous acid, lower alkanesulfonic acid [e.g.

metanesulfonic acid, ethanesulfonic acid, etc.], sulfurous acid, thiosulfuric acid, sulfuric acid, aliphatic carboxvlic *9 acid acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, valeric acid, isovaleric acid, 2-ethyibutyOc acid, trichloroacetic acid, etc.] or aromaticcarboxylic acid benzoic acid, etc.]; a symmetrica and anhydride; an activated amide with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazoie; or an activated ester [e.g.

cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH3)2N ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2 4 -dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, onMnv7 ophenYl ester, phenvi thioester, P-nitronhenyl :-hioesr-er, p -cresyl thioester, carboxymethyl thioester, pyranyl es t er, -ovr-idvl ester, pi peridivI ester, 8-gu-inolyl thioester, etc.J, or an ester with a N-hvdroxy compound [e.g.

N, Ndimehvlhdroxlamie, -hydroxy-2- (2 4) -pyridone, N-hnvdroxysuccinimide, N-hvdroxyphha72mide, 1-hydroxy-lHbIenzotriazole-, etc.!, and the li ke. These reactive der i, 'es can oorionallv be selectedl fcom them according to t he kind of t zh e c omp oun d t o b e u s ed.

The rea ctio-'I s -usually carried out- in a conventional solvent such- as water, alcohol Tmethanol1, ethanol, etc.], aceton-e, d-ioxane, acetoniTtrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, NNdimtbvforamie, yr-idine or any other organic solvent vote* i which does not adversely influence the reaction. These conventional solvents may also be used in a mixture with water.

C 9 ~in thsraton, when the comound is used in a fre acd frr ora sltthereof, the reaction is preferably carried outz i-n the o)resence of a conventional condensing U::agent suz,-ch as N,N'-dichlorohexvlc-a--bod.imi-de; N-cyclohexyl-- -morr-holinoethylicarbod'iLide; 9 *N-cyclohexyl-"-N'- 4 -diethylarinocycl ohexvl,) carbodiirnide; N,N'q-diLethyIlc-arbodi-imide; N,N'-dii sopropylcarbodiimTide; N-ty N-( 3 -di-methylaminopropyl) carbodJinide; -oentametLhyle-neketene-N-cyclohexy'Limoi-ne; di'phenylketene-N-cyclohexylimLi-ne; ethoxyacetylene; I alk-oxv-1 -hloroethylene; trialkyl phosphe ethy polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chlo-ride); phosphorus trichioride; di-phenyl phnosphorylazide; thiJenyl chloride; oxalyl chloride; lower alkvyl haloformate ethyl chloroformate, isopropyl chloroformate, etc.]; tri~henyliohosphine; 2-et-hvl-7hydroxybenzisoxazoliuL~r salt; 2-ethyl-5- (m-sulfoiphenyl) isoxazolium hydroxide intramolecular salt; 24 1-(p-chlorobenzenesulfonyloxv)- 6 -chloro-lH-benzotriazole; 2-chlorc-l-methylpyridinium iodide; 1-( 3 -dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; so-called vilsmeier reagent prepared by the reaction of N,Ndimethylformamide with chionyl c-loride, phosgene, tricnhoromethyl chloroformate, phosphorus oxychloride, etc.; or the like.

The reaction may also be carried our in the presence of an inorganic or organic base such as alkali metal carbonate, alkali metal bicarbonate, tri(lower)alkylamine, pyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, or Sthe like.

1The reaction temperature is noe critical, and the eaction is usually carried our under cooling to warming.

Process 3 The object compound (Ib) or a salt thereof can be

S

prepared by reacting the compound (III) or its reactive derivative at the carboxy group or a salt thereof with the S 20 compound (VI) or a salt thereof.

The reaction mode and reaction conditions of this reaction are to be referred to those as explained in Process .2.

Process 4 The object compound (Id) or a salt thereof can be prepared by subjecting the compound (Ic) or a salt thereor to an acylation reaction.

The reaction can be carried out in the manner disclosed in Example 20 mentioned later or similar manners thereto.

Process The compound (Ie) or a salt thereof can be prepared by reacting the compound (Id) or a salr thereof with the compound (VII) or a salt thereof.

ft C*

C

C

C CCC

C*

C.

C CD

C

This reaction is usually carried out in a solvent such as water, alcohol methanol, ethanol, etc.), benzene, N,N-dimethy forma ide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, acetonitrile, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.

The reaction temperature is not critical and the reaction is usually carried out under cooling to heating.

The reaction may be also carried out in the presence of an inorganic or an organic base such as alkali metal sodium, potassium, etc.), alkali metal hydroxide sodium hydroxide, potassium hydroxide, etc.), alkali metal hydrogencarbonate sodium hydrogencarbonate, potassium hydrogencarbonate, etc.), alkali meral carbonate sodium carbonate, potassium carbonate, etc.), tri(lower)alkylamine rrimethylamine, triethylamine, diisopropylethylamine, etc.), alkali metal hydride sodium hydride, etc.), alkali metal (lower)alkoxide (e.g.

sodium methoxide, sodium ethoxide, etc.), pyridine, lutidine, piccline, dimethylaminopyridine, N-(lower)alkylmorpholine, N,N-di(lower)alkylbenzylamine, N,N-di(lower)alkylaniline or the like.

When the base and/or the starting compound are in liquid, they can be used also as a solvent.

Process 6 The object compound (Ig) or a salt thereof can be prepared by subjecting the compound (If) or a salt thereof to a reduction reaction.

The reaction can be carried out in the manner disclosed in Example 29 mentioned later or similar manners thereto.

C

Process 7 The object compound (Ih) or a salt thereof can be prepared by subjecting the compound (Ig) or a salt thereof to acviation reaction.

The reaction can be carried out in the manner disclosed in Example 31 mentioned later or similar manners thereto.

The object compound and a pharmaceutically accepcable salt thereof have pharmacological activities such as Tachyk1nin antagonism, especially Substance P antagonism, Neurokinin A antagonism or Neurokinin B antagonism, and therefore are useful for treating or preventing Tachykininmediated diseases, particularly Substance P-mediated diseases, fcr example, respiratory diseases such as asthma, bronchitis chronic bronchitis, acute bronchitis and diffuse panbronchiolitis, etc.), rhinitis, couph, expectoration, and the like; 15 onphtalmic 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, 20 osteoarthricis, and the like; pains or aches migraine, headache, cluster headache, toothache, cancerous pain, back pain, neuralgia, etc.); and the like.

Further, it is expected that the object compound and a pharmaceutically acceptable salt thereof of the present invention are useful for treating or preventing ophthalmic diseases such as glaucoma, uveitis, and the like; gastrointestinal diseases such as ulcer, ulcerative colitis, irritable bowel syndrome, food allergy, and the like; inflammatory diseases such as nephritis, and the like; circulatory diseases such as hypertension, angina pectoris, cardiac failure, thrombosis, Raynaud's disease, and the like; epilepsy; spastic paralysis; pollakiuria; cystitis; bladder detrusor hyperreflexia; urinary incontinence; Parkinson diseases; dementia; AIDS related dementia; Alzheimer's diseases; Down's syndrome; Huntington's chorea; carcinoid syndrome; disorders related to immune enhancement or suppression; disorders caused by Helicobacter pylori or another spiral urease-pcsitive gram-negative bacterium; sunburn; angiogenesis or diseases caused by angiogenesis; and he like.

It is furthermore expected that the object compound (I) and a pharmaceutically acceptable salt thereof of the present invention are useful for treating or preventing chronic obstructive pulmonary diseases, particularly chronic pulmonary emphysema; iritis; proliferative vitreoretinopathy; psoriasis; inflammatory intestinal diseases, particularly Crohn's diseases; hepatitis; superficial pain on congelation, burn, herpes zoster or diabetic neuropathy; tenalgia attended 15 to hyperlipidemia; poscoperative neuroma, particularly of mastectomy; vulvar vestibulitis; hemodialysis-associated 'v itching; lichen planus; laryngopharyngitis; bronchiectasis; coniosis; whooping cough; pulmonary tuberculosis; cystic fibrosis; emesis; mental diseases, particularly anxiety, 20 depression, dysthymic disorders and schizophrenia; demyelinating diseases such as mulriple sclerosis and amyotrophic lateral sclerosis; attenuation of morphine withdrawal; cedema, such as oedema caused by thermal injury; small cell carcinomas, particularly small cell lung cancer (SCLC); hypersensitivity disorders such as poison ivy; fibrosinc and collagen diseases such as scleroderma and eosinophiic fascioliasis; reflex sympathetic dystrophy such as shoulder/hand syndrome; addiction disorders such as alcoholism; stress related somatic disorders; rheumatic diseases such as fibrositis; and the like.

Furthermore, the object compound and a pharmaceutically acceptable salt thereof of the present invention are Central Nervous System (CNS) penetrant.

For therapeutic purpose, the compound and a pharmaceutically acceptable salt thereof of the present invention can be used in a form of pharmaceutical preparation containing one of said compound, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral, external including topical, enternal, intravenous, intramuscular, inhalant, nasal, intraarticular, intraspinal, transtracheal or transocular administration.

G0 The pharmaceutical preparations may be solid, semi-solid or solutions such as capsules, tablets, pellets, dragees, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, cataplasms, gels, tapes, eye drops, solution, syrups, aerosols, suspension, emulsion, or the 15 like. If desired, there may be included in these preparations, auxiliary substances, stabilizing agents, wetting or emulsifying agents, buffers and other commonly used additives.

While the dosage of the compound will vary depending 20 upon the age and condition of a patient, an average single dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound may be effective for treating Tachykinin-mediated diseases such as asthma and the like. In general, amounts between 0.1 mg/body and about 1,000 mg/body may be administered per day.

In order tc show the utility of the object compound (I) and a pharmaceutically acceptable salt thereof, the pharmacological test data of some representative compounds of the present invention is shown in the following.

A. Evaluation of NK 1 antagonist transport efficiency to the cental nervous system using a h-NK receptor binding assay Test Method Administration of test compound and extraction of the compound from brain Male SD rats were given an i.v. injection of a solution containing a test compound (1 mg/kg). 5 Min later the animals were anesthetized by ether, bled and perfused through the aorta ascendens with 20 ml of saline. The brain was rapidly removed, weighed and homogenized in 4 vol. ice-cold distilled water by using Polytoron (KINEMATICA). To extract -he test compound, 500 iL of the homogenate, 100 p~ of methanol, 500 ~1 of 0.1 N NaOH and 4 ml of ethyl acetate were mixed by shaking for 10 min at room temperature. The organic phase (2.5 ml) was recovered by centrifugation at 3,000 rDm for 10 min, dried and dissolved in dimethyl sulfoxide.

15 h-NK 1 receptor binding assay Crude CHO cell membrane preparation

*Q

.9 9*

C

CHO cells permanently expressing h-NK, receptors were harvested and homogenized with a Dounce homogenizer at 4 0 C in a buffer (0.25 M sucrose, 25 mM Tris-HCL (pH 10 nM MgCl 2 1 mM EDTA, 5 fpg/ml p-APMSF). The homogenate was centrifuged (500 x g, 10 min), and the pellet was resuspended in the same buffer, homogenized, and centrifuged. The two supernatants were combined and centrifuged (100,000 x g, 1 hour). The crude cell membranes thus isolated were resuspended in a buffer (25 mM Tris-HCI (pH lu mM MgCl 2 1 mM EDTA, 5 ug/ml p-APMSF) and stored at -800C until use.

125 -BH-Substance P binding to the prepared membrane Cell membranes (6 ug/ml) were incubated with 1 25

I-BH-

Substance P (0.1 nM) with or without the extracted compounds in 0.25 ml of a medium (50 mM Tris-HCl (pH 5 mM MnC! 2 a.

a. a a a. a ptg/ml chy-mostatin, 40 p1g/nl bacitEracin, 4 ig/ml leuceptin, a/ml p-APMSF, 200 tag/mi- BSA) at 22'C for 90 min. At the end o the i-ncubation period, the contents were quickly f-iltered through a Blue Mat(.- 11740 filter (pretreated with 0 1~polvet11vlenimine for 3 hours orior to use) by using SIKA:TROIN Cell Harvester. The filter was then washed with a w a s hi--g buaf f er 0 inLN T7r_4s HCI (poH 7 5 mM Mn CI The rad _4oa:- 4v was count ed b y ing an aut o gamma cocunte r C j AS TAR 5 4 2C All data p3resented are spec'ic bndi:'nn defined as that displaceable by 3 4 unlabeled Substance P.

7T] e st- R es ui 15 All- of the following Test Compounds showed more than or ate of 1 2 5 T-BH-Substance P binding to h-NK 1 -eceotors at- the dose of mg/kg.

Test Compounds The object compounds of the Examples 7, 111, 12, 22, 23, 24-(2), 2 6, 3 5, 3 6, 3 7 (6C) 46, 47, 51, 53- 54, 55, 58, 71, 72, 73, 74, 76, 77, 81, 82-(5), 82-(10), 82-(12), and 86 a.

a a a a. aa.

3. Ernesis in the ferret [ITest Method Ind~ vidually housed adult male ferrets (Marshall Farms, 1.4 to 2.2 k-g) were given an i.p. injection of a solution ccontatining a test compound. 30 Min later the emetic resconses (retching anid vomiting) were induced by adrn 2 -istration of intra-gastric co'p-per sulfate (40 mg/kg/mi) and observed for the next 30 nmm. -he timing and number of recnasand vomiq-ts observed were recorded -or each animal.

An -div ial an-Imal was tested with at least 10 days bDetween ex-eriments.

es Resl of the following Test Compounds showed 100% inhibizt'on rate of emesis in the Ferret at the dose of 325 15 Tes t comp.-ounds The object compounds of the Examaples 12, 22, 23 24-(2) and (6) The following Preparations and Examples are given for the purpose of illustrating this invent-ion.

(to be continued- on the next page) Examnle 1 mxture orF 2 R) 3 ,Sbs ifliunromethyl)benzovil-2 (5 g) and 3-bromo-oropanol 1.68 g) iJn N, N-dime thy! forimamide (40 m'l) was heated at -h oe oDresence of pooassium carbonate '4.5g.Afe9 hlours, the reaction mr.xture was poured into water (0 l and extracted with1, ethylv- aceta--te. The extract was washed won t-1 bine and dried over magnesi~an suifate. After a vaoora -toon of th e solven~t, the obtained residue was 'Ourified by clun chromatoc-ranny on siiagel using dic'h 1 ooehae -methanol' (30:1) as an eluent to giLve (2R)-1-L[3,5is tr ucmeylbnzv3-4- 3 -hydroxyropvyl) (1H-in lol 3-I lmet2V phioioera zine (5 36 as 1owder ~(Neat-) :3600-3100, 1625, 1275, 1170,12, 15898 cm- N MR (DMSO-d 6 5) 0 (16H, in); 6. 6-8 .2 (3H, i) .n 10.84 (1H, s) MAS S :514 454 Examole 2 following compound ew-as obtained accor-ding to a similarianner t-o tLhat of Example 1.

-1 '3 5-3-s (trifiu,-orometvl)benzol2(3,4dime oh-vlbenz ylI) 3 -hydroxyoDropoyl) piperazine I Nuj c1) :3400 (br) 3000-2700, 1625, 1430, 1270, 1120cm NM-R (DMES-d 6 5) 1 ,7 (2H, 7L); 2.05-4.9 (19H, 6) 6.5S- 8 .2 1,6 H, mn) MALSS 503 (M±1) Exam-cle 3I mixt-ure Of tiloontv~e~\;12 (l-indo--meth-)oicerazine (0.3 2-brcomo-47chloroacetophenone (0.2 g) and Potassium carbonate (0.16 g) a a.

in NN-clnecvlfcmamde ~)was stirred at room termoerature for I hour and 20 minutes. *:he reaction mixture .\as courled. into ater (20 and extracted wi th ethyl acetate. The organic laver was washed with water and dried 3 over magnesium sulfIate. ftrevaporation off the solvent, toe.- cot:ained residue was pur-i::-ed by column chromato graphy on s~ 1 ~gel, using :oic -ehy ac7~ 14:1 as an eluent.

cns containing cbjec- ve cornPound were collected and ccnce-nt~ae- under reduced -pressure. The obtained product was di'ssol ved-- in ethyli ace tat-e, t reated with 4_N hydrogen c'-lcri]'(_e eth ,vl aceta te solu-,t ion ann- t-hen evaporated under reauced corssure T-he residue was T:curated with n-hexane to give (2K) 3, 5-bis (tri fliorcmeth l) benzol]-4-(4c'nioro-c nenylcarbony-me-nyi (1-indol-3-ylmethyl) pipceraztn.e 15 vdrror'hloride 10.31 g) as a no-wder.

McO 2 14000C (de c.) rt 20 -22 .60 (C=O 5, MaeH) TR (Nujol) 3500-3100, 2700-2150, 1690, 1635, 1275, 1100 cr6' N1YR (DMSO-d 6 li);6.4-8.3 (12H, m} 0. 7-11.05 (2H, in) MASS 608 (M-i1) (f-'ree)

S

Exaincle 4i Th folowing Cormoound wa s obtained according to a similar :,manner to that O-f Exa.=ple 3.

hienyl carbonylm,-ethyl 1 (lH-indol-3-vlInethyl) piperazine hydrochlocride JD -55.20 MeCH) 7 R (-Neat) :3700-3100, 2_700-21510, 1635, 1415, 1275, 1130 cin<1 NI'jhR (DMSO-d 6 6) :3.0-5.2 (11-H, mn); 6.8-8.3 (10H, in); -10.97-, (lE, s) MAkS: 6 51 1 fr e 6 14 Examole A mixture of 2 R)--F13,5-bs(trfioromehlbenzoyili2? (iH--indol-3--vlmethvi')pipoerazine (0.3 2-brorqo-3'- :Iuooaceonheone(0.19 oj) and potassium carbonate g) MT-dmet~vio~mmld '5r~)was stirred at room Lenrcuecr oran 0miue. The reaction mixicure w::s -cured -,nco water (20 ml) and extracted wit ethy'nl acetate. The organi-c layver was washed witLh water and dr-ied over magnesiumrc sualfate. A fter evaporation of the solvent th1,e resultina residue was purif'ied by column chromatography on silica gel u-sing roluene-ethvi acet_;te (2:1 as an eluen-.

on .octai nedl croduct was dissolved in ethayl acetate (2 r-l) .nd tr5 eatedi -wit'h 4N hydrogen ch-rloride in ethvi acetate Cucn(14Ll The resulting precipitate was collected by iltaton addida 0CfrShours to give (21R -1 ,-bi4s (t-r ifluoromethvl) benzoylI (3lu, o ra ohenvl-r b on y l.ne-h v, )-iido3-ylmethyl)piperazine hdrochl-__oride (0.2 a) as a Lowder.

mc:19 5',C (de c.) 9 9 L~.J MeORH) 9~*99 (ujo) :3200, 2650-220"", -1695, 655, 2270, 1125 m-i NR(DMSO-dE, 5):3.3-5.3 (lIEH, 6.6-8.3 (12H, in); J10.8-11.4 (2H, in) MPS S 592 (free) A ,nal. Calcd. for C 3 0

H?

2 4

F

7 N 0 2 HCl C 57.38; H 4.01; N 6.69 Found :C57.23; H 3.79; N 6.49 he f ollowing compoundis were obta-ined according to a _sLiar inanne- to that of Exam-ole S.

-C>

*9 0* 9*

C.'

2 1R)i- 3 ,5-3i-s(tr -fL-uoromethyi,)benzoyii (3,4difiluoro~oh-envloarbonvrnet -hvi) (1K-indo±-3vlrnetoYl) ciperazine bvdfoc'rloride Mnp :171'C (dec.)' 1 2C (C0. 5, MeO-U iR 3550-3100, 2650-21,50, 1690, 1640, -1510, 12 75 13 0 z> YR(DvSO-d6, 6) 30-. n 7.6-8.3 (11H, mJ 0.71. H2, n MAs S 610 (free) Alnai Calodci. for 7 3

F

8 2

*C

C 55.78;: H 3.74; N 6.50 7ound 5.34; H 3.72; N 6.41 (2)1L 2 SS B is f, Io ne v I) be z o v I 2 (1 Hindo -13 v_=ze:2vI 4 4 -nei:hyviphenyl caronyine-hlvi piperazine hvdrochl!or2'ae in:203'C (dec.) -37.4' MeOKl) R 3550-3100, 2650-2150, 1690, 1640, 1280, I17; 3,11 25E cm7 NMRP (D)MSO-d 6 5) 2.43 (3K, s; 3. 1-5. 3 IK in); 6 8 .3 (12KH, mn); 10. 8 -11. 2 '2KH, MkS S 587 -iie t, \/Ioen\7caron "-,ae:hv1 -2 H_4ndo- 3 ;vLern ~v 1-c~era zine hydr-och lor ide ri '6 0 c (dec.) 2-3 6 .8 (C =0 IR (NuJol) 3600-315C, 2700-2300, 1685, 1635, 1275, 1130 cm 1 MNR DMS-J 6 6) 2.34 3.2-5,.3 (11H, mn); 3 (11lH, mn); 10. 6-11. 2 (2H, mn) TMASS 60' (-free) Ana-l. Caloci. for c 32

H,,F

6

N

3

O

2 HTC'1.H C 58.42; -H 4.93; N 6.39 7cund- C 58.46; H 4.90; N 6.27 S 4) 2 R)I 1 3-B i S(t r if uo romethvi) ben z o 4 -f uo ro 3 mver:hvl phenvlcarbonylmethvl) (lH-indol-3- \v Iecnv I ninpera zine h-ydrochlocr ide c -21.2 MeOH) ~R (nio;3600-31,00,, 2700-2200, 1'685, 1635, 1275, 0 -~1130 cm',i NMR (_DMSO-d 6 6) 2.34 (3H, 3.1-S.3 6.6-8.3 (11H, mn); 10.7-11.2 Tn) MASS 606' (M4 1) (free) *1.

S. 5 9

S

is ExamplIe 7 A xzue of 5-bis (trifluoroinethyl)benzoyjj, -2- (1K-ind~~~ -_-ylm_-ethyl)piperazne (2 n),14 (kbromornP.ehv!-)phenyilethanone (107 mng) and potassium carbonate ,42 mg 'n a cetonitrile (2 ml) was refluxed for 4.5 ours.

A-ft1er cooling> thne mixture was evaoorated in vacuo. Etyl acet ate and water were added to the residue and the orgarnic layer Tvwas Separated, washed with brine, dried over magnesium sul__fate, a7nd evaoorated in- vacuc. The r-esidue was purified by column~ -_'romatoccraohy on sJilica gei with a -mixture o-r thane and methanolI as an eluent to give acet-vl-benzv1-)-i,-F[35-b'is (tr f uoromet-hyL) benzoyl,] (1Hindol--3-yi m-.ec-hvi-)pioerazine (0.30 q) To a solution of this p-',erazine (0.30 g) in ethv! acetate was added 4N hydrogen chloride in ethyl acetate solution (0.13 ml) and the whole Vas eva-oorteld i-'n vacuo. The residue was triturated wrna mixture of ethyIl acetate and et.-her to give ace tvibeny F ,Sbs(r4furmty ezy 2 1H lndol-3-yImetnyi pperaz-ine hydrochloride (283.5 mg) as a coowde-r.

In 72'C (dec.) r.1 2 -30.00 (C=0.27/ MeOH) NIR -Nuo) 3350, 1675, 1655, 1635, 1610, 1275 crc>

T

MR CDlP5 '2.36-5.60 (I ci); 6-10-9.30 13H, 1,2.93 1K br s) MA7S S 8 58 (free) *0 C

C.

Exa-mole 8 -r o k'xb z~llrmtv enzovi'Q? (1-ndo--l. v~1e~1~ (0.3 g) 2-broruo-4' dme iamnoaetohen~e 0.2g) nd cozassium~r carbonate 1 -N,N-dimethvl, forma-mide 5 i)was sti rred at roomr ,eruerat11re -for 2 hours. Th'-e _reacti-_on mixture was poured 'r v wte (20 ml) and extracted with ethyl acetate. The organs c layer was washed with water and dried over magnesium 15 sul -,fate After evanoratlon cf the solvent, the resulting reidue was pourified by column chromatgah nslc e USin g toluene-ethyl acetate as an eluent. Fractions contain 4na objective compoound were collected and evaporated ,,ner reduced pressure togv 2)L-3- 20 bi S tr ifuc -romPethyl-) benzoyi4 v (4-diJrethyl ar.*no,-henyarony vmnl inc (0.26 g)mc:18500 (dec.) 44.60 M,_eOH) IR (Nuj o 3300', 16570, 150 1290-11.50 ,r- _NMI (DMSO-c6 o) 2 9 11 H 3. 03 6KH, s,, 0.5-82 12K 108 0 (l1H, s)

C

CC C C

C

C

,LksS 6 17 1) E~xampvle 9 A i~r~of 3 ,S-bis(t ri-F-Luororuetrhyl)benzoyli-2- (3 Id-c--IoezI _~eaJn hydrochloride (200 rug) 4-nitrobenzyi chloride (158 mug) and triethvlainine (2-68 41l) InM m, was refluxed over night. After cool., the crec-Liitates were 1 t7ered of f and thre fil4trate _3 .ias evanoratedc i-n va=cuo T-he residue was purified by column 38 .romatograohv on Silica gel with a mixture of toluene and eth, yl aceta te as an e Iu-en to give f is (r 1o--omethy1)-benzov-iil (,3,4-dichl-orobenzyl)-4-(4ntcrbenvl) roeazin (19.8mg) 1 7 (eat 3100-2750, 1770, 1730, 1635, 1520, 1440, 134 0, 12 75S, 13 0 c NMR (DMSO-d 6 ,5 2.iC-5.4ClQ mIHi); .85-3.30 (IH, _n) xa-Tiole T-he fcllowing compound was obtained according to a sinilar ma'=er to tnat or Example *i -F*7 int:metv, hevl) itrcbenzvl )o-'erazine TR (Neat) 3100-2750, 163-5, 155,1430, 1340, 1275, 13 0 cm_- -NMR (DMSO-d 6 5) 2.00-4.85 (17H, mn); 6.50-8.10 (10H, Ex:amole_1 To a mixture of 5-b-'s(trrif- Luoro-methy]-)ben-zoyl--( 3, O-dira,-ethv-lb--enzyi,)op:' erazt-ne (0.25 g) and 4a7cetvlbenzo'c acid (0.09 g' 4- dichloroinethane (8 ml) was added t rie__hylami ne 0 .2 ml at room temperature. 2-Chloro- -mty~~dinu I odide (0.17 g! was added, and the mtxture wias srrcat. room temoerat~ure '2.5 hours. The resulting mixture was concentrated under reduced pressure and the residue was *oartittoned between eth-yl acetate and water. The crganic layer was washed withl aaueous sodium bicarbonate sollut ion ana dried over magnesiumr s ulIfate. A71.fter evanoration of h solvent, t-he residue was ourified by columan chorratooraphy using e _hy7 acetate n-nexane as an eluen:- to afford (?2R)-4-(4-acetywo-enzovl')-1-[3,5bis(tri-fluoromethv) )ben zovl] -2-(34--dimethvibenzyl)ninerazine lirYRcDMS-d,- 5) 9 4 (SHj Min; 2. 5-5.2 (10H, m); Cz 6.4,-8.2 11i0H m) I'~L~S 591(M+-, Exainol e 12 To a= mixture of (2-R)-1--13,5-bi-s(t-r ifluoromethyl)ben-zov- 4-di-chlorobenzvl)pioerazl:ne hydrochloride (200 arg and aoe t vlb e n zo 1c a c id (57 mg) in dic'hioromethane l)was added t-riethylaiine 1171 tu) room. temperature. 2or o-T~r-v a~vicLniuTm iodide (107, mg) was added, and. n e ixt ure was st-irred room zemoerat-ure for 1.5 Irours. The 15 esalring mixture was washed successively with aqueous 0.1N hydrogen chloride solutilon, aqueous saturated sodium hydrogen carbonate solution and brine, and dried over magnesium sulfI ate Aft ier eva-ooration of th-e solvent, the residue was Iurf, i e d b y colu11mn chromaatogra-ohy usIng rcbiene-ethyl acetate 2~ a51 aS an- elue n t to give (2P)-4-(4-acet-vlbenzovl)-'L-[3,5- 2 ,M ZR(Neat-) 31~00-2850, 1,685, -1630, 1440,125 1130 cm'1 NTMR (ZMSO-d,, 6) 15-5.15 (9Kl, 2. 62 (3H, s); 6.8-3.3 (10K,;i1, S -'633 631 Anal =Caco:. for C 9 9K 22 6 Cl 2 2 C35.17; K3.51; N 4.44 Found :C 55.22; K 3.53; N 4.28 Exainole 13 (2R-1~3,-Bs(:ifuoroinethvl benzoyl]-2- 4d e thylben zy pipe ra zine fumnarat e (7 85 mng) was added to a mixture o-f 2_N sodium hydroxide solution (5 ml) and ethyl acet-at e. TIhe orarc laver was senarated, wash-ed wi--n brine, dried over magnesium sulfate, and evaorated in vacuo to give d- e -hylbenzvl'-)qioerazi ne. LA solution of this pciperazine in N N-me~vforamid (7ml) was added t.o a mixture Of 2acetvl-benzo _:cld (.230 mg), -3dmt'~~oov)Q ervcrodfad hvdrochloride ('295 mg) and 1 nvarxvpezctrazce (208 nc) i4n _T,Y-dimethylfommd (3 rml) and--' whole was stir_4red at room temperature overnight The :m-xtr ;aw oured into satufated sodi-un h~ydrogen carbonate soluion(78 ml) and t:he result ing precipitatces were filtered o~r. ne >rt was evaporate d In vaou o to give .0.0 -l 3,-b'Iis (trif luorom-etn-vl')benzovli-2-/3, 4dimer~hylbenzvl)pioeraziLne (0.45 g) as a nowder.

rap 8 2 C ]29 -22.7' 0. 33 MTeOCH) R (CH 2 C1 2 1750, 1635, 1615cm NM1,R (CDC! 1.554 (18H, mn); 20 6 .4 0- 8.0 (10 H, -L) MASS 59 1 (M) Exampole 14 Ie ~o lowi'nc comnooun. was obtained according to 2 5 s im- ilar mr~anner to th1-at of Examp-le 13.

benzovl 1 (3 ,4-d--im-ethv-ibenzvl)Pip:erazirne FUIL1]1 5. 8' (C=0.26, MeCK) IR (Nuj-ol) 1688, 1630 -i NIMR (CDCl--, 5) :2.05-2.32 (6H, in); 2.63 (3H, s); 2.-5-.40 (9H, in); 6.40-8.15 (10K, in) M AS 9 M~l Examole To a mixture off r3, bis -tu u-rcmet1)benzol]-2- (Ii do-3-lmvethvL) -otoerazine (250 mg) 2-methoxviohenylaoetic acid (92 mig) and oxvc)enzotr~azole (75 mc)O in diohloromethane (8 ml) was added (3,---di-methvlaminocro-cv1-) -3-et-hylcarbodilmide h-ydrochl-or-id2 (106 mg) at room temperature. After 3 hours, t=e rea;ction -mixture w,.as poured into acueous sodium Liarones~--4= and' extrac-:ed with di chiorom ethane. The ev ~t ct was w a sh-e d w it---h br ne a n d d ried o ve r ma gne si um re. Afer- evaoorat.Ion oi tne -ovnt he residue was nurift ed by colum-7n ch-romatography on sil ica gel using ethyl acetate -n-hexane as an eluent to give etn-cxyp'h-enyl'methyl-carbony)pioerazine (290 mig) as a powder.

NMR(MSO-d, 5 :2.65-5.3 1,14-H, mn); 6.4-8.2 (12H, irn); 10.8 M1.' i) n~s S 604 1(M+i-) 20 S -xamnle 16 T foi owilng compounds were obtained according to a sinii 1 man-ner to that of Examo,.le 10 1) 2 P -4-(3-AcetLvi-enzoyl) 3, 5-bis (trifluoromethyl) benz-ov', 1-2- (lH-in-dol--3-y-l-methvl)pi-cerazi"ne L D 4-23 (C=0.29, M,,eOF-) OR Nuol :3260, 1690, 63,10,1275 cmn1 NMRV-P (CD)Cil,5 1.55-S.46 (12H, mn); 6.55-8.50 (13H, mn) IA-S S: 602 (M) (,2-R)-4-(2-Acetyl benzoyi'--3,-bis(t,-ri-'luoromethy1)ze-nzovl] (1H-i*ndol-3-yl-met-hyiL)piperazine !n 90-192C 2 1 0 (C=0 28, Me O-) (ujol) 3300, 2700, 1750, 1720, 1635, 1630, 1275 cm,- NMR (CDCi 3 1 1.46-5.45 (12H, in); 56.54-8.25 (13H, -m) nAS S 602 (M) Examole _1s 1 nx u r e of (R 3 f S: vl~e~hypp,:raz.ne (0.4 g)and Ehiomoroholine (0.8g in dry N,N-\--dii.ethylfi-ormamide (4 were added i-(3d~~ine~-hv- amrtnoroov)-3-ethylcar-bodii-Tde hydrclid (01 J) and l-hnvdrox vbenzc-IriJazoie (r7 g a: ro te p r u e M- T-e 3 h ourL-s, the reaction rixture was poured into aa-ueous sodium bmioarbonate solution (40 ml) and zhe resulting Pr-ecipitate was collected by filtrazion. The crude product obtaine-d was Purifie d by column chromatography on silica gel using toiluene-ethvl acetate as an eluent to give 4- (t-hiom-oroholIn ocarbonyl-methvl,) pJoerazi ne 42 g) -10.0~ MeOH) aD T* I(N.,e a 3650-3100, 1-34, 1274, 1170, 1122, 898 c-m' 2'T4R DMS-d~, 5 :2.00-5.00 (19H, mn); 6.60-8.20 (8H, in); 10.86 11H, s) MASS 99 (M-1) Example 18 ne oI'1-owi:ng compoun d was Obtained according to a s imT ilIar mranner co that o f Examl e 17.

2 R)-l-F3,5-Bis(tr-ifluoromehy)bezol'i4[(4-(4 f.'luorophenyl) -1-piperazinyl) carbonylmethyli (1H-indol-3ylmethyl) piperazine hydrochloride rn-O 183'C (dec.) D5 -2 .0 MeOH) TR (Nujol, 3600-3100, 2650-2150, 1680-1580, 1510, 17 5, 1130 _cm, NR (DMSO -cid 6) 3.05-5.15 \119H, mr); 6.6-8.3 (12H, 0a 1040 2KH, br s; 11.02_ (1H, s) NL S S 676 f-ee,' *5SS S* S

S

*5

S

5*04 *5*S

S

~xa mo Ie a stirred mixture of (2R)-1-F3,5- )oerazone (200 raig) and 4-cvcloet-ierzn 6 mag) in drv N, N-i _me t hvlfo raaride (5 ml) were added d -ne- ,viam-no-propy1) -3-ethvlcarbodjiraide hydrochloride (82 -Tag) and 1,-hy.dr-oxybenzotria- -zole mng) at room temperature.

7hours, the reaction .'<yture was poured into water ml)" and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. After evanoration of the solvent, the residue was purified by coliumn chromatography on si±~ca cre using dichloromethane- 20 rethancl (10:1) as an eluen: and then treated with 4N hydrogen Chloride in ethylI acetate solution (80 4.1) to give (2R)-iE35-b;is (tri flu,-ororaeth'yl,)benzovll- r (4-cooetl1 pDi-erazinyl) carbony~nechy- 1 J-2- (-I'-'---dol-3-vlra.,ethyl-)piperazane h-ydrochl oride ('10 rag).

ran 270'C (dec.) i- 20 5, MeOHK) !R (Nuajol) 3270, 2430-2150, 1630, 12-75, 1180, 55 S

S

S 5.55.

NMR (DMSO-d 6 5) .4 5-5. 0 (26Kn, 6.55-8.25 (8H, in); 10.90 11.21 (2H, br s) MA7S S 650 (M+1L) (free) Anal;. Calod. fork C 3 3 3 2 K\=0-)Ci, C 57.77; KH 5.58; N 10.21 Found S 57. 9 1; KH 5 64; N 10 .18 scIurion cf mezhanesi.lfonvl chloride (1.1 g) in dicn- orcme E-nane (14 ml) was added t:o a stirred solution of idol--vie~hi~oieraine(4.99 g) and triethvla.mine g) i:n dichlorometh'ane (50 ml) at ice-bath te-mperature over a 2-mnue periodi. After being stirred at t-he sam.,e _em-oer-azture for I -our, the rea cti-on -mixture was diluted wiLth di_4chl.o ro m ea ae 5 0 m.M and -I-he r w a shed wi _,thI wa t er an d aaueous sctum1-, botarbonate solution. The dichloromethane ver was cried over magnesium suttIaue and concentrated under reduced pressure. The residue was ourified by column *Cnrcmacograpnv on si-lica gel using aich--orome" hnane-mqet-hanoI (0:l)as an eluent to give hs 4trifluoro,7erchy; benzovM (I-i ndo 1 -3-v7"methvl)-4-(3m.ethyl .vsul,-fonyloxypropyl'i--perazine (4.31 g) as a powder.

M.ASS 592 (M-11) Examole 21 go'.2 The followlng compound was obtained according tc a smlar manner t-o that: of Exa-mple 5-Bis (cril--Fuorom-ethyl)benzovl] di-ethvl-ben-zyl) 4- (3-me thyl sl fonvloxypropyl) piperazine IR (Njol1 2950-2703, 1635i 1430, 1350, 1275, 1165, NMRP k!:MSO-d 6 5 1 8- 4. 95 9H, mn); 3. 19 (3 H, s); 4 .3 1 H, t J =6 .21-1z); 6.957-8.2 (6H, m) M_,AS S 581 I'M-1) Examo)le 22 A mxture of 2 R)-l-'3,5-b-'is(tr4--Fluoromethvl)benzoyl]-2o-S-vlmethvl)-4-(3-methvlsu' 4-orvloxypropyl) piperazine (0.2 S---azaoz cvcioF3.2-2]nona-ne 10.05 g) and tr-iethyla ine (0.0 ml'nNNdmtylommd 1 was heated at After 6 h-ours, th1e react ion mixture was coured into water m_1 and t-he result-ing precto-tate was collected by f"ilr-aton. The crude product was dissolved in ethanol (2 7- and t-hen treated wit-h 17. 6% hydrogen chloride in ethanol o sol-utioLn (0.3 ml) to give 2 1R) (3-azabicyclo13 .2 .2]non- 3-yl )-romv" J-1-,3,S-biJs Itrif-- '-,oromt-h rvl )benzoyll-2- (11-indol- 3 -%7ln.et'h v I) p 1 oe ra z n-e d41h vdr ac h 1 o riJ-de 10.12 g as a n owC!e r.

mn 94-202'C J 305 eF 0 T. (_Nujol) 3600-310C, 2750-2000, 1680-1550, 1275, 112,126, 9010 cm' TER (CMSO-d 6 5) 1.5S0 2 0 (9Hi) 6.60-8.25 (8H, mn); 9.80 (1H, br 10.96 (IH, 11.60 (lH, br

B

B.

B

*B.t

B

B. Ba

B

B

a Fxam-ole 23 At -mixture of (2R,)-l-7'3,5-b,,s(tErifi---uoromethyl)benzoyl1-2- (l-i-ndol-3-ylnethyl) (3-methyl ,-'suli-fonvloxypropyl) piperazine (0.2 t'--oor-oholine (0.042 gr) and triethylamine (0.09 ml) 20 n dry acetonitrile (2 ml) was stirred at 90'C for 15 hours.

The rea ction ixt+ure was concentrated under reduced pressure and in resultina residue was ocarctct.__oned between ethyl1 acetate annd water. T'n~ organic l-aver was washed with brine and dried over magnesium sulffate. After evaporation of thne solvent, the residue was -ourtried by column chromnatography on 4 7~ gel u-sing ethyl acetate-metlhianol (10:1) as an eluent to giv\,e 4: 7 3,-bsr~lcromethy1)v benzovl! 4 l-do!- 3 vl meth-L-) (3 -thiomo r-hol in-o-or o Qvl) pioDe ra zine The zmrod uct obtained was dissolved in ethanol and treated with 17.6,? hydrogen chloride in ethanol solution to give (2R)-l- ,F3, 5-b 4-1S (tr--i-flu-orometLhyl)benzoyl] (lH-indoi,-3-ylieth'l) -4- 3 -thomrocinooroovl) oierazine dihvdrochloride 19 g) as a -oowder.

MeOR) IR (Nujol) :3650-30510, 275-0-1980, 1635, 1274, 1170, 1123, 900 mq- 6 6) 2.20-5.20 ('23K, in;6.50-8.25 (8H, 1) 10 96 (1 H, 11.00-11.90 (2K, mn) >LAks S 59-9 (free) (3 Thiomor-oho-iinoc-opyfl)-- )13, 5-bis (trifluoromethl )b'i enzoyl]-2- ,2-.--i'nol-3-y-l-mrhv)picerazine dimaleate La -1 (C=0.25, MeOK) 1- R (Njol). 3350, 2720, -1690, _620, 1605, 1280, *3 0 c-m IN\YR (DMSO-d 6 65) 1 .70-S.12 6 .14 (4KH, s) 6.55-8.32 (8K, in), 10.90 (1K, s) z-xainDle 2/ The ffollowing co-mpounds were obtained according to a siilar manner tothat of Exampole 23.

5-Bis (trifluoroinethy'l)benzoyll (I-H-indol-3- 0 Ime~hv (3-rnor-cholino-crocv1 )oI-ceraz~re c.hvdr-ocbko f 'de mc 26500C (dec.) cL1 C6. (C=0 MeOK) IR (Nujol) 3650-3100, 2-50-2200, 12655, 1275, 1120cm NMR (D)MSC-d 6 5) 2.2-24 (2H, mn); 3.0-5.25 (21H, im); 6.55-8.25 (8H, mn); 10.96 (1H, 11.1-12.85 (2KH, in) MASS 583 (free) n0?2. C a ICad. fo r C 9

H

3 9 6 N -2HCl-0. 4H 9 0 C 52.56; K 5.29; N 8.45 Found C 52.54; K 5.33; N 8 (2-R)--[L3,5-Bis(tri-fiuoromethyl)benzoylj-2-(3,4dimethylbenzvl) (3-thioinorpholinop)royl)pi-oerazine e di hydrochlo 1ride nIM 272'C (dec.) Lra-11_60 5, MeOH) IR(uj ol) 3650-31001, 275-0-2650, 15,1270, 51120 c NR(Dmso-d,,, 5) -2 2 5(8H, 2.7-5.2 (21H, in,); 6-6-8.25 (O6H, 11511.75 (2H, LL) MASZS S 5383 (M -I (f r-=e Examole A mix ture of( 2 R) -l1- 5-b is r ifluoromethyl) ben zcxv! 2 rIK-i nd i eh1 3 me h ls lf n L o y r yl p o a i e (200 mc) an 2 1 3 ,4-7etrahydroisoauinoiine (90 mg) in met-hanol ml.) was stirred for 1.5 hours at reflux e 7.e ra ru re. The reaction rr.xtre was evaporated under reduced -oressure and the residue was purified by column cnromatography on silica gel using ethy'l acetate-methanol (10:1) as an eluent to give 2 benzovl] (i-H-indol-3-ylm-.ethyl) [3-F[1,29,3,4- )fl etrhvdrisoucnoln--yl~rcp]Jpj~raine(167 Mig) as a ocwder.

IC,,20 9.60 Veo-) TRQ (Neat) :3260, 1630, 1430, 1380, 1-350, 1270ci- MTMR kDMSO0-d 6 5) 1 .6C-4.93 (21KH, in); 6.60-3.37 1 2H m 10,. 85 (1 H, s Exam-ole 26 '7h= oliowing compound was obtained according to a similar manner to that- of Example 5-Bis (t L- -4-f 1 uoromnetchv1)benzov1) (1K-indol,-3vylmoeth)vl,) (4,5,6',7-tetLrahydrothi-eno 2-c]pyridi-- YI) pronv 1 1 0p-'ra:zine F]D 18 MeOH) -R (Neat 3260, 1630, 1430, 1350, 1275 c- MR (DMSO-d 6 5) :1.55-4.97 (21H, mn); 6.30-8.24 (1iOH, mn); 10 .385 1H, s) MAS S :635 (M-1) ~xeno~e27 i itre of (2R LF3, 1-bs (tri-1fl-uoromnet-hy1 benzovl1.] -2 i r0- ino--ietv) (-m,,ethvlsu-i -o-nvloxvpropyl) piCerazine mg Ld -no-!-,Dhen,'Kiperf -ine hyvdrochloride (0 mng) n Ie thao 0 5 1 l wa trred at reflux temperature iJn the oresence of socaiumn~ carbonate (100 ing) After 2 hours, the reacttcnr inixt,:ue was evaporated under reduced pressure. The r-esidouc was extr-aczed with ethyl acetat-e and the extract was concetrated under reduced oressure. Th_- e residue was 5 our iFie d by coum ch-ora o grao -hv on silca gel using ethyl acet-ate-methI-anol (10:1) as an eluent to give b07 (tr -iuorometh'l) benzoyl] -4-13- (4-cvano-4- :heny-Liperidino)propcyl] (1H-indol,-3-ylmethyl)piperazine (89 mng) as a powder.

[f L :t IC=0.5, MeON) NM?. (DMSO-d 6 5) 1.52-4.96 (23H, mn); 6.60-8.26 9 (3H, mn); 10. 85 (INH, s) MAS S 682 'Exam-ole 28 A mixture o~f \'2,)-l-[3,5-bi's(tril---:Iuororethyl)benzoyll- 2 1t 4 n-dol -3--vlmerhvl) (3-mr.ethylsulfonyl7oxyprop yl) pip~erazine '200 mg) and s~o-'r n'an-i-, 4'-piperidine] (70 mng) in acetonitrrie, (3 ml-) was refluxed for 1.5 hours. The reaction mixture was evaporated under reduced pressure and then the residue was ourified by column chromatography on silica gel using dichloromethane-inethanol (10:1) as an eluent 'to give (2R,)-l,-[3,-bi)Es(trifluororniethyl)benzoyl1-4-[3-(s~ciro{inaanylm-Peth_-yi)picerazJne (208 mng) as a powder.

D~2 -2.4 1 MeOCH) R(Near-) 3260, 1630, 1435, 1380, 1350, 1275 cmC' NML-'R (DMSO-d 6 _.-500 27H, mn); 6. 62-8. 28 (12H, in); 10.88 (1H, s) 'M'ASS 683 -'xamole 29 A- -,,nixture of (2-R)-l-L3,5-bisttri-fluoromethvl)benzovll-2- 4-dichcro-benzyl) (4-n-irrobenzyl p-ieraz ine (157 mug), ammo ni chlride mc a n d ron cowder (157 mug) in a u~ oferhnol(5 ml) and water (.25 ml) was refluxed .5S hours. After cooling, ro-e p-recpitates were filtered off and t-he -fil-trate was evaporated in vacuo. The residue wascurifiea by column chromratography on silica gel with a Mixture of toluene and ethyl acetate as an eluent to give '2R) (4-einoezl 5-biJs(triJfluoromethyl) benzovl] -2- 3, 4.-dichlorob -enzvl)pip-erazi-ne (128.4 mug) TSR (Neat) 3350, 29-70-2700, 1630, 1515, 1460, 1430, 12975, 1130 cm'1 20 NR(DMSO-d 6 6) 1.95-5.05 (13H, mn); 6.'50-8.25 H, m) MSS 592 590 (M) Examoie Th-ne following comp~ound was obtained according to a similar -manner- tc t'haz of Examocle 29- '21R) (4-Ainin-obenzvl-) -1 3, 5-bis (rifluoroinethyl) benzcyl 1 4-d-irethylbenzyl1) pioperazine (Neat) 3450, 3300, 3100-2650, 1625, 1515, 1435, 1275, 1125 cm (L)MSO-dr, 6)1. 90-4. 80 in); 4. 98 (2H, s); 6.40-8.20 (1R, in) MAS S 5-50 (M±1) Exaranle 31 P ir--id ne 2 3 P!l) and acervi11 chl Ior i de 10' Lu!) were sirccess4-e~v added to a solution of k(2R)-4-(4-aminobenzvl)-1- L 3, 5-bis (-:r-'If,iforomieth y1-)benzoyll 4-di'chlorobenzyl) -c ci )e r z 'ne113 c an I h hl wa stirred at room t e mne ra ture fo nours. The miLxture was pooured into water anncccserratd o± ws e +ared with ethyl acetate. The exratwas washed wiThn water, dri ed over- magnesium sul-fate and voo~a in vacuc. The residue was purified by column 1 0 chnromatoaranhv on silica gel- with a mixtulre of toluene and :ethyli acetate as an eluent to give acetvlamLinobenzy 5-bis(tri;fluoro-met-hyl) benzoyl] -2- 3 ,4-dichlorobenzvl)pinerazine (98.3 mg) The obtained :15 piperazzine wias d'ssolved in ethyl, acetate 4N Hydrogen is chorild in et.hvyl ace-Late solution (43 pil) was added to the solution and the mixture was evaporated in vacuo. The residue was trtturated with n-hexane to give acetvlamiL-nob-en-zv,) -[3,5-bis(tri4luorom~ethylI)benzovl]-2- 4--d-'ichlorc,benzvi )piaerazine hvdrochioride (92 rag).

Tct1.20 MeOH) So R ('Neat) 3600-3150, 2750-2100, 1635, 1600, 1525, 1415, 1270, 1130 cm,-i NMR (DIMSO-d 6 5) 2.07 (3H, 2.85-5.15 (1lH, in); 6.80-8.30 (10H, in); 10.13 (1H, s) MAS 632 (free) Examocle 32 Th following compound was obta-ined according to a siJmil1a -r a~.er to that of Example 31.

5 (4-A-lcet ylaminobenzv,) bi-s(t-i-flucormethyl) be-nzoyl] 4-dimethv'Lbenzyl)pi-perazine hydroch'loride 2 23.20 MeOH) IR (Nujol) :3650-3100, 2-750-2100, 1640, 1600, 1530, 1275, 12170, 1130 cmJ TYR 56 1.95:-2.10 (9H, mn); 2.80-5.05 (11l1, in); 6.50-3.30 (ICH, m) (1H, s) 11.00-111.40

H

L, s 592 1 f r e e 33-pea-n a vlmeth---vl,) (thiocmorpholinocarbonv>7.ethvi-ieazn a .64, convertec. to the corresponding hv.drochloride by treatment wih17. 6 hyvdrogen chloride ic. e-hano 1 solution.

Nujol) 3 650-31 00, 2 750-193 80, 16338, 1 2 76, 1171, )0 C~ crr.

N~R M0, ):25.5 19H, 6. 60-8. 25 (8H, 10.99 s sotASS :599 (free) Premoaration ,see& 20 mxture of forma'ldeh')yde (3'3 in wat-er, 20.7 ml) and mo,.rohol ne 17.1I ml was adju sted to inE 3.5 with diluted SU suitric acid. Propargyl alcohol (10 g) potassium- iodide (G 3 n comncer (T T sulfate a01 were added to the solution adthe whole was s-tirr-ed at- 00o for- 6 hours.

A -F t er- co oling, te n s o 1ub 1e miat-:e rial was removed by f:I t fr-t4o n nd te p H o f th e f 11t r a te was adjusted 'to 9 with 23sodiu-m hyd--roxide solut on. brine (-100 ml) was added to t 11 to I o n and tne solution was extracted with mixture of ethyl acet atle ann ethanol (10:1) eight times and then with n-butano-I3 4t tmies The com-bi'ned extract was dried over macnesium sui1fate and eva,,oorated in vacuo. The residue was I I e d in- reduced oressulre to give 4-morholino-2-butyn-lo' (1.03 g) Y, 7-at 3350, 2850, 1105, 1000 cm-n NMR~~2 'CDl, 518 (1K, br s) 2. 57 (4H, r, J=4.7Hz), 3.31 (2H, J=-L.9Hz), 3.75 (4H, t, ~-47K),4.30 (2H, J 9Z) KTS S 156 (M 1 The fcliowtng compound was obtained according to a si-mil-;r m-anner- to that of Preiraration 11with the except-ion of ocurliflcatiLon by- colun crro Tatoafra-ohv on sli_'ca gel using a oitr F e v-1 acetate an-- me -hano I 30: 1) as an eluentL Lnszead of dis :illation in reduced pressure.

0***4-Thiomorohol-no-2-btyl-1--01 TR Nea) 3350, 2900, 2800 1330, 11115, D110 0cm 'TR CDC-, 1.93 (IH, br 2.65-2.90 (8H, in), 332 '2H, tJ=1.9.z), 4.30 12H, t, J=l.9Hz) MA-S S 172 (M +1) Prenaration 3 io-v 1 chlor-de (2.1 ml1) was added to a solution of 4 morno 2 o--buyn-0l(1.7 r.i dichlcnoroirnetha.,:ne (10 ml) -ce bath cooling. After S~ ~rrtng for 0.5 hour ,-the oltinwas eva-norate. in- -\acu-o. The residue was trit-urated wito-L ethyl acetate to give 4-morphol--ino-2-b)utynyl! chloride nvcro h.c ~r e 9 1 g) Mo I 162- 1 65 0

C

IRT (Nujol) 2640, 2510, 2450,- 2350 cm- 1 -NYR (DMSO-d 6 5) 3.31 (4H, br 3.92 (4H, br s), 4.21 (2F, t, J=l.9Hz), 4.57 (2H, t, J-=1.9Hz), 12.23 (Ibr s) MASS :174 MN) (free) Pre-oaration .4 The following compound was obtained according to a similar maanner to that of Preparation 3.

4-7Thicmcolono-2-utylyl chniorlde hydrochloride MD* 185187 0

C

iR(uc) 2600, 2450, 2380, 1280, 1260, 1160, 915 c~ NYR Y, SDMO- d~5 2.58 4.0 8 H, mn), 4.21 (2H, r/ J"=2.OHz), 4.58 (2H, t, 1.8(1H, br s) S 190 (f ree) Prec-ara-ion -0 A mixture of' 4-ch loro-1- (4-Lluorophenvl--butaloe (500 ethylene glycolI (247 mg) and catalytic amount of t len e su Iocn-_ c cd mono-hydrate in benzene (5 mTl) was -ef'uxed 'or 20 hours oiitnr concT-nuous remova 1 I of water u.-sing *Dean-Stark apparatus. After cooling, the solution was washed successively with I-N NaOH solution and brine, dried over maanesium sulfate, and evaporated i~ vacuo to give 4-chioro- 1-(4florohenvl)1btin cy> -tylene acetal (613.2 mg) as an oil.

_R INeat'- 2950, 2-870, 16-00, 1500, 1220, 1030 cm 1 i NNMR (DMSC',-d 6 I 1.6CC-I. 8 0 2 7m) 1 .90-2.00 (2H, 7.50 (4H, m) M AS S 245 209 7xamtole- 34 A txue f(2R) -[3,5-)bi-s(I-i-Fluoroinethyl)benzoylI 2 (2_-nacohthvlirnethv 1 )oinerazine (1.0 g) and 3-brornropanol (330 mg) in NN---jre-thyltFormam~de (2.5 m)was stirred at roo.m teiperaclure in the Dresence of powdered potassium carbonate (444 mng) .After 17 hours, the reaction mixture was diluted wltn. et-hyl- acetate (30 ml) and t:hen wasned successively with water and brine, and dried over magnesiJum sulfate.

Evanoration of the solvent in vacuo gave

B

B

*OB*

B

B.

-nhrh'vlm e:hvl) oierazine 19 g) iF..Ne:~ 3425, 1635, 1 30, 1340, 12-75, 1170, 1130 cm -1 NMR~~ (Od, )1.50-5.28 (16H, 7.40-7.93 (10H, m) N_ s S 525 Fx amn 1e A mitre of 7 '--3,53-hbis tr -1uo romnethvl) ben zovl 2 2 r~hh~e}v~ieaie(200 mng) and (4-chloro-2butvnvi mor-oline hvdrochlor-ide 95 ing) in N, Ndev'-c -no.anide (05 ml', was sti'r-red at- room. temperatur in the Toresence of powdered pootassium carbonate (177 mg) After h ours, t-he reaction mixture was diluted with ethvl acetate 15(30 rlI) and t~hen washed successively with water and brine, and dried over :ma-.nesiumi sulfate. After evao~oration of the solvent in vacuo, the resulting residue was purified by col-umn c-hromatography on silica gel using ethyl acetate as an eluent. The product obtained was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate (4-mror-ob-)o 1 -'-o-2-butynvl) (2-naohthv-Ime thyl) piperaz ine dihvdroc"--oIr-I'de (257 mg) -U.21 -21.50 MeOH) I. (Nu-ol, 3350, 2550, 1630, 1275 cm'i NMR (DS 5),6 2 .80 -5.31 (2 IH 7.0-8.28 (10H, m) MA S S 6 04 (free) 04' Be

B

0 Ixamnle 36 A mxueOf (2R) L3, S-bis (trJ fl-uorometlhyl) benzoyl A-diohloroben-zy'L)pioerazi-ne hydrochloride (150 mg) and 1- 4-clor-2-utnylmorholnehydrochlor--ide (63 mg) -in -N,N-dim-et'hv,'lformamide (0 .5 ml) was stirred at room 33- temcerature 'n the oresence of nowdered notassium. carbonate mg A-ft-er 17 h-ours, tne react-'on mixture was diluted wi- acetate, (30 ml :nen was!hed successively with water a:nd zrlne, and dried ove nagnes sulfate. After eva,,ora7tton o:f the solvenlt inl vac&o, tne resulting residue was ourified by column chromatography on silica gel using a m:ixture or ethyl acetate and methanol (10:1) as an eluen-t to give 121R) l-3, 5-bis 1 -rifluoromethyl) benzoyl]1 (3,4d ichilorobenz vl 4- (4 -mor-pho 11-o- 2-butyvnyl) piJpera zine. T he crcutob tai ned was dissolved i- ethyl a;cetate and treated withn 4N hydrogen chloride in ethv-l acetate solution to give (2R) 1-bis (tiluorooiethvl1)bhenzol]'l-2- 4ncniorobenzyl) (4-m7crpholi-no-2-butylcnyl)piperazine d-ihvdrochloride 155 mg) -2 j3*9 e-i .(Neat)r 3400, 2350, 1640, 1425, 1275 cmn -N-iR (DMSO-d; 6 2.91-5.20 (211H, mn), 7.0-8.26 (6H, mn) MSS 622 l) (free) ExamplIe 37 The following compiounrds were obtained according to a similar -manner t o that of Example 7.

piperaz7,'-- dibydrochloride mc 65-1690C aJD 0.4' (C=0.26, MeOHF) R(Nujol) 3350, 29550, 2320, 1635, 1550,120 1120 cmC 1 NMR (DMSO-d 6 5) 2.80-5.25 (21H, mn), 6.56-8.30 (8H, 10),-10.6 11, s) _Lk: 593 (-free) bi-s t----fluoromethyl) benzoyli 4dimezrhy lbenzyl) piperazine dihydrochloride mc~~ '5-2 0

C

_c,1 21 S'5 26, MeCK) T.R (Nujol' 13350, 2650, 2300, 1655, 1640, 1275, 1120 c-m' NM--R 'DYSO-d 6 5) .2-30(7H, mn), 2.64-5.0 mn), 6.60-8.30 '6F, ra) MKA SS 582 (free) 1- (3)~a~~O~O~uvly)L s (L----iFluoro-Trethv1) bec-Iovii 4-dirner-hylbenzvl- Piioerazine dihvdroohloride mc16 2 170 'C (C=0.27, MeCK) b (Nuj o1) 3350, 2650, 2320, 16555, 1640, 1275, 1125c MIR (DMSC-d 6 5) 2.04-2.35 (7K, 2.65-5.25 mn), 6.57-8.28 (6H, mn) MA~SS 5 ,98 t -e) a

S

a a.

(4 (R)-4-(4-ThnJoiorho1Io-2-hutynvl)-1-[3,5- -s fluoroinethyl) benzoy-I] J-2- (2-iT- ndo1--3v IT.et--v1) o-Lcerazine dihvd-rochloride -c 66-1-700C L~ -D NeOCK) TR(Njo1 3350, 2650, 2300, 1635, 1275, 1125 c-m1 -NmNR (DMSC-d 6 5) 2.53-5.30 (21H, in), 6.54-8.30 (8H, 10.98 (1K, br '12.10 (2K, br s) M AS S 609 1(M) (,free) 2)4(2-Y-orchol Jnoeltbv!_)_l_ bDenzovi-- 4-diiethvlben-zyl)pi-per-azine 2c 23-2280 -1 .0 .28f NeCK) U U

U

U

U.

U

*UU.

20

US

U

U

R INjl 330 25I50C 1630, 1,170, 1275, 1120 cm- MR? (DMSO-d 6 5) :1.95-5.25 (27H, mn), 6.50-8.32 (6H, r) 10.80 -11.0 2, b r m) MAS S 558 (free) (2R)-4-(2-Thi-oior, h-o',inoethv,) 'JIs (t---'fluorornethyv) b~enzovi--,] 2- H-indo1_-3vi miet'rvl )o_-'eraz4re d 41h v ir o ch o r de FCC28. c 1 (C=3.39, MeOK) Rl (Nujol) 3350, 2600, 1,640, 1275, 1125 cm~ NM(DMso-d 6 5) 2.60-5.30 (21K, mn), 6.50-8.30 (8H, in), 109H1, s) I11. 10-1J2 .10 (2H, br i) MASS 5_85 (fr-ee) (2-Moroholinoethvl)-' biis (trifluoroinethyl) benzov! 1 1 ido 1 -3y1Imet}-yll)piperazine dihydrochiorijde M_:170-1760C Fa] 2 3-5 (C=0.30, MeOH) IR (Nujol) 3350, 2570, 1640, 1275, 1125 c NM?. (MSO-d-- 6 5) :2.60-5.30 (21H, mn), 6.55-8.40 (8H, 10.95 (1K-H, s) 11.10-12.04 (2H, br mn MAS S 569 (re bis (r'ri-Fl-uoro-methy1 benzovl] 4-di-inethylbenzyl) -cnperazine dihvdrochlor-cde ITO 2 61 .500 ra,28. -1.9 0 2 D IR (Nujol) 3350, 2350, 1640, 17,13 NM(DMSO-d 6 5) :2.00-5.30 (27K, mn), 6.60-8.30 (6K, in), 10.60-12.00 br in) MASS :574 (free) Examole 38 A- mixture of (2R,)-1-F3,5-bis(triflu-oromech-v1)benzoy1>2;-) ~lK±nol-3v~mthy~p~era~ne(300 mg,4-chloro-1-(4foroohenvl)-1-butanone cyclic ethylen-e acetal (161 mg), notassiu,-. carbonate '182 mg), a:nd notassium iodide (109 mg) acp o47ril (10 ml!) was refluxed for 20 hours. After cooi the sol'uble material was removed by fil1tration and :e :i_!_-raze was evapoorated in vacuo. The residue was cv co I-am chromatoarachv on s ili'ca gel wi th a mixture of toluene and ethyl acetate as an eluent to give -4-LF4, 4-etLhyienredioxy-4- /4--Fluoropheny1)butylj-1-[3, ~.bis (tri!fluoromethyl)benzoyl1-2- (1K-indol-3ylme thyl)piperazine as a nowder. This compound was further oiriLed b-y -washing with dilsocropy)l ether.

1c: 45-1460C (Nuj~ol) 3200, 1620, 1600, 1275,12 m NTMR (DMS0-d 6 5):1.35-1.55 (2K, 1.80-4.90 (17H, 6.55-8.20 (12H, in), 10.87 (1H, br s) vA S S 664 (M+1) Examole 39 To a stirred mixture of bLs (trifl--1uoromethy)l)benzoyl] (carboxymethyl') (1H-indol-3ylmethy1)piL-eraziJne (0.2 g) and 3-azabiJcyc!o[3 .2.2]nonane (0.05 g) in dry N,N-dimethylformamide (2 ml) were added 1-(3d ime rhvliami_1noorocyl) -3 ethyl carbodiimiJde hydrochloride (0.082 q) and 1-hydroxybenzotriazole (0.058 g) at room temperature.

Aft-er 6hours, the reaction mixture was poured into aaueous sodium bicarbonate solu--tion (20 ml1) anrd the resulting oreci-ctate was collect:ed by filtration. The crude product obtained was purified by column chromatography on silica gel using tI-oluene-et~_vI acetate as an eluent and treated with hydrogen chloride in ethanol solution to give 2 4 3 -azabicvclo[3.2.2]non-3-yl)carbonylmpethyl>..1-r3,s.

bis (trri-Fluoromethyl)benzo-yll-2- (1H-indol-3vrrnethv)ierazine -hydrochloride !k0 2 g) as a white powder.

2a -23 C=0.5, MeOH)-! R (lijol 365S0-3100, 2750-2000, 1637, 1276, 1172, 1130, 900 cmK NMIR (DMSO-d 6 65) I. 50-1 .75 (SH, mn), 2 .07 (2H, br s), 31-5-5.10 (15H, in,6.60-8.25 (8H, mn), 10.15 (11-1 hr 11.00 (1H, s) MiASS 621 (tree; Exarle To a st irred ~imx-ture of 5)1-35 ,s(trfuoromethvl)bezovoy44carboxbenzyl)- 2 ±'H-"ndo'l- 3. 3-ylinethyl p pera z lne 15 0 mg, and di e th)y'lainine hydrochl oride (28 mg) 14n- dry .tlicnlorometh-ane (5 ml) were added a solution of 1- (3-dimaethylainnpropy1) -3-ethvlcarboJiide (40 mg) in dchorinthne(1 rl!) and 1-hydroxybenzotriazole (34 mLg) at room teioeracEure. After 5 hours, the reaction mixture was iooured into aaueous sodium bicarbonate solution (20 ml) The oraan-c z aver was separated and washed with brine and dried over magnesiumir sulf:ate. T he crude product obtained was oCurified by coiuinrn chromatography c*n silica gel using ethyl acetate n-n-hexane to crive h iS (t ri fi''inrv) ben zoyvl), Ndiethyl ain~ocarbonyvII bDenzyl]-2-(WH--ido-3-v-,inoethvl) Lperaz4Lne (107 mg) as a owder.

-40.3' (C=0.5 M-eOH-) TR (Neat) 3250, 1620, 1430, 1275, 1L130 cm NM(CDCl 3 65) 1.10-5.00 (25H, mn), 6.40-8.00 (8H, ma), 9. 14 (1111, s) MASS 645 (M+1) Sxam Le 4 Toasc__rred -mixture of iS (rfuriehl benzoyli, (3-hydroxypropyl) (2n-aphthylmethyl1) pinerazine 1 g) and t ri-ethyl amine (425 mng) in dLhooehn (10 ml) was added dropwise methanesulfonyl chloride (252 mg) at ice-bath tempnerature. After 2 hours, the recinmixture was washed with- water and then dried over maanesiam sul_,fate. After evap~oration o:f the solvent, the resulting residue was chromatographed on silica gel using ethyl acetate as an eluent to give (2R)-1-'L3,5fuoromet -hyl)benzoyll-2-(2-naphthy .lmethvl) (3- M zthIyl'su1f on y Iox y p r o p1) p ip e r aziJn e 98 8 mg R Na) 1635, 3, 1350, 1280 430, -,-117 0, 113 0 cm- NYR (C D C1 3 ,5 1. 59 (3H, s) 1. 90-5. 28 (15H, 7.40-7.90 (10H, m) HASS 6 03 I Examnle 42 h "fcllowing compDounds were obtained according to a *simi14lar manner t-o that of Example 41 F3, 5-Bis (trif luoromethyl) benzoyl] 2 3 4 dichl -1orobenzvl) (3-m-ethnvlsulfonvloxypropyvl)piperaz ne (Neat 1630, 1470, 1430, 1340, 1270 cm'1 c(CDCl 3 5) 1.55-5.14 (13H, in), 3.04 (3H, s), 7.00-7.95 (6H, m) (2R)-'--1,5-3Bs(tL 1fluoromethyl)benzoyl1- 2 2 n a ohth_?)vl re thyl -14 2 -Tmethylsulf -onyloxyethyl)pipDerazine ~(Neat) 1635, 1430, 1350, 1275, 1170, 1125c Exam-ole 43 Amixture of (2R) 5-bi s(tr 4fluoro-methyl)beZ l- 2 2-nap~h'1 ~ty-l--n-hyl) 3-methylsulifony Ioxvp ropy!) pi-pera z ine \250 mO oopoie(43 mg) and triethylamine (46 mng) in drv maethanol ml) was refluxed for 2 hours. The reaction mx- e was concentratEed under reduced -pressure and the res~trgre~idue was purified by columron chromatography on Silica gel using ethyl acetate as an eluent. The product cbtained was dislved in e-:hvi acetate and treated with 4N n-vdoa en c- oi de 41newr'yi a cet ate so 1r-tion to give -1- 4 3 ,---i'--'cl--,-oromet'hvi)benzoylj (2-na-chthvlmethvl) (3th-icmocrcho Iinocropyi p ier a zine dihvdrochlori4de (195 mgr) 253 Cc j 23.0' MeOH) 7 Nji 3400, 20,1640, 1275, 1170, 1130 cm' NM1(~ 3 5,1 15 0- 5 .69 (923H, 7 73 4-7. 93 (0 H, m) MA SS 610 kM+I) (free.

Exa mole 44 T-he f ollowing cormounds were obtained according to a s Hlar manner to that- of Exarmple 43.

21R)-1-3,D-Bis(zr.i'flu:oomethv 1 ')benzovw,-9-(2mperhvi) 4(2--qcr-ho1_ noeTrv1) pi- eraz ine **dih-vdroo-hioride Lcx]#l n 25.2' MeOH) ZR(ujo 1) 340 510 2425, 1635, 1425,125 170 1130cm NMIF (D-MS-d 6 5) 2. 53 (21, i) 7-8.24 (10K, mn) MAPS S 5 80 M1 (free) IR-2 F3,5-BiJs uiforone-thyl) benzoyi1 250 naoht-hvlme thy I) 4- 1,2 h 1omo rio 1 o ~e ty) p ipe ra z ine d _hydroch lo r ide lot] D 23.70 MeOH-) 7 \ujo, 2350, 1640, 1270, 1180 cm- 1 NMR DMO- 6 ,5 2.80-5.31 1,211-, in), 7.03-8.20 (10H, in) M-AS S 596' (free) yi-methy)-4-r3--(4-oxoo-'pe-r----o)-rooyli1pp-eraza-ne 24 L JD -110.00 MeOH) i~ (ujl) 3270, 1720, 1625, 1430, 1340, 1275, NMk, (CD1, 1.66-5.20 (231Hn, 6.6 9- 8 .2 8 (BK 8 mH MASS 595 (m+1) dio-hcrobenzyl) (3-thi'ornorpho-i-onopropv1)pio~erazine di-nvcrochloride [cXj~ +2.20 MeOH) :R(w~1 3400, 2400, 1650, 1280crf .NYMR (DMSC-d 6 5)2.10-5.20 (231H, 6.92-8.32 (6H-, 11.12-11.72 (2K, mn) MASS 628 (free) 15 s(trifluoromethyl)benzovlj-2-(3,4c'-Il /5-benv' (3-irnorpholinoporocy-) pi' perazine dihydrochlor-ide *e..9 ot19 D 1 2.3' MeOK) TR: (Nujol) 3400, 25510, 2450, 1650, 1280 -i NR(DMSO-d-, 5) 2.10-5.20 (23H, in), 6.94-8.34 (6K, in,11.08--11.76 (2H, mn) MAS 61 ',free) 1 2-R)-4-[3-(4-Aoetylioeridino)prooyl]-1-[3,5bis (trifluoroinethyl) benzoyll (lH-indo1--3ylmnetb- y1',io-'rera-azne dihvdrochloride D 7.2' MeOH) f. Nujol) 3300, 2600, 1700, 1630, 1275 cmr7' MR(DMSO-d 6 1.67-5.24 (24K, 2.16 (3H, s), 6.62-8.28 (8H, mn), 10.95 (1KI s) MASS 623 (free) mis (tr-'-f"-Luoroxnethyl)benzoyl]---(1K-ifldoi-3ylinethyl) Dip)erazirie dihydrochloride 100 .40 p .000 4 0. 2 .Oo 63 5*O(C=0.5, MeOK) 7 R (Nujol) 3600-3100, 2700-2250, 1660-1580, 1270, -11120 CrJm NIMP, (DMQO-d 6 5) 2.20-2.40 (2H, mn), 3.00-5.20 (19H, 6.40-8.25 (8H, mn), 10.97 (1K, mn), 11.20-11.90 MAlZ S S 53,5 (14+1) (free) (-s('riFl uoronechl- benzoyl J (1H-indol-3ylinethyl) pi-perazine trihvdrochloride F X 2~ 5- 8O MeOK) 7R- (Nujol) 3600-3100, 2750-2300, 1630, 1275, 1120 q- (DMSO-d 6 5 2.05-2.45 (2H, mn), 3.05-5.20 (21H, in6. 60-8. 05 (13H, mn), 10. 97 (1H, s) i1. 00-11.85

I)

MAS S 658 (14+1) (free) '2'-,)-4-[3-(4-C-vciohexyl-i-p bis (tr .luorornerhyl) benzoyl] (1K-indol'--3vlr-nerhlvl )pJiperazine t-rihydroohloride 7o 250 0 C (dec.) 7.8' MeCH) TP, (Nujol) 3600-3100, 2650-2200, 1640-1600, 1370, 1270, 1120 crn' 1.00-2.40 (11H, inL).. 3.00-5.30 (23KH, 6.60-8.30 (8H, mn), 10.97 -11 30-12.30 (3K, in) MAS S :664 (14+1) (free) Exainnie fmixture o-f (2RP) 5-bis (rrifluororaethyl)benzoyl]-2- (1H-indoi-3-ylnechyl) (2-r~ethvisulfonyloxyethyl)piperazine (200 rng), 4-aminoinorpholine (36 mag) and triethylanine (52 mng) in dry meE-anol (5Sl was refluxed for 2 hours. The reaction mixture was concentrated under reduced pcressure and the -resulting residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate solution. The organic layer was wahdwith brine and dried over magnesium sulfate.

A- .fter evaooration of the solvent, the residue was pourified by column cnr__omatograpn~v on silica gel using a mixture of ethyl acetate and methanol (10:1) as an eluent to afford (2R)-1- [L2-(morrnhoi_,noar--no)et-hyllpiperazi-ne (55 mg).

'(XI'22 MeOH) eas (Nuol) :3300, 1615, 1275 cm- N DMSO-d 6 2.14-3.10 (21H, im), 6.0-8.26 (8H, :00M0 i 10 91 1, 1 s) *to 15 LkS S 584 (M4+1-) sea.Exaimnle 46 A mixture of (2R) 5-bis (trifluoromethyl)benzovl]- 2 (1_,-indol-3-ylmethyl) (3-mrerhylsulfonyloxypropyl) piperazine (100 mg) and 4-pohenylp)iperidine (60 mng) in acetonitrile (3 ml wa reluxed for 2 hours. Th-ecion mixture was concentrated under reduced roressure and the resulting residue was purified by column chromatography on silica gel using ethyl acetate-methanol as an eluent to give (2R)-I- 13- (4-phenylpiperidino)propylilp-' erazJ-ne (90 mg).

ra, 2 0 24.6' MeOH) IR (Neat)" 3250, 1630, 1430, 1275, 1130 cIG 1 NM(DMSO-d 6 5) :15-4.93 (24H, in), 6.60-8.28 (131H, mn), 10.87 (1IH, s) MASS :657 (M-I) Examole 47 A solution of (2R)-2-(3,4-dichlorobenzyl)l1- 3 5 bis (trt:±L-'uoromethy'L)benzovyl- 4 -(2-hydroxyethYl)piPeraZine mg) in ethyl acetate (3 ml) was treated with 4N hydrogen chloride in ethyl acetate soluation (0.2 -ml) and the resulting :nix+-:ure was concentrated in vacuo to give t(2R)-2-(3,4dichl,-Iorobenzvl) 5-bis(trifluor-omethyl)benzoyl]-4- (2hydroxyethyi)poJoerazine hydrochloride (45 mg) as a powder.

(Neat) 3260, 2S50, 1640, 1425, 1275 cr7' :2.680- 5. 53 (13H in) 6. 91 32 6H, iL) 10 96 (lI H b r s) M-IAS S 530 (free)

S

S

*5S*

S.

S

S. 4~ C S 4*SW

S

0* Se a

S

S

OSS@Ss

S

Exa -Ole 48 Th--e -Fo illowing comrepounds were ob ta ined according to a siil±ar manner to that of Exainole 47.

15 (1 (2R) -4--(4-A-minobenzyl)-- 1 S-bis (trifluoroinethyl) bDenzovl-- 4-diinqethylbenzvyl)piperazine dihydrochloride rnp 17900 (dec.), 16.6' MeOH) 20 IR(uo) 3400-3050, 2650-2300, 1660-1580, 1275, 11L25 cmi NR(DMSO-d 6 5) :2.00-2.20 (6KH, mn), 2.80-5.05 (11H, mn), 6.45-8.25 (10H, 11.40-11.90 (2H, in) MAS2 S 50 (NH-I) (fLree) robenzf-)-1-[3,5'-b-s(-rifluoroTnet hyl) benzoy'l 4-d iinet-hybenzvl) oirerazine dihydrochloride ito :14000 (dec.) 25 -18.4' MeOH) ~(Nujo 1) 3600-3200, 2650-2200, 1640, 1520, 1350, 1275,7 1130 ci- NMR-P (D2MSC-d 6 ,5 2 .00-2.2C (6H, mn), 2.80-5.00 (IlKH Tm), 6.50-8.40 (10K, ma) MAS S 580 (-Free) Exarnole 49 To a solution of 2 R)-4-F4,4-ethvleneioxv4(4- -F 7"oirochenvl)budty-] (r3 ,5--i:rifluororethyl)benzoyl-2- (1-ino-3-ylmet-yl) pip erazine (2 10 mg) in ethyl' acetate was added 4N hydr',_ogen chloride in ethyv 1 acetate solution (0.5 ml) and t:he whole was stirred at roomr t-emperature for 23 hours.

The solution was evaporated in vacuo. The residue was trlturatea wirh mnixture of-' ethyl acetate and diisonroovl ee-e to rivge R'-4 -{4-(,4-f-iuoroh-envl 4b4-(ri-fioromnethyi)benzoyl1-2-(1:ir-do- 3 y~lmethvl)piperaz'Lne hydrochloridie (183.7 mg).

MC 1610C (dec.) Lxj-' 14.2 MeOH) 7R (Nujo 1) 3400-3150, 2650-2300, 1675, 1635, 1595, 1280-1250, 1275, '125 cm NMI _R (DMSC-d 6 ,6 2.00-2.25 (2H, mn), 3.05-5.20 (13H, mn), 6.55-8.25 (12H, mn), 10.95 (1H, 11.10-11.50 (1H, mn) MASS 620 (free) Preoaration 6 Tetrahydr-ofuran. (15 ml) was added to 70% solution of sooflm bi's (2-methoxvet hoxy) aluminum,, hydride in toluene (49.7 under an atmosphere of nitrogen and then cooled.

A solution of 4-mor7Qholino-2-butyn-1-ol (3.0 g) in t~etrahydrofur,_an (,15 ml) was added dropwise mnaintaining the reaction temperature 4-50C. After being stirred for mi.nutes, t:he reaction -mixture was allowed to warm to room t emD erI-atu re After 1 hour, water (6 ml) and 10% aqueous sodium hydroxide solution (4.5 ml1) were added cautiously and then filtered. The filtrate was dried over potassium carbonate and concentrated under reduced poressure to give an oily product, which was purified by column chromatography on ilica gel using ethyl acetate-methanol to afford 4 -morpholino-2-buten-_1ol (1.08 g).

9 999.

b I(Neat) 3350, 1450, 1110, 990, 855 cm',-

NR(CDC!

3 65) 2.48 (4H, t, J.4.7Hz), 2.77 (1H, s), 3.02 12H, d, j=3.4Hz), 3.73 t, j=4.7Hz), 4.15 d, J=4OHz), 5.64-5.96 (2H, m) MASS :158 (M+1) Precaration 7 ?}Horl ohi-ride 1(0.96' wsadded droows toa soluti on of 4 -mror-oholino-2-buter 1 l-1oI 1.03 g) ir d ichicorome than~e (10 ml) at ice-bath temperature. After 3 hours, the reaction mixture -was evaporated under reduced Poressure and the resulting residue was triturated with ethyl acetate to give 4 -moro~holiJno-2-butenyi chloride hydr-ochloride (0.98 g).

15 mp 155-160 0

C

R (Njol) 2750-2700, 1275, 1255, 1120, 1073, 1065, 975 cm--' MR(DMSO-d 6 5) :2.80-3.55 (4H, mn), 3.64-4.10 (6H, mn), 4.26' (2H, d, J=5.7Hz), 5.90-6.25 (2H, rn), 11.82 (1KI, br s) MASS 176 (fr-ee) Examole Amixture of 2 R)-l-r 3 ,5:,bis(tri-Fluoro.m ethyl)benzovll-2 25 (lK-indol-3-ylimetlhyl )pip-erazi-ne (0.20 5-rorpholino-3penty-nyl chloride hydrochloride (0.175 potassium carbonate (0.303 g) and pootassium iodide (10 Tng) in dry acetonitrile (4 ml') was stirred under reflux for 60 hours.

Atrremoval of the solvent, the resulting residue was dissolved with eth-yl acetate. The solution was washed with brine, dried over magnesium sulfate and evaporated under reduced preassure. The residue was purified by column chromatography on silica ge 1 I using t oluene ethyl acetate as eluent and treated with 4N hydrogen chloride in ethyl acetate solution to give 99 9* 9 4 9 999*99 9 9 bis (trifluoromethyl) ben zoyl 1 (lH-indol--ylmethyI) mor~o~fo-3Pertyny~pierainedihydrochbloride (0.174 g S9 l95~ 0 C=0-5 Me OH) K~o) 3600-31510, 2700-2300/ 1640f 1280, 11-7c, s d 2. 90C-57. 20 (2 3H, 06, 68 0 30 (8H, C 10.95 11-,5, 11.79 2 H, b r s) >LAS D C 7 1 603 67(-r)(free) An al d ~or C 31

K

3 2

F

6

N

4 0Cq 2 HC2K01.1KS 2 0 2.0 H 5.28, N 7.93 Found C 52.72, H 5.54, N4 7.60 Exam,_Qiep S ~a mixture of (2R)-1-r3 ,S--bis(trifluoronethyl)enzcvii 213,4-imethvibenzv)pipoerzine (0.2 gr) i-methyl- 4 formyi--1,4-pyrazole 50 mg) and Sodiu t:ri-acetoxvborohydride (11 Tmg) indoirrehn 2m)was added one drop *of acetiLc acid. After being stirred at room temoerature overnight, thne solution was evacorated under reduced Prssur. Theresut~n~residue was partitioned between ethy aceta:e anrd acueous sodium hydrogen car-bonate solution. Th--e orgn--claver was separated, dried over magnesium. sulfate and evaoorated uandIer reduced pressure. The residue was our-i-fied bvclm cnromatography o silica ge'usingety ita -e-nanol zs =-uenc- and treated' wit h 4N hydrogen chloride e hyl- ace za :e s olu ti.o n to g iv e 2R 1 L"3 5 -bi-"s triJfIUo 0roCmaethy1)b,'enzoyl 1 4-dimet'hylbenzyi -(i-nethy' -1H- Pvrazol-- 4 -vl)m.etLhvllpiperazin-e hydrochloride (,97 ma).

mp :243-244oC 1 -16.8' MeOH) (7Nujol) 3350, 2750-2000, 165- 65 1275, 1165, 1 13 0 cm-7' NYIR~ 1~ 6 .97-2.28 (7H, in), 2.78-5.10 (13H, m),6.50-8.30 (8H, mn), 11.24-11.74 (1H, br m) MASS 1,P01) :539 (free) Anal Caloc-d. for C?-/H 2 8

F

6 N,,O.HCi' 2.27H 2 0O C 52.00, H 5.56, N 8.98 C 51.82, H 5.15, N 8.99 xarnoie 52 e fol lowIng comPounds were obtained according to a slil~r ma:nner to that of Examole 51.

-o4oeraz i_ e Cdi 'rlvdrochlorjde ,a.JD -1 8 0 3, MeCK) TR (Neat) 335C, 25-50, 1640, 14210, 1275, 1170, 1-.30 c-mn' -N-vYR (DMSO-d, 2~ .07 (3H, 2.17 (3H, 2.72- .10 (11K, 3.88 (3H, 6.60-9.08 (8H, -m) MA SS 53-9 (free) (1 2 R'/-l-3,5Bis(tifuoroethy)benzoy1>-2.( 3 4 v benl-) F ;_irethyilHinid azoi',2y-)nechv~l olpeazie Qnvdrochlcro4 e -12.100 (C=0C5 MeCK) Net) 3350, 2500, 1640, 1430, 1280, 1175, NY 6) .37 3H, 2.16 (3H, 2.53- .4 3 4 (3H, s, 6.47-8.26 (8H, m) HT S S 5-39 (free) ExamnoIle 53 Thefollowing Compounds wi~ere obtained according to a Sim.,ilar -manner to that of Example 43.

2 R-l-{3,5r-Bis(crifi-uoronethy1)benzoy]2( 3 ,4 dimet~hnv'benzyl) -4-(3-mornhoinopropyl piperazine d ih v d r c hIor id e 2 2 0- 2 3 0 La ~~17 3 3, YM.eOH) 9R IN-- o1 3350, 2650, 1655, 1635, 1620, 1445, 1370, 12 70 cmn N R(MSO-d 6 5) 1.92-5-22 (29H, mn), 6.56-8.28 (6H, 11), 11.3 (,21H, b r s) MASS (APCTI) 572 (free) Anal. Calcd. for CqaK 3 5T 6

-N

3

C

2 2HCi1 C 5z:4 .0 4, 5. 7 9, N 6 52 Fo u nd 53.-72, H 5.80, N 6.29 )2 2R) -4-2 LFN N-B is (2-iehoxethi ainnoethy 1 1-3,5b is zr 4f lucr o -me t hyvi)b1- enz o y -2 3, 4 d ime -Lh v b e nzvY1) C3icerazi'ne d-I vcirooh~oride Ccl6 MeOH) (Nujol,) 3350, 26-50, 1,655, 1633, 1620, 1445, 1370, 1270 cmn' NMTVR (DMSO-d- 6 6) .92-5.22 (27H, in), 3.32 (6FT s) 6.56-8.28 ,'6H,i) (AP 604 (free) ~a1.Cald. Or C 30

H

39

F

6 3

O

3 2H r1-1 .6H 2 0 S 1.08, -H 6.32, N 5.96 Found C 51.06, H 6.40, N 6.14 15 b *0 4 (3 (R T,5Ss'rfuorzrezhy1) benzov> -2--(1K-indol-3yvI'-e-,'nvYi, L-3- 2,3, 6 -te-trahvdropyri-din-1-yl)proopvllpiperazine dihvdrochloride -2.30' MeOH) R :N~1 3500-3100, 2700-2400, 1630 o NMR(DM- 6 6 2.20-4.20 (21H, in), 5.72 (1K, d, -J'10.2Hz), 5.93 (1H, d, j=10-.2Hz), 6.55-8.23 (8H, ,0.Q95 (IN, br s) MASS k(APOI-) 579 (free) Anal. Calod. for C 30

K

3 2

F

6

N

4 .2H-Cl.2H 9 0 C52.41, H 5.57, N 8.15 Found :C 5 2 .0 3, H 5.77, N 7.7 2 bi-s (trif luromethvl)benzoyii 2- (3 4--dichlorobenzy-) Oloeazedilhydrochloride no15000 (dec.) T R1 (Y,,,jol 3500-3100, 2700-24CO, 1630, cm-i (DMSO-d 6 5: 1 6 0-3. 90 (2 9K,_ 6.-9 0- 8. 30 6k, 06 TVNT SS (ADP 5 650 (m+iL) (free) Anal. Calod. fo 3 K5lTNO2C.- .2 2 N 5.67 C 5025 H 5.60, N 5.32 pier zr e -r ydroch 1 ode '1t: 2000C .c~ 8 340' MeON) (Nuj ol) 3300, 2700-2400, 1630, 1450 cm 1 _NILR (DMSO-d 6 6) 1.60-3. 90 (34H, 6. 90-8. 30 mn) YAS S 1,FAD- 693 695 (free) Anal Cai'cd. fLor C 7 2 5 6 N, 0*31HClI C49.36, H 5.40, N 6.98 Found L9.81, K 5.75, N 6.75 7-xainnle 54 Asolut1ion of= 2 R) -L[ 3 ,5-bis (trl fiuoroinethyl) benzoy 1 2 -(3,4-dimethylb-enzyl)/-- 4 -morpholino-2-butynyl)piperazine (141 ing) in methanol (10 mnl) was hydrogenated over 10,- P-d-C at- room t-emperature under 2-3 at-omos. After removal of t-he cat:alvst by fiLltration, t-he filtrate was concentrated -,=der reduced oressure he residue was purifi'ed by column chromatography on silica gel using dichloroxaethane-inethanolI as eluent_ an rea ted with 4N hydrogen chloride in ethyl aceta:e solution 7:o give 2 R -1 -F 3 5-b-is(trif luorom ethyl) nioerazine dihvn-drochloride (106 mg).

D ~C 1_ 2 9 0 JD -13.50 Me-OH) jciA 3300, 270C-2400, 1645, 1500o, 1445, 1370, 1270, _1170 m NM,-R (D_,MSO-d 6 65) 1.70-5.22 (3K ),6.36-8.28 (6K,/ :YIkSS (7APC, 5 86 4+1) (-Free) 9 Examcle The followi ng compound was obtained according tc a maIner zo thna t o f E x arrrole 2 R) 3 5Bis (trif luoroethyl)benzoyi2 <iHindol- 3 vylmethv-l)-4-(5-moriohoinopentyl)p4-pier;:zine di-hydrochloride R Near) 400-3200, 2700-2400, 1640, 1430 c<-1 'YR(DMSO-d 6 5) 1.50-5.20 (27H,, 6.60-8.30 (8K, in), 10.80-11.50 (3H, mn) HAS S 611 4+1) (free) A-na-l. Calcd. for C 31 3 6 6 4 2 20 .3H-~ C 52.67, 1- 5.79, N 7.92 Foudnd C 5 2.66, K 6.13, N 7.76' Exainole 5-6 s23 sou zion of 2 3 2- 3 4 -dinlethylb enzvl)-4- (S-iorpholino-3-pentynyl)piperazine '200 n) a treated with 4_N hydrogen chloride in ethy'l aCe--e o give 'R -3 7-i u rm t v bezvl 2 3 4dmehbnzvl) (5-rmorpholino3pTentvnvl piperazi ne dihydrochloride.

(x 225.2o (C005, MeOH) R (Na 1 3700-3100, 2920, 2750-2250, 1635, !S00, 1430C, l2 7 5 117 0, 112 0cm =MR (DMS__O-d 6 5) 2.05-2.20 (6H, in), 2.75-5.15 (23H, m) 0'.65-8.28 (6H, in), 11.60-12.20 (2H, mn) MASS 596 (M-JI) /free) An~C a If or C lH 3 S6\To 2 2Ci.1s' HO 'C 5 3.53, H 5.80, IN 6.04 ;ound C53. 47, H 6.14, N 5.91 Examinoe 577 (2R) F~3, 3-Bis 'trif 11uoromerhvi' benzoyl7 2- (3,4d imethyiben zym p iperaz ine fu_= r e 9.13 g) was treated wi th aaueous10'z" sodium hydroxide soluto (6m)an acu o s i n 05 it! n dichloromethane (65 ml) The organic layer was separated, I 15 wshdw-e~r dried over inagnestuin sul'ate and evapCorated un-der reduced pressure. A mixture of (2R) 1- F3, obtained by thre above pOrocedure, potassium carbonate (3.60 g) and 1, 4 -di4chloro-2-butyne (1.9 ml1) in N,N-dimethylformamide 72 ia Ue or, 4 .urs room temperature.

TTF,_

-mixture -wa coured into water (360 m)and extracted with ethyl acetate. ,e extrac~t was washed with brine, dried over magnesium sulfate and evaporated under reduced poressure.

The rnsiduewas ouri fe b olm 'ie bycoimnchromatography on silica 999.25 gel uasina tocluene-etzhyl aceta:te as eluent to give (21R)-1- (4cio-o2b-yv~'-ea n (42.865 g).

ZR (eat) 1706, 165 15 03 1 2 75,125c NTMR (CDCI 3 65) 2.05-5.20 (19H, ma),6.074(Hm MAS(APC7) 53 (+1 Examole 58 -A mixture of S--bi;s(trif----luoroinethyl)benzovlji2- 3 4 -dimeoh:Invl-benz yl 4 -chiloro -2 -butynyl) pipera zine (0.49 g) -ehlopoiehydroc_'loride (0.15 g) Dotassium carbonate (0.39 g) and potassium iodide (10 mg) in dry N,NdimethylIformamide (5 ml) was stirred for 5 hours at room te,- oe r a ur~ e he milxture was poured into water and extracted Witn et-hyl acetare. The extract was washed with brine, dried over ma=gnesi sul fate and evaporated u,-nder reduced pressure.

7 residuae was purified by colfumn chromatography on silica gel us Invg- ethl cetate :as el-L.ert and treat zec with 4N hyrge chloride in ethyl acetate so'lution to give (2R) -1- -2--(3-methv1 I o Lazi ne dihIydrochlrd 2 .5710(=O0 MeOH) \T (Nj1) 3300, 2700-2400, 1650, 1430 cm.- 1 NM TD'MSo-d 6 5) .2C--.22 (29F, in), 6.60-8.20 (6H, in12.20-12.40 mn) MLASS (APCT) 59' (free) *Anal. Calcd. for C 3 1

H

3 5

F

6

N

3 0 2 .9HCl-.7H 2 0 C 53.25, H 5.82, N 6.01 Found C 53.28, H 5.97, N 5.80 Examole 59 The following compounds were obtained according to a siilarmanner to that of Example 518.

dimr~ethvlbenzyl) 4- 2 -mroethoxymethylmorpholino) 52 butyvnyl I piceraz'ne dihydrockloride 150-16-7-C D-8.860 MeOH) :Njl 3300, 2700I,-o -2400, 1640, 1430 cm-1 NTIM P D MS0- d 6 1 5) :2.00-5.22 128H, in), 3.25 (3H, s), 6. 50-8. 20 (6H, in) 12 .20-12 .40 (2H, mn) MASS (APCI) 626 (free) Anal. Calcd. for C 3 2

H,

3 7

F

6

N

3 0 3 .2HC1.H 2 0 C 53.64, H 5.77, N 5.86 Fcur:d C 53.60, H 5.94, N 5.67 -j ,i (-ri -Fuoromer-hy1)benzoyl2-( 3 4 ,l alrnerflviberzvi) r4- 2 -f -luoromeE-h-vlrporpholi mo) -2ta-cynylliierazinre di4hydroobhoc-ide 1 '7 8, C, LL] -875' (07 MeOH) ~R (ujoi 300,2700-2400, 1635, 1500Cm WNYR (D)MS-d~ ,1 2 .0 0 22 (28, 06) 6. 5 0 -8.20 (6K i MAS(AECI): 61- (free: .31 347 C 52.85, H 5.44, N 5.96 9.Found C 52.82, K 5.45, N, 5.74 d-'-et'-.-v1bernzv')--4- 3 ,3-di-me~hvlinorpho14roa9.2.

bazynv1 ]piperazine dihydrochioride OR (.Nu jol1 3300, 2700-2400, 1635- cm NMR 1DMSO-d,, 5) 1.30-1.40 (6K, mn), 2.OC-5.22 *Lk 9 S (ALDCT) -10 (M !H ee) 2 5 A n a l C a l o d o r C 3 2 K 3 7 7 6 N 3 2 2 C 52. 82, F 6. 09, N 5. 68 Fourd C 52.84, K 5.89, N 5.78 2

R>

1 '_3,z-3is :ilooe~1benzoyll 2 3 4 t diehiez-44( L )-methoxynethylpyrrolidifo)- 2 -butvnvilpoioerazine dihvdrochloride mc 95-1970C D ~j9.79- MeON) 7p, (Njol) :3450, 2700-2400, 1640, 1450 cr.-i NI4R (MSO- 6 65) 2.00-5.22 (28Kr, inL), 3.32 (3H, s), o. 82 0 (6H, mn, I11.50- 11.70 2H, m) MSS PC T 6 1C M±)(ree) An l. Cal cd. for 3 7 F6-N 3

O

2 l2'~ C 5-3.49, H 6 .0 3, N 5. C 53.66, H 5.73, N 5.82 bc vnvy p p er a z in e diJh vd r och io ri-,d e ~28 -7.220 (C=0.63, MeOH) ~R (N~oI; 3300, 2700-2400, 1635, 1440 c JMR(DMC-d 6 6) 2.00-5.22 (28H, 3.32 (3H, s), :00.06_50-8.2e (6H, KASS (APC7): 626 (-free) Anai. Calcd.foC 3 H7 6

O

3 2l C 52.32, H 5.90, N 5.72 Found C 52 .3 5, /H 6.11 N 5.4 3 Exarnoie owes mitx7-ure of1 2 3 ,5-bs(tr-,luoromethy)benzo7i2?- 4 -dimL,)ethyl',ben,-zvl)pizerazine (0.38 q),poasucrbne '0.42 3 -S--pyridyl) -2-propyny1 chloride hydrochloride 9 ml) and smrall amount o f otas sium i-,odide in N, Ndme~vfo~rm~de(10 l) wsstirred for 2 hours at tuewas Doured into water and extrfacted with ethyl ac e7-a t:e. Thne extract was washed with brine, dried over rmagnes-i_,, s,.

1 fate and evaporated ucnder reduced pressure. The residue was Our-ified by column chromat:ography on silica gel sigthlacetate as eluent and treated with 4N hydrogen C 0 r 41d e in ethyl acetate solution to give p y i d v1 i-ron ynvllp pe ra z re dih'-ydr ochlcri'Lde 0. 26 a) Fa] 2 8 .4 -10.13' MeOH)

L

R Nu joii) 3300, 2700-2400, 1630, 1450 cm.< NMTR (DMS-d, 6) 2 .0-5 22 (171-, mn), 6.5c0-8 .20 (SNH, .70 8.B (2H, r~ 6ACI 50 free) Anal Calcd. -for C 3 0

H

2 7

-F

6

N

3 0-2H--.8H 2 0 C 52.76, H 5.11, IN 6.15 d C .7A 4~ ,.96

S

*5*e S. rExamle 6 L(E-~-h~oo-2but~L/ -~napthvrvehv Pperazine ,1g) OM :oorc'PhoY 1e 0.0 54 ml) and powdered *potassium carbonate '100 mg) in dry acetonitrile (3 ml) was heated at 0 C fo .r Ihou rs. Additional potassium carbonate(00m 15 ad thioinrhi 00.0 54 m were ad~ded and then the result~rn n~tre was further heated at- the same temperature.

Affter 2 hours, the reaction mixture was cooled and then f:1>tered. The filtrate was concentrated under reduced pressuL-re an-d the resulting residue was Purified by coilujn, Chnromatograpihv on si-'lica gel using a mi~xture of dichnloromethane and methanol The obtained product was di-ssolv,,ed- i-n ethyl acetate and treated with 4N hydrogen chloride ~nethyl" acetate (0.6 mlj) to give bis trif iuorcmethy1) benzovl 2 -naphthylm-,ethyl)-4-((E)-4 25 tioiorpoc~o~2butnyipip~az nedihvdrochloride (190 mg).

710: >230 0

C

-14.50~ MeOH) A(_Nulo1) 3650-3100, 2410, 1640, 1274, 1130 cmI NR(DMSO-d 6 5) :2.55-5.30 (21H, mn), 6.00-6.30 (2H, 70 0-90 OH) 9. 5 5

S

*SS*S*

S S MASS :622 (free) Examnole 62 The following compounds were obtained according to a 357 somilar- Manner to tnat=! of Exa-mole 61.

n) a\ p W3yl me -B1S- )(-4-if)uoorphvl bnol-uzn I ieraz-n '06 C= 5 1 H

T

R M~1)360U-3100, 2450, 1639, 1273, 1130 cm.-

NYR(DMO-

6 1 5 20-.30 (21K, 6.10-6.30 /2H, 7) 7.G00-38. 25 10KH, ma MI-S S 06/ 1Nil -Free) ,imaecn-v 1 _'menzvl -4-tchi om-rholi"no-2ctDzenvlp ioerazine dihydrochioride rn >2 30 C 15 52C0 (C=O0. 2 5, DMSO0) IR ,Nu 3600-3100, 24530, ,642/ 12-74, 1130 crn 1 NM',R DM S0-d 6 5- 2.10-5.10 ('27K, Tr), 5.90-6.30 (2H, 6.65-7.05I (3H, 7.57 (2H, s) 8.05 (1KH, s) MAkS S: 600 (free) Ex;-mnle 63 T, mixt-ure of 2 R) -i- 3 ,5-bis (rLrif -1u-orornethyl)benzovlli,4- (450 3 3,-dimethylmnorrpholine hydrochloride (130 mg) ana cowder ad pccasscura,, carbonate (350 -g)In dvacetonitr ie -awas heated at- reflux teiracerature for 3 hours. Addit-ional -ccasstura, carbonate (350 mag) and 3 3 -dimethylrnorpholine hydrchlrid (10 rag) were added and then the resultin :7 1x u re wa S fu rt h er he a ted at re fiux t em e ra tu r e. After 6 3 0 hus c react~on maix-Lure was cooled and then filtered.

The filtrate was concentrated under reduced pDressure and ".he resul1--na resiauc, was purifi ed by column chroraatograohv on sii'ca ge- -'ing a raxtulre of dichloromethane and metnhanocI '30:1 obtained productz was di'ssolved in ethyl acetate a;;nd treated with 4N hydrogen chloride in ethyl acetate SO -UtJ Cn -C Ci-ve 2 R) 5-bis (trifluo fonethyl) benzovii9 (3 4 die~vbenzv!M 3 -dime th-vlmoropho 1 no) 2 2Duzenvlo er:z,.-ne d 4hvdrochloY-de (370 a- ZR(Njc) 3400, 2450, 1639, 1274, 1130 c~ ~T(DMSC-d., 5):13-.40 16H, mi), 2.10-2.18 (6H, in;. m 2.T052 1K 6.10-6. 3 (2Hn, 6. .3 C (6H, 2, 11.20-12 00 MS S 612 f1 (fe e Exa-mule 64 (2K 3,zo.

ooety )be zv -2- 3, 4 dimer v b e nzv I pipe ra zie (10g), 14-dichloro-2naucene (0.31 a' nd powdered porassiam carbonate (0.4 c) in rv ac etcni_ rii (1'0 mi) was heatLed a 5 0-C After 4 h~ours, the reaction mix-Eure was cooled and then fil-tered. The -Fiitrate was concentrated under reduced pressure and the resulting residue was purl fled by column chromatogra-phyv on silica gel usi ng a ixreOf toluene and ethyl1 acetate (4:1) L-3 give 2Rb2Fs(trifI l ,eti 1.enzoyil as an 0i1.

ZR :3460, 1638, -1272, 1 125, 900-c 2 5 NR I''CD C 1, 5) 2.00-5.20 (19HK, 5.75-6.00 (2K, in), 6.6 0- 8. 00 (6H, mi) YKA S 533 Examole 657 The following compound was obtained according to a si-ilar manner :o thatL of Example 64.

2 R-,l:'3,5-Bis(~cfuoromeuhyl)benzoiJ- 2 2 nazhr-hvlc7'i-ethviz,) 4 -chloro-2-butenylipipoerazine 77R (Near) :11637, 1273, 1128, 900 cmn NYMR (CDCI 3 5) 2.05-5.20 mn), 5.80-6.00 (2H, in7.10-8.10 1,1H, MAS S 555 (M+l) xam-ole 66 i nrur of 2 R)-l-L3,5--bis(triFiuororethyl)benzoyli2g ±i-ndo-3--vilme-hyi) 3 -nehvsulfcnvboxyprcpoyl)piperazine ng,4-aminomorpholine (36 ingr) and triethylamine (52 mgr) i vmechano 1 (7 -l1 was refluxed for 2 hours. The rezacr:on Pxrewas concentrated under reduced pressure and t:he resulting residue was parttt1-ioned between ethyl acetate and aaueous sod4im hydrogen carbonate soltion. The organic ayer was wasnec w-i'th brine and dried over magnesium su 1 fat e.

'fe evacoration of the solvent, -hn= residue was purified by 'S column chroina togrraphy on s t±lica gel using a mixture of ethyl *wo acetat e and methanol (10:1) toc afford an oily product, whiLch 6 00 was t-reated with 4N hydrogen chloride in ethyl acetate **too" solution (0.5 ml1) to give 2 3 ,S'-bis(tri-fluorome'thvl)- .0.06. benzoyI 1-2- (lH1--indol-3-y methy1) r3- (morpcholinoamino) oronyll)pipera zinc dihydrochlcr-ide (58 ng 0:0. r.23 004*L JD -3.60' MeOH) ~R (Nj 30,20,1630, 1420, 1275 ci-- NYMR (DMSO-d 6 5) 2.00-5.24 (23H, mn), 6.60-8.28 (8H, 10.9_4 (1H, 11.50 (l1H, br s) MA S S 598 (free) Examinle 67 he following compounds were obtained according to a similar manner toc that- of Exam-ole 66.

ci-oerazl-ne dihydrochlcr-Ide F 20 -2.60' MeC) IR (_Nuj'o 1) 3350, 2600, 1640, 1280, 1175, 1130 cm- 1 6. 60- 8.2 4 (8H n, 10.9 s) TMiSS 597 (M (free- 'Q2RV-'-S,5Bs(z-rJ fiucrcnehyl)b-enzoyl1i2 (1-ji-do1-3- Y-Imerthvi (c-is-2, 6 -dlimet}hylmorphol 'no) propyi-1 Pp'er-=z ne cinvdrochloride R Jto)3350, 260O13) 1640, 1280 cmc' N-iMR 'DMSC-ci,,5 1.20 (6H, mn), 2.08-5.20 (21H, 6.63-'.33 10.94 IH, s) MSS 61(M-) (free) S(3) -R I -F 33BS -B sil Iu cr o e t h )bezovl12-(3,4- I" nv e n 4 -,f 2 -(l--4imdazo-yiehvl'iorajn *i Qhvdroo- -oride *cx aD- -16.20' MeOH) IR 3350, 2700, 2575, 1640, 1430, 1280, 1170, 1130 cm7' NMRc' ms0 (DMSC- 6 ,5 2.04 -5.20 2.09 (3H, s), 2.1 s I, 6 .55-.22 (8H, mn), 9.29 s) NILAkS S 539 QM-1) (free) dm Ti nrv 1hen z vj1 -4 3- (o roholl4no ainino) prop y j p i pe ra z ne d h vd r ochloride -14-100 MeOH) 7ZR (Nj ol) 3350, 2550, 1640, 1430, 1280 01fl 1 INY-R (DMSO-d 6 5 1.97-5.14 (23H-, mn), 2.10 (3H, s), 2.18 (3H, ),6.64-8.24 in), 10.92 (111, br s) MLASS 5 '87 (free) 2 R,-lil3,5-Bis(triflioroffethy)beolzl2( 3 4 o4rech--ybenzyl)-4<,2-(-< -yme-yaioetlhyl) pi cerazi-ne rcrihvdrochioride 82 3t590 (C0.5, MeOH) R Nu3400, 2600, 1640, 1430, 1280, 1170, 1130 cia MR (DMSO-d 6 5) 2.07-5.20 (13K, rn), 2.10 (3H, s), S 2.18 (3H, 4.50 (2H, 6.60-9.09 (1OH, m), 10.32 (1H, br s) MASS 5779 (free) '2 R) 3, 5-Bi s i -f luorome uhyI) benzoy 2 -3,4- _meryhv benvl (2hommc_0-4 oh! Diea- _w--4cchiride 7 -0.90' MeOH) 1P (Nluol) 3400, 2600, 2450, 1640, 1430, 1280 o-m NR (DMSO-d, 6) 2.04-5.17 (23, 2.10 (3H, s), 15 2 18 (3H, 6.62-8.26 ,6K, a) MASS 572 (free) 5-Bis (ncriflucromehyl)benzoyll m yet y-benzyi' 3 -homorphoin oproyl) piperazine dihydrochicride MeOK) IR (Nujol) 3400, 2600, 1635, 1430, 1280 crn' ±MMR (DMSO-d 6 6) 1.73-5.20 (25K, 2.10 (3K, s), 2.18 (3K, 6.62-8.24 (6K, n) MA4SS 586 (free) 1, 2 Lr 3 S, B s t r i f u o ro me t h v b e n z o v 2 1 H- i r d o 1 3 yirmeth-vi) (3-homonorp'ol inoropyl)piperazlne ihydrochioride a17 -5.50' eOH) IR (Nujol) 3300, 2650, 1640, 1275 cmn1 NMR (DMSO-d 6 6) 1.90-5.23 (25K, inn), 6.62-8.34 (8H, in), 10.95 (1H, s) S 597 (free)

S

*S.S

S

S.

S

83 (1 -f3 i r i-l cr~o t v,)b n o ,4 dl-chi or-obenzyl) -4-13- 4 -acetvlz)iL-eridino)propy1 1 oiLoeraz ire cihvdrocho-ir-d laID 2.20' MeOH) 1-(uo) 330 60 700, 1630, 1275 on NhR(D-MSO-d- 5 1.69-5.21 (24H, mn), 2.16 (3H, s), 6.97-8.36 16H,rn (10; (2R) F3, 3 B sz(7- -,-fiuoromeri~hvi)befzovi2-( 3 4d i ,qe t v lbe nz v 1) 4- F 3- 4 ac e tv 1 r ipe 1- 1dI'n o) pr o pyi Poli ne razz_4n e d ihyvd _-oochi1 or id e T,13Q (C=0j.5, MeOH) '01u~h) 3425 3375, 2500 1705, 160 27 m 15 NMR (DYSO-d 6 :1.67-5.20 (24H, mn), 2.16 (6H, s), 2.13S (3H, 6.62-8.25 (6H, mn), 10.60 br s), 1.4 9 (1K, b~r MSS 612 (free) (2 R) 1- L' 3 E iS tr f -Iur ore t h y )b e z o v1' 3 ,4 dcli'nlrobenzv) 4(2r1rooietvt iein d ihyvd ro lo r ide ra-2 C 6.10' MeOH) IR N~ji; 33570, 2600, 1630, 1270 cm' N MR E;DM.SOC- d 6 5 2.14-5.16 (21H, mn), 6.93-8.27 (6KH, in) MAS S 5:98 (Mi) (free) (12) 2 R)-lilj3,5-Bist,-rif-l-luoromethv1-)benzo11]2 (1H-indol-3- 3 0 y *'vie thyj 4 -methoxyiper d no) Proy ]p ipera z ne F jl 6.70' MeOH) IR (Nuj--ol) 3300, 2550, 1625, 1270 cm'1 NMR(DMo- 6 5) 1.57-5.20 (2Km), 3.27 (3H, s), 6 .60-8-28 (8H, iTn), 10.95 s) 5* S S

S

S

84 M,4AS S 61, (free) (13) 2 R)-1-[3,5-Bis(trifluormethyl)benzoyli2-(3,4dlrnethnylbenzvl) (2-rethoxvethyl)

-N-

he~v'aniinojethvl loipcerazine dlhdrochloride MM:222oC (dec.) 7-3 -12.500 MeOln) IR (Nujol) 3380, 2400, 1644, 1275, 11130 crn'- NM(DMSO-d 6 65) 2.0-2.3 (7H, 2.88 (3M, 3.33 (3M, 2.3-5.3 (18H, 6.6-8.3 (6M, MASS 560 (free) dinethv'lbenzvl) 4 3 -(hexarnethyl enei.Tino) propyl] wierazine dih)ydrochioricde 26 L~]D 11.700 k(C=0.5, MeOM) TR (Near) 3400, 2600, 1640, 1430, 1280 cm'i NYNR (DMSO-d 6 5 1.49-5.20 (27H, mn), 2.10 (3M, s), 2.19 (3H, 6.67-8.23 (6M, mn) 20 MA,-2kS S 584 (M 1l) (free) 2 R)--,-f.3,5-Bis(t--ifluoromethy)bezoy12-(3,4- ~1me~yibezv)--12- (4 -pridyl me thy!am ino) ethyl] Pc~cerazine rhvdroc'hl-or-de C, 12 0.20' MeOM) IR ('Neat) 3400, 2600, 1640, 1430, 1280, 1175, 1130 cm- I NMR- (D-MSO-d 6 6) 2.10 (3M, 2.18 (3H, 2.64- 5.20 (13H, mn), 4.16 (2H, 6.40-8.97 (10H, r.) MAS S :579 (free) (16) 2 R)-l,-F 3 ',S-Bist rifiuoromvetv)bezoy2(3,4dim-ethyibenzyl) 4-triazol-3ylainino) proirvl] piperazine diJhydrochioride [a]X 4 D 10.50' MeOH) IR (Neat; 3075, 2700, 1675, 1640, 1430, 1280, 1170, 1130 cJ N-Mh4R 'Dm-SO-d 6 5) 2.05-5.20 (153K, mn), 2.09 (3H, s), 2.18 (3H, 6.60-8.34 (9H, rm) MASS 569 (free) Exarruole 68 -A mixture o-f ,2R)- 1 L3,5-bis(tr--Fluoromethvl)bDenzovl]-2- (2-achhvlne~vl;piperazn '300 mg,4-thi-omorpholino-2butynyl cloride hydrochloride (10ig ndDwee pDotassium carbonate f210 :rag) in1 dry acetonitrile (3 ml) was refiuxed for 7.5 hours in the presence of potassium iodide mag) The reaction mixture was cooled and then filtered.

7e f iltrat-e was concentrated under reduced- oressure and the resul-4na residue was ourif ied by column chromatography on sillca g; el uiaa mixture of ethyl acetate and methanol The obtained poroductc was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate solution (0.6 ml1) to give (2R)--f13,5-bis(trifluoromethyl)benzov!l1-2- (2-naohthylmethyl) (4-th~niomorpoholino-2-butLvnyl) papoerazine oihydrochloride (300 mg).

mp:152-156'C F(X- 27 47.300 C=0.5'J MeOH) 0: TIR (NuLjol) :3350, 2500, 1637, 1275, 1125 cm'i NMIR (DMSO-d 6 5):2.70-5.30 (21H, in), 7.00-8.20 (1OH, m) MA-S S: 620 (M4-1) (free) Examvole 69 A mixture of (2R I35b s-L--i--lurpitv~e zy ]2 4-dim- ethy) lbenzyl) (4-ch'loro-2-but-ynvl) piperazine (200 mng) 1-cyclohexvlo-J-erazine (63 rag) and powdered potassium carbonate (210 mg) in dry N,N-dimethylformamide (2 ml) was stirred for 12 hours at room temperature. Additional l-cyclohexylpiperazine (25 mng) was added and after 2 hours th- -eatin 7mixt-ure was poured into water (20 ml) and extra-ctLed wit- ethyl acetate. The organic laver was washed w~ brie and dried over magnesium sulfate. Af ter evacora-L-on of the solvent, the result1-ing residue was ourt: ied by column chromatography on silica gel using a mixtufe ofc dichloromethnane and methanol (30: 1) .The obtained oprocuct was diJssolved i-n ethyl acetate and treated with 4N hvdr-ocfen chl-'oride In ethyl acetate solution (0.6 ml) to give dimL-eth,-benzl)4F4(4cycloexyl--orerazinlyl)-2 butynyli ie razine tri4hvdrochloride (220 mg).- 75-1 a,252 T) 7.20o MeOH) 'R (Nujol) 3370, 2750-1920, 165 1276, 1126 cIM WI- NR S d 6 02- 5. 20 (38H, in), 6. 60-8. 30 (6H, o. so HASS :664 (free) F~xamole ?otC-assium carbonate (187 mng) and 2-(chloromethyl)pyridine hydrochloride (81 mog) were added to a solution of (tr-i"F uov-oriethryl) benzoylj 4docm-etnhvlb.Ienzyl,)pniperazin--e (200 mg) inN,N-dimethylform-amiTde o so (4 ml) at roomr temperatEure with stirring. After 2 -hours, the react4-on ixture was poured into water (50 -ml1) and extracted with ethvi =cetac-e. The organic layer was washed with water and tEhen dried over magnesium. sulfate, and evaporated under reduced pressure. The obtained residue was purified by colum-n chromatography on silica gel -,sing a mixture of ethyl' acetate and t oluene and treated with 4N hydrogen chloride in ethyl acetate solution to afford his (tri-fluoromethyl)benzoyl] 4-dimiretlLhylbenzyl) (2pyridylmethyl)pi-perazine dihydrochloride (123 mng).

2aA 3 28.30' MeOH) 7R (Nujol) :3360, 2560, 1640, 1278, 1130 c- -NNR (DMSO-d 6 5) 2.0-2.3 (l0H, in), 2.6-5.8 (9H, mn), 6.6-8.7 (1OH, m) MAS S 536 (free) Exarmole 71 Lndlar ca-alyst- (Pd-OaC-Pb(OAc)q) (40 mg) was added _C a soluti-on of 2 R)-l- 3 ,S-bi-s(tri-Fluoromet-hyl)benzoyll- 2 (lHi 1o- 3-vlwTrehy)4-(4-mnorph no'- no- 2 -butynyl)pioerazirne in methanol (8 The mixture was st-irred for 2 hours under ,_-cgen at 25 0 C and then filtered. The filtrate was conce ntrated un-der reduced pressure and 'the resulting residue was chr-omatographed on silica gel with dichloromethaneme-tharol 1) as e'luent to give materiLal which on treatment wvith 4-N- hydrogen chloride in ethy-.-l acetate solution afforded (2R) 3, 5-bis (t-rifluoro-methyl)benzoyvl1-2- (1H-indol-3- 15 y]'e-In. 4- 4 -morphol ino-2-but env! Ipiperazine dihvdrochl,_cri4de (104 mg) 12 +0.40o MeCH) T-R (Nujol) 3700-3150, 2750-2300, 1635, 1275, 1170, 1120 cm'1 NMR (DMSO-d 6 ,5 3.00-4.10 (21H, in), 6.05-6.35 (2H, m,6. 80-85.10 (8H, mn), 10.72 (1H, s)I MAS S 595 fr e e Examnle 72 The following compound was obtained according to a simoillar manner to that of Example 71.

(2R -Bis (cri-fluoroiethyl)benzoyl-i2-(3,4dimet-hylbenzyl) r(Z) 4 -mornholino-2-butenyl piperazine diby,-,vdrchlor ide rip :243-246 0

C

LF I 2 1 -5.30' MeOH) IR (NujT, ol)1 3600-3150, 2600-2300, 1645, 1275, 1170, 113Q0 cm- 1 (DMSO-d6, '5) NMR D~s-d 6 5) 2.10-2.20 (6H, in), 3.0-4.2 (21H, c,6. 05-6. 35 (2KH, 6. 80-7.10 (3H, mn), 7. 60 (2H, 8) 8. 09 (1H, s The NMR snectrum of this compound was measured at 9000 M'ASS 584 (free) Examnple 73 A solution of 2 P4)-l-[ 3 1 5 -bis(trif!loromethyl)benzoyl] ?-IKinoi3-lmthi 4 in-rcrhc-'-iLn-2-butynvl)pieraz -e n methanol (10 ml) was hydrogenated in the presence of Pd-carbon (50 at room teinoerature. A--fter completion of he rea;ctLion (1 h-our and 20 -minutes), the reaction mixture was filt1-ered and then chrornatograpned onr silica gel wotn.

ri--r,-lorornethane-methanl (20:1) to gi4ve material which on treatmen- with 4N hydrogen chloride in ethyl acetate solution affrded 2 R)-i-L' 3 ,5-bis(trifi-P- uoromtivl)benzoyl-2-(!H i ndo',-3-ylinethyiL) 4 mor )holinobutyl) piperazine dihydrochlori-de (165.1 mg).

[u]21 7.100 MeOH) TR (N\ujol1) 3700-3150, 2720-2450, 1635, 1275, 1180- 5....1080 cm NMIR (DiMSO-d 6 5) 1.70-2.00 (4KH, 2.95-5.20 (21H, in), 6. 60-8.25 (8H, mn), 10.95 (1H, s) 11.10-11.80 ~MAkS S 597 (free) Examole 74 The -following compound was obtained according to a simlarmanner to that of Example 73.

3 ,-Bis (trifiluoromethl)benzol..2-(3,4-~ dimet -hvlbenzyl) (5-morpn)o linopentyl)piperazine dihydrocchlcride mp :235-2380c -13.900 MeOK) T?.(Njol :3500-3100, 2600, 1630, 1270, -1180-1060 CM NYh4R (D SO-d~,6) 1.2-2.0 (6H, in), 2.0-2.5 (8H, mn), 2.6-5.2 (19H, in,6. 6-8 .3 1.26 (2H, im) MKASS :600 (free) Exam-ole -s(t -rifluoronec hy1,)benzoy'Li-2-(3,4diin~etb-)v 1 -ber-,zv)pioerazine (200 mg) and potassiumn carbonate (167 ing) were added to a mixture of 4-morpholino-2butenyl chloride hydrochloride (105 ma) and aceton-itri'le (3 T 'n resulting mixture was heated at reflux temperature uLnder Afi g ter 16 hours, the reaction mixture was evaicorated under reduced pressure and the residue was -oartiti-oned between ethyl acetate and water. Th.--e organic hase was se-carated and washed witrh brine, and dried over maaneslrn su'l;:ate. T"he solvent was removed in vacuo to leave an which was chromatograpohed o-n silica gel with dichloroinethane-methanol (50:1) as eluent to give material which on t~reatment with 4N hydrogen chloride in ethyl acetate ?C2 solution (0.2 ml) afforded (2R)-l-[3,5-bis(t'-.rifluoroinethyjjbenoyl-2-(3,4-dimethylbenzy')-4-[ (E)-4-inorpholino-2butenv-liioiperazine di4hydrochloride (194 mng).

236-2420C 0 6 19.6 [cc D 10.8' MeOH) 3350, 2900, 1645, 1275, 1185, 1,170, 1 135 cm'i- NY R (DMSO-d 6 6) :2.16 (3H, 2.20 (3H, 2.60- 4.80 (19H, mn), 3.91 (4H, t, J=4.8Hz), 6.04-6.40 (2H, mn), 6. 74-7 .15 (3H, mn), 7 .61 (2H, s) 8. 08 (1H,

S)

The NMR spoectrum of this compound was measured at MA S S: 584 (free) Examiple 716 The ffollowing compound was obtained according to a :n--rmanner to that of Examnle (2-Rl) 5-Bis (rrifluoromethvl) benzovlj (lH-indol-3- 7 vlm-Lethyl(-- 4 -mqorpho-linc-2-butenyl-Ipiperazine aihvdroc}horide mc 123-128 0

C

3, MeOH) IR (uo) 35,25-2000, 165z5, 1635, 1275, 1175, 1125 cm'1 NMR I( DM SO- d 6 6) :2.60-5.00 (17H, mn), 3.89 (4H, t:, j=4.8Hz), 6.0 40 2 H, mn) 6.7 0- 7 .5 0 (5K, im) 7.80 (2H, 8.03 (iLH, 10.74 (1H, s) The INYR spectrum of this compound was measured :9 15at 90 0

C.

Lk :LSS 5-95 (free) Exarriole 77 To astired mixture of (2R)-l-F3,P bis t o e h lh n o i 4n o -im t v p1DLerazi-ne (0.2 g) and 1-methyl-4z--formy-1KH-pyrazole (0.05 g) 0. in dichloromethane (2 mvl) under nitrogen atmosphere was added sodium triacetoxyborohydride (151 mng) at room tem-perature.

After 4 hours, the reaction -mixture was evaporated under 25 reduced pressure, and ethyl acetate (20 ml) and aqueous sodium hydrogen carbonatEe solution (10 ml) were added -to the residue. The organic layer was separated and washed with blrne, dried over magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by column chromatography on sil-1ica gel using a mixture of ethyl acetate and methanol (50:1) The obtained product was d 4 ssolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl- acetate solution to give bis(trif4-luoromethyl)benzoyli-2- (lH-indoi-3-ylmethyl)-4-[\ (1 methyl.--l-cvrazol-4-yl)methyljpip~erazine hydrochloride (154 ma) MC:1 22-136 0

C

rt 18 .8 9.S0(=0

,MO

TR (Nujol) :33570, 2750-2000, 1655, 1640, 1275, 1175, I1125 cm~ HIMIR (DMYISO-d 6 5) :2.80-5.20 (14H, in), 6.50-8.30 mb), 10.90 (IH, 11.40-11 .90 (1H, br s) M'IASS 550 (free) Exarnole 78 Amixture of (2R) F3,S-bsrifluoromethyi)benzoyl>-2- 4-diJmethvlbenzyl') -4-f 2- (merL-hvlsulfonyloxy) ethyl] pioperazine (200 mg), 2-ethoxyethyla-ipe (0.044 n.1) and triethylamine .:00 (0.098 ml) i-n acetcnitrile (5 rnl) was refluxed for 1.5 -hours.

T1he reaction mixture was concentrated under reduced pressure .0and 7:he reuig resi1due was partitioned between ethyl .0 ~acetate a-nd aafueous sodium hydrogen carbonate solution. The organic layer was washed with brine and dried over magnesium 0 0 sulfate. After evaporation of the solvent, the residue was *o ourified by column chromatography on silica gel using a mixture of diLchloromethane and methanol (20:1) 'to a-fford an *00 Oily product, which was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate solution *to give 2 R)-l-[3,5-bis(trifluoroieThyl,. )benzol]2(34, t- iety 11 ,e izvly -1 4- [92- (2etoxetylmno) ethylipiperazine dihyd~rochi-oride (64.5 mg) r 22 LG(JD 6.70' NMeOH) IP (Neat) 3400, 2650, 1640, 1430, 1280, 1170, 1150, 900 cin' NM'R (DMSO-d 6 5) 1.63 (3H, in), 2.0-2.30 (6H, in), 2.6-5.3 (20H, in), 6.6-8.3 (6H, in), 9.2-9.6 (1H, brs 1 2 -11 .8 (1K Alir s) MLAS S 560'D(M+l) (free) Preoaration 8 To a mixture of N-(tert-butylcarbonyl)-4-fluoro-Dphenylalanine (5.25 N-benzylglycine benzyl ester hydrochloride (5.41 g) and triethylamine (9.04 ml) in dichloromethane (50 ml) was added 2 -chloro-l-methylpyridinium iodide (5.21 g) at room temperature, and the mixture was stirred for 2.5 hours. The mixture was evaporated under reduced pressure, and the resulting residue was dissolved into ethyl acetate. The ethyl acetate solution was washed with diluted hydrochloric acid, saturated sodium hydrogen carbonate aqueous solution and brine successively, and dried over magnesium sulfate. After evaporation of the solvent, the resulting residue was chromatographed on a silica gel using a mixture of toluene and ethyl acetate as an eluent to give (2R)-N-benzyl-N-benzyloxycarbonylmethyl-2-(tert- 15 butoxycarbonylamino)-3-( 4 -fluorophenyl)propanamide (9.62 g).

23.6 r]D 3 6 9.100 MeOH) IR (Nujol) 3350, 1735, 1680, 1650 cm-1 NR (DMSO-d 6 6) 1.24, 1.30 (9H, 2s), 2.70-2.90 (2H, 3.85-4.80 (5H, 5.12 (2H, d, J=3.2Hz), 6.95- 7.45 (14H, m) MASS 521 (M+l) Preparation 9 o an ice-cooled solution of (2R)-N-benzyl-N- 25 benzyloxycarbonylmethyl-2-(tert-butoxycarbonylamino)-3-(4fluorophenyl)propanamide (9.48 g) in dichloromethane (55 ml) was added 4N hydrogen chloride in dioxane solution (54.6 ml) The mixture was stirred at the same temoerature for minutes and at room temperature for one hour. After removal of solvent by evaporation, excess aqueous sodium hydrogen carbonate solution was added to the resulting residue.

The mixture was warmed at near 50°C for several minutes and the resulting precipitates were collected by filtration and washed with water and dried in vacuo to give (3R)-l-benzyl-3- 4 -fluorobenzyl)piperazine-2,5-dione (5.00 g).

93 F~x 27 3 -20-30' MeOH) IR (Nujol) 3200, 3050, 1665, 1220 cm'1 N R (DT-MSC-do-, 6) :2.90 (1H, d, j=17.3Hz),, 2.88 (1H, ccd, J=13.711Hz, 4.7Hz), 3.15 (IH, dd, J=13.7Hz, Ai.T 3.53 (IH, d, J=17.3Hz), 4.15 (IF, d, u=14.4Hz), 4.26 (1H, mn), 4.63 (iF, d, J=14.4Hz), 6.80-7.40 (9H, mn), 8.33 (1H, br s) 7AS S 313 (M+1) re-caration 1 To an ice-cooled suspension of li"thium aluminum hydride '1.2 g) i_ tetrahydrofuran (91 ml) was added (3-R)-i-benzyl-3a(4- 1 uorobenzy)piperazine-2,5-di-one (4.95 g) by small portons. The ixtue ws-s:rred at the same temperature is for 15 minutes and at room temp~erature for one hour. After removal of solvent by evaporation, aaueous sodium hydrogen carnonate solution was added to the resulting residue.Th iixture was warmed at near 50"C for several minutes and the *...resulting precipitates were collected by filtration, washed with water and dried in vacuc to give (3.R)-l-benzyl-3-(4f 1 u o 1be n z v -o oe ra z ince (4.60 g) as an oil.

T R (Neat) 3300, 1215 cm_ NYR (DMSC-d 6 ,6 1.90 (2H, in), 2.45-2.90 (SF, mi), a. 6, 3.30-3.45 (4H, in), 6.95-7.35 (9H, m) 25 MASS :285 (M+1) Prenaration 11 A mixture of (2R)-4-benzyl--[r3,5-bis(trifluoromethyl)benzovll-2-(4--Flu,-orobenzyl)piperazine (7.92 ainmoniuin formate (2.38 g) and 10H inaladium charcoal (0.79 g) in a mixed solvent of ethanrol (80 ml1) and water (8 ml) was stirred for 1.5: h)ours at 60'C under nitrogen atmosphere. The reaction mixture was cooled to room temperature and filtered through Celiteu pad. The filtrate was concentrated under reduced poressure and the residue was dissolved into ethyl acetate. Th-e solution was washed with water and brine su,.ccessively, dried over raanesium sulfrate, and evaporated .nder reduced pressure to give (2.R)-1-[35 b)is :ilooehlben zoyl],-2- (4-fluo rob enzyl)piperazine '6.04 g)j as an oil_ -l1X127.8.5 MeOK) IR (Neat) 3300, 1630, 1150 cr- NR (DMSO-d 6 5) 2.53-3.80 (8H, TP), 4.25 (1H, i) C.9-750 H5, mn), 7.64 (1H, br 8.13 (1H, br s) MATS S 435 Prenaration I? Ihe following compoounds were porepoared by a similar manner to that of Preparation 8.

(I (2RP) -N-Benzyl--N-b-enzyloxvcarbonyrechyl-2- (tertbutoxycarbonylami-no) (4-iethoxyphenyl) pro~anami'de 0 foc D +6.600 MeOH) IR (Neat) 3300, 1740, 1700, 1650, 1240 cm'1 INMR (DMSO-d 6 5) 1.27, 1.31 (9H, 2s), 2.76 (2H, mn), 3.69, 3.70 (3H, 2s), 3.95-4.90 (5H, 5.13 (2H, d, J=4.9Kz), 6.70-73 1K n MAUS S 533 (M+1) 0 5 K2 (21R) -'N-Benz v!-N-benzyvloxycarbonvlneth vl-2 (tert-butoxycarbon~v 1 amino) (4-tri-fl-uorone-hv'Lphenyl) propana-ro.ide +9.00' MeOK) IRP (Nu-jol) 3350, 1735, 1720, 1670, 1650 cmn' NMR (D-MSO-d 6 5) 19, 1 .27 (9K, 2s) 2. 90 (2H, mn), 4.00-4.75 (5K, mn), 5.12 (2H, 7.10-7.60 (15K, mn) MASS :571 (M±1) -N-Benzy1-N-ber'7yloxycarbonylinechyi-2- (tertbutoxvcarbonylamino) (1-naphthyl) prooanainide Lu 0.60' MeOH) L1?. (Neat) 3300, 2970, 1740, 10,14 xf NMIR (DMSO-d 6 6) 1.18, 1.26 (9H, 2s), 3.20-3.50 (2H, mn),(H i),7 3.90-5.20 .0-8.10 (17H, mn) MA8S S 553 (M+ii) PrenaraTionr 13 The following compounds were prepared by a similar manner o of o Prerara i- raion 9.

"OtI7.9 -38.600 MeOK) R'Q (N\ujol) 3250, 1680, 1640, 1245 cm- NMR (DMSO-d 6 65) 2.60 (1K, d, j=17.2Kz), 2.80 (1K, dd, J=13.6Hz, 4.7Hz), 3.09 (1K, dd, J=13.6Kz, 153.8K-z), 3.46 (1K, d, j=17.2Hz), 3.67 (3H, 4.1 (1KH, Ci, J=1 4. 4Kz), 4.22 br s) 4. 65 (1K, d, u= 1 4.4KHz), 6.63 (2H, d, J=8.7Hz), 6.93 (2H, d, j=S.7Kz), 7.10-7.40 (5K, in), 8.30 (1H, br s) *MA2S S 325 (M+1) (3-R)-1--Benzvit-3- 4 dione F26.8 -12.000 MeOK) L ID I R (Nujo 1) 32510, 1680, 1650 cm'i INMYR (:DMS0-d6-, 6) 2.85 (1H, d, j=17.4Kz), 3.00 (1K, dd, J'=13.4Kz, 4.8Hz), 3.25 (1K, dd, J=13.4Hz, 3.59 (1H, d, J17.4Kz), 4.08 (1H, d, J=14.4KHz), 4.35 (1H, br 4.74 (1K, d, J=14.4Kz), 7.00-7.15 (2H, mn), 7.25-7.35 (5KH, mn), 7.48 (2K, d, J8=.lHz), 8.41 (1K, s) MALSS :363 (M 1) 3) (3R) -1,-Benzvl-3- (l-naphf T -P (Nuj o 1) :3250, 1685, 1655 cm-' -NMR (DMSO-d 6 6) :2.92 (1H, d, J=17.2Hz), 3.40-3.65 .0 o.

a.

(3H, M) 4.31 (3H, 7.03 (2H, in), 7.29 (5K, Mn), 7.54 (2H, in), 7.82 dd, J=6.Hz, 3.0Hz), 7.94 m) 8.14 (1m, i, 8.31 (1KI, d, MJLSS 345 Breoaration 14 The following compounds were prepared by a similar manner to tnat of Prenaration 3 R)-if-enzyl-3-(4 -me hoxbenzy-)piperazine (Neat) 3250, 1240 cm.' NMIR (DMSO-d 6 6) 1.60-2.00 (4H, 2.40-2.90 3.30-3.50 (2H, mn), 3.70 (3H, 6.81 (2H, d, J=8.6Hz), 7.07 (2H, d, j=8.6Hz), 7.15-7.40 (6H, m) 15 MASS 297 (3R)-1-Benzvi-3-( 4 -triflu-,orommethylbenzyl)piperazi -5.80' MeCH) iR (Neat) 3250, 2925, 2800, 1320 cin 1 NWI (DMSO-d 6 6) 1.72 (1H J=10.Oz), 1.91 (1K, 2.55-2.95 (6H, 3.30-3.50 (3K, 7.15-7.35 (6H, 7.40 (2H, d, J=8.OHz), 7.60 (2H, d, MAS S 335 (M+1) (3R)-l-nenzvil-3- (l-naphzhvlmethl)piperazine 1- 27.6 11 8 Ct -2.8 MeOH) -R (Neat) 3300, 3050, 2925, 2800 cmir NMR (DMSO-d 6 6) 1.75-2.05 (2K, 2.50-3.60 (9H, 0 in), 7.10-7.65 (9H, 7.77 (1K, d, J=7.9Hz), 7.90 (1K, 8.12 (1H, dd, J=7.11z, 2.3Hz) MASS 317 (M+1) Preoaration The following compounds were prepared by a similar a *O O# a 3 manner to th~at of Preparation1.

meznoxvbenzyl) piperazine D 32.60 (C05, MeOiK) -R (Neat 3300, 1630, 1280 cm 1 _NMS (DMYSO-d 6 5) 2.40-3.55 (9KH, rn), 3.72 (3H, s), 6.70-8.45 1,7H, in) HAS S -47 I 2R)--(3,S-Bs~trfluromehvlbenzovl]-2-(4t rifuo roe -hyibenzyl) piperazine NII I M'O-d6, 5) 2.60-3.70 (9H, mn), 7.15-7.40 (21H, 7 _50-7.75 (4H, mn), 8.12 (1K, s) 1. MAS 4 85 M+ 1 0. 3 (2R)iF 13, 5-Bis (trif lurornethvl) benzoyl] (1- *naphtrhylmerhyl) piperazine a,128.1124.110' MeOH) 1 R (Neat) 3340, 3050, 2950, 2825, 1630 cm'1 NMRP (DMSO-d, 2.50-4.30) (9H, in,7.10-8.55 (10H, mn) too*MAS S :467 (M+1) 9 Precaration 16 25Ainxture off l-rehv-1H-oyrazole-4-carboxaldehyae g) and -etl hosphonoacezate (4.52 g) in N,Ndime thyl fo riamide (20 ml) was stirred under ice-cooling.

Aft:er several minutes, sodium hydride (1.09 g, 60% in ,viner-a! oil1) was added to the mixture, which was stirred for 1 hour at the same temperature. The resulting mixture was poured i-nto ice-water, neutralized with aqueous ammonium acetate solution and extracted with ethyl acetLate. The organic layer was washed with brine, dried over magnesium sulfate and concentr-ated under reduced pressure. The resulting residue was chrornatocraphed on a silica gel using a mixture ot hexane and etnyvI acetat e as an eluent to give etLhyl- (E)-3-(l--Methyl- 1H-oyr-azol-4-v acryl!ate.

R ci) 2975, 1700, 1635 ci-'- NM?. (DM---SO-d 6 5) :1.32 (3H, J=7.lHz), 4.23 q, 6.16' (1H, d, 7.54 (1H, s), 7.5(1,dJHCz, 7.69 (1KH, s) Drepararlon 17 1 0 Aso.-ution of 2-(E)-3-(1,-m-rethy1-1K-pyrazol-4-y1)acrvlace 7} n etra-hydrof'uran (50 nil)' was hydrogenated over pa 1 a-i chbarcoal (0.2 ar) at room t:emcoerature at 2 atm of hydrogen. After removal of catalyst by filtration through ce:e oan, the filtrate was concentrated under reduced ressure to give ethyl 3-(1-mrehvl-1'H-oyrazo-4,-yl)- TR (Neat) 2950, 1725cm NIVIR (DMSO-d 6 5 1.24 (3=t 7.lHz), 25 2,t 2.78 (2H, t, J=7.5Kz), 3.84 (3H, 4.13 (2H, q, 7.18 (1KH, 7.31 (1H, s) %LkSS 183 (M+1) V, Prenarazio-ib~ T--o an ice-cooled solution of ethyl 3-(-m.ethyl-1H- 2 pyrazol -4-yi;)propionate (1.05 g) in tetrahydrofuran (10 ml) was added l-ithium a~uminum. hydride (0.22 g) under nitrogen atmos o'ne r e. A-fter the mixture was stirred for 30 minutes, water and 159: sodium hydroxide aqueous solution were added successively to the mixture. The resulting precipitates were filter-ed off through Celite® p-ad and the filtrate was extracted with ethyl acetate. The organic layer was washed with- watr, ried over magnesium slf-,-:ate and concentrated under reduced pressure to give 3-(1-met-hyl-1H-pyrazol-4-yl)- -prop;ano -I.

i-P. (Neat) 3300, 2930 CMn7 _NMR (DMSO-dA 1 1.87 (2H, 2. 55 (2H, t, 6Fz), 3. 68 (2H, tJ6.l1rz), 3. 85 (3H, 7. 16 MASS 14 1 (M-rlI Prenaration i To a Szolu tion oxalvl' chloride (0 .361 ml) in dichl--oromethare (10 Cole below -65'C with a dry icea:cetone bDath, a- solution of dimethylV sulfoxide (0.381 irr 1 in ic' 1 oromethane mI r) was added wit h effici ent s- irrino- over minutes After 20 minutes below -O65 3 C, a solution of 3- 9. (i-merh'-v-lF',--pyrazo'L-4-yl) -1-propanol in dichloromethane (2 m, m) was added to th)e mixture over 10 miLnutes below -65'C and too 0.the mixture was stirred at the same temoerature for 1 s a-ri then a-4S- -40 for 30 i-nnutes After :addition o-f zriethvlami ne droowise to the mixture over minutes followed by stirring for 15 miuei hdohoi acid solution was added to the mixtu-,re. The resulting t rmixture was extracted with a mixture of dichloromethane and methanol several times. The extract was concentrated under 9*R*reduced pressure and the resulting -residue was on-romatog~raphed on a si lica gel using a mixture of dichloromethane and methanol, as an eluent to give methyl -lH- yrazo1-4--v)-i oroan11 TIR, (Neat,) 2925, 1720 cm- 1

N

T

MR (EMSO-d 6 :2.651--2.90 (4H, in), 3.86 (3H, s), 7.17 (1H, 7.32 (1H, 9.80 (1H, s) M4ASS 139 7_xamnle 79 To a mixture of 3, S-biLSzrifluoromethyl)benzoic acid (4.13 g) and pyridine (0.041 ml1) in tet-rahydrofuran (12.5 mal) -11as added oxalyl chloride (3.25 a) over 15 minutes at 22-38-C and the -mixture was stirred at 55'C for 4 hours. The acid chloride solution obtained above procedure was added to an 100 ice-cooled solution of (3R)-1-benzyl-3-(4-fluorobenzyl)piperazine (4.51 g) and triethylamine (4.83 g) in dichloromethane (45 ml) under 5 C for 30 minutes. After being stirred for 2 hours at room temperature, the mixture was washed with water and brine successively, and dried over magnesium sulfate. After evaporation of the solvent, the resulting residue was chromatographed on a silica gel using a mixture of toluene and ethyl acetate as an eluent to give (2R)-4-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(4fluorobenzyl)piperazine (0.87 g) as a syrup.

27. 5 [a]D 5 -11.500 MeOH) IR (Neat) :1740, 1150 cm-1 NMR (DMSO-d 6 5) 2.00-4.40 (11H, 6.80-7.50 7.74 (1H, br 8.13 (1H, br) S 15 MASS 525 (M+1) Example The following compounds were prepared by a similar manner to that of Example 79.

(2R)-4-Benzyl-l-[3,5-bis(trifluoromethyl)benzoyl]-2-(4methoxybenzyl)piperazine 28.0 [a]D -21.40' MeOH) IR (Neat) 1740, 1640, 1270 cm-1 NMR (DMSO-d 6 5) 1.70-2.40 (3H, 2.60-3.80 (11H, 6.60-7.60 (10H, 7.65-8.55 (2H, m) MASS 537 (M+1) 2 R)-4-Benzyl-l-[3,5-bis(trifluoromethyl)benzoyl]-2-(4trifluoromethylbenzyl)piperazine IR (Neat) 2950, 2800, 1765, 1740, 1640 cm-1 NMR (DMSO-d 6 5) 1.70-4.30 (11H, 7.13 (1H, d, J=7.8Hz), 7.20-7.70 (10H, 8.13 (1H, d, J=7.8Hz) MASS 575 (M+1) nptylme-.hvi-1 Piperaz ine Ct 7-9 7Q 0 C= 0 ,MeO 7 R o C 0c NMIR W4MSO-d, 2.00-4.40 $Imi), 7.00-8.55(5, MLAS S 557 (M-1) ~xam-cle 81, The _folowina compound was prepared by a similar manner f: ccxamole diinTech,-vbenzv)43(cis2,6-d4ne-hyimopholino)prpy1, pe-z in dih y d ro choi d e LI-110 5, MeOK) R 3400, 2550, 2450, 1640, 1430, 1280, 1175, 0-1130 orK'i N-I4R (DMSO-d 6 6 1.14 (6M, in), 2.05-5.24 (9KH,i) 20 2.10 2.18 (3H, 6.

6 4-8.24 (6H,m) MASS 600 (fee Ana 1 C aIcd f o r C 3 lH 3 9

F

6

N

3 0 2 *2HCi-_. 35H 2 0 C 52.08, K 6.29, N 5.77 Fo,,nd 52.08, K6.44, N 5.88 Exarmole 82 The following compounds were obtained according to a scinclar manner zha: of Example 223 1)( 2 R--r3,5-Bi-s(- -uor-foomethyl)benzovl-2-(3, 4 odimet)hvlbenzyl) 3 pyr.idylrmezhyl!) -3-aminoprocyl] jp: perazine :-rihydrochloriae Da128. -13-60' (C0.25, leOH) (Neat) 3600-30,20-90 1270, 1125 cmK NMIR (DMSO-d6, 6) 2.09-5.20 (24K, in), 6.60-9.00 H i, -n) MASIS 593 (free, A~al. Calod. for C 2 1

H-T

34 NO l C 48.10, H 5.86, N 7.24 Found C 47.89, H 5.75, N 7.02 j '21 I 3 ,S-Bisrrrifiooet~v 'bnov2oirnernyibenzyl) (N-lorolino-2-aminoethyl)piperaz-ne nihydrochloride I -26.80' (C=0.25, MeOH) (Near) 3600-3000, 2800-2000, 1630, 1274, 1120 crn' MR !DMSO-d 6 2.02-5.2' (28f, 6.50-8.30 (6H, T,) MASS 573 (free) Anal. Calcd. for C 2 8

H

3 4

F

6

N

4 0q'2HC1'9/2H 2 0-1/4cH 3 co 2

C

2

H

5 C 46.53, H .33, N 7.48 Found. C 46.64, H 6.23, N 6.67 (2R)-1-i3,5-is (:r-illuoromethyl)benzoyli-2-(3,4oirethvlbenzvl) (N-mr,.o-nhclino-4-arnino-2butynyl)piperazine dihydroohloride -28.0 .e- D 9.80' (C=0.25, MeOH) )Nea:) 3600-3000, 2600-195C, 1630, 1273, 1120 cm NMR (DMSO-d 6 2.10-5.2 0 28H, 6.20-8.30 (6H, n) MLASS 597 (free) 2 1) -r3, 5 -B i s (r i fluo r ome tIlv) benzovi 4 di-ethvlbenzvl) FN- me h 3 yr icylmrehv 2aminoethyijpiperazi ne :rihvdroohloride [c 8 -11.80 (C=0.25, MeOH) 1K (Nujol) 3600-3100, 2700-1950, 1630, 1275, 1122 cm 1 NMR (DMSO-d 6 6) 2.10-5.20 (24H, 6.60-7.80 (6H, mi), 8.10-8.35 (2H, 8.70-8.95 (2H, n) MASS 593 (Mri-i) (free) Anal. Calcc. for C 3 1

H

3 F 4 0*3HCi-7/2Hqo C 48.67, H 5.80, N 7.32 103 Found C 48.88, H 5.88, N 6.79 S a

*SSS

S

-iethnv 1 benzyl) -4-1 -Nl-(3-pvridvITmethvl) 4-amino.2.

butenylioperazine trihydrochlioride _C41 8 .3 10.40O (C=0.25, MNeOK) -R I-Neat) :3600-3100, 2800-1950, 1630, 12-1,12 C-1 NMp $lDmso-d 6 5) 2.09-5.20 (22H, in), 6.05-6.25 (2H, 6.60-9.010 ('LOH, m) MAS S :605 (free) Ana'.. Calod. for C l 2

H

34

,F

6 N,,0-3HCl*5Ho C 47.80, H 5.89, N 6.97 Found C 47.81, H 5.53, IN 6.48 15 (R--S-Bs (zrJf Iucromreth1) benzoy1 4 diinethvibenzy'L) -N-inTorpholino-4-aml-noc-2-butenylI piperazine dihydrochlorlide [a]28-5 6.400 (C=0.25, MeOK-.) IR (NuJol) :3600-3000, 2750-1950, 1620, 1273, 1120 crr7' 20 NR(DTMSO-d 6 2.09-5.20 (28H, mn), 5.80-8.30 (8H, mn) MKAS S 599 (free) Anal. Calod. for C 3 0

H

3 6

F

6

N

4 0 2 *2HCI-7/2H?0 C 49.05, H 6.171, IN 7.63 Found :C 49.15S, H 6.16, N 7.41 R--3 -is(r iooehv~ezyj2 2 n~phthvlmethyl) (3-pyridylm-,ethyl) -2aminoethvlpierazine trihydr-ochioride 2 8.5 S -11-000 (C=0.25, MeOH) 0 TR (Near' 3600-3100, 2800-1950, 1630, 1273, 1120 cm-7 -NMR (-MSO-cd 6 :2 .50C-5-20 (16KHn, 7. 00-9. 00 (14K, mn) AS S 601 (free) Anal. C'ald. for C 3 2

H

2 0

F

6

N

4 03H-I14H 2 0 C 49.15, H 5.28, N 7.16 Found :C 49.26, H 5.24, N 6.80 5.

a S

S

.9* S S f'3,5-Bis(tr, -Fluoronerhy1)benzoy11-2-(2naphthvlnirethyl) (N-morpholino-2-a-minoethyl)piperazine dihivdrochlorlde La]D 34.80' (C=0.25, MeOH) IR- 'Nea-r) 3600-3100, 2800-1950, 1630, 1273, 1120 oin- 1 NMR (DMSO-d 6 5l) 50-5. 30 (22H, n) 7. 00-8. 20 (10H, mn) MAS S 595 (free) Anal. Caird. for C 3

H

2 6 4 2 jC-11/3H0 C 49.12, H5.68, N 7.64 Found :C 49.04, H 5.57, N 7.39 9) k'2R)-13r, S-Sis (rri fl urom-ethv1l) benzoyl (2naphthvlin-re-hyl) (N-Txnoholrno-3-ainnopropyi) pioerazi ne ~dirnvdrochloride is 2 8 .6 40.10' (0C=0.25, MeOH) R Nuo 3650-3100, 2800-1970, 1636, 1275, 1 123 c NIMR (DMSO-d, 5) :2.20-5.30 (24H, mn), 7.00-8.20 (1CMI, im), 10.60-11.80 (3H, mn) HASS :610 (-free), -Anal. Calcd. for C 3

H

3

F

6 N1O 2 -2HCl-3Ho C 50 62 H 5. 75 N 7.62 Found C 50.72, H5.58, N 6.99 (2Rl)-1-[L3,5z-Bis(tr-fluroinethvnyi)benzolj,-2-(2na-pn-.vrhvlmethviL) N- (3--oyri"dvlinTethyl) -4-aino-2- ]3utenv'lpiper-az~ne tr±hvdroohloride 28. c: 2 10.40o (C=0.25, MeOH) IR (Nujol) 3650-3100, 2750-1930, 1620, 1272, 1122 cmn 1 NTMIR (DMSO-d 6 3.00-5.30 (16H, mn), 6.00-6.30 (2H, mn), 7.00-9.10 (14H, mn) 627 (free) Aal. Calcd. for C 3

H

3 6 N 0 -3 HC -2H 2 I?0 C _52.89, H'T S.09, N 7.26 Found :C 52.73, H 5.09, N 7.16 naphr-hyl-methyl) -N-moroholino-4-amino-2burLenvi] pipera zine dihYdrochloride 2D 13.0C0o (0=0.257 -MeOH) R (Neat) 3650-3000, 2750-1970, 1630, 1274 cm', NMR (MSO-d, 6) 2.80-5.30 (22H, mn), 6.15-6.50 (2H, mn), 7.00-8.25 (10H, rTn) MS 621 (free) -B-is (t rifluorcmpet-hvl)b'enzov'i-2--(2an-1}c- 1 .erhvl) 13 yrd vlme hv -3 am-o-or-oy 1 jpJoerazine rrii'rydrochlcride L 28. 24.60' (C=0.23, MeOK) Z(Nujl) 3600-3100, 2750-1950, 1630, 1273, ji_21 cmi- NMIR (IDMS-d 6 5) :2.20-5.30 (18H, 7.00-91 1K n MA7S S 65(1 (free) A~a. Clo. fr' 3 3 3 2

F

6 1N 4 03C03 2 0 050.56, H 5.36, N 7.15 Found C 5 0 .5,3 1K -7 5 .3 8, N 6 .9 4 Examo-e 83 Tbe following compounds were obtained according to a similar manner to rthat of Exa-mple naon.-Itl'vlmre-Ehvl (4-homomoroho7;ino-2-butyny1')piperazi-ne dihvdrochloride I C41D 19.800 MeOK) 'Neat) :3400, 25:00, 1640, 1430, 1280, 1175, 30130 cin NMR, (DM.SO-d 6 5):.05-73.34 (23H, 7.05-8.20 m) S 6 18 M I Anal ~aca. or 3 3 3 3 6 3 0 2 '2HCL2.9 2 0 C 53.37, K 5.53, N 5.66 Found :C 53.38, H 5.47, N 5.67 1C6 (2 -i'lc or t v )e zv -3 f~o o 4 :.e:',v_'benzvl) F 4 -morphol-ito-2 -but enyijpiper az-ne ihvdrcch_oriie D *Q (0=0.5z, MeO0H) ±R '(N-Ljol) 2400, -1645, 1275, 11-3 5 cirL MR(DMSO-d 6 5) 2.2C (311, s) 2.80-5.20 (21H, in), 6. 00-8 .26E (mi) 2MAS S 588 (M-f1I) (free) T,%al. Calcd. for C 29

H

2

F

7 3 0 2 .2T-Cl C 52. 74, H 5-.19, N 6.36 Found C 52 .39, H 5 .20, N 6.29 2 R)-l-f 3 ,5-Bis(rrifl-uromethy)benzovl>2(3fluoro-4 *.*.iethrvilbanzvl)-4-L E)-'4-ch1oro--Lutenv'piperazine (Neat) 1640, 1430, 1275, 1130 cm 1 .NT4R (DMSO-d 6 5) 1.91-4.93 (13H, in), 5.71-8.20 (8H, mn) M~ SS 53-7 MI 2 R)-l-r3,5-Bis(tr-',-luoroiethv)benzoyl]-2(3,4 20 di--e-r-ylbenzyl) 4 -morniholino-2-butynyl)piperazine dhvdrochl or ide ic:98-10-''C ~4R(DMSO-d, 5) 20R (25SH, mn), 5 .7 4 (l1H, br d), b.89 (1H, br 6.6-8.2 (6H, in) lMA S: 578 (-Free) A~a1 CacS. or 3 1 h 33 6

N

3 O.H~9 9 C 54.23, H 5.73, N 6.12 d :C 53.99, H 5.88, Nl 5.93 Examnele 841 The following compounds were obtained according to a s~mi±Lar manner to that of Exa.motle SC.

fl--'uorobenzyl) 4 -thi-omorrholino-2-butynyjpiperazine I U dihvdoch lo i de 8 180 0 C (dec.) MeOK) TR (Nu o 1) 3350, 1630, 1125 c" NMR (DY S0-d 6 6) 2.60-4.30 (21, in), 6.85-7.25 (3H, 7.46 (2K, br 7.75 (11, br 8.16 (1H, d, J=9.4Hz) MASS 5a88 (MVi (free) Anal. Calod. for C 2 8

KS

2

F

7 N-Os2KC>K 5 0 C 49.56, H 4.75, N 6.19 Found 49.47, H 5.13, N 5.93 L-3,5-Bis Er i fluoroinernyl)ben-zoyl]i (4e t I- eth xvbenzvl) 4 thJomorpholino-2-butynyl1piperaz 15 a'ihvdrochloride c _197C (dec.) L]28.1 8.60o MeO) 1. (Njol) :2500, 1640, 1275 cin 1 NYR (DMSC-d 6 2.60-4.70 (24H, ra), 6.70-8.30 (7H, m) 0.M; MSS 600 (free) 2~al. Clcd. for C 2 9 3 1

F

6

N

3 0 2 S.2KCl.1 3K 2 0 C 50.05, K 5.16, N 6.04 Found C 50.06, K 5.36, N 5.77 (2 I[ 3, 5-B i s r i fluorone thyl benzo vl]- 2 (4 r- 1uoromeFylbenzv1) -4 (4-:noraoro o zynyvi)oioerazlne dihydrochloride M-0 173"C (dec.) [cl1 0 +9.600 MeOK) 19. (Nujol) 2400, 1640 cm7 1 X0D /TCMJSO-d 6 6) 2.70-5.3 0 "1 H 7.22 (1H, a, J=7.7Kz), 7.41 (LK, 7.50-7.80 (4H, 8.18 1, d, J=7.Oz) 4ASS 638 (M 1) (free) An a. Cald. f or C 2 9 H 2 8 7 9

N

3 OS 2HC1l1.3H 2 0 .108 C 47.46, H 4.48, IN 5.73 Found C 47.43, H 4.51, N 5.51 2 3 5-Bis tr 1IF Iu orfo me th benz oy I2 n phyl-met-hyl) 4 -rhiozmoroholi _no-2-bu_,vnyl) piperazine o_ ihydrochloride 1-1 9102 (dec.'" .r 215.60' 5, _MeOK j ol 25300, 16357 cm- NMR (IDMSO-d 6 5) :2.65-4.80 (21KH, 7.10-8.60 (10H, mn) MA8S S 620 (free) ?xal Calcd for C 3 H- F 6 N CS-2HCl. 4H 2 C 54.92, K 4.87, IN 6.00 ound 5 C 548, K 5. 0 4, N 5 Examnole The following comr~ound was obtained according to a similar manner to that of Example 51.

k2R) 1 3, 5- B is fI uo ro m e th vl) b en zo v 1 -2 dimethylbenzvl) (1--methvl-1K----ovrazol-4'yi) propvllolJoerazine hydrochloride 16 3 -16 C_ -19.80' MeCK) 1.(jo) 2550, 1635 cJ NMR (DMSO-d 6 5):1.90-2.25 (6K, mn), 3.00-4.0'; (ISH, br), 6.65-8.25 (8H, in) LS S 567 (free) Anal Cal cd. -for C, 2 qH 3 2 F6N,,O-HCl-H 2 0 33 C 56.08, K 5.68, N 9.02 Found :C56.44, K 5.76, N 8.98 Exainocle 86 T"he following compound was obtained according to a s imilar manrto that of Example 61.

15

V

V V

V

(21R) 1- F3, Zb-Bs(IL,- oor-tylbezo nl dihydroch ioride 1002 (dec.) ,a2S* -0.63' (C=0 MeOH) 7-(Njo, 3660-33.3C, 2700-2300, 16-40, 1445, 1430, 1370, -2-70 cm.- NM DS- 6 5) :1.-1.50 c: (6H, in), 2.85-5.25 (19H, mn), 6.05-6.30 (2H, 6.65-8.25 (8H, iTn), 10.97 (11H, br 11 .40-12 .20 (2H, m MAS S 623 'tree) Exam-ole 87 The following compound was obtained according to a siml ar -manner to than_ of Exampcle 54.

dimrnethyl'-benzvl-)-4-13- 3 -pyri-dvl'prooyl,-Ioiperazine d ih yd ro c h Io)r ide t631680C 2.7.

MeOH) 7 t (Nujol) 3600-3300, 2700-2300, 1635, 1445, 1430, 280 cm- NR (DMSO-d 6 5) 1.92-5.22 (29H, mn), 6.56-8.28 (6H, 1.43 (2H, br s) 564 (_Free) Ana]- Calcd. for C3QoH lFN 3 2HCI1.4H 2 C 53.01, H 5.60, N1 6.18 Found C 5 3. 0 4, H 5.-9 8, N 5. 7 7 110- COMPARATIVE EXAMPLE S S *5 S S *5

S

*5*S

S

*5*S 55 5

S

S

The same as the test method shown on Pages 28 30 of the description of the present patent application.

P:\OPER\PDB\111&97.SPE- 15/11/99 -111- Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

SS

S.*f c e

S

*r S

S.

*S

0* a

Claims (2)

1. A compound of the formula: Y-R 2 o 1 11 I\ R C-N N R 4 R 3 e wherein Y is a bond or lower alkylene, R is aryl which may have suitable substituent(s), 10 R 2 is aryl or indolyl each of which may have suitable substituent(s), R 3 is hydrogen or lower alkyl, R 4 is chloro (lower) alkenyl; chloro (lower) alkynyl; pyridyl (lower) alkylamino (lower) alkyl; 15 pyridyl (lower) alkylamino (lower) alkenyl; N-(lower alkyl)-N-[pyridyl (lower) alkyl]amino- (lower) alkyl; triazolylamino (lower) alkyl; lower alkyoxy (lower) alkylamino (lower) alkyl; bis[(lower) alkoxy (lower) alkyl]amino (lower) alkyl; N-(lower alkyl)-N-[(lower) alkoxy (lower) alkyl]amino-(lower) alkyl; hydroxy (lower) alkyl; lower alkylsulfonyloxy (lower) alkyl; phenyl (lower) alkyl which may have lower alkanoyl, amino, lower alkanoylamino, di (lower) alkylaminocarbonyl or nitro; lower alkoxyphenyl (lower) alkylcarbonyl; P:\OPER\PDB\I 106-97-spe.doc-12/04/00

113- lower alkanoylbenzoyl; benzoyl (lower) alkyl which has lower alkyl, chlorine or di (lower) alkylamino; benzoyl (lower) alkyl which has halogen and lower alkyl; dihalobenzoyl (lower) alkyl; di (lower) alkylbenzoyl (lower) alkyl; 3-fluorobenzoyl (lower) alkyl; 3-(4-fluorobenzoyl) propyl; 4,4-ethylenedioxy-4-(4-fluorophenyl) butyl; piperazinylcarbonyl (lower) alkyl which has cyclopentyl or halophenyl; (2-pyridyl) (lower) alkyl; (3-pyridyl) propyl; (3-pyridyl) (lower) alkynyl; imidazolyl (lower) alkyl which may have lower alkyl; pyrazolyl (lower) alkyl which may have lower alkyl; 15 thiomorpholinylcarbonyl (lower) alkyl; (3-azabicyclo[3.2.2] non-3-yl) carbonyl (lower) alkyl; or thienylcarbonyl (lower) alkyl, 1,2,3,6-tetrahydropyridyl (lower) alkyl, 1,2,3,6-tetrahydropyridyl (lower) alkynyl, 1,2,3,4-tetrahydroisoquinolyl (lower) alkyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl (lower)-alkyl, Ssaturated heterocyclic (lower) alkyl, *saturated heterocyclic (lower) alkenyl, saturated heterocyclic (lower) alkynyl, saturated heterocyclicamino (lower) alkyl, saturated heterocyclicamino (lower) alkenyl or saturated heterocyclicamino (lower) alkynyl, each of which may have suitable substituent(s), and a pharmaceutically acceptable salt thereof. P:\OPER\PDB\lI 106-97-spe.doc-12/04/oo -114- 2. The compound of claim 1, in which Y is lower alkylene, RI is C 6 -Cl 0 aryl which may have 1 to 3 mono(or di or tri)halo(lower)alkyl, R2 is C 6 -C 1 0 aryl or indolyl, each of which may have 1 to 3 suitable substiuent(s) selected from the group consisting of lower alkyl, lower alkoxy, mono (or di or tri) halo (lower) alkyl and halogen, R 3 is hydrogen, and R 4 is chloro (lower) alkenyl; chloro (lower) alkynyl; pyridyl (lower) alkylamino (lower) alkyl; pyridyl (lower) alkylamino (lower) alkenyl; :N-(lower alkyl)-N-[pyridyl (lower) alkyl] amino-(lower) alkyl; triazolylamino (lower) alkyl; lower alkoxy (lower) alkylamino (lower) alkyl; bis[(lower) alkoxy (lower) alkyl]amino (lower) alkyl; N-(lower alkyl)-N-[(lower) alkoxy (lower) alkyl] amino-(lower) alkyl; hydroxy (lower) alkyl; lower alkylsulfonyloxy (lower) alkyl; phenyl (lower) alkyl which may have lower alkanoyl, amino, lower alkanoylamino, di (lower) alkylaminocarbonyl or nitro; lower alkoxyphenyl (lower) alkylcarbonyl; lower alkanoylbenzoyl; benzoyl (lower) alkyl which has lower alkyl, chlorine or di (lower) alkylamino; benzoyl (lower) alkyl which has halogen and lower alkyl; dihalobenzoyl (lower) alkyl; di(lower) alkylbenzoyl (lower) alkyl; 3-fluorobenzoyl (lower) alkyl; 3-(4-fluorobenzoyl) propyl; 4 4 -ethylenedioxy-4-(4-fluorophenyl)butyl; piperazinylcarbonyl (lower) alkyl which has cyclopentyl or halophenyl; (2-pyridyl) (lower) alkyl; P:\OPER\PDB\11106-97-spe.doc.12/04/00 -115- (3-pyridyl) propyl; (3-pyridyl) (lower) alkynyl; imidazolyl (lower) alkyl which may have lower alkyl; pyrazolyl (lower) alkyl which may have lower alkyl; thiomorpholinylcarbonyl (lower) alkyl; (3-azabicyclo[3.2.2]non-3-yl)carbonyl (lower) alkyl; or thienylcarbonyl (lower) alkyl, 1,2,3,6-tetrahydropyridyl (lower) alkyl 1,2,3,6-tetrahydropyridyl (lower) alkynyl, 1,2,3,4-tetrahydroisoquinolyl (lower) alkyl, 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl (lower) alkyl, saturated heterocyclic (lower) alkyl, d h saturated heterocyclic (lower) alkenyl, saturated heterocyclic (lower) alkynyl, S* 15 saturated heterocyclicamino (lower) alkyl, saturated heterocyclicamino (lower) alkenyl or saturated heterocyclicamino (lower) alkynyl [wherein "saturated heterocyclic moiety" is saturated 3 to 8-membered heteromonocyclic group containing 1 to 4 .:nitrogen atom(s); 20 saturated 3 to 8-membered heteromonocyclic group containing 1 or 2 oxygen atom(s) and 1 to 3 nitrogen atoms(s); saturated 3 to 8-membered heteromonocyclic group containing 1 or 2 sulfur atom(s) and 1 to 3 nitrogen atom(s); or saturated heterocyclic group of the formula: (CH2) -N (CH 2 (CH 2 t (CH 2 r (wherein q, r, s and t are each integer of 1 to 6), P:\OPER\PDB\ 1106-97-sp.do-1204/00 -116- each of which may have 1 to 3 suitable substituent(s) selected from the group consisting of cyclo(lower)alkyl, lower alkanoyl, lower alkyl, mono (or di or tri)halo(lower) alkyl, lower alkoxy, lower alkoxy(lower)alkyl, halogen, C 6 -C 1 0 aryl, cyano, oxo and bivalent group of the formula: 3. The compound of claim 2, in which Y is lower alkylene, R is phenyl which may have 1 or 2 mono (or di or tri) halo(lower)alkyl, 10 R 2 is phenyl, naphthyl or indolyl, each of which may have 1 or 2 suitable n substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, mono (or di or tri) halo (lower) alkyl and halogen, R 3 is hydrogen, and R 4 is chloro (lower) alkenyl; chloro (lower) alkynyl; pyridyl (lower) alkylamino (lower) alkyl; pyridyl (lower) alkylamino (lower) alkenyl; N-(lower alkyl)-N-[pyridyl (lower) alkyl] amino-(lower) alkyl; triazolylamino (lower) alkyl; lower alkoxy (lower) alkylamino (lower) alkyl; bis[(lower) alkoxy (lower) alkyl] amino (lower) alkyl; N-(lower alkyl)-N-[(lower) alkoxy (lower) alkyl]amino-(lower)alkyl; hydroxy (lower) alkyl; lower alkylsulfonyloxy (lower) alkyl; phenyl (lower) alkyl which may have lower alkanoyl, amino, lower alkanoylamino, di (lower) alkylaminocarbonyl or nitro; P:OPER\PDB\ 1106-97-spedo-12/4O -117- lower alkoxyphenyl (lower) alkylcarbonyl; lower alkanoylbenzoyl; benzoyl (lower) alkyl which has lower alkyl, chlorine or di (lower~alkylamino; benzoyl (lower) alkyl which has halogen and lower alkyl; dihalobenzoyl(lower) alkyl; di (lower) alkylbenzoyl (lower) alkyl; 3-fluorobenzoyl (lower) alkyl; 3-(4-fluorobenzoyl) propyl; 4 4 -ethylenedioxy-4-(4-fluorophenyl)butyl; piperazinylcarbonyl (lower) alkyl which has cyclopentyl or halophenyl; (2-pyridyl) (lower) alkyl; (3-pyridyl) propyl; (3-pyridyl) (lower) alkynyl; imdzy (lwr*aklwic a*hv*oerakl (lower) alkyl which may have lower alkyl; thiomorpholinylcarbonyl (lower) alkyl; (3 -azabicyclo[3 .2.2]non-3 -yl)carbonyl (lower) alkyl; or thienylcarbonyl (lower) alkyl, 1,2,3 ,6-tetrahydropyridyl (lower) alkyl, 1,2,3 ,6-tetrahydropyridyl (lower) alkynyl, 1,2,3 ,4-tetrahydroisoquinolyl (lower) alkyl, ,6,7-tetrahydrothieno [3 ,2-c]pyridinyl (lower) alkyl, saturated hleterocyclic (lowr)lky, sauae heeocci (lower) alenl saturated heterocyclic (lower) alkenyl, heterocyclicam (lower) alkyl, saturated heterocyclicamino (lower) alkeyl, o saturated heterocyclicamino (lower) alkynyl [wherein "saturated heterocyclic moiety" is pyrrolidinyl, piperidyl, piperazinyl, hexamethyleneimino, morpholinyl, homomnorpholinyl, thiomnorpholinyl or 3-azabicyclo [3 .2.2]non-3 each of which may have 1 or 2 suitable substituent(s) selected from the group consisting of cyclo(lower)alkyl, P:\OPER\PDB\l I 106-97-sp.doc-12A4/0OO -118- lower alkanoyl, lower alkyl, mono (or di or tri) halo(lower)alkyl, lower alkoxy, lower alkoxy (lower) alkyl, halogen, phenyl, cyano, oxo and bivalent group of the formula: 4. The compound of claim 3, in which Y is lower alkylene, R' is phenyl which may have 1 or 2 mono (or di or tri) halo (lower) alkyl, R2 is phenyl which may have 1 or 2 suitable substituent(s) selected from the group consisting of lower alkyl, lower alkoxy, mono (or di or tri) halo (lower) alkyl and 10 halogen, naphthyl or indolyl, R3 is hydrogen, and R 4 is (2-pyridyl) (lower) alkyl; (3-pyridyl) propyl; (3-pyridyl) (lower) alkynyl; imidazolyl (lower) alkyl which may have lower alkyl; pyrazolyl (lower) alkyl which may have lower alkyl; pyridyl (lower) alkylamino (lower) alkyl; pyridyl (lower) alkylamino (lower) alkenyl; N-(lower alkyl)-N-[pyridyl (lower) alkyl]amino-(lower)alkyl; triazolylamino (lower) alkyl; lower alkoxy (lower) alkylamino (lower) alkyl; bis[(lower) alkoxy (lower) alkyl] amino (lower) alkyl; N-(lower alkyl)-N-[(lower) alkoxy (lower) alkyl]-amino (lower) alkyl; 1, 2 ,3,6-tetrahydropyridyl (lower) alkyl 1,2,3,6-tetrahydropyridyl (lower) alkynyl; 1,2,3, 4 -tetrahydroisoquinolyl (lower) alkyl; or 4,5,6,7-tetrahydrothieno[3,2-c]pyridinyl (lower)-alkyl. P:\OPER\PDB\l 1106-97-spe.doc-12/04/00O -119- A process for the preparation of the compound of the following general formula: Y-R 2 1 11 R -C-N N-R4 R3 wherein Y is a bond or lower alkylene, R' is aryl which may have suitable substituent(s), R 2 is aryl or indolyl each of which may have suitable substituent(s), R 3 is hydrogen or lower alkyl, 10 R 4 is chloro (lower) alkenyl; chloro (lower) alkynyl; pyridyl (lower) alkylamino (lower) alkyl; pyridyl (lower) alkylamino (lower) alkenyl; N-(lower alkyl)-N-[pyridyl (lower) alkyl]amino- (lower) alkyl; triazolylamino (lower) alkyl; lower alkyoxy (lower) alkylamino (lower) alkyl; ,*.bis[(lower) alkoxy (lower) alkyl]amino (lower) alkyl; N-(lower alkyl)-N-[(lower) alkoxy (lower) alkyl]amino-(lower) alkyl; hydroxy (lower) alkyl; lower alkylsulfonyloxy (lower) alkyl; phenyl (lower) alkyl which may have lower alkanoyl, amino, lower alkanoylamino, di (lower) alkylaminocarbonyl or nitro; lower alkoxyphenyl (lower) alkylcarbonyl; lower alkanoylbenzoyl; PA\OPER\pDB~lI 106.97-W.do-2O4O 120 benzoyl (lower) alkyl which has lower alkyl, chlorine or di (lower) alkylamino; benzoyl (lower) alkyl which has halogen and lower alkyl; dihalobenzoyl (lower) alkyl; di (lower) alkylbenzoyl (lower) alkyl; 3-fluorobenzoyl (lower) alkyl; 3 -(4-fluorobenzoyl)propyl; 4,4-ethylenedioxy-4-(4-fluorophenyl)butyl; piperazinylcarbonyl (lower) alkyl which has cyclopentyl or halophenyl; (2-pyridyl) (lower) alkyl; (3-pyridyl) propyl; :(3-pyridyl) (lower) alkynyl; imidazolyl. (lower) alkyl which may have lower alkyl; pyrazolyl (lower) alkyl which may have lower alkyl; thiomorpholinylcarbonyl (lower) alkyl; (3-azabicyclo[3 non-3 -yl) carbonyl (lower) alkyl; or thienylcarbonyl *9***(lower) alkyl, 1,,,-etayrpriy lwe)akl ,2,3,6-tetrahydropyridyl (lower) alkynl, 1,2,3,4-tetrahydroisoquinolyl (lower) alkyl, 4,5,6,7-tetrahydrothieno [3 ,2-c]pyridinyl (lower)-alkyl, saturated heterocyclic (lower) alkyl, saturated heterocyclic (lower) alkenyl, saturated heterocyclic (lower) alkynyl, saturated heterocyclicamino, (lower) alkyl, saturated heterocyclicamino, (lower) alkenyl or saturated heterocyclicamino, (lower) alkynyl, each of which may have suitable substituent(s), or a salt thereof, which comprises P:\OPER\PDB\ I 106-97-spe.doc-12/ 4 /00 -121- reacting a compound of the formula: Y-R 2 O R 1 C-N N-H R 3 or its reactive derivative at the imino group or a salt thereof with a compound of the formula: W-R 4 10 or a salt thereof to provide a compound of the formula: \°4 Y--R 2 O R 1 C--N N--R S.R3 or a salt thereof, in the above formulas, Y, R 1 R R 3 and R 4 are each as defined above, and W1 is a leaving group, or reacting a compound of the formula: P:\OPER\PDB\I 106-97-spe.doc-12/04/00 -122- Y-R 2 o R'-C-N N-H R 3 or its reactive derivative at the imino group or a salt thereof with a compound of the formula: 0 II HO-C----R or its reactive derivative at the carboxy group or salt thereof to provide a Scompound of the formula: x 2 Y-R 00 o o R C--N N-C--R R .3 or a salt thereof, in the above formulas, Y, R 1 R 2 and R 3 are each as defined above, and R 5 is lower alkoxyphenyl (lower) alkyl or lower alkanoylphenyl, or P:\OPERPDB\ I 106-97-spc.doc-12/4/) -123- reacting a compound of the formula: Y-R 2 O O R -C-N N-C--OH R 3 or its reactive derivative at the carboxy group or a salt thereof with a compound of the formula: H-R 6 or a salt thereof to provide a compound of the formula: Y-R 2 O O i 11 R -C-N N--C--R R or a salt thereof, in the above formulas, Y, R 1 R 2 and R 3 are each as defined above, X is lower alkylene, and R 6 is piperazinyl which has cyclopentyl or halophenyl; or thiomorpholinyl, or subjecting a compound of the formula: P:\OPFR\PDB\I 116-91-sp.d-12/4OO 124 Y-R 2 0 R N-X-OH R3 or a salt thereof to an acylation reaction to provide a compound of the formula: Y-R 2 0 R-C-N N-X-R 7 913 R 3 or a salt thereof, in the above formulas, X, Y, R 2 and R 3 are each as defined above, and R 7 is acyloxy, or reacting a compound of the formnula: Y-R 2 0 R 1 -C-N R R 3 or a salt thereof with a compound of the formula: P NOPER\PDB\I I 106.97- p..d.c-214/00 125 H-R' or a salt thereof to provide a compound of the formula: Y-R 2 0 1 1 N-X-R 8 or a salt thereof, in the above formulas, X, Y, R2 and R 3 are each as defined above, and R. 8:P is pyridyl (lower) alkylamino; N-(lower alkyl)-N- [pyridyl (lower) alkyl]amino; triazolylamino; morpholinoamino; 10 lower alkoxy(lower)alkylamino; bis [(lower)alkoxy(lower)alkyl] amino; N-(lower alkyl)-N- [(lower) alkoxy (lower) alkyl] amino; 9.....imidazolyl; pyrazolyl; or 1,2,3 ,6-tetrahydropyridyl, 1 ,2,3,4-tetrahydroisoqunolyl, ,6,7-tetrahydrothieno [3 ,2-c]pyridinyl or saturated heterocyclic, each of which may have suitable 4*toosubstituent(s), or P:\OPFR\PDB~l 1106-97-p.doc-2i40 126 subjecting a compound of the formula: Y-R 2 0 R 1 -C-N NX S. S S 5 S. PS 55 S *~SS S 5*5* or a salt thereof to a reduction reaction to provide a compound of the formnula: Y-R 2 II NH 2 R 1 -C-N N-X- or a salt thereof, in the above formulas, X, Y, R 2 and R3~ are each as defined above, or reacting a compound of the formula: *P S S S S *SSSS. 5 NH 2 or a salt thereof with a compound of the formula: P:\OPER\PDB\lI 106-97-sp.doc-12/04/00 -127- W2-R 9 or a salt thereof to provide a compound of the formula: Y-R 2 0 NHR 9 R -C-N N-X- R or a salt thereof, in the above formulas, X, Y, R 1 R 2 and R 3 are each as defined above, W 2 is a leaving group, and **o 10 R 9 is lower alkanoyl. 6. A pharmaceutical composition which comprises, as an active ingredient, a compound of claim 1 or a pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers. 7. A method for treating or preventing Tachykinin-mediated diseases which comprises administering an effective amount of a compound of claim 1 or a pharmaceutically f acceptable salt thereof to a human being or animals. 8. Use of a compound of claim 1 for manufacture of a medicament for treating or preventing Tachykinin-mediated diseases. Dated this 12 t h day of April 2000 Fujisawa Pharmaceutical Co., Ltd. By its Patent Attorneys DAVIES COLLISON CAVE